Title of Invention

"AZABICYCLIC HETEROCYCLIC COMPOUND"

Abstract Azabicyclic heterocyclic Compound of general formula (I), or one of its salts with a base or an acid: in which R1, R2, R3, X, A and n are as herein described in the specification and claims.
Full Text The invention relates to new heterocyclic compounds, their preparation and their use as medicaments, in particular as anti-bacterial agents.
In the journal J. Org. Chem. , Vol. 37, No. 5, 1972,
pages 697 to 699 the preparation of a bicyclic derivative
with molecular formula C10H18N2O is in particular
described.
In the journal J. Org. Chem., Vol. 45, No. 26, 1980, pages 5325-5326 the preparation' of bicyclic derivatives with molecular formulae C6H9NO2 and C7H11NO2 is in particular described.
In the journal Chemical Reviews, 1983, vol. 83, No. 5, pages. 549 to 555 the preparation of bicyclic derivatives with molecular formulae C10H18N2O and C7H12N2O is in particular described.
In the journal Angew. Chem. Int. Ed. 2000,- 39, n° 3, pages 625 to 62 8 the preparation of a compound with molecular formula C12H12N2O is in particular described.
No particular use of these compounds in the therapeutic field has been described in these documents.
A subject of invention is the compounds corresponding to the following formula (I):
(Formula Removed)
in which:
RI represents a hydrogen atom, a COOH, CN, COOR, CONR6,R7,
(CH2)n.R5 or CR radical,
^"xXlLJp
R is chosen from the group constituted by an alkyl
radical containing from 1 to 6 carbon atoms, optionally
substituted by a pyridyl or carbamoyl radical, a
-CH2-alkenyl containing a total of 3 to 9 carbon atoms,
aryl containing from 6 to 10 carbon atoms or a r alkyl
radical containing from 7 to 11 carbon atoms, the ring of
the aryl or aralkyl radical being optionally substituted
by an OH, NH2, NO2/ alkyl containing from 1 to 6 carbon
atoms, alkoxy radical containing from 1 to 6 carbon atoms
or by one or more halogen atoms,
R6 and R7 being identical or different are chosen
from the group constituted by a hydrogen atom, an alkyl
.containing from 1 to 6 carbon atoms, aryl containing from
6 to 10 carbon atoms and aralkyl radical containing from
7 to 11 carbon atoms, optionally substituted by a
carbamoyl, ureido or dimethylamino radical, and an alkyl
radical containing from 1 to 6 carbon atoms substituted
by a pyridyl radical,
n' is equal to 1 or 2 and R5 is chosen from the
group constituted by a COOH, CN, OH, NH2, CO-NR6R7/ COOR,
OR, OCOH, OCOR, OCOOR, OCONHR, OCONH2, NHR, NHCOH, NHCOR,
NHSO2R, NH-COOR, NH-CO-NHR ou NHCONH2, R, R6 and R7 being
as defined above;
R2 represents a hydrogen atom or a (CH2)n'iR5 group, n'i
being equal to 0, 1 or 2, and R5 being as defined above;
R3 represents a hydrogen atom or an alkyl radical
containing from 1 to 6 carbon atoms;
A represents a bond between the two carbon carriers of RI
(Figure Removed)
and R2 or a group, R4 representing a
hydrogen atom or a (CH2)n-iR5 group, n1! and R5 being as
defined above, the dotted line representing an optional
bond with one or other of the carbon carriers of the
substituents RI and R2;
n is equal to 1 or 2;
X represents a divalent -C(0)-B- group attached to the
nitrogen atom by the carbon atom,
B represents a divalent -0-(CH2)n"- group attached to
the carbonyl by the oxygen atom, an -NR8- (CH2) n«- or -NR8-
O- group attached to the carbonyl by the nitrogen atom,
n" is equal to 0 or 1 and R8 is chosen from the group
constituted by a hydrogen atom, an OH, R, OR, Y, OY, Y1;
OYi, Y2, OY2, Y3, OCH2CH2SOmR, OSiRaRbRc and SiRaRbRc radical,
Ra/ Rb and Rc individually representing a linear or
branched alkyl radical containing from 1 to 6 carbon
atoms or an aryl radical containing from 6 to 10 carbon
atoms, R being as defined above and m being equal to 0, 1
or 2 ;
Y is chosen from the group constituted by the COH,
COR, COOR, CONH2, CONHR, CONHOH, CONHSO2R, CH2COOH,
CH2COOR, CH2CONHOH, CH2CONHCN, CH2tetrazole, protected
CH2tetrazole, CH2SO3H, CH2SO2R, CH2PO(OR)2, CH2PO (OR) (OH)
CH2PO(R) (OH) and CH2PO(OH)2 radicals,
YI is chosen from the group constituted by the SO2R,
S02NHCOH, S02NHCOR, SO2NHCOOR, S02NHCONHR, S02NHCONH2 and
SO3H radicals,
Y2 'is chosen from the group constituted by the .
PO(OH)2, PO(OR)2, PO(OH) ('OR) 'and PO(OH) (R) radicals,
Y3 is chosen from the group constituted by the
tetrazole radicals, tetrazole substituted by the. R
radical, squarate, NH or NR tetrazole, NH or NR tetrazole
substituted by the R radical, NHSO2R and NRS02R, R being
as defined above;
it being understood that when n is equal to 1 and A
(Figure Removed)
represents a group in which R4 is a hydrogen
atom and
- either X represents the -C (O) -O- (CH2) n» group in
which n" is 0 or 1,
- or X represents the -CO-NR8- (CH2)n» group in which
n" is 1 and R8 is the isopropyl group,
- or X represents the -CO-NR8- (CH2)n.. group in which
n" is 0 and R8 is hydrogen or phenyl,
All three of Rlf R2 and R3 cannot represent a hydrogen
atom at the same time.
A subject of the invention is also the salts of
these compounds which can be obtained with bases or
organic or inorganic acids, together with the internal
salts in which form certain compounds may, under certain
conditions, be present.
The asymmetrical carbon atoms contained in the
compounds of formula (I) can independently from one other
have the R, S or RS configuration, and a subject of the
invention is also therefore, the compounds of formula (I)
presented in the form of pure enantiomers or pure
diastereoisomers or in the form of a mixture of
enantiomers in particular racemates, or diastereoisomer
mixtures.
A result of the latter is that the substituents R1;
R2, and R4 taken individually on one hand and X on the
other hand can be in cis and/or trans position in
.relation to the ring on which they are fixed and that a
subject of the invention is therefore the compounds of
formula (I) presented in the form of cis isomers or trans
isomers or of mixtures.
By alkyl radical containing from 1 to 6 carbon
atoms, is meant a methyl, ethyl, propyl, isopropyl, as
well as linear or branched butyl, pentyl or hexyl
radical.
By -CH2-alkenyl radical containing from 3 to 9
carbon atoms, is meant for example an allyl radical, or a
butenyl, pentenyl or hexenyl radical.
By aryl radical containing from 6 to 10 carbon
atoms, is meant a phenyl or naphthyl radical.
By aralkyl radical containing from 7 to 11 carbon
atoms, is meant a benzyl, phenethyl or methylnaphthyl
radical.
By alkyloxy radical containing from 1 to 6 carbon
• atoms, is meant in particular a methoxy, ethoxy, propoxy,
isopropoxy, as well as butoxy, isobutoxy, sec-butoxy or
tert-butoxy radical.
By halogen atom, is meant a fluorine, chlorine,
bromine or iodine atom.
By radical squarate, is understood the radical of
formula:
Among the acid salts of the products of formula (I),
those formed with inorganic acids, such as hydrochloric,
hydrobromic, hydriodic, sulphuric or phosphoric acids or
with organic acids such as formic, acetic,
trifluoroacetic, propionic, benzoic, maleic, fumaric,
succinic, tartaric, citric, oxalic glyoxylic, aspartic,
alkanesulphonic, such as methane and ethane sulphonic,
arylsulphonic. acids, such as benzene and
paratoluenesulphonic acid can be mentioned amongst
others.
Among the base salts of the products of formula (I),
those formed with inorganic bases such as, for example,
sodium, potassium, lithium, calcium, magnesium or
ammonium hydroxide or with organic bases such as, for
example, methylamine, propylamine, trimethylamine,
diethylamine, triethyla'mine, N,N-dimethylethanolamine,
tris (hydroxymethyl) amino methane, ethanolamine,
pyridine, picoline, dicyclohexylamine, morpholine,
benzylamine, procaine, lysine, arginine, histidine, Nmethy.
lglucamine, or also phosphonium salts, such as the
alkyl-phosphoniums, aryl-phosphoniums, alkyl-arylphosphoniums,
alkenyl-aryl-phosphoniums or quaternary
ammonium salts such as tetra-n-butyl-ammonium salt can be
mentioned amongst others.
Among the compounds of formula (I) , a particular
subject of the invention are those in which n is equal to
I as well as those in which A represents a
— C(H)
group as defined above/ and in particular among these,
those in which R4 represents a hydrogen atom.
Among the compounds of formula (I) , a particular
subject of the invention is also those in which X
represents a -CO-B divalent group in which B represents
an -NR8-(CH2)n" - group as defined above and more
particularly, among these, those in which R8 is a Ya or
QYi group, in which Y is as defined above.
Among the compounds of formula (I) , a quite
particular subject of the invention is the compounds with
the following names:
trans -7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-
2-carboxamide and its base salts, in particular sodium,
trans -7-oxo-N-(phenylmethyl)-6-(sulphooxy)
-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and its base
salts, in particular sodium,
trans -7-oxo-N-(4-pyridinyl methyl)-6-(sulphooxy)
-1,6-diazabicyclo[3,2,1]octane-2-carboxamide'and its base
salts, in particular sodium,
trans -7-oxo-N-(3-pyridinyl methyl)-6-(sulphooxy)
-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and its base
salts, in particular sodium,
trans -7-oxo-N-(2-amino 2-oxo ethyl)-6-(sulphooxy)
-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and its base
salts, in particular sodium,
phenylmethyl trans-7-oxo-6- (sulphooxy) -1, 6--
diazabicyclo [3,2,1] octane-2-carboxylate.
Another subject of the invention is also a process
allowing the preparation of the compounds of formula (Figure Removed)
This process is characterized in that it comprises:
a) a stage during which a compound of formula (II) is
reacted with a carbonylation agent, if appropriate in the
presence of a base:
HZ" 7*3 (ID
in which:
R'i represents a hydrogen atom or a CN, protected COOH
COOR' , (CH2)n'RI
5, CONR6,R7 or protected radical.
R6 and R7 being as above defined and R1 and R'5 having the
definitions of R and R5 above respectively, in which the
reactive functions optionally present are protected;
R'2 represents a hydrogen atom or a (CH2)n'1R'5 group, n1!
and R'5 being as defined above;
R3 is as defined previously;
A' represents a bond between the two carbon carriers of
* —C(H>— R;
R'i and R'2 or a i group, R'4 representing a
hydrogen atom or a (CE2)n'1R's group, n'i. and R's being as
defined above, the dotted line representing an optional
bond with one or other of the carbon carriers of
substituents R'i and R'2-;
n is as defined previously;
HZ represents . an HO-(CH2)n"-, HNR' 8- (CH2)n-,~ or HNR'8-Ogroup,
n" being as defined previously and R'8
representing a hydrogen atom, protected OH, an R' , OR'
radical, a Y' or OY' radical, Y' being chosen from COH,
COR', COOR', CONH2, CONHR', protected CONHOH, CONHSO2R' ,
protected CH2COOH, CH2COOR' , protected CH2CONHOH,
CH2CONHCN, CH2tetrazole groups substituted by R',
CH2SO2R', CH2PO(OR')2, protected CH2SO3, protected
CH3PO(OR')OH, protected CH2PO(R')OH, protected CH2PO(OH)2,
a Y'a or OY'i radical, Y'i being chosen from the S02R',
S02NHCOH, S02NHCOR' ,S02NHCOOR' , S02NHCONH2, S02NHCONHR' and
protected SO3H groups, a Y'2 or OY'2 radical, Y'2
representing a protected PO(OH}2, protected PO(OH)(OR'),
protected PO(OH)(R') or PO(OR')2 group, or a Y'3 radical,
Y'3 being chosen from the protected tetrazole, tetrazole
substituted by the R' radical, NH or NR' protected
tetrazole, NH or NR' tetrazole substituted by the R1
radical, NHSO2R' and NR'S02R' groups, R' being as defined
above;
with a view to obtaining an intermediate compound of
formula:
(III)
in which:
R'1/ R'2/ R-3, A' and n have the same meanings as above and
either Xi is a hydrogen atom and X2 represents a -Z-CO-X3
group, X3 representing the remainder of the carbonylation
agent, or X2 is a -ZH group and X1 represents a CO-X3
group, X3 being as defined previously;
b) a stage during which the . intermediate obtained
previously is cyclized, in the presence of a base;
and in that:
c) if appropriate, stage a) is preceded and/or stage b)
is followed by one or more of the following reactions, in
an appropriate order:
- protection of the reactive functions,
- deprotection of the reactive functions,
esterification,
- saponification,
- sulphation,
- phosphation
- amidation,
- acylation,
- sulphonylation;
- alkylation;
- introduction of a double bond;
formation of a urea group;
introduction of a tetrazole group;
- reduction of carboxylic acids;
- dehydration of amide to nitrile;
- salification;
- ion exchange;
- resolution or separation of diasterisomers,-
- sulphide oxidation to sulphoxide and/or
sulphone,
As carbonylation agent, a reagent such as phosgene,
diphosgene, triphosgene, an aryl chloroformate such as
phenyl chloroformate or p-nitrophenyl chloformate, an
aralkyle chloroformate such as benzyl chloroformate, an
alkyl chloroformate such as methyl chloroformate, an.
alkenyl chloroformate such as allyl chloroformate, an
alkyl dicarbonate such as .-tert-butyl dicarbonate,
carbonyl-diimidazole and their mixtures can be used.
The reaction preferably takes place in the presence
of a base or a mixture of bases which neutralise the acid
formed. It can in particular be an amine such as
triethylamine, diisopropylethylamine, pyridine, or
dimethylaminopyridine. However, the reaction can also be
carried out using the starting product of formula II as a
base. An excess is thus used. An example is given in
the experimental part.
If appropriate, the product of formula II is used in the
form of an acid salt, for example a hydrochloride or a
trifluoroacetate.
As a base in stage b) , amines, or also hydrides,
alcoholates, amides or carbonates of alkali or alkalineearth
metals can also be used.
The amines can be chosen for example from the list
above.
As hydride, sodium or potassium hydride can in
particular be used.
As an alkali metal alcoholate, potassium t-butylate
is preferably used.
As an alkali metal amide, lithium
bis(trimethylsilyl) amide can in particular be used.
As carbonate, sodium or potassium carbonate or
bicarbonate can in particular be used.
If appropriate, the intermediate of formula III can
be obtained in the form of an acid salt generated during
the carbonylation reaction and in particular a
hydrochloride. It is then used in the cyclization
reaction in this form.
Optionally, cyclization can be carried out without
isolation of the intermediate of formula III.
The reactions mentioned in stage .c) are in general
standard reactions, well known to a person skilled in the
art.
The reactive functions which are suitable,
optionally, for protecting are the carboxylic acid,
amine, amide, hydroxy and hydroxylamine functions.
Protection of the acid function is in particular
carried out in the form of alkyl esters, allyl, benzyl,
benzhydryl or p-nitrobenzyl esters.
Deprotection is carried out by saponification, acid
hydrolysis, hydrogenolysis, or also cleavage using
soluble compounds of Palladium O.
Examples of these protections and deprotections are
provided hereafter in the experimental part.
Protection of the amines and amides is in particular
carried out in the form of benzylated derivatives, in the
form of carbamates, in particular allyl, benzyl, phenyl
or tertbutyl, or also in the form of silylated
derivatives such as tertbutyl dimethyl, trimethyl,
triphenyl or also diphenyl tertbutyl-silyl derivatives.
Deprotection is carried out, depending on the nature
of the protective group, by sodium or lithium in liquid
ammonia, by hydrogenolysis or using soluble compounds of
Palladium O, by the action of an acid, or by the action
of tetrabutylammoniura fluoride.
Examples are provided hereafter in the experimental
part.
Protection of the hydroxylamines is carried out in
particular in the form of benzyl or allyl ethers..
Cleavage of the ethers is carried out by
hydrogenolysis or using soluble compounds of Palladium 0.
An illustration is provided hereafter in the
experimental part.
Protection of the alcohols 'is carried out in a
'standard' manner, in the form of ethers, esters or
carbonates. The ethers can be alkyl or alkoxyalkyl
ethers, preferably methyl or methoxyethoxymethyl ethers,
aryl or preferably aralkyl ethers, for example benzyl, or
silylated ethers, for example the silylated derivatives
mentioned above. The esters can be any cleavable ester
known to a person skilled in the art and preferably
acetate, propionate or benzoate or p-nitrobenzoate. The
carbonates can for example be methyl, tertbutyl, allyl,
benzyl or p-nitrobenzyl carbonates.
Deprotection is carried out by means known to a
person skilled in the art, in particular saponification,
hydrogenolysis, cleavage by soluble compounds of
Palladium 0, hydrolysis in acid medium or also, for the
silylated derivatives, treatment by tetrabutylammmonium
fluoride.
Examples are provided in the experimental part.
The sulphation reaction is carried out by the action
of SO3-amine complexes such .as S03-pyridine or S03-
dimethylformamide, by operating in- pyridine, the salt
formed, for example the pyridine salt, can then be
exchanged for example by a salt of another amine, of a
quaternary ammonium or of an alkali metal. Examples are
provided in the experimental part.
The phosphation reaction is carried out for example
by the action of a chlorophosphate such as dimethyl,
dibenzyl or diphenyl chlorophosphate.
The amidation reaction is carried out from the start
with carboxylic acid using an activation agent such as
alkyl chloroformate or EDCI, by the action of ammonium
hydroxide or of an appropriate amine or of their acid
salts. Examples are provided hereafter in the
experimental part.
The acylation and sulphonylation reactions are
carried out on the hydroxyureas by the action of an
appropriate halide or carboxylic acid anhydride or of an
appropriate sulphonic acid halide respectively. Several
examples are provided hereafter in the experimental part.
The alkylation reaction is carried out by the action
of an alkyl or substituted alkyl halide on the
hydroxylated derivatives, in particular by a free or
esterified carboxy radical. Illustrations are provided
hereafter in the experimental part.
The optional final introduction of a double bond,
which is then preferably situated between the carbon
atoms carrying R4 and RI, is carried out by the action of
a halogenated derivative of selenium then oxidation,
according to methods known to a person skilled in the
art. An example appears hereafter in the experimental
part.
The formation of a urea group, which relates to the
substituent R8 is preferably carried out by the action of
an appropriate isocyanate on the free NH. An example
appears hereafter in the experimental part.
The introduction of a tetrazole group is carried out
by the action of a halogenated derivative, preferably
fluorinated, of the protected tetrazole. Deprotection
can be carried out by hydrogenolysis.
The reduction of acids to alcohols can be carried
out by the action of a borane or via an intermediate
mixed anhydride, by the action of an alkaline
borohydride. The mixed anhydride is prepared for example
using an alkyl chloroformate. An example is provided in
the experimental part..
The dehydration of amide to nitrile can take place
under carbonylation and cyclization reaction conditions.
Oxi'dation of sulphides to sulphoxides and/or
sulphones can be carried out by means -of a peracid such
as metachloroperbenzoic acid or perphtalic acid or of any
other appropriate reagent known by those skilled in the
art.
Salification by acids is optionally carried out by
the addition of an acid in soluble phase to the compound.
Salification by bases can concern either the compounds
comprising an acid function, in particular a carboxy
function, or those comprising a sulphooxy function or
phosphoric acid derivative or those comprising a
heterocycle having an acid character. In the first case,
the operation is carried out by adding an appropriate
base such as those mentioned previously. In the second
case, the pyridinium salt is directly obtained during the
action of the SO3-pyridine compound and the other salts
are obtained from this pyridinium salt. In either case,
it can also be carried out by ion exchange on resin.
Examples of salification appear hereafter in the
experimental part.
Separation of enantiomers and diasterisomers can be
carried out according to techniques known to a person
skilled in the art, in particular chromatography.
As well as via the processes described previously,
the compounds of formula (I) can of course be obtained by
methods which use at the start a compound of formula (II)
in which R'i, A', R(2/ R3 and HZ have the values which
lead directly (without conversion) to those of the
compounds that need to be prepared. If appropriate,
those with these values which will contain reactive
functions such as those mentioned above are then
protected, deprotection occurring following cyclization
stage 'b or at any other appropriate moment in- the
synthesis. Protection and deprotection is then carried
out as described above.
Such methods are provided hereafter in the
experimental part.
The products of general formula (I) have a very good
antibiotic activity on gram(+)bacteria such as
staphylococci. Their effectiveness on gram (-) bacteria,
in particular on coliform bacteria is particularly
notable.
These properties render said products as well as
their acid salts and pharmaceutically acceptable bases
suitable for use as medicaments in the treatment of germ
sensitive infections, in particular staphylococcia, such
as staphylococcal septicemias, malignant staphylococcia
of the face or skin, pyoderma, septic or suppurative
wounds, anthrax, phlegmons, erysipelas, acute, primative
or post-influenzal staphylococcia, broncho-pneumonia,
pulmonary suppurations.
These products can also be used as medicaments in
the treatment of colibacilloses and related infections,
in proteus, klebsiella and salmonella infections and in
other conditions caused by gram (-) bacteria.
A subject of the present invention is therefore
also, as medicaments and in particular antibiotic
medicaments, the products of formula (I) as defined above
as well as their salts with pharmaceutically acceptable
acids and bases.
A more particular subject of the invention is, as
medicaments, the products of formula (I) as described
above in which n is equal to 1 as well as those in which.
A represents a
group as defined above, arid in particular .those in
•which R4 is a hydrogen atom.
A quite particular subject of the invention is, as
medicaments, the products of formula (I) in which X
represents a divalent -CO-B group in which B represents
an -NR8-(CH2)n" - group as defined above and more
particularly, among these, those in which R2 represents a
YI or OYi group, in which Y1 is as defined above.
Among the compounds of formula (I) , a quite
particular subject of the invention is, as medicaments,
the compounds with the following names:
trans -7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-
2-carboxamide and its base salts, in particular sodium,
trans -7-oxo-N-(phenylmethyl)-6-(sulphooxyJ
-1,6-diazabicyclo [3,2,1]octane-2-carboxamide and its base
salts, in particular sodium,
trans -7-oxo-N-(4-pyridinyl methyl)-6-(sulphooxy)
-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and its base
salts, in particular sodium,
trans -7-oxo-N-(3-pyridinyl methyl)-6-(sulphooxy)
-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and its base
salts, in particular sodium,
trans -7-oxo-N-(.2-amino 2-oxo ethyl)-6-(sulphooxy)
-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and its base
salts, in particular sodium,
phenylmethyl trans -7-oxo-6-(sulphooxy)-1,6-diazabicyclo
[3,2,1] octane-2-carboxylate.
A subject of the invention is also the
pharmaceutical compositions containing at least one of
the compounds according to the invention as defined above
as active ingredient.
These compositions can be administered by buccal,
rectal, parenteral, in particular intramuscular route, or
by local route in a topical application on the skin and
the mucous membranes.
The compositions according to the invention can be
solids or liquids and be presented in pharmaceutical
forms commonly used in human medicine such as for
example, plain or sugar-coated tablets, gelatin capsules,
granules, suppositories, injectable preparations,
ointments, creams, .gels; they are prepared according to
usual methods. The ' active ingredient (s) can be
incorporated with the excipients usually used in these
pharmaceutical compositions, such as talc, gum arabic,
lactose, starch, magnesium stearate, cocoa butter,
aqueous or non aqueous vehicles, fatty matter of animal
or vegetable origin, paraffin derivatives, glycols,
various wetting, dispersing or emulsifying agents,
preservatives.•
These compositions can in particular be presented in
the form of a powder intended to be dissolved
extemporaneously in an appropriate vehicle, for example,
apyrogenic .sterile water.
The administered dose varies according to the
illness treated, the patient in question, the
administration route and the product considered. It can
be, for example, between 0.250 g and 10 g per day, by
oral route in man, with the product described in Example
1 or also between 0.25 g and 10 g per day by
intramuscular or intravenous route.
The products of formula (I) can also be used as
disinfectants for surgical instruments.
Finally, a subject of the invention is the products
of formulae (III), as defined previously as well as their
salts with acids and in particular their hydrochlorides,
as. new industrial products and in particular as
intermediate products necessary for the preparation of
the products of formula (I).
The products of .formula (II) are known or can be
prepared according to methods known to a person skilled
in the art. References to the literature as well as
preparations are provided hereafter in the experimental
part.
The following examples illustrate the invention,
without however limiting its scope.
Examples
In the examples which follow the following
abbreviations have been used:
DEAD: diethyl azodicarboxylate
TEA: triethylamine
DMAP: 4-dimethylamino-pyridine
EDCI: 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide
hydrochloride
THF: tetrahydrofuran
AIBN: 2,2'-azo-bis-isobutyronitril
M: molecular molar weight
MS: mass spectrometry
El: electronic impact
SIMS: secondary ion mass spectrometry
FAB: fast atom bombardment
Example 1
diphenylmethyl cis~7-oxo-6-oxa-l-azabicyclo[3,2,1]octane-
4-propanoate
3.16 g (10.6 mmoles) of the hydrochloride of 3-oxo-
1-(phenylmethyl)-4-piperidinepropanoic acid (M = 297.7 g)
(described in the Japanese Patent'Application J54098-772)
is .mixed with 100 ml of ethanol and cooled down to 10°C.
Under a stream of nitrogen, -1.84 g of NaBH4 is added over
15 minutes, whilst maintaining the temperature between 8
and 13°C. The temperature is left to rise to ambient
temperature and the reaction medium is left in contact
for 1 hour 30 minutes. Another 380 mg of NaBH4 is added
and the reaction medium is left to react overnight at
ambient temperature.
The solvent is evaporated off under reduced
pressure, the residue is taken up in 50 ml of water and
the pH is adjusted from 10 to 2 using concentrated
hydrochloric acid. The reaction medium is evaporated
again under reduced pressure. The solid residue
(approximately 10.8 g) is washed twice with 100 ml of
ethanol then the solvent is evaporated off under reduced
pressure.
3.10 g of the hydrochloride of 3-hydroxy-l-
(phenylmethyl)-4-piperidinepropanoic acid (M = 299.7 g)
is thus obtained, which corresponds to a yield of 97%.
The 3.10 g (10.3 mmoles) of the compound obtained
previously, is diluted with 100 ml of ethanol then added
to 900 mg of Pd/C at 10% by prehydrogenated weight and in
30 ml of ethanol.
The reaction medium is left under a hydrogen
atmosphere at -normal pressure overnight, then the
catalyst is eliminated by filtration and the ethanol is
eliminated by evaporation under reduced pressure.
1.90 g of the hydrochloride of trans-3-hydroxy-4-
piperidinepropanoic acid (M = 209.6 g) is obtained i.e a
yield of 88%.
1.79 g (8.54 mmoles) of the compound obtained
previously is mixed with 20 ml of ethanol and 20 ml of
water.
Then concentrated soda is added until the pH is
approximately 8.5.
Then, 1 ml of allyl chloroformate and concentrated
soda are added so as to keep the pH between 8 and 9.
The reaction mixture is extracted with ethyl acetate
then the aqueous phase is acidified to pH 2- by the
addition of concentrated hydrochloric acid and reextracted
with ethyl acetate. After drying and
evaporation of the solvent under reduced pressure, 1.69
of crude product is obtained which is taken up in a
mixture of dichloromethane and ethanol, then the solvent
is filtered and again evaporated under reduced pressure.
1.40 g of trans-3-hydroxy-l-[(2-propenyloxy)
carbonyl] -4-piperidinepropanoic acid (M = 257 g) , i.e a
yield of 60% is thus obtained.
3.24 g (12.6 mmoles) of the hydroxy-acid above and
6.4 g of triphenylphosphine are dissolved in 60 ml of THF
at 0°C under a nitrogen atmosphere. 2.5 ml of DEAD is
then added and after 15 minutes the reaction mixture is
21
evaporated under reduced pressure in order to obtain 12 g
of crude product. The- reaction medium is purified by
chromatography on silica by progressively eluting with a
mixture of dichloromethane and ethyl acetate 9/1, 8/2,
7/3 to separate the cis and trans lactones.
2.72 g of cis lactone in a mixture with reduced DEAD
and phosphine oxide is thus obtained.
This product is again placed in solution in 10 ml of
DME and 8 ml of a IN NaOH solution is added. After 1
hour of contact, the reaction mixture is extracted twice
with ethyl acetate, then acidified to pH 2 with 2N HCl,
and re-extracted with ethyl acetate. After drying and
evaporating the solvent under reduced pressure, 1.07 g of
hydroxy-acid is obtained.
1.0 g of crude hydroxy-acid is dissolved in a
mixture of 5 ml of dichloromethane and 2 ml of methanol,
then treated with an excess of diphenyldiazomethane in
dichloromethane, until the starting product disappears.
The solvent is evaporated off under reduced pressure and
the product is purified by chromatography in order to
produce 1.39 g of diphenylmethyl cis-3-hydroxy-l-[(2-
propenyloxy)carbonyl]-4-piperidinepropanoate (M = 423 g)
i.e an overall yield of 26 %.
1.2 g (2.83 mmoles) of the product obtained
previously is then dissolved under a nitrogen atmosphere
in 23 ml of dichloromethane. Then 390 ul of acetic acid
then 860 p.1 of Bu3SnH and 70 mg of Pd(PPh3)4 are added.
The solvent is evaporated off under reduced pressure
in order to obtain 3.82 g of crude product which is
washed with petroleum ether. 1.27 g of product is
obtained which is filtered on silica with
dichloromethane, then with a 95/5 then 90/10 mixture of
j
dichloromethane and methanol. 0.87 g of diphenylmethyl
cis-3-hydroxy-4-piperidinepropanoate (M = 339 g) is thus
obtained, i.e. a yield of 77%.'
400 mg (1.00 mmole) of the compound obtained
previously is dissolved in 25 ml of dichloromethane, 80/xl
of diphosgene (C13COCOC1) , 336 /ul of TEA, 144 mg of DMAP
are added.
The reaction medium is left to react at ambient
temperature for five hours 30 minutes, then diluted with
dichloromethane, followed by washing with an aqueous
solution of tartaric acid at 10%, then with a solution of
sodium • phosphate buffer at pH 7, the organic phase is
dried over sodium, sulphate, then . the. solvent is
evaporated off under reduced pressure. 380 mg of crude
product is thus obtained..
Purification is carried out by chromatography on
silica, eluting with a dichloromethane/ethyl acetate
• mixture 95/5 with 0.1% water.
184 rng of the compound of the title (M = 365.43 g) ,
i.e. a yield of 50% is obtained.
NMR spectrum of the proton
In CDC13, at 300 MHz, chemical shifts of the peaks in ppm
and multiplicity:
1.60 to 1.88 (m) : NCH2-CH2-CH; 2.48 (m) : CH2-CH2-CO; 2.78
(d) - 2.90 (m) - 3.33 to 3.47 (m) : CHs-N-CEb; 4.50 (d) :
CHO-CH2; 6.89 (a): C02CH (C6H5) 2 ; 7.33 (m) : (C6H5)2.
IR (CHCls) : 1784, 1734, 1600, 1585, 1496 cnf1
M5(positive electrospray) m/z: [M]+ = 365
Example la
Cis-7-oxo-6-oxa-l-azabicyclo[3,2,1]octane-4-propanoic
acid
176 mg (0.482 mmoles) of the product obtained previously
is dissolved in 10 ml of acetone. 90 mg of Pd/C is added
at 10% by weight.
The reaction medium is left to react under a
hydrogen atmosphere at normal pressure for 3 hours. 25
mg of catalyst are also added and the reaction is left to
continue for 1 hour 15 minutes.
The catalyst is filtered out then the solvent is
evaporated off under reduced pressure in order to obtain
146 mg of product.
The product is reacted in 10 ml of acetone with 35
mg of Pd/C at 10% by weight under a hydrogen atmosphere
and the reaction is left to complete for 1 hour.
The catalyst is then separated out by filtration and
the filtrate is evaporated under reduced pressure. 137
mg of crude product is obtained which is crystallized
from a mixture of ethyl ether and petrol ether. 75 mg of
the sought product (M = 199 g) , is thus obtained i.e. a
yield of 78%.
NMR spectrum of the proton
In CDC13, at 250 MHz, chemical shifts of the peaks in ppm
and multiplicity:
1.30 to 1.63 (m) and 1.88 (m) : NCHb-CHz-CH; 2.25 (t) : CH2-
CEb-CO; 3.06 (m) and 3.38 (m) : CHz-N-CHs; 4.65 (d) : C-CHOCH2;
12.08 (s): Mobile H.
IR (Nujol) : 1785, 1717 cm"1
MS (FAB) m/Z:[M+H]+ = 200; 159
Example 2
diphenylmethyl trans-7-oxo-6-oxa-l-azabicyclo[3,2,1]
octan-4-acetate
94 mg (0.259 mmoles) of the hydrochloride of
diphenylmethyl trans-3-hydroxy-4-piperidine-acetate
compound (M = 361.87 g) (described in Eur. J. Med. Chem -
Chim. Ther - 1982 - 17(6)531-5) and 7 ml of
dichloromethane are mixed together under an inert
atmosphere.
The reaction medium is cooled down using an ice bath
and 19 jul of diphosgene is injected. The reaction medium
is agitated for 25 minutes, then 72ul of TEA is injected.
The reaction medium is agitated at ambient temperature
for 30 minutes and the solvent is evaporated off under
• reduced pressure. •• •
The reaction medium is then taken up in 7 ml of
toluene.
36 uI of TEA then 31 mg of DMAP are added.
The reaction medium is heated for 15 minutes at
100°C, then left to return to ambient temperature,
followed by washing with 2 times 4 ml of tartaric acid at
10% in water, then with 4 ml of water saturated with
sodium chloride.
The reaction medium is dried over magnesium sulphate
and filtered, the solvent is then evaporated off under
reduced pressure.
78 mg of oil is obtained which is chromatographed on
silica, with a 95/5 mixture of dichloromethane and ethyl
acetate as eluent.
35.7 mg of expected compound (M = 351.405 g) , in the
form of white crystals is thus obtained, i.e. a yield of
39 %.
Example 2a
Trans~7-oxo-6-oxa-l-azabicyclo[3,2,1]octan-4-acetic acid
38.7 mg (0.110 ramoles) of the product obtained in
Example 2 as well as 2 ml of acetone and 38 mg of Pd/C
catalyst at 10% by weight are mixed together under an
inert atmosphere.
The reaction medium is placed under a hydrogen
atmosphere at normal pressure.
The reaction medium is left to react for 45 minutes,
then the catalyst is eliminated by filtration and the
solvent is evaporated off under reduced pressure.'
32.6 mg of crude product is thus obtained.
Recrystalization is carried out from ethyl ether in
order to obtain 14.2 mg of white crystals of the expected
compound (C8H10NO4 - M=185.181 g) , i.e. a yield of 69 %.
Example 3
diphenylmethyl cis-7-oxo-6-oxa-l-azabicyclo [3,2,1]
octan-4-acetate
1.5 g (5.78 mmoles) of trans-1-[(1,1-
dimethylethoxy)carbonyl]-3-hydroxy-4-piperidineacetic
acid (described in Eur. J. Med. Chem - Chim. Ther - 1982
17(6)531-5), 7 ml of dichloromethane, 3.03 g of
triphenylphosphine and 22 ml of tetrahydrofuran are mixed
together.
A solution of 0.91 ml of DEAD in 2.5 ml of
tetrahydrofuran is added. The reaction medium is left to
react for 3 hours 20 minutes, then 8.7 ml of IN soda is
added and agitation is carried out for 1 hour 15 minutes.
Followed by extracting twice with ethyl acetate,
then adjusting to pH 2 with 2N hydrochloric acid, then
extracting three times with ethyl acetate.
The organic phases are combined and washed with
water saturated with sodium chloride, then dried over
magnesium sulphate, filtered and the solvent is
evaporated off under reduced pressure.
1.37. g of white crystals of 1,1-dimethylethyl
(3a.alpha.,7a.alpha.)-hexahydro-2-oxo-furo[2,3-c]pyridine
-6(2H)-carboxylate (C2H21NO5-M=259.304 g) is thus
obtained, i.e. a yield of 91 %.
1.37 g (5.28 mmoles) of the compound obtained
previously and 32 ml of dichloromethane are mixed
together under an inert atmosphere.
An excess of a solution of diphenyldiazomethane in
dichloromethane is introduced, until the starting product
disappears.
The solvent is then evaporated off under reduced
pressure and 2.81 g of crude product is thus obtained
which is purified by chromatography on silica, using
dichloromethane, then a 95/5 dichlororaethane/ethyl
acetate mixture as eluent.
2.00 g of white crystals of diphenylmethyl cis-1-
[ (1,1-dimethylethoxy)carbonyl]-3-hydroxy-4-
piperidineacetate, (M = 425.528 g) is obtained, i.e. a
yield of 89%.
0.6 g (1.41 mmoles) of the compound obtained
previously and 1.93 ml of a solution of hydrogen chloride
in methanol at 7.3 mol/1 are introduced,
The reaction medium is agitated at ambient
temperature and after.15 minutes, 1 ml of dichloromethane
is added.
After another 15 minutes, the reaction medium is
evaporated under reduced pressure.
Dichloromethane is also added, then the reaction
medium is again evaporated. This operation is repeated
several times.
The product is then crystallized from ethyl ether.
0.44 g of the hydrochloride of diphenylmethyl cis-3-
hydroxy-4-piperidineacetate with molecular formula
formula, C2oH23NO3/HCl (M = 361.871 g) is thus obtained,
i.e. a yield of 86%.
This reaction also leads to the formation of
variable quantities of (3a.alpha.,7a.alpha.)-hexahydrofuro
[2,3-c]pyridin-2(3H)-one lactone hydrochloride,
,(M=177.6g) .
0.28 g (0.77 mmoles) of the compound C2oH23NO3, HCl
obtained previously and 19 ml of dichloromethane are
mixed together under an inert atmosphere.
60jil of diphosgene is added at 0°C and agitation is
carried out. After 25 minutes 0.32 ml of TEA is
introduced. 94 mg of DMAP is then added and the reaction
medium is left to return to ambient temperature.
The reaction medium is agitated for 4 hours 15
minutes, then washed successively with an aqueous
solution of tartaric acid at 10% then with water
saturated with sodium chloride.
Followed by drying over magnesium sulphate,
filtering and the solvent is evaporated off under reduced
pressure.
0.265 g of expected compound, with molecular formula
C2H2N04 (M = 351.405 g) is thus obtained i.e. a yield of
98%.
NMR spectrum of the proton
In CDC13, at 250 MHz, chemical shifts of the peaks
in ppm and multiplicity:
1.82 (m) : NCH2-CH2; 2.30 to 2.70 (m) : CO-CH2-CH; 2.93 (d)
- 2.99 (dt) and 3.45 (m) : CHs-N-CH; 4.60 (d) : CH-CHO-CH2;
6.87 (s) : C02CH(C6H5)2; 7.10 to 7.35 (m) : (C6Hs)2.
IR (CHClaQ = 1786, 1734; 1600, 1587, 1496 cm'1.
MS (SIMS)m/z: [M+Nar = 374*.
'Example 3a
cis-7-oxo-6-oxa-l-azabicyclo[3,2,l]octan-4-acetic acid
55 mg (0.156 mmoles) of the product obtained in
Example 3, 3 ml of ethyl acetate and 55 mg of Pd/C
catalyst at 10% by weight are mixed together.
The reaction medium is placed under a hydrogen
atmosphere at normal pressure.
The reaction medium is left to react for 1 hour 30
minutes, then the catalyst is filtered out and the
solvent is evaporated off under reduced pressure.
38 mg of crude product is thus obtained which is
crystallized from a mixture of pentane and ethyl ether.
In this manner 16 mg of white crystals of expected
compound (M = 185.181 g) is recovered, i.e. a yield of
55%, . . '
NMR 'spectrum of the proton
In CDC13, at 250 MHz, chemical shifts of the peaks
in ppm and multiplicity:
1.63 to 1.86 (m) and 1.91 (m) : NCHa-CHg; 2.27 to 2.49
(m) and 2.54 (dd) : CO-CH^-CH; 2.98 (d) and 3.54 (d) : CHg-
N-CH2-CH2; 3.04 (dt) and 3.41 (dd) : CH2-N-CH2-CH2; 4.71
CH-CHO-CH2.
IR (Nujol) : 1784, 1734, 1686 cm"1.
MS (SIMS) m/z: [M+HJ+ = 186+, 167+.
Example 3b
methyl cis-7~oxo-6-oxa-l-azabicyclo[3,2,1]octan-4-acetate
78 mg (0.421 mmoles) of the compound obtained in
Example 3a is then dissolved in 1 ml of dichloromethane.
An excess of diazomethane is added dropwise until a
yellow coloration remains, then the solvent is evaporated
off under reduced pressure.
80 mg of crude product is thus obtained which is
purified by chromatography on silica, eluting with a
dichloromethane/ethyl acetate mixture 95/5.
8.2 mg of expected compound (M = 199.208 g) is thus
obtained i.e. a yield of 10%.
Example 4
cis-7-oxo-6-oxa-l~azabicyclo[3,2,1]octan-4-acetonitrile
61 mg (0.38 mmoles) of (3a.alpha.,7a.alpha.)-
hexahydro-furo [2, 3-c]pyridin-2 (3H) -one hydrochloride
(M=177.6g) prepared in Example 3 is dissolved in 1 ml
ofan ammonia solution at 4.17 mol/1 in methanol.
The reaction medium is agitated for 5 hours, the
solvent is evaporated off under reduced pressure, then 1
ml of.the ammonia solution in methanol is again added .and
the reaction is left to continue for 18 hours.
The solvent is evaporated off under reduced pressure
and 79 mg of cis-3-hydroxy-4-piperidineacetamide with
molecular formula C7H1402N2 (M = 158 g) is thus obtained.
i
75 mg of the compound obtained above in solution in
9 ml of dichloromethane is mixed under an inert
atmosphere.
The reaction medium is cooled by an ice bath and 30
/zl of diphosgene is introduced.
The reaction medium is kept at 0-5°C for 40 minutes,
then 0.16 ml of TEA is introduced and 5 minutes
afterwards, 46 mg of DMA.
Agitation is carried out for 4 hours at ambient
temperature.
The reaction medium is washed twice with 2 ml of
tartaric acid at 10 % in water, then with 2 ml of a
saturated aqueous solution of sodium chloride.
The reaction medium is dried over MgSO4, filtered
and the solvent is evaporated off under reduced pressure.
35 mg of crude product is thus obtained that is taken up
in a 30/70 mixture of ethyl acetate and dichloromethane.
The impurities are filtered out and the filtrate is
evaporated under reduced pressure.
23 mg of expected compound (M = 166.18 g) is thus
obtained in the form of oil, i.e. a yield of
approximately 26%.
IR (Nujol) : 2241, 1777 cm"1.
MS (El) m/z: {M]+ = 166, 137, 82, 55, 42.
Example 5
3-benzoyl-l,3-diazabicyclo[2,2,1]heptan-2-one
1.01 g (5.43 mmoles) of 1,1-dimethylethyl 3~amino~lpyrrolidinecarboxylate
(M = 186.25 g) (described in the
Patent Application WO 9801426) and 10 .ml of.
dichloromethane are • mixed together under an inert
'atmosphere, the solution is cooled down to 0°C, then 0.76
ml of TEA is added dropwise.
Agitation is carried out for 15 minutes whilst
maintaining the temperature at 0°C, then 0.63 ml of
benzoyl chloride is added.
The reaction medium is left to return to ambient
temperature, then diluted by adding 10 ml of
dichloromethane.
The reaction medium is then washed with an aqueous
solution of tartaric acid at 10%, followed by drying over
magnesium sulphate, filtering and the dichloromethane is
eliminated by evaporation under reduced pressure.
1.30 g of 1,1-dimethylethyl 3-(benzoylamino)-1-
pyrrolidinecarboxylate (M = 292.36 g) is thus obtained in
the form of a yellow oil. The corresponding yield is
82%.
1.30 g (4.46 mmoles) of this compound is mixed with
10 ml of methanol.
The solution is cooled down to 0°C, then 6.12 ml of
a solution of hydrogen chloride at 7.3 moles/1 in
methanol is introduced progressively.
The solvent is then evaporated off under reduced
pressure.
1.01 g of-N-(3-pyrrolidinyl)-benzamide hydrochloxide
(M = 226.707 g) is thus obtained in the form of brown
oil, i.e. a yield close to 100%.
1.01 g (4.46 mmoles) of the compound obtained
previously, as well as 10 ml of dichloromethane are mixed
together under an inert atmosphere.
The reaction medium is cooled down to 0°C, then 1.36
ml of TEA is added dropwise.
Agitation is carried out for 15 minutes, then 1.44
ml of diphosgene is added dropwise.
• The reaction medium is kept at 0°C for 30 minutes,
then left to return to ambient temperature.
The reaction medium , is then diluted with
dichloromethane, washed with an aqueous solution of
tartaric acid at 10%, then with water.
Followed by drying over magnesium sulphate,
filtering and concentrating by evaporation of the solvent
under reduced pressure in order to obtain 0.615 g of
crude product.
The crude product is purified by chromatography on
silica eluting with a. 90/10 mixture of
dichloromethane/acetone.
In this way 0.320 g of the chloride of 3-
(benzoylamino)-1-pyrrolidinecarboxylic acid which
crystallizes is recovered. The corresponding yield is
28%.
0.585 g (2.31 mmoles) of the previous compound is
then dissolved under an inert atmosphere in IB ml of
tetrahydrofuran.
The solution is cooled down to -78°C, then 2.55 ml
of. a I M solution of lithium bis (trimethylsilyl) amide is
added dropwise to tetrahydrofuran.
A yellow solution is obtained which is kept at -78°.C
for 20 minutes, then agitation is continued for 1 hour
whilst the temperature is allowed to rise. At 0°C 350 uI
. of acetic acid, then 5 ml of tartaric acid in solution at
10% in water are added. The reaction medium is diluted
with ethyl acetate then washed with a solution of
tartaric acid at 10% then with a phosphate buffer
solution- at pH = 7, then with water.
The organic phase is- dried over magnesium sulphate,
filtered and concentrated, by evaporation of the solvent
under reduced pressure.
0.315 g of crude product is thus obtained, in the
form of a yellow solid.
This crude product is purified by chromatography on
silica eluting with a mixture of dichloromethane and
ethyl acetate 90/10.
0.140 g of expected compound Ci2Hi2N202, (M = 216.24
g), in the form of a white solid, i.e. a yield of 28% is
in this way recovered.
IR (CHCls) : 1801, 1775, 1675; 1620, 1603, 1582 cm"1.
MS (positive electrospray) m/2: [M]+ = 216, 105, 77.
Example 6
Potassium salt of trans-6-[(phenylmethoxy) carbonyl]-2~
oxo-l,3-diazabicyclo[2,2,1] heptan-3-acetic acid
1 g (3.12 mmoles - M = 186.25 g) of 1-(1,1-
dimethylethyl) and 2 -(phenylmethyl) trans-4-amino-l,2-
pyrrolidinedicarboxylate (described in J. Org. Che.m.
1991, 56, 3009-3016), 10 ml of tetrahydrofuran, 560 ul of
allyl bromoacetate and 660 ul of TEA are mixed together.
The reaction medium is left to react under agitation
at ambient temperature for 14 hours, then for 3 hours at
50°C.
Followed by diluting with ethyl acetate and washing
with an aqueous solution of tartaric acid at 10%, then
with a saturated aqueous solution of sodium chloride.
The organic phase is dried over magnesium sulphate,
filtered then the solvent is evaporated off under reduced
pressure.
1.21 g of crude product is thus obtained which is
purified by chromatography on silica, eluting with a
mixture of dichloromethane and ethyl acetate 80/20.
0.;99 mg of 1-(1 ,.1-dimethylethyl) and 2-(phenyl
methyl) trans-4- [ [ [ (2-propenyloxy) carbonyljmethyl] amino] -
1,2-pyrrolidine dicarboxylate with molecular formula
C2H3oN2O6 (M = 418 g) is thus recovered.
6 ml of a 4 M solution of hydrogen chloride in ethyl
acetate, is added under a nitrogen atmosphere and at 0 °C
to 0.99 g (2.36 mmoles) of the compound obtained
previously. The reaction medium is then left to react at
ambient temperature for 15 minutes.
The solvent is evaporated off under reduced
pressure. A crude product is obtained which is
crystallized from ethyl ether in order to obtain 0.95 g
phenyl methyl trans-4-[[[(2-propenyloxy)carbonyl]
methyl]amino]-2-pyrrolidinecarboxylate dihydrochloride,
with molecular formula C7H23N2O4, 2HC1 (M = 394 g) .
0.5 cj of this product is dissolved in 20 ml of
dichloromethane and 1.3 ml of 2N soda and 3ml of water
are added. The solution is left to settle, followed by
extracting with dichloromethane, drying over magnesium
sulphate, then filtering and the 'solvent is evaporated
off under reduced pressure.
339 mg of free diamine is thus obtained. The
corresponding yield is 83%.
100 mg (0.314 mmoles) of the diamine obtained
previously is dissolved in 5 ml of acetonitrile at 0°C
and under.a nitrogen atmosphere.
21 ul of diphosgene is added. After 15 minutes of
contact, this solution is added, under a nitrogen
atmosphere and over 4 hours, to a mixture containing 38
mg of DMAP and 88 ul of TEA. in 10 ml of acetonitrile
j
heated to 70°C.
After the addition is finished, the reaction mixture
is again-heated for one hour, then cooled down, diluted
with ethyl acetate and washed successively with an
aqueous solution of tartaric acid, at 10%, then with a
saturated aqueous solution of sodium chloride. After
drying over sodium sulphate, filtration and evaporation
of the solvents under reduced pressure, 58 mg of crude
product is obtained. This product is purified by
chiromatography on silica eluting with a dichloramethane /
ethyl acetate mixture 8/2 in order to produce 19 mg of 2-
propenyl trans-6-[(phenylmethoxy)carbonyl]-2-oxo-l,3-
diazabicyclo[2,2,1]heptan-3-acetate with molecular
formula C18H2oN2O5 (M = 344.57 g) , i.e. a yield of 17 %.
24 mg (0.069 mmoles) of the previous compound is
then dissolved in 250 I of dichloromethane. 3 mg of
Pd(PPh3)4 is introduced under a nitrogen atmosphere, then
150 l of a 0.5 M solution of potassium ethyl-2 -hexanoate
in ethyl acetate is added. After several minutes, it
forms a precipitate which is centrifuged and washed twice
with 500 p.1 of ethyl acetate.
24 mg of expected compound C15H15KN2O5 (M = 342 g) , is
obtained i.e. a quantitative yield.
NMR spectrum of the protion
In DMSO, at 300 MHz, chemical shifts of the peaks
in ppm and multiplicity:
1.83 (ddd) and 2.56: N-CH2-CHN-CH2; 2.50 and 2.79 (d) :
N-CH2-CHN-CH2; 3.23 (d) and 3.41 (d) : =C-N-CH2-C=O; 3.62
(ddd): 0=C-CHN- CH2; 4.13 (s) : N-CH2-CHN-CH2; 5.16 (s) :
=C-0-CH2-C6H5; 7.38 (m) : C6H5-CH2.
MS (positive electrospray) m/z: [2MK + H]+ = 723, [2MK +
Na]+ = 707, [MK + K]+ = 381, [MK + Na] + = 365; [MK + H] =
343.
Example 7
• methyl trans-3-benzoyl-2-oxo~l,3-diazabicyclo[2,2,1]
heptane-6-carboxylate
0.471 g (1.93 mmole) of 1-(1,1-dimethylethyl) and 2-
methyl trans-4-amino-l,2-pyrrolidinedicarboxylate
(described in J. Org. Chem. 1991, 56, 3009-3016) and 3.5
ml of dry dichloromethane to dissolve it are mixed
together under a nitrogen atmosphere.
The solution is cooled down to 0°C, then 269 p.1 of
TEA is added dropwise.
The reaction medium is agitated for 15' minutes
whilst maintaining at 0°C, then 224 pi of benzoyl
chloride is added dropwise.
The temperature is then left to return to 20°C over
one hour.
The reaction medium is diluted with 30 ml of
dichloromethane, then washed with an aqueous solution of
tartaric acid at 10%, then a solution saturated with
sodium bicarbonate, then with water.
The reaction medium is dried over magnesium
sulphate, filtered, and concentrated by evaporation of
the dichloromethane under reduced pressure.
0.6 g of a yellow, oil is thus obtained which is
purified by chromatography on silica using a
dichloromethane/methanol mixture 99/1 as eluent.
In this way 0.499 g of 1-(1,1-dimethylethyl) and 2-
methyl trans-4-(benzoylamino)-1,2-pyrrolidine
dicarboxylate with molecular formula C1BH24N205 (M = 348 g)
is recovered i.e. a yield of 74%.
0.400 g (1.15 mmole) of the compound obtained
previously is mixed under a nitrogen atmosphere with 3 ml
of ethyl acetate in order to dissolve the compound, then
the solution is cooled down to 0°C, 2.89 ml of a solution
of 4 mole/1 of HCl in ethyl acetate is added.
At the end of 15 minutes, agitation is continued at
ambient temperature for 1 hour.
The solvent is then eliminated by evaporation under
reduced pressure.
In this way 0.350 g methyl trans-4-(benzoylamino)-2-
pyrrolidinecarboxylate hydrochloride with molecular
formula C3H15N203, HCl (M= 284.744 g) is thus obtained in
the form of a beige solid.
0.327 g (1.15 mmole) of the compound 'obtained
previously, placed under a nitrogen atmosphere, is mixed
with 4 ml of dichloromethane.
The suspension is then cooled down to 0°C, then 352
ul of TEA is added. The reaction medium is agitated for
15 minutes at 0°C, then 138 u1 of diphosgene is added.
Agitation is continued .for 5 minutes at 0°C, then the
reaction mixture is left to return to ambient
temperature. It is also left to react for 30 minutes.
The reaction medium is then diluted with
dichloromethane and washed with an aqueous solution of
tartaric acid at 10%, then with water and dried over
magnesium sulphate.
After filtering the solvent is eliminated by
evaporation under reduced pressure. 0.360 g of crude
product is thus obtained which is purified by
chromatography on silica eluting with a
dichloromethane/acetone mixture 95/5.
93.7 mg of methyl trans-4-(benzoylamino)-1-
(chlorocarbonyl)-2-pyrrolidinecarboxylate hydrochloride
(Ci4Hi4N2O4, HC1 (M = 310.74 g) is thus recovered, i.e. a
yield of 26 %.
93.7 mg (0,301 mmole) of the compound obtained
previously, is mixed under a nitrogen atmosphere with 3
ml of tetrahydrofuraru The temperature of the solution
is lowered to -78°C, then 332 ul of lithium
bis (t ri methyl silyl) amide in 1M solution is added
dropwise into tetrahydrofuran and the reaction medium is
kept at -78°C for another 5 minutes.
The reaction medium is agitated for 30 minutes at
ambient temperature.
The solution is then cooled down to 0°C, and 55 /il
of acetic acid is added. 20 ml of ethyl acetate and 3 ml
of a phosphate buffer at pH = 7.0 is added. The solution
is left to settle, followed by washing with water, drying
over magnesium sulphate, filtering and concentrating by
evaporation. 76 rng of a foam is thus obtained which is
purified by chromatography on silica eluting with a
dichloromethane/acetone mixture 97/3.
5 mg of pure expected compound, with molecular
formula • (C14Hi4N2O4, HC1 (M = 274.279 g) , is recovered i.e.
a yield of 6%.
IR (CHC13) : 1805, 1779, 1743, 1669; 1603, 1589, 1486 cm"1,
MS (El) tn/z: [M]+ = 274, 215, 169, 105, 77.
Example 7 a
phenylmethyl trans-3-benzoyl-2-oxo-l,3-diazabicyclo
[2,2,1]heptane-6-carboxylate
The operation is carried out in a similar way to
that indicated in Example 7, starting from 0.92 g of 1-
(1,1-dimethylethyl) and 2-phenylmethyl trans-4-amino-l,2-
pyrrolidinedicarboxylate (described in J. Org. Chem.
1991, 56, 3009-3016) in order to obtain the expected
compound with an overall yield of 5.4 % over 4 stages.
Example 8
phenylmethyl trans-2-oxo-3-(phenylsulphonyl)-1,3-diaza
bicyclo [2,2,1] heptane-6'-.carboxylate
2.97 g (9.26 mmoles) of 1-(1,1-dimethylethyl) and 2-
(pheriylmethyl) trans-4-amino-l,2-pyrrolidinedicarboxylate
(described in J. Org. Chem. 1991, 56, 3009-3016) with
molecular formula CE24N2O4 (M = 320.392 g) are mixed
together under a nitrogen atmosphere and 25 ml of
dichloromethane is added. The reaction medium is cooled
down to 5°C and 1.3 ml of TEA is added. Agitation is
carried out for 10 minutes and then 1.63 g of
benzenesulphonyl chloride is added.
The reaction medium is left under agitation at 5°C
for 15 minutes, then the temperature of the reaction
medium is left to rise to 20°C for a duration of 45
minutes.
The reaction medium is diluted ' using
dichloromethane, followed by washing with an aqueous
solution of tartaric acid at 10%, then with phosphate
buffer at pH = 7.0, then with a saturated aqueous
solution of sodium chloride. The reaction medium is
dried over -magnesium sulphate and the solvent is
evaporated off under reduced pressure.
4.5 g of crude product is thus obtained which is
chromatographed on silica eluting with a dichloromethane
and ethyl acetate mixture 90/10.
4.06 g of 1-(1,1-dimethylethyl) and 2-(phenyl
methyl) trans-4- [(phenylsulphonyl)amino]-1,2-
pyrrolidinedicarboxylate with molecular formula C23H28N2O6S
(M = 460, 552 g) is thus recovered, which corresponds to
a yield of 95%.
3.83 g (8.31 mmoles) of the sulphonamide obtained
previously is mixed with 10 ml of. anhydrous methanol.
The solution is cooled down to 0°C and 8.2 ml of a
solution of 10 mol/1 of hydrochloric acid in methanol is
added at this temperature.
The- solution is agitated at 0°C for 5 minutes, then
the temperature is left to rise to ambient temperature.
After 30 minutes, the methanol is evaporated off
under reduced pressure, the reaction medium is taken up
several times in methanol then in dichloromethane. The
hydrochloride is then crystallized from ethyl ether.
In this way 3.2 g of phenylmethyl trans~4-
[phenylsulphonyl) amino] -2-pyrrolidinecarboxylate hydrochloride,
with molecular formula C18H2oN2O4S, HC1 (M =
396.896 g) is thus obtained, which corresponds to a yield
of 96 %.
2.78 g (7 mmoles) of the hydrochloride obtained
previously is mixed under an inert atmosphere with 28 ml
of dichloromethane.
The reaction medium is then cooled down to about 0-
5°C, then 2.15 ml of TEA is added.
Agitation is continued- for 15 minutes at a
temperature comprised between 0 and 5°C, then 0.46 ml of
diphosgene is added.
The reaction medium is kept at this temperature for
4 minutes, then a 10% aqueous solution of tartaric acid
is added, the reaction medium is diluted using
dichloromethane, decanted, washed with a saturated
aqueous solution of sodium chloride, dried over magnesium
sulphate, and concentrated under reduced pressure.
In this way 3.1 g of a yellow oil is obtained which
is purified by chromatography on silica, eluting with a
dichloromethane/ethyl acetate mixture 9/1.
1.82 g of phenylmethyl trans-1-(chlorocarbonyl)-4-
[ (phenylsulphonyl) amino] - 2 - pyrrolidinecarboxylate,
with molecular formula . CigHigClOsS (M = 422.89 g) is
recovered, which corresponds to a-yield of 61%.
1.81 g (4.28 mmoles) of the carbamoyl chloride
obtained previously is mixed under an inert atmosphere
with 31 ml of tetrahydrofuran.
The solution obtained is cooled down to -70°C, then
4.7 ml of a 1M solution of lithium bis(trimethylsilyl)
amide in tetrahydrofuran is added at this temperature
over 10 minutes.
The reaction medium is agitated for 45 minutes at
70°C, then the temperature is left to rise to about 0°C.
The reaction medium is kept at this temperature for 2
hours 30 minutes.
Then 295 ul of acetic acid is added.
The reaction medium is diluted with dichloromethane,
then washed with a 10% aqueous solution of tartaric acid,
with a phosphate buffer solution at pH = 7 and with a
saturated aqueous solution of sodium chloride.
Followed by drying over magnesium sulphate, and
concentrating to dryness under reduced pressure.
The crude product is purified by chromatography on
silica, using a dichloromethane/ethyl acetate mixture
95/5 as eluent.
In this way 244 mg of expected compound with
molecular formula C19H1SN2O5S (M = 386.429 g) is obtained,
which corresponds to a yield of 14%.
NMR spectrum of the proton
In CDCla, at 400 MHz, chemical shifts of the peaks in ppm
and multiplicity:
2.15 (m) : 0=C-CH-CH2; ' 2.85 (d) and 3.08 (d) : 0=C-N-CH2;
3.62 (m) : O=C-CH-N-CH2; 4.94 (s) : 02S-N-CH-CH2; 5.16:
C02CH2C6HS; 7.34 (m) :' C6H5; 7.57 (m) - - 7.68 (m) and
8.03 (m) : SO2C6HS. . •
IR (CHCla) : 1780, 1743; 1586, 1499cm"1.
MS (positive electrospray) m/z: [2M+Na] + = 795;
[M+Na+CH3CN] + = 450; [M-f-Na] + =409; [M+H] + = 387.
Example 9
phenylmethyl trans-3-benzoyl-4-methyl-2-oxo-l,3-diazabicyclo[
2,2,1] heptane - 6 - carboxylate
18.69 g (58.52 mmoles) of 1-(1,1-dimethyl-ethyl) and
of 2-(phenylmethyl) 4-oxo-l,2 pyrrolidinedicarboxy.l ate
(described in Chem. Pharm. Bull. 43(8)1302-1306 (1995))
with molecular formula G17H21N05 (M = 319.361 g) and 500
ml of anhydrous ethyl ether are mixed together under an
inert atmosphere.
A suspension of 10 g of CeCl3 in 50 ml of anhydrous
ethyl ether is added to the solution obtained.
The suspension is agitated for 30 minutes at 20°C,
then cooled down to -60°C.
20 ml of a 3M solution of MeMgBr in ethyl ether is
then added.
The reaction medium is left to react for 1 hour at
-60°C, then the temperature is left to rise to 0°C over
30 minutes. Neutralization is carried out with a 10%
aqueous solution of NH4C1, followed by extracting with
dichloromethane, filtering, the organic phase is washed
with water, dried over magnesium sulphate, and
concentrated to dryness under reduced pressure.
19.33 g of an oil is thus obtained which is purified
by chromatography on silica eluting .with a
dichloromethane/terbutylmethyl-ether mixture 90/10.'
7.21 g of 1-(1,1-dimethylethyl) and 2-(phenylmethyl)
. cis-4-hydroxy-4-methyl-l,2-pyrrolidinedicarboxylate, with
molecular formula C18H25NO5 {M = 335.404 g) is obtained
i.e. a yield of 36%, as 'well as 2.5 g of the alcohol
epimer.
3.17 g (9.45 mmoles) of the compound obtained
previously and 70 ml of dichloromethane are mixed
together under an inert atmosphere. The reaction medium
is cooled down to 5°C and 2.3 ml of TEA, then 1.28 ml of
methane sulphonyl chloride is added dropwise.
The reaction medium is agitated for 45 minutes at
5°C..
Followed by washing with a 10% aqueous solution of
tartaric acid, then with a phosphate buffer solution at
pH 7, then with water.
The organic phase is dried over magnesium sulphate
and concentrated to dryness under reduced pressure.
3.9 g of an oil is thus obtained which is purified
by chromatography on silica eluting with a
dichloromethane/ethyl acetate mixture 90/10.
2.75 g of 1- (1,1-dimethylethyl) and 2 - (phenylmethyl)
cis-4-methyl-4-[(methy1sulphony1) oxy]- 1,2-
pyrrolidine dicarboxylate with molecular formula
C19H27NO7S (M = 413.494 g) is recovered which corresponds
to a yield of 70%.
A solution of 2.54 g (6.14 mmoles) of the mesylate
obtained previously in 40 ml of dimethylformamide is
prepared.
519 mg (7.98 mmoles) of NaN3 is then added at 20°C,
the reaction medium is heated at 50°C for 2 hours. After
cooling down, it is poured into 250 ml of water and
extracted with 250 ml of dichloromethane. The. organic
phase is washed with water, then dried over magnesium
sulphate and evaporated. to dryness under reduced
pressure.
2.4'g of crude product'is obtained which is purified
by chromatography on silica, with a dichloromethane/ethyl
acetate mixture 95/5 as eluent.
1.66 g of 1- (1,1-dim'ethylethyl) and 2-(phenylmethyl)
trans-4-azido~4-methyl-l,2-pyrrolidinedicarboxylate with
molecular formula C8H24N4O4 (M = 360.42 g) is thus
recovered, (titre approximately 30% by weight) which
corresponds to a yield of approximately 25%.
1.85 g of the azide obtained previously (i.e.
approximately 1.7 mmole) is dissolved in 18 ml of
toluene.
1.38 ml of Bu3SnH and 84 mg of AIBN are then added
at 20°C.
The reaction medium is taken to 75°C and kept at
this temperature for 2 hours.
The toluene is evaporated off followed by redissolving
in ethyl acetate. A saturated aqueous solution
of potassium fluoride is agitated for 30 minutes at
ambient temperature.
The reaction medium is filtered on clarcel, it is
left to settle and the organic phase is dried over
magnesium sulphate.
After evaporation of the solvent under reduced
pressure, 3 g of an oil is obtained which is
chromatographed on silica, eluting with a
dichloromethane/methanol mixture 9/1.
560 mg of 1-(1,1-dimethylethyl) and 2-(phenylmethyl)
trans-4-amino-4-methyl-l,2-pyrrolidinedicarboxylate with
molecular formula CisEbsCU (M = 334.419 g) is recovered.
The yield is therefore quantitative.
578 mg (1.72 mmoles) of the amine obtained
previously is mixed under an inert atmosphere with 30 ml
of dichloromethane.
The reaction medium is cooled down to 5°C and 290 /il
of TEA, then 240jzl of benzoyl chloride are added
dropwise.
Agitation is continued at 5°C for 30 minutes.
The reaction medium is diluted with dichloromethane,
washed with a 10% aqueous solution of tartaric acid, with
a saturated aqueous solution of sodium carbonate, then
with water, the organic phase is dried over magnesium
sulphate, and the solvent is evaporated off under reduced
pressure.
950 mg of an oil is thus obtained which is purified
by chromatography eluting with a dichloromethane/ethyl
acetate mixture 90/10.
In.this way 732 mg of 1-(1,1-dimethylethyl) and 2-
(phenylmethyl) trans-4-(benzoylamino)-4-methyl-l,2-
pyrrolidinedicarboxylate with molecular formula C25H3oN2O5
(M = 438.528 g) is recovered, which corresponds to a
yield of 97%.
636 rag (1.45 mmoles) of the amide obtained
previously is dissolved in 1.9 ml of ethyl acetate,
followed by cooling down to about 0-5°C with an ice bath,
then 3.2 ml of a hydrogen chloride solution at 4.6 mol/1
in ethyl acetate is added.
The temperature is left to rise to 20°C, then after
1 hour, the solvent is evaporated off under reduced
pressure.
The hydrochloride is then crystallized from ethyl
ether.
In this way 570 mg of the • hydrochloride of
phenylmethyl trans-
4-(benzdylamino)-4-methyl-2-pyrrolidinecarboxylate
with molecular • formula C2oH22N2O3, HCl (M = 374.87 g) , in
the form of a white powder is recovered. The yield is
therefore quantative.
100 mg (0.267 mmole) of the hydrochloride obtained
previously is dissolved under an inert atmosphere in 1.5
ml of dichloromethane.
The reaction medium is cooled down to about 0-5°C,
then 90 ul of TEA is added.
The reaction medium is agitated for 15 minutes at
5°C, then 20 ul of diphosgene is added.
Agitation is continued for 30 minutes at 5°C.
Then, the reaction medium is treated with a 10%
aqueous solution of tartaric acid, extracted with
dichloromethane, the organic phase is washed with a
saturated aqueous solution of sodium chloride, dried over
magnesium sulphate, and the solvent is evaporated off
under reduced pressure.
130 mg of an oil is thus obtained which is purified
by chromatography on silica eluting with a
dichloromethane/ ethyl acetate mixture 9/1.
72 mg of phenylmethyl trans-4-(benzoylamino)
-1-(chlorocarbonyl) - 4 - methyl - 2 - pyrrolidinecarboxylate
with molecular formula C2H2N2O4Cl (M =
400.865 g) is then recovered, which corresponds to a
yield of 67%.
373 mg (0.930 mmole) of the compound obtained
previously is dissolved in 9 ml of tetrahydrofuran.
The solution is then cooled down to -70°C and 1 ml
of a 1 M' solution in lithium bis (trimethylsilyl) amide
tetrahydrofuran is added over 5 minutes.
The reaction medium is left to warm up to 0°C over
.45 minutes, then 69 of acetic acid is added.
The' reaction • medium • is 'then diluted with
dichloromethane, washed with a 10% aqueous solution of
tartaric acid, then with a phosphate buffer solution at
pH=7.0, and with a saturated aqueous solution of sodium
chloride.
The organic phase is dried over magnesium sulphate,
concentrated to dryness under reduced pressure, in order
to obtain 330 mg of a crude product which is purified by
chromatography on silica, eluting with a
dichloromethane/ethyl acetate mixture 98/2 containing
0.1% TEA by volume.
In this way 123 mg of the expected compound with
molecular formula C21H20N204 (M = 364.404 g) is
recovered, which corresponds to a yield of 36%.
NMR spectrum of the proton
In CDC13, at 300 MHz, chemical shifts of the peaks
in ppm and multiplicity:
1.76 (s) : CH3; 2.11 (dd) and 2.73 (ddd) : N-CH-CH2;
2.93 (dt) and 3.00 (d) : N-CH2; 3.96 (ddd): N-CH-CH2;
5.21: C02CH2C6H5; 7.36 (m) : CH2C6H5; 7.43 (t) and 7.57 (tt)
and 7.72 (d) : COC6H5.
IR(CHC13) : 1776, 1745, 1682; 1601, 1580, 1498 cm"1.
MS (positive electrospray) m/z: [2M + Na] + = 751; [2W -i-
H]+ = 729; [M + Na] + = 387; [M + H] + = 365
Example 10
1-propenyltriphenylphosphonium salt of phenylmethyl
trans-2-oxo-3-(sulphooxy)-1,3-diazabicyclo[2,2,1]heptane-
6-carboxylate
15 g (46.71 mmoles) of 1-(1,1-dimethylethyl) and 2-
(phenylmethyl) cis-4-hydroxyl,2-pyrrolidinedicarboxylate
(commercial product) with molecular formula Ci7H23NO5 (M =
321.377 -g) is dissolved under ah inert -atmosphere in 225
ml of anhydrous dichloromethane.
5.42 ml of 2,6-lutidine is added to the solution.
Followed by cooling down to -70 °C, then 8.25 ml of
trifluoromethanesulphonic anhydride is introduced over 5
minutes.
The reaction medium is agitated for 10 minutes at
-70°C then 4.43 g of O-allyl-hydroxyl-amine is introduced
at -70°C.
The reaction mixture is then left at ambient
temperature for 27 hours.
The reaction mixture is diluted with
dichloromethane, then washed with a 10% aqueous solution
of tartaric acid, with a saturated aqueous solution of
NaHCO3/ and water.
The organic phase is dried over sodium sulphate, and
the solvent is evaporated off under reduced pressure.
48
In this way 23 g of a crude oil is obtained which is
purified by chromatography on silica, the eluent being
successively a 95/5, 90/10, then 80/20
dichloromethane/ethyl acetate mixture.
7.18 g of 1-(1,1-dimethylethyl) and 2-(phenylmethyl)
trans-4- [ (2-propenyloxy)amino]-1,2-pyrrolidinedicarboxylate
with molecular formula C2oH28N2O5 (M =
376.456 g) is recovered, which corresponds to a yield of
40%.
3.25 g (8.63 mmoles) of the compound obtained
previously is dissolved in 3.5 ml of ethyl acetate.
The reaction medium is cooled down to about 0-5°C,
then 19 ml of a 4.6 mol/1 solution of hydrogen chloride
in ethyl acetate is added. The reaction medium is l e f - t o react whilst
agitating at about 0-5°C for 40 minutes.
The solvent is evaporated off under reduced
pressure, followed by taking up several times with
diethyl ether, whilst extracting the liquid supernatant.
In this way 2.54 g of the hydrochloride is obtained
in the form of a white precipitate, which is dissolved in
55 ml of dichloromethane under agitation. 7.3 ml of 2N
soda is added. After decantation, the organic phase is
dried over sodium sulphate.
The dichloromethane is evaporated off under reduced
pressure.
2.12 g of phenylmethyl trans-4-[(2-propenyloxy)
amino]-2-pyrrolidinecarboxylate with molecular formula
C1BH2oN203 (M = 276.337 g) is thus obtained in the form of
an oil i.e. a yield of 89%.
4.14 g (15 mmoles) of the compound obtained
previously is dissolved under an inert atmosphere in 1.5
1 of acetonitrile.
The reaction medium is cooled down to about 0-5°C
and 1.14 ml of diphosgene is added. Agitation is carried
out for 15 minutes whilst being maintained at 0-5°C, then
4.6 ml of TEA, and 1.83g of DMAP in 80 ml of acetonitrile
are added successively.
The temperature is left to rise to ambient
temperature and the reaction medium is left to react for
26 hours, then half of the solvent is evaporated off
under reduced pressure.
Then, the reaction medium is treated with a 10%
aqueous solution of tartaric acid, then extracted with
dichloromethane. The organic1 phase is washed using, a
saturated aqueous solution of sodium chloride, dried over
magnesium sulphate and • the solvent is evaporated off
under reduced pressure.
43 g of crude product is thus obtained which is
purified by chromatography on silica eluting with a
dichloromethane/ethyl acetate mixture 90/10 containing
0.1% TEA.
312 mg of phenylmethyl trans-2-oxo-3-(2-
propenyloxy)-1,3-diazabicyclo[2,2,1]heptane-6-carboxylate
with molecular formula Ci6H18N204 (M = 302.33 g) is
recovered which corresponds to a yield of 7 %.
70.2 mg (0.232 mmole) of the compound obtained
previously is dissolved under an inert atmosphere in 2.3
ml of dichloromethane. 26.5 ^il of acetic acid and 134 mg
of Pd(P(Ph)3)4 are then introduced.
The reaction medium is left to react for 40 minutes
at ambient temperature, then the temperature is lowered
to -20°C and 2.96 ml of a solution of an SO3-pyridine
complex at 0.314 mol/1 is added. The reaction medium is
left to react for 2 hours and 30 minutes then
dichloromethane is added and evaporation is carried out
under reduced pressure, followed by taking up in 40 ml of
dichloromethane and washing with 5 ml of water. The
organic phase is separated and dried over sodium
sulphate, then the solvent is evaporated off under
reduced pressure.
In this way 280 mg of crude product is obtained
which is purified by chromatography on silica, eluting
successively with a dichloromethane/acetone mixture 80/20
containing 0.1 % of TEA, then a dichloromethane/acetone
mixture 50/50 containing 0.1 % of TEA.
34.0 mg of expected compound, with molecular formula
C34H33N207SP (M = 644.689 g) is recovered in the form of a
yellow oil, i.e. a yield of 23%.
NMR 'Spectrum of the proton
In CDC13, at 400 MHz, chemical shifts of the peaks
in ppm and multiplicity: '
2.00(m) and 2.48(m): CH2~CH-C=O; 2.72(d) and 3.12(s): CHCH2-
N; 3.75(m): CH2-CH-C=02; 4.71(s) CH-CH2-N; 5.18 [AB]
CH2-C6H5; 7.35(m): CH2-C6H5 and 2.29(m): CH3-CH=CH; 6.62
and 7.21 CH3-CH=CH; 7,60-7.85 P(C6H5)3
MS (negative and positive electrospray) m/z:
[Manion]" = 341
[Meat ion] + = 303
Example 11
1-propenyltriphenylphosphonium salt of methyl trans-2-
oxo-3-(sulphooxy)-1,3-diazabicyclo[2,2,1]heptane-6-
carboxylate
The operation is carried out as in Example 10, but
starting from 207 mg of 1- (1,1-dimethyl ethyl) and 2-
methyl cis-4-hydroxy-l, 2-pyrrolidinedicarboxylate.
12 mg of the desired product of formula C7Hi0N207S (M
= 266.231 g) is thus obtained.
'MS (negative and positive electrospray) m/z:
[Manion] = 265
[Mcation]+ = 303
Example 12 a
diphenylmethyl trans-7-o.xo-6-oxa-l-azabicyclo [3,2,1]
octane-3 -carboxylate
8 ml of dichloromethane and 347 mg (Immole) of
diphenylmethyl cis-5-hydroxy-3-piperidinecarboxylate
hydrochloride (described in Acta Chem. Scand. Ser. B
35(4) 289-294) are mixed together under an inert
atmosphere.
The reaction medium is cooled down to 0°C, then 346
uI of TEA and 72 p.1 of diphosgene are added.
The reaction medium is left to react for 15 minutes
whilst maintaining the temperature at 0°C, then the
solvent is evaporated off under reduced pressure,
followed by taking up in 25 ml of dry toluene and
filtering to eliminate the TEA hydrochloride.
553 Ul of TEA is added to the filtrate and heating
is carried out under reflux; for 4 hours.
The reaction medium is then diluted with ethyl
acetate and washed with an aqueous solution containing
10% tartaric acid, then with a saturated aqueous solution
of sodium chloride, and the organic phase is dried over
magnesium sulphate.
Evaporation under reduced pressure is carried out
and 339 mg of crude product is recovered which is
purified by chromatography on silica, eluting with a
toluene/ethyl acetate mixture 70/30.
In this way 146 mg of the expected compound (M =
337.378 g) is recovered, which corresponds to a yield of
43%.
NMR spectrum of the proton
In CDC13, at 250 MHz, chemical shifts of the peaks
in ppm and multiplicity:
2.15 (ddd) and 2.73 (dq) : N-CH2-CHO-CH2; 2.92 (tt) :
02C-CH-; 3.00 (d) and 3.45 (d) : N-CH2-.CHO; 3.48 (dd) and
4.07 (dd) : N-CH2-CH-C02;" 4.79 (dt) : N~CH2-CHO; 6.90 (s):
C02-CH-(CSH5)2; 7.33 (tn) : (C6H5)2.
IR(CHC13) : 1792, 1734; 1600, 1585, 1497 cm"1
MS (El) m/z: [M]+ = 337, 292, 183, 167.
Example 12b
trans-7-oxo-6-oxa-l-azabicyclo[3,2,1]octane-3-
carboxylic acid
320 mg of the compound obtained in Example 12a, 17
ml of acetone and 70 mg of Pd/C catalyst at 20% by weight
are mixed together.'
• Agitation is carried out under'a hydrogen atmosphere
at normal pressure.
At the end of 2 hours 30 minutes, 70 mg of catalyst
is added and left to react for another 1 hour 30 minutes,
then the reaction medium is filtered.
The solvent is evaporated off under reduced pressure
and 350 mg of crude product is thus obtained which is
crystallized from pentane.
Filtering is carried out and 158 mg of the sought
product with molecular formula C7H9NO4 (M = 171.154 g) is
thus recovered in the form of a grey solid. The
corresponding yield is 89%.
NMR spectrum of the proton
In DMSO, at 300 MHz, chemical shifts of the peaks in
ppm and multiplicity:
2.10 (ddd) and 2.43' (dm): N-CH2-CHO-CH2; 2.83 (tt) :
02C-CH-; 3.13 (d) and 3.27 (dm) :' N-CH2-CHO; 3.40 (dd) and
3.72 (d) : N-CH2-CH-C02H; 4.81 (m) : N-CH2-CHO; 12.54
(broad s): CO2H.
IR (nujol) : 1782, 1692 cm"1.
MS (El) m/z; [M] * = 177, 155, 127, 82, 70.
Example 12c
(4-nitrophenyl)methyl trans-7-oxo-6-oxa-lazabicyclo
[3,2,1] octane-3-carboxylate
30 mg (0.175 mmole) of the acid obtained in Example
12b and 0.5 ml of dichloromethane are mixed together
under an inert atmosphere. 26.8 mg of 4-nitrobenzylic
alcohol, 2.2 mg of DMAP and 37 mg of EDCI are then added. .
The reaction medium is left to react whilst
agitating for 2 hours at ambient temperature.
The organic phase is then diluted with
dichloromethane, washed with a 10% aqueous solution of
tartaric acid and a phosphate buffer solution at pH 7.
After drying the organic phase over sodium sulphate,
and evaporation of the solvent under reduced pressure, 57
mg of crude product is obtained which is purified by
chromatography on silica eluting with a toluene/ethyl
acetate mixture 85/15.
The product is then crystallized from a mixture of
ethyl ether and pentane in order to produce 34 mg of
white crystals of the sought compound (M = 306.277 g).
The corresponding yield is 63.5%.
NMR spectrum of the proton
In CDC13, at 300 MHz, chemical shifts of the peaks
in ppm and multiplicity:
2.14 (ddd) and 2.84 (dm): N-CH2-CHO-CH2; 2.90 (tt) :
02C-CH-; 3.10 and 3.49 (dm); N-CH2-CHO; 3.43 (dd) and
4.14 (bd) : N-CH2-CH-C02; 5.27 [AB] : . C02-CH2-C6H5; 7.56 and
8.24 [AA'BB1]: C-C6H5-N02.
IR (CHC13) : 1199, 1789, 1741; 1609, 1526, 1495 cm"1.
MS (El) m/z: [M] + : 306, 170, 136, 126, 106, 82.
Example 13
6-(phenylmethyl)-1,6-diazabicyclo[3,2,1]octan-7-one
Stage A:
30.7 ml of TEA is added at about 0-5°C to a solution
of 20.71 g of 3-amino-pyridine in 200 ml of methylene
chloride, then, 25.5 ml of benzoyl chloride is added
dropwise over 15 minutes and the reaction medium is left
to return to ambient temperature. After 1 hour under
agitation, the reaction medium is washed with water, then
with a saturated solution of sodium bicarbonate, then the
organic phase is dried over sodium sulphate and the
.solvent is evaporated off under reduced pressure. 42.2?
'.g -of expected crystallized product (M = 198.226 g) is
obtained.
Stage B:
4.3 ml of concentrated hydrochloric acid and 500 mg
of rhodium on aluminium at 5 % by weight are added to a
solution of 10 g of the product obtained in stage A in
200 ml of methanol. The reaction medium is placed under a
hydrogen atmosphere at a pressure of 60-110 bars for 15
hours.
The reaction mixture is filtered, rinsed with
methanol then the filtrate 'is concentrated under reduced
pressure. The hydrochloride of the expected product is
obtained in a mixture with 10 % hydrochloride of the
starting product.
The product is taken up in 250 ml of methylene
chloride and 1.1 equivalent of IN soda is added. After
agitation for 15 minutes, the methylene chloride is
decanted, the organic phase is washed with water, dried
and evaporated under reduced pressure. The residue is
chromatographed on silica eluting with a methylene
chloride - methanol - triethylamine mixture 92/8/3.
7.4 g of expected crystallized product is obtained,
i.e. a yield of 72 %.
Stage C: N-(phenylmethyl)-3-piperidinamine
20 g of the product obtained as described in stage B
is dissolved in 600 ml of 1,2-dimethoxyethane. 14.8 g of
lithium aluminium hydride is added to the solution over
30 minutes. The reaction medium is heated under
agitation and under an inert gas at 75 - 80°C for 16
hours then cooled down to 0°C and 11 ml of water is added
over 45 minutes, without exceeding 12°C. The reaction
medium is agitated for 10 minutes, filtered and the
precipitate is washed-'with methylene chloride. The
filtrate is concentrated under reduced pressure. 17.8 g
of expected product is obtained, in the form of an oil
which is distilled under reduced pressure (boiling point:
114 - 121°C / 0.8 mbar) . 16 g of expected product is
recovered, i.e. a yield of 86 %.
Stage D: 6-(phenylmethyl)-1,6-diazabicyclo[3,2,1]octan-7-
one
1.06 g of the product obtained in stage C is
dissolved in 28 cm3 of toluene, then cooled down to 0°C
and 337 of diphosgene is added under an inert gas.
Then the temperature is left to rise and maintained for 2
hours at 20°C. The reaction medium is concentrated under
reduced pressure then the residue is chromatographed on
silica eluting successively with methylene chlorideacetone
95/5 then 80/20 and finally methylene chloridemethanol,
triethylamine 92/8/3 and 362 mg of expected
product C13H6N20 (M = 216.85 g) is obtained i.e. a yield
of 30%.
CPV/Mass spectrometry (El) m/z: [M]+ = 216, .125, 91.
IR (CHC13) : 1718; 1498 cm"1.
Example 14
6-benzoyl-l,6-diazabicyclo[3,2,1]octan-7-one
Stage A: 3-(benzylamino)-1-piperidinecarboxylic
5 g of product obtained in stage B of Example 13 is
dissolved in 1.25 1 of anhydrous toluene under a nitrogen
atmosphere then 3.4 ml of TEA is added and 1.47 ml of
diphosgene is introduced at 0- 5°C over 3 minutes. After
20 minutes at 0-5°C, the reaction medium is heated to
20°C, it is maintained under agitation for 75 minutes,
then the solvent is evaporated off under reduced
pressure. The residue is chromatographed on silica
eluting with a methylene chloride-acetone mixture 8/2.
3.44 g of expected product is obtained (yield of 52.6 %).
Stage B
6-benzoyl-l,6-diazabicyclo[3,2,1]octan-7-one
48 mg of sodium hydride at 50% dispersed in oil and
20 ml of THF are introduced under a nitrogen atmosphere.
The reaction medium is cooled down to about 0-5°C, then
266 mg of the product obtained in stage A is added in one
The temperature is left to rise to ambient
temperature, then 60 /^l of acetic acid and 10 ml of
phosphate buffer at pH 7 are added.
A little ethyl acetate is then added, then the
reaction medium is decanted and re-extracted with ethyl
acetate. The organic phase is dried over magnesium
sulphate, then the solvents are evaporated off under
reduced pressure.
The crude product is chromatographed on silica
eluting with dichloromethane containing 2% acetone.
143 mg of the sought product C H O s (M: 228.25 g)
is thus obtained. The corresponding yield is 62%.
NMR spectrum of the proton
In CDC13, at 250 MHz, chemical shifts of the peaks
in ppm and multiplicity:
1.20 - 2.15 (m) and 2.42 (tn) : NCH-CH-CH-; 2.80 (d)
- 2.93 (d) ; 3.11 (m) ; 3.28 to 3.58 (m) : CH2-N; 4.54 (m) :
CH-N; 7.43 (m) ; 7.55 (m) ; 7.69 (m) : C6Hs
IR (CHCI3) : 1758, 1672; 1605, 1586, 1492;
MS (El) m/z; [M] + = 230, 125, 105, 77
Example 15
7-coco-1, 6-diazabicyclo [3,2,1] octan-6-acetic acid
Stage A:
5-t (I/1-dimethylethyl)dimethylsilyl]-1 6-diazabicyclo[3-
2-1]ootan-7-one] .
843 mg of lithium is placed under a nitrogen
atmosphere and 320 ml of ammonia is condensed at -70°C.
7.56 g (34.8 mmoles) of the product obtained in Example
13 in 160 ml of tetrahydrofuran is added at -70°C over 10
minutes. Agitation is carried out for 5 minutes then the
ammonia is distilled under a stream of nitrogen whilst
heating slowly at 20°C./ 7.9 g of (1,1-
dimethylethyl)dimethylsilyl chloride in 10 cm3 of
tetrahydrofuran is added slowly at 20°C to the obtained
suspension then maintained under agitation for 10
minutes. 160 cm3 of ethyl acetate then 60 cm3 of a 10 %
aqueous solution, of tartaric acid is then added.
Decanting is carried out followed by re-extracting with
ethyl acetate, the organic phase is washed with water,
dried over sodium sulphate and the solvent is evaporated
off under reduced pressure. The oil obtained is
chromatpgraphed on silica with 10 % water, eluting with
methylene chloride then a • methylene chloride-acetone
mixture 8/2 and 3.04 g of expected product is obtained
(yield: 36.2 %).
NMR spectrum of the proton
In CDC13, at 250 MHz, chemical shifts of the peaks
in ppm and multiplicity:
0.21(3) and 0.40(S): SiCH3; 0.97(S): SitBu; 1.5 to 1.8(m)
and 2.07(m): N-CH-CH2-CH2; 2.85 (d) and 3.32 (m) ; -CH-CH2-
N: 2.93 (dt) and 3.32 (m) : -CH2-CH2-N; 3.65 (m) : CH - N.
IR (CHC13) : 1710; 842 cm"1.
MS (El) m/z: [M]: 240, 225, 183, 100, 83, 57.
Stage B:
phenylmethyl 7-oxo-l,6-diazabicyclo[3,2,1]octan-6-acetate
1.44 g (5.99 mmoles) of the product obtained in
,stage -A is dissolved under a nitrogen ••atmosphere in 14.4
ml of tetrahydrofuran then 941 UI of phenylmethyl
bromoacetate is added and then 6 ml of a 1M solution oftetra-
n-butyl ammonium fluoride in tetrahydrofuran is
added dropwise. The reaction medium is agitated for 10
minutes at 20°C then diluted with 15 ml of ethyl acetate
and 5 ml of an aqueous phosphate buffer solution at pH =
7 is added. The reaction medium is decanted, reextracted
with ethyl acetate, the organic phase is washed
with water, dried over sodium sulphate and the solvent is
evaporated off under reduced pressure. The oily residue
is chromatographed on silica with 10 % water eluting with
a methylene chloride-acetone mixture 8/2. 140 mg of the
expected product is obtained. The corresponding yield is
•9%.
IR (CHCla) : 1746, 1720 cm"1.
MS (El) m/z: [M]+ = 274, 183, 155, 139, 91, 83.
Stage C: 7-oxo-l,6-diazabicyclo[3.2.1]octane-6-acetic
acid
137 mg of the product obtained in stage B is
dissolved in 1.5 ml of ethyl acetate, then added to the
solution of 14 mg of palladium on carbon at 10 % and
placed under a' hydrogen atmosphere. After 15 minutes
another 15 mg of palladium on carbon is added and the
reaction medium is maintained under agitation for 15
minutes. The catalyst is filtered out, followed by
rinsing with ethyl .acetate, then with acetone and
methanol and the solvent is evaporated off under reduced
pressure. A total of 68 mg of crude product is obtained
which is crystallized from ether. 58 mg of the expected
product with molecular formula C5H18N203 (M = 274.321 g)
is obtained. The corresponding yield is 63 %.
"NMR spectrum of the proton
In CDC13/ at 400 MHz, chemical shifts of the peaks
• in 'ppm and multiplicity:
• ' 1.48 (m) , 1.63 (m) , 1.73 (m) and 1.86 (m) : N-CH-CH_2
CHg; 2.85 to 3.00 (m) , 3.14 (dm) and 3.64 (m) : CH2-N-CH2
and CH-N; 3.78 and 4.14 [AB]: CON-CRg-CO.
MS (El) m/z: [M]+ = 184, 139, 125, 111, 97, 83.
Example 16
7-oxo-N-phenyl-l,6-diazabicyclo[3,2,1]octane-6-
carboxamide
1 ml of tetrahydrofuran and 99 mg (0.41 mmole) of
the compound obtained in stage A of Example 15 are mixed
together under an inert gas.
50 Ul of phenyl isocyanate then 450 p.1 of a 1M
solution of tetrabutylammonium fluoride in THF are added
successively.
The reaction medium is left to react for 10 minutes,
then diluted with ethyl acetate, and washed with water.
The reaction medium is decanted and the organic phase is
dried over magnesium sulphate. The solvent is evaporated
off under reduced pressure. 140 mg of crude product is
thus obtained which is purified by chromatography on
silica using a dichloromethane/ethyl acetate mixture
90/10 as eluent.
21 mg of the compound of the title, with molecular
formula C3H5N30 (M = 245.283 g) is recovered which
corresponds to a yield of 20%.
NMR spectrum of the proton
In CDC13, at 250 MHz, chemical shifts of the peaks
in ppm and multiplicity:
1.78 (m) , 2.02 (m) and 2.17 (m) : N-CH-CHs-CHa; 2.88 (d)(,
3.13 (dt) and 3.42 (m) : CHz-N-CHs; 4.49 (m) : CH-N;
7.11(t); 7.34(t) and 7 . 54 (d) : ' CgHs; 10.05: NH .
IR (CHC13) : 3302, 3266; 1734; 1700; 1602, 1553, 1501 cm'1.
MS (El) -m/z: [Ml*: 24-5, 153, 126, 119, 98, 92.
Example .17a
6- [1-(phenylmethyl)-lH-tetrazole-5-yl]-1,6-diazabicyclo
[3,2,1]octan-7-one
480 mg (2 mmoles)- of the compound obtained in stage
A of Example 15 is placed under an inert gas.
Then a solution of 712 mg of 5-fluoro-l-
(phenylmethyl)-IH-tetrazole in 1.5 ml of tetrahydrofuran
then 2 ml of a 1M solution of tetrabutylammonium fluoride
in THF are added. The reaction medium is left to react
for 1 minute.
The reaction medium is then diluted with ethyl
acetate washed with water, decanted, the organic phase
is dried over magnesium sulphate and the solvent is
evaporated off under reduced pressure.
1.06 g of an oily product is obtained which is
chromatographed on silica in a dichloromethane/ethyl
acetate mixture 90/10.
143 mg of the expected compound with molecular
formula C4H6N60 (M = 284.324 g) is thus obtained in the
form of an amorphous white product. The corresponding
yield is 25%.
NMR spectrum of the proton
In CDC13, at 250 MHz, chemical shifts of the peaks
in ppm and multiplicity:
1.80 (m) , 2.04 (m) and 2.67 (m) : N-CH-CH2-CH2; 2.83 (d) ,
2.85 (dm), 3.10 (dd) and 3.44 (dd) : CH-N-OHa; 3.99 (m) :
CH-N; 5.63 and 5.88 [AB] : C6H5-CH2; 7.18 (m) and 7.32 (m) :
Example 17b .
6-(lH-tetrazole-5-yl)-1,6-diazabicyclo[3,2,1]octan-7-one
120 mg of the product obtained in Example 17a and
2.4 ml of a methanol/ethyl acetate mixture 90/10 are
mixed together then 2.4 ml of THF is added until total
dissolution is obtained.
24 mg of palladium catalyst on carbon at 10% is then
added, then the reaction medium is agitated under a
hydrogen atmosphere. After 3 hours of reaction, the
catalyst is filtered out, followed by rinsing with a
tetrahydrofuran/methanol mixture, then the solvent is
evaporated off under reduced pressure. The product is
then crystallized from ethyl ether.
72 mg of the compound of the title with molecular
formula C7H10N6O (M = 194.198 g) is thus obtained, in the
form of a white crystallized product. The corresponding
yield is 88%.
NMR spectrum of the proton
In DMSO, at 300 MHz, chemical shifts of the peaks in
ppm and multiplicity.
1.63 (m) , 1.89 (m) and 2.07 (m) : N-CH-CHa-CHa; 3.14 to
3.20 (m) and 3.43 (m) : CH2-N-CH2; 4.51 (m) : CH-N.
IR (Nuol) : 1744; 1594 cm"1.
MS (El) m/z: [M]+ = 194, 165, 124, 111, 98, 83, 68, 56,
41.
Example 18
6-acetyl-l, 6-diazabicyclo [3,2,1] octan-7-one
140 mg. (0.582 mmoles) of the compound obtained in
stage A of Example 15 is dissolved in 1.4'ml of THF.
55 il of acetic anhydride then 0.58 ml of a 1M
solution of tetrabutylammonium fluoride in THF are added
successively.
The reaction medium is then diluted with ethyl
acetate, washed with water, decanted, the organic phase
is dried over magnesium sulphate, then the solvent is
evaporated off under reduced pressure.
In this way 116 mg of a crude oil is obtained which
is chromatographed on silica with a
dichloromethane/acetone mixture 80/20.
18 mg of expected compound, with molecular formula
C8Hi2N2O2 (M= 168.196 g) is thus obtained, which
corresponds to a yield of 18 %.
NMR spectrum of the proton
In DMSO, at 300 MHz, chemical shifts of the peaks in
ppm and multiplicity:
1.65 to 2.20 (m) : N-CH-CHs-CH; 2.54 (s) : CH3CO-N; 2.83
(d) , 3.33 (dm), 3.10 (m) and 3.45 (dd) CHs-N-CH; 4.55
(m): 0=C-N-CH.
IR (CHC13) : 1758, 1696 cm"1.
MS (El) m/z: [M]+ = 168, 140, 126, 98, 43.
Example 19a
6-(phenylmethoxy)-1,6-diazabicyclo[3,2,1]octan-7-one
44.02 g (0.22 mole) of 1,1-dimethylethyl 3-oxo-lpiperidinecarboxylate
(C10H7NO3, M = 199.251 g)
(described in J. Med. Chem. 1986, 29, 224-229) is
dissolved in 440 ml of ethanol.
38.79 g of 0-benzyl-hydroxylamine hydrochloride is
then added. 54 ml of pyridine is then introduced
dropwise into the suspension.
The reaction medium is left to react whilst
agitating for 4 hours at approximately 25°C, then the
solvent is evaporated off under reduced pressure. The
react ion'• medium is taken up by a mixture of
dichloromethane and ethyl acetate, then filtered and
rinsed with dichloromethane, then with a mixture of
dichloromethane and ethyl acetate. The filtrate is then
concentrated to dryness under reduced pressure.
69.8 g of a light yellow oil is thus obtained which
is purified by chromatography on silica. The eluent used
is a cyclohexane/ethyl acetate mixture 80/20.
57.21 g of 1,1-dimethylethyl 3-[(phenylmethoxy)
imino]-1-piperidinecarboxylate, with molecular formula
C17H24N2O3 (M = 304.39 g) is recovered, in the form of a
very pale yellow oil. The corresponding yield is 85%.
24.82 g (0.0815 mmole) of the oxime obtained
previously is dissolved in 163 ml of ethanol cooled down
to -10°C under nitrogen. Then 25 ml of a borane-pyridine
complex is added, then 204 ml of 2N hydrochloric acid is
added dropwise over an hour and quarter. The solution is
agitated for 1 hour and a quarter at -5°C, then treated
with 100 ml of a saturated sodium hydrogen carbonate
solution, then with 35 g of sodium carbonate, which are
•added in small fractions. The pH is then 7-8.
The reaction medium is extracted with ethyl acetate.
The organic phases are combined, dried over sodium
sulphate, the solvent is evaporated off under reduced
pressure. 39.0 g of a colourless oily liquid is thus
obtained that is taken up in 400 ml of ethyl acetate.
The solution is washed with a 0.05 N aqueous
solution of hydrochloric acid, then the organic phases
are combined and the solvent is evaporated off under
reduced pressure.
35.5 g of an oily colourless liquid is recovered
which is purified by chromatography on silica, eluting
with a dichloromethane/ethyl acetate mixture 95/5, then
with a dichloromethane/ethyl acetate mixture 80/20.
17:'89 of 1,1-dimethylethyl 3- [ (phenylmethoxy) amino] -
1-piperidinecarboxylate with molecular formula C17H26N2O3
(M = 306.41 g) is thus recovered in the form of a
colourless oil. The corresponding yield is 72%.
6.72 g (21.9 mmoles) of the piperidine obtained
previously is dissolved in 22 ml of ethyl acetate cooled
down to -10 °C. 28 ml of a 4.0 mol/1 solution of
anhydrous hydrochloric acid in ethyl acetate is added
dropwise over 30 minutes.
After 1 hour at 0°C, 40 ml of ethyl ether is
added, the dihydrochloride precipitate is filtered and
washed with ethyl ether.
In this way 3.87 g of a white solid is obtained.
Another 1.80 g of the desired product is obtained by
crystallization of the filtrate.
The product obtained is taken up in 60 ml of IN soda
and 120 ml of ethyl acetate. After decantation, the
aqueous phase is saturated with sodium chloride, then
extracted twice with ethyl acetate. The organic phases
are combined and dried over magnesium sulphate then
concentrated to dryness under reduced pressure.
3.67 g of N- (phenylmethoxy) -3-piperidiriamine, with
molecular formula C12H18N2O (M = 206.29 g) is thus
obtained, which corresponds to a yield of 81%.
518 mg (2.5 mmoles) of ' the compound obtained
previously is dissolved in 5 ml of anhydrous
dichloromethane, then 0.5 ml of TEA is added.
The whitish suspension obtained is cooled down to
-65°C, then 12.5 ml of a 0.10 mol/1 solution of
diphosgene in dichloromethane. is added over 15 minutes
After reaction for 45 minutes, the colourless
solution is diluted with 15 ml -of dichloromethane and
treated with 15 ml of water.
The medium is left to settle, then the aqueous phase
is extracted with 20 ml of dichloromethane.
The combined organic phases are dried 'over magnesium
sulphate, then concentrated to dryness under reduced
pressure. A pale yellow oil is thus obtained which is
purified by chromatography on silica eluting with an
ethyl acetate mixture 90/10, then a dichloromethane/ethyl
acetate mixture 80/20.
In this way 196 mg of expected compound with
molecular formula C13H16N2O2, (M = 232.28 g) is recovered
in the form of a colourless oil. The corresponding yield
is 34%.
NMR spectrum of the proton
In CDG13, at 300 MHz, chemical shifts of the peaks in ppm
and multiplicity:
1.59 (m) and 1.93 to 2.18 (m) : N-CH-CHg-CHs,- 2.73 (dt) ,
2.94 (dt) , 3.17(dt) and 3.40 (dd) : CHs-N-CHs; 3.29 (t) :
W-CH; 4.89 (d) : N-0-CH2- (CeH5) ; 7.38: C6H5.
IR (CHC13) : 1747; 1498 cm"1.
MS (El)' m/z: [M]+ = 2 3 2 , 91.
Example 19b
6-(acetyloxy)-1,6-diazabicyclo[3,2,1]octan-7-one
95 mg (0.41 mmole) of the compound obtained in
Example 19a is dissolved in 5 ml of methanol, 8 mg of
palladium on carbon at 10% by weight is agitated, then
the suspension is placed under a hydrogen atmosphere
under normal pressure for 1 hour at 25° C, then the
catalyst is filtered out.
V
After evaporation of the solvent under reduced
pressure, 70 mg of white crystals are obtained.
The crystals are taken up in 2 ml of anhydrous
dichloromethane. The solution is cooled down to -10 °C
•under nitrogen. Then- 70 • l of pyridine, then 40 UI of
acetic anhydride are added and agitation is carried out
for 20 minutes. The reaction medium is concentrated
under reduced pressure and 75 mg of white crystals are
obtained which are purified on silica, eluting with a
dichloromethane ethyl acetate mixture 80/20.
49 mg of expected compound (M = 184.20g) is
recovered in the form of a white solid. The
corresponding yield is 65%.
NMR spectrum of the proton
In CDC13, at 300 MHz, chemical shifts of the peaks
in ppm and multiplicity:
1.60 to 2.2: N-CH-CHs-CHs; 2.24 (s) : CH3; 2.95 (d) and
3.54 (dm): N-CHj-CH; 3.07 (dt) and 3.54 (bdd) : N-CH2-CH2;
3 .94 (bt) : O=C-N-CH.
IR (CHC13) : 1798; 1764 cm"1.
MS (El) m/z: [M]+ = 184, 142, 125, 43.
Example 19c
6-(benzoyloxy)-1,6-diazabicyclo[3,2,1]octan-7-one
The operation is carried out in a similar manner to
that described in Example 19b starting with 205 mg of the
compound prepared in Example 19a and 200 mg of benzoic
anhydride.
In this way 64 mg of expected compound with
molecular formula Ci3Hi4N203 (M = 246.27 g] is obtained
i.e. a yield 30%.
NMR spectrum of the proton
In CDC13, at 250 MHz, chemical shifts of the peaks
in ppm and multiplicity:
1.64 to 1.95 (m) and 2.10 to 2.35 (m) : CH-CH2 -CH2; 3.02
(d) and 3.65 (dm): N-CHs-CH; 3.13 (dt) and 3.55 (bdd) : NCH2-
CH2'; 4.09 (bt) : O=C-N-CH; 7.49 (m) : 7.65 (tt); 8.12
(m) : C6Hs. • • •'
IR (CHC13) : 1774, 1756/1602, 1585, 1495 cm"1.
MS (El) m/z; [M]+ = 246, 105, 77.
Example 19d
6- (1-oxopropoxy)-1,6-diazabicyclo[3,2,1]octane-7-one
The operation is carried out in a similar manner to
that described in Example 19c, starting with 163 mg of
the compound prepared, in Example 19a and 70/zl of
propionyl chloride.
In this way 17 mg of expected compound with
molecular formula C9Hi4N2O3 (M = 198.23 g) is obtained,
i.e. a yield of 12 %.
NMR spectrum of the proton
In CDC13, at 300 MRz, chemical shifts of the peaks
in ppm and multiplicity:
1.25 (t) : 0=C-CH2-CH3; 1.65 (m) , 1.78 (m) and 2.10 (m) :
N-CH-CEfe-CHa; 2.52 (m) 0=C-CH2-CH3; 2.94 (d) and 3.55
(bd) : N-CHs-CH; 3.07 (dt) and 3.48 (dd) : N-CHj-CHs; 3.93
(m) : N-CH2-CH.
IR (CHC13) : 1792; 1763 cm"1.
MS (El) m/z: [M]+ = 198, 170, 142, 125, 97, 57.
Example 19e
6- [ t(4-methylphenyl)sulphonyl]oxy]-1,6-diazabicyclo
[3,2,l]octan-7-one
' The operation is carried out in a similar manner to
that described in Example 19d, staring with 139 mg of the
compound prepared in Example 19a and 126 mg of tosyl
chloride.
In this way 77mg of expected compound with molecular
formula 'CiaHieCS (M = 296.35 g) is obtained, i.e. a
yield of 44%.
NMR spectrum of the proton
In CDC13, at 250 MHz, chemical shifts of the peaks in ppm
and multiplicity:
1.55 and 2.99 (m) : N-CH-CHg-CEb; 2.45 (a): CH3; 2.89
(d) , 3.00 (dt) , 3.29 (dt) and 3.39 (dd) : CKb-N-CH; 4.04
(m) : N-CH; 7.35 and 7.91 [AA'BB1] CH3-C6H4-S02.
IR (CHC13) : 1775; 1599, 1495, 1383; 1193, 1180 cm"1.
MS (El) m/z: [M]+ = 296, 155, 141, 125, 91.
Example 19f
6- [ (methylsulphonyl)oxy]-1,6-diazabicyclo[3,2,1]octan-
one
The operation is carried out in a similar manner to
that described in Example 19e starting with 211 mg of the
compound prepared in stage 19a and 80/il of mesyl
chloride.
In this way 50 mg of expected compound with
molecular formula C H C S (M = 220.25 g) is obtained
i.e. a yield of 25%.
NMR spectrum_of the proton
In CDC13, at 250 MHz, chemical shifts of the peaks
in ppm and multiplicity:
1.56 and 2.38 (m) : N-CH-CHs-CHs; 3.00 (d) , 3.12 (dt) and
3.49 (m) : N-(CH2)2; 3.26 (s) : CH3; 4.12 (m) : N-CH.
IR (CHC13) : 1775; 1381, 1187 cm"1.
MS (El) m/z: [M]+ = 220, 141, 125, 97, 79.
Example 19g
6- [ (4-nitrophenyl)sulphonyl]oxy]-1,6-diazabicyclo
t3.,2,l]octan-7-one-
The operation is car'ried out in a similar manner to that •
described in Example 19f starting with 270 mg of the .
compound prepared in Example 19a and 283 mg of 4-
nitrobenzenesulphonyl chloride.
In this way 205.5 mg of expected compound with
molecular formula Ci2Hi3N3O6S (M = 327.32 g) is obtained
i.e. a yield of 54%.
NMR spectrum of the proton
In CDC13, at 250 MHz, chemical shifts of the peaks
in ppm and multiplicity:
1.64 (dt) , 1.84 (m) , 1.99 (m), 2.31 (dm): NCH-CIfc-CHg;
2.94 (d) , 3.30 (dt) , 3.04 (dt) , 3.40 (bdd) : N(CH2)2;
4.14: 0=C-N-CH; 8.25 and 8.41 [AA'BB1]:
IR (CHCla) : 1776; 1610, 1590, 1538; 1393, 1191 cm-i
MS (El) m/z: [M]* = 327, 186, 141, 125, 111.
Example 20
6- [[(4-methylphenyl)sulphonyl] amino]-1,6-diazabicyclo
[3,2,1] octan-7-one
5 g (25.1 mmole) of 1,1-dimethylethyl 3-oxo-lpiperidine
carboxylate (described in J. Med. Chem. 1986,
29, 224-229} (C10H17N03, M = 199.251 g) is dissolved in 50
ml of dichloromehane.
4.67 of tosylhydrazine is then added to the solution
and left to react for 2 hours under agitation, then the
solvent is evaporated off under reduced pressure.
9.56 g of 1,1-dimethylethyl 3-[2-[(4-methylphenyl)
sulphonyl]hydrazono]-1- piperidinecarboxylate, with
molecular formula CnH2sN3O4S (M = 367.47 g) is thus
obtained, with a quantitative yield.
4.5 g (12.2 mmoles) of the compound obtained
previously, 90 ml of a methanol/tetrahydrofuran mixture
50/50, and a few grains of bromocresol green are mixed
together under an inert gas.
1-. 62 g of NaBH3CN is then added, then the reaction
medium is cooled down to 0-5°C, and, a solution of 0.7
mol/1 of gaseous hydrogen chloride in methanol is
introduced in such a way as to keep the pH of the medium
between 3.8 and 5.4.
The reaction medium is left to react whilst
agitating for 2 and a half hours.
2/3rds of the solvent is evaporated off under
reduced pressure, then 200 ml of dichloromethane is added
and the medium is washed with a saturated aqueous
solution of sodium bicarbonate.
The organic phase is dried over sodium sulphate and
the solvent is evaporated off under reduced pressure.
In this way 4.48 g of 1,1-dimethylethyl 3-[2-[.(4-
methylphenyl) sulphonyljhydrazi.no] - 1-piperidine
carboxylate with molecular formula C17H27N304S (M = 369.486
g) is obtained.
The corresponding yield is 99%.
4.48 g of the compound obtained previously and 9 ml
of ethyl acetate are mixed together under an inert gas at
0°C, .
30 ml of a 4 mol/1 solution of gaseous hydrogen
chloride in ethyl acetate is added, agitation is carried
out for 15 minutes followed by filtering and the
hydrochloride is washed with ethyl acetate. Drying is
carried out under reduced pressure and 3.48 g of 2-(3-
piperidinyl)hydrazide dihydrochloride of 4-methylbenzenesulphonic
acid, with molecular formula CHigNsOjS,
2HC1 (M = 342.289 g) is obtained. The corresponding
«
yield is 84%.
3.48 g of the compound obtained previously and 5 ml
of demineralized water are then dissolved. 10.2 ml of an
aqueous solution of 2N soda is added under vigorous
a g i t a t i o n .
'A precipitate is formed after 1 to 2 minutes of
contact. Agitation is then carried out for 10 minutes,
then the precipitate is filtered and washed with water,
then ethyl acetate.
The solid obtained is dried under reduced pressure.
In this way 2.21 g of 2-(3-piperidinyl)hydrazide of
4-methyl-benzenesulphonic acid, with molecular formula
Ca2Hi9N3O2S (M = 269.328 g) is obtained. The corresponding
yield is 81%.
500 mg (1.85 mmole) of the amine obtained previously
and 20 ml of tetrahydrofuran are mixed together under an
inert gas.
112 UI of diphosgene then 517 UI of TEA and 23 mg of
DMAP are added to the suspension obtained, at a
temperature comprised between 0 and 5°C.
The reaction medium is left to react whilst
agitating and leaving the temperature to rise to 20°C.
The reaction medium is then diluted with ethyl
acetate, then washed with a 10% aqueous solution of
tartaric acid, then with demineralized water.
The organic phase is dried over magnesium sulphate,
then the solvent is evaporated off under reduced
pressure.
769 mg of a crude product is obtained which is
dissolved in 7 ml of dichloromethane and 517 U1. of TEA.
The reaction medium is left to react overnight under
agitation.
The reaction medium is diluted with dichloromethane,
washed with water, dried over sodium sulphate and the
solvent is evaporated off under reduced pressure.
The foam obtained (395 • mg) is purified by
chromatography on silica with a. dichloromethane/ethyl
acetate mixture 80/20.
44 mg of the expected compound, with molecular
formula C13H17N3O2S (M = 295.362 g) is recovered. The
corresponding yield is 8%.
NMR spectrum of the proton
In CDC13, at 250 MHz, chemical shifts of the peaks
in ppm and multiplicity:
1.55 to 1.80 (m) and 2.18 (m) : N-CH-CHs-CH; 2.42
(s) : CH3; 2.88 (d) and 2.93 (m) ; N-CHCH; 3.18 to 3.32
(m) : N-CH2-CH2; 4.08 (m) : N-CH-CH2; 6.98 (bs) : NH.
IR (CHCljj : 3264, 1737, 1599, 1490 cm'1.
MS (positive electrospray) m/z: [M + Na] = 318, [M + H]
_
Example 21
6-[(4-methylphenyl)sulphonyl]-1,6 diazabicyclo[3,2,1]
octan-7-one
305 mg (1.52 mmole) of 1,1-dimethylethyl 3-amino-lpiperidinecarboxylate
(described in J. Med. Chem. 1992,
35, 4334-4343), with molecular formula C10H2oN202 (M =
200.282 g) is dissolved in 3 ml of anhydrous
dichloromethane.
212 U1 of TEA is then added, then the solution is
cooled down to 5°C and 278 mg of tosyl chloride is added.
The reaction medium is agitated whilst allowing the
temperature to return to 20°C and left to react for 2
hours.
The reaction medium is then diluted with
dichloromethane and washed firstly with a 10% aqueous
solution of tartaric acid then with a phosphate buffer
solution at pH
The organic phase is 'separated and dried -over
magnesium sulphate, then the solvent is evaporated off
under reduced pressure. An oil is thus obtained which is
purified by chromatography on silica eluting with a
dichloromethane/ethyl acetate mixture 9/1.
440 mg of 1,1-dimethylethyl 3-[[(4-methylphenyl)
sulphonyl]amino]-1-piperidinecarboxylate (described in J.
Med. Chem. 1992, 35, 4334-4343) with molecular formula
CI7H26N204S (M = 354.472 g) is recovered. The
corresponding yield is 82%.
A mixture of 425 mg of the compound obtained
previously and 2.1 ml of a trif luoroacetic acid
/dichloromethane mixture 50/50 are cooled down to 0-5°.
The reaction medium is kept under agitation at 5°C
for 30 minutes.
The solvent is then evaporated off under reduced
pressure in order to obtain 403' mg of 4-methyl-N-(3-
piperidinyl)-benzenesulphonamide trifluoroacetate with
molecular formula C H F 5 S (M = 368.377 g) .
228 mg of the compound obtained previously is placed
in suspension in 2 ml of methanol. The reaction medium
is treated with an excess of DOWEX 21K 20-50 Mesh resin
activated with soda.
After filtering, the resin is rinsed with the
methanol, then the filtrate is evaporated under reduced
pressure.
In this way 123 mg of 4-methyl-N- (3-piperidinyl) -
benzenesulphonamide with molecular formula Ci2H18N202S (M =
254.353 g) is recovered.
118 mg of the amine obtained previously is dissolved
under an inert gas in 1.2 ml of dichloromethane.
98 Ul of TEA then 28 Ul of diphosgene are then
introduced successively. The reaction medium is. left to
react' whilst agitating for , 30 minutes at 0-5°C. The
reaction medium is diluted with dichloromethane, the •
organic phase is washed with a 10% aqueous solution of
tartaric acid, then with water. After drying over sodium
sulphate, filtration and evaporation of the solvent under
reduced pressure are carried out, the crude product is
purified by chromatography on silica using a
dichloromethane/acetone mixture 95/5 as eluent.
In this way 112 mg of the chloride of 3-[[(4-
methylphenyl} sulphonyl] amino] -1-piperidinecarboxylic
acid, with molecular formula C3H17ClN203S (M = 316.308 g)
is obtained. The corresponding yield is 76%.
Under an inert atmosphere/10 mg of sodium hydride
(in suspension at 55-65% in oil) and 2 ml of anhydrous
tetrahydrofuran are mixed together.
71 mg of the product obtained previously is then
added.
The reaction medium is agitated at ambient
temperature for 15 minutes, then 12 Ul of acetic, acid and
2 ml of phosphate buffer solution at pH=7 are added.
Agitation is carried out again for 5 minutes, then 5
ml of ethyl acetate is added, the reaction medium is left
to settle, then re-extracted with ethyl acetate. The
organic phase is then separated and dried over magnesium
sulphate, filtered, and the solvent is evaporated off
under reduced pressure.
In this way 65 mg of crude product is obtained which
is purified by chromatography on silica, eluting with a
dichloromethane/acetone.mixture.95/5.
In this way 40 mg of expected compound, with
molecular formula C13Hi6N2O3S (M = 280.348 g) is recovered.
•The corresponding yield is 64%.
• NMR spectrum of the proton
In CDC13, at 250 MHz, chemical shifts of the peaks
in ppm and multiplicity (presence of two confomers
90/10):
1.46 (m) , 1.76 (m) and 2.08 (dm): NCH-CHs-CH^; 2.44
(s) and 2.45 (s) : CH3; 2.82 (d) and 2.98 (m) and 3.28 to
3.50 (m) : -N-(012)2; 4.55 (m) and 4.65 (m) : CO-N-CH; 7.33
and 7.78, "7.35 and 8. 02 [AA'BB1] CH3-C6H4-S02.
IR (CHC13) : 1758, 1598, 1995, 1367, 1169 cm"1.
MS (El) m/z; [M]+: 280, 216, 155, 125, 97, 91.
Example 22
6-oxa~l-azabicyclo[3,2,1]oct-3-en-7-one
5 ml of dichlorome thane and 68 mg of 1,2,3,6-
tetrahydro-pyridin-3-ol hydrpchloride (M = 135.5 g)
(described in Chem. Pharm. Bull. 30(10)3617-3623(1982))
are mixed together under an inert gas.
33 U1 of diphosgene is added and agitation is
carried out for 5 minutes at 0°C. Then 140 U1 of TEA and
61 mg of DMAP are added.
The reaction medium is left to react at ambient
temperature for 2 hours, then diluted with
dichloromethane and washed with a 10% aqueous solution of
tartaric acid then with water. After decanting the
organic phase is dried over magnesium sulphate. The
solvent is evaporated off under reduced pressure. 5 mg
of crude product is thus obtained which is purified by
chromatography on silica, eluting with dichloromethane
then a dichloromethane/ethyl acetate mixture 95/5.
In this way 3 mg of expected compound, with
molecular formula C6H7NO2 (M. = 125 g) is recovered. The
corresponding yield is 5%.
Example 23
phenylmethyl trans-3-benzoyl-2-oxo-4-oxa-l,3-diazabicyclo
[3,2,1]octane-7-carboxylate
5.50 g (13.7 mmoles) of 1-(1,1-dimethylethyl) and 2-
(phenylmethyl) cis-4-[(methylsulphonyl)oxy]-1,2-
pyrrolidine dicarboxylate (described in J. Org. Chem.
1991, 56, 3009-3016), with molecular formula Ci8H2sN07S (M
= 399.466 g) and 110 ml of dimethylformamide are mixed
together under inert gas, then 2.58 g of Nhydroxyphtalimide,
then 1.52 g of potassium hydrogen
carbonate are added.
The reaction medium is heated under agitation at
100°C and kept at this temperature for 4 hours.
The reaction medium is cooled down to 20°C, 220 ml
of water and ice are added, then the medium is extracted
with isopropyl ether.
Followed by' drying over magnesium sulphate, then
evaporating to dryness under reduced pressure.
The residue is chromatographed on silica, eluting
with a dichloromethane/ethyl acetate mixture 90/10.
In this way 3.06 g of 1-(1,1-dimethyl ethyl) and 2-
(phenylmethyl)trans-4-[(1,3-dihydro-l,3-dioxo-2Hisoindol-
2-yl) oxy]-1,2-pyrrolidinedicarboxylate, with
molecular formula C25H26N207 (M = 466.494 g) is recovered.
The corresponding yield is 47%.
3.24 g (6.94 mmoles) of the phthalimide obtained as
before is dissolved in 33 ml of dichloromethane.
372 Ul of hydrazine hydrate is "added.
The reaction medium is again agitated for 2 hours 30
minutes at 20°C.
The precipitate formed is filtered, rinsed with
dichloromethane, then the solvent is evaporated off under
reduced pressure.
2.91 g of crude product is obtained which is
purified by chromatography on silica, eluting with a
90/10, then 80/20 and 50/50 dichloromethane/ethyl acetate
mixture.
In this way 942 mg of 1- (1,1-dimethylethyl) and 2-
(phenylmethyl) trans-4-(aminooxy)-1,2-pyrrolidine
dicarboxylate, with molecular formula C 1 7 O s (M =
336.39 g) is recovered in total. The corresponding yield
is 40%.
853 mg of the compound obtained previously (2.53
mmoles) and 8.5 ml of anhydrous dichloromethane are mixed
under an inert gas.
The reaction medium is' cooled down to about 0-5°C,
then 706 Ul of TEA and 588 Ul of benzoyl chloride are
added.
The reaction medium is agitated for 10 minutes at 0-
5° C, then left to heat up to 20° C and left to react for
another 30 minutes.
The organic phase is washed with a 10 % aqueous
solution of tartaric acid, then with water, then decanted
and the organic phase is dried over sodium sulphate. The
solvent is evaporated off under reduced pressure.
In this way 1.38 g of product is obtained, which is
mixed with 25 ml of dichloromethane. The reaction medium
is cooled to about 10 - 15° C and 123 Ul of hydrazine
hydrate is added.
The reaction medium is left to react whilst
agitating at 20°C for two and a half hours.
The solvent is evaporated off under reduced
pressure-.
' 1.13 g of crude product is thus obtained which is
purified by chromatography on silica, eluting with a
dichloromethane/ethyl acetate mixture 80/20.
In this way 948 mg of 1-(1,1-dimethylethyl) and 2-
(phenylmethyl)trans-4-[(benzoylamino)oxy]-1,2-pyrrolidine
dicarboxylate, with molecular formula C24H28N206 (M
440.50 g) is recovered.
The overall yield is therefore 85%.
948 mg of the compound obtained previously is
dissolved in 2 ml of ethyl acetate.
The reaction medium is cooled down to 0-5°C, then
4.7 ml of an approximately 4.6 M solution of gaseous
hydrogen chloride in ethyl acetate is added in one go.
After 1 hour, the solvent is evaporated off under
reduced pressure and the product is taken up 3 times with,
ethyl ether.
The solvent is evaporated off under reduced
pressure. In this way 842 mg of phenylmethyl trans-4-
[(benzoylamino)oxy]-2-pyrrolidinecarboxylate
hydrochloride, in the form of a friable white foam with
formula C19H2oN2O4,HCl (M = 376.84 g) is obtained.
The yield is quantitative.
47 mg (0.125 mmole) of the hydrochloride obtained
previously under an inert gas is dissolved in 0.5 ml of
dichlorometharie. 25.2 Ul of pyridine is added, then the
reaction medium is cooled down to 0-5°C and 9.5 ptl of
• diphosgene is added.
The temperature is left to rise to 20°C, the
reaction medium is diluted with dichloromethane, then
washed with a 10% aqueous solution of tartaric acid then
with water.
The organic phase is decanted and dried over sodium
sulphate. The solvent is then evaporated off under
reduced pressiire.
In this way 43.8 mg of crude product is obtained
which is purified by chromatography on silica eluting
with a dichloromethane/ethyl acetate mixture 90/10.
34.9 mg of phenylmethyl trans-4-[(benzoylamino)oxy]-
1-(chlorocarbonyl)-2-pyrrolidinecarboxylate, with
molecular formula C2oH9ClN2O5 (M = 402.83 g) is recovered.
The corresponding yield is 69%.
13 mg (0.032 mmole) of the compound obtained
previously is dissolved in 4 ml of toluene.
9 f1 of TEA and 7.8 mg of DMA.P are added.
The reaction medium is heated at 100°C overnight.
The solvent is evaporated off under reduced pressure
then the residue' is purified by chromatography eluting
with dichloromethane.
In this way 4.3 mg of the expected compound, with
molecular formula C2oH8N2O5 (M = 336.37 g) is recovered.
The corresponding yield is 40%.
NMR spectrum of the proton
In CDC13, at 300 MHz, chemical shifts of the peaks
in ppm and multiplicity:
1.97 (ddd) and 2.85 (ddd) : N-O-CH-CHg-CH; 3.80 (dd)
and 4.'14 (dd) : N-O-CH-CHg-N; 4.75 (dd) : N-CH-CH2; 4.93
(t) : N-0-CH-CH2; 5.04 and 5.31 [AB] : O-CH2-C6H5; 7.77: and
7.25 to 7.50 (m) CH-CgHs and OC-CgHs-
IR (CHC13) : 1735; 1612, 1575, 1496 cm'1
Example 24
3-benzoyl-l,3-diazabicyclo[2,2,2]octan-2-one
Under a nitrogen atmosphere, 2.4 g (10 mmoles) of N-
(4-piperidinyl)-benzamide hydrochloride (described in J.
Med. Chem. IN. 17(1974), -736-739), with molecular formula
Ci2Hi6N2O are dissolved in 30 ml- of dichloromethane. .
The reaction medium is cooled down to 0°C, 2.8 ml of
TEA and 0.66 ml of diphosgene are added.
After a few minutes, the reaction medium is diluted
with dichloromethane, then washed with a 10 % aqueous
solution of tartaric acid, then with water. The organic
phase is decanted, dried over magnesium sulphate and the
solvent is evaporated off under reduced pressure. The
residue is purified on silica eluting with a
dichloromethane/ethyl acetate mixture 90/10.
1.62 g of the chloride of 4- (benzoylamino) -1-
piperidinecarboxylic acid, with molecular formula
C3H5ClN205 (M = 266.5 g) is obtained. The corresponding
yield is 61%.
1.21 g (48 mmoles) of the compound obtained
previously is dissolved under a nitrogen atmosphere in 37
ml of tetrahydrofuran.
The solution is cooled down to -78°C, then 5 ml of a
1M solution of lithium bis(trimethylsilyl) amide in
tetrahydrofuran is added dropwise.
The reaction medium is maintained at -78°C for 15
minutes then the temperature is left to rise to ambient
temperature and left to react again for an hour.
The solution is cooled down to 0°C, 720 ul of acetic
acid is added. A precipitate forms. Dilution with ethyl
acetate followed by washing with a 10% aqueous solution
of tartaric acid and with a phosphate buffer solution at
pH = 7.0.
The organic phase is decanted and dried over
magnesium sulphate. Filtration is carried out, then the
solvent is evaporated off under reduced pressure. The
crude product is purified by chromatography on silica
eluting with a dichloromethane and ethyl acetate mixture
90/10.
In this way 0.214 g of expected compound, with
formula C8H4N202 (M = 230 g) is obtained crystallized
from ethyl ether.
The corresponding yield is 20%.
NMR spectrum of the proton
In DMSO, at 250 MHz, chemical shifts of the peaks in
ppm and multiplicity:
1.71 to 2.02 (m) : (CH-CHN; 3.14 (t): N-(CH2)2; 4.84
(m) : (CH2)2-CHN; 7.39 to 7.65 (m) : CgHs.
IR (CHC13) : 1735, 1682; 1618, 1602, 1582; 1488 cm"1.
MS (positive electrospray) m/z: [2M + Na]+ = 483; [M+Na +
CH3CN]+ = 294; [M+Na] + = 253
Example 25
diphenylmethyl trans-7-oxo-6-oxa-l-azabicyclo[3,2,1]
octane-2-carboxylate
15 ml of dichloromethane and 197 mg (0.633 mmole) of
diphenylmethyl trans-5-hydroxy-2-piperidinecarboxylate
(described in Rec. Trav. Chim. (1959), 78, 648-658), with
molecular formula C19H2NO3 are mixed together under an
inert atmosphere.
The reaction medium is cooled down to 0°C, then
42 ul of diphosgene, 177 ul of TEA then 77 mg of
DMAP are added successively.
The reaction medium is left to react for 4 hours at
ambient temperature.
Followed by washing with a 10 % aqueous solution of
tartaric acid, then with a saturated aqueous, solution of
sodium' chloride.
The organic phases are combined and dried over
magnesium sulphate, the solvent is evaporated off under
reduced' pressure and 195 mg • of crude product is thus
obtained which is purified by chromatography on silica,
eluting with dichloromethane containing 0.1% water.
An oil is recovered which crystallizes from a
pentane/ ethyl ether mixture.
In this way 108 mg of the expected compound is
recovered in the form of white crystals corresponding to
the molecular formula C2oH19NO4 (M = 337.338 g) .
The corresponding yield is 51%.
NMR spectrum of the proton
In CDC13/ at 400 MHz, chemical shifts of the peaks
in ppm and multiplicity:
1.86 (m) and 2.03 (m) : N-CH-CH2-CH2-CO; 2.27 (m) : N-CHCH2-
CH2-CO; 3.07 (d) and 3.29 (m) : N-CH2-CHO; 4.31 (dd) :
N-CH-CH2; 4.73 (m) : N-CHs-CHO; 6.93 (s): CO2-CH-(C6H5) 2;
7.27 to 7.41 (m) : CH(C6H5)2;
IR (CHC13) : 1788, 1736; 1496 cm'1;
MS (SIMS) m/z: [M+Na]+ = 360, [M+li]+ = 344; [M]+ = 337,
167
Example 26a
(4-nitrophenyl)methyl trans-7-oxo-6-oxa-1-azabicyclo
[3,2,1]octane-2-carboxylate
66 ml of dichloromethane and 1 g (3.56 mmole) of (4-
nitrophenyl)methyl trans-5-hydroxy-2-piperidine
carboxylate with molecular formula C13H6N205 (M = 280.282
g) are mixed together under an inert atmosphere.
The reaction medium is cooled down to 0°C, and 0.24
ml of diphosgene is added. The reaction medium is left
to react whilst agitating for 10 minutes at 0°C, then
left to warm up to ambient temperature. The solvent is.
• evaporated off under reduced pressure.
The residue is • dissolved in 66 .ml of toluene and
0.99 ml of TEA is added.
The flask is immersed in an oil bath at 110°C and
kept there for 15 minutes. It is then left to return to
ambient temperature.
The reaction medium is washed with a 10% aqueous
solution of tartaric acid, then with a saturated aqueous
solution of sodium chloride.
The organic phase is dried over magnesium sulphate
then the solvent is evaporated off under reduced
pressure.
In this way 0.885 g of crude product is obtained
which is purified by chromatography on silica eluting
with a toluene/ethyl acetate mixture 85/15.
In this way 0.184 g of expected compound, with
molecular formula C14H14N2O6 (M = 306.276 g) is recovered
in the form of a yellow oil.
The corresponding yield is 17%.
NMR spectrum of the proton
In CDC13, at 400 MHz, chemical shifts of the peaks
in ppm and multiplicity:
1.92 (m) and 2.07 (m) : N-CH-CH2-CH2-CO; 2.22 (m) and
2.30 (m) : N-CH-CH2-CH2-CO; 3.17 (d) and 3.35 (dm): N-CHz-
CHO; 4.28 (dd) : N-CH-CH2; 4.79 (m) : N-CH2-CHO; 5.33 [AB] :
CO2-CH2-C6H4NO2; 7.56 and 8.25 [AA'BB1 ] : CH2-C6H4-NO2
IR (CHC13) : 1791, 1745; 1609, 1526, 1495 cm"1;
MS (El) m/z: [M] + = 306, 262, 136, 126, 82, 55
Example 26b
trans-7-oxo-6-oxa-l-azabicyclo[3,2,1,]octane-2 carboxylic
acid
140 mg (0.457 mmole) of the ester, obtained in
Example 26a, 7 ml of acetone and 28 mg of Pd./C catalyst
at 20% 'by weight are-mixed together.
The reaction medium is then left to react for 25
minutes under agitation and a hydrogen atmosphere at
normal pressure.
The catalyst is filtered out and the solvent is then
evaporated off under reduced pressure.
In this way 137 mg of the expected compound, with
molecular formula C7H9N04 (M = 171.152 g), is obtained in
the form of an oil, mixed with one mole of p-toluidine.
The corresponding yield is 97%.
NMR spectrum of the proton
In DMSO, at 400 MHz, chemical shifts of the peaks in
ppm and multiplicity:
1.84 (m)'-and 1.95 to 2.05 (m) : N-CH-CHs-CH-CO; 3.13
(d) and 3.24 (dd) : N-CH-CHO; 4 .'02 (dd) : N-CH-CH2; 4.81
(dm): N-CH2-CHO.
Example 26c
methyl trans-7-oxo-6-oxa-l-azabicyclo[3,2,1]octane-2-
carboxylate
17.25 mg (0.1 mmole) of the acid obtained in Example
26b is dissolved in 3 ml of dichloromethane.
The reaction medium is treated with an excess of
diazomethane in solution in dichloromethane, then the
solvent is evaporated off under reduced pressure.
30 mg of crude product is thus obtained which is
purified by chromatography on silica, eluting with a
toluene/ethyl acetate mixture 90/10.
6.7 mg of the expected compound (M = 485.187 g) is
recovered.
The corresponding yield is 36%.
Example- • 2 7
(4-nitrophenyl)methyl cis-7-oxo-6-oxa-l-azabicyclo
[3 , 2 ,1] octane -2-carboxylate
0.802 g (2.034 mmoles) of (4-nitrophenyl)methyl cis-
5-hydroxy-2-piperidine-carboxylate trifluoroacetate
(described in Rec, Trav. Chim. (1959), 78, 648-658), with
molecular formula C3H1EN2O5, CF3C02H (M = 394.303 g) is
introduced under a nitrogen atmosphere into 40 ml of
dichloromethane is introduced followed by cooling to 0°C.
0.135 ml of diphosgene is added. The reaction medium is
agitated for 15 minutes at 0°C, then the temperature is
left to rise to ambient temperature and agitation is
continued for 35 minutes.
The solvent is evaporated off under reduced
pressure.
This product is dissolved in 40 ml of toluene and
1.1 ml of triethylamine. The reaction mixture is taken
to 100°C for 35 minutes, then left to cool down to
ambient temperature.
The reaction medium is washed with water then with a
phosphate buffer solution at pH = 7 .
The organic phase is dried over sodium sulphate and
the solvent is evaporated off under reduced pressure.
0.56 g of a crude product is thus obtained which is
purified by chromatography -on silica, eluting with a
dichloromethane/acetone mixture 95/5.
In this way 110 mg of the expected compound, with
molecular formula C H O g , (M = 306.275 g) , is recovered
in the form of an oil .
The corresponding yield is 17%.
NMR spectrum of the proton
In CDC13, at 300 MHz, chemical shifts of the peaks
in ppm and multiplicity:
1.80 to 1.94 and 2.10 to 2.45: N-CH-CHs-CHs-CO; 3.07 (d) ,
3'. 04 (dm) and 3.86 (dd) : CH-N-CEb; 4.80 (t) : O--C-O-CH;
5.28 and 5.43 [AB] : 0=C-O-CH2-C6H5; 7.61 and 8.24 [AA'BB1]
IR (CHC13) : 1801, 1794, 1745, 1704; 1609, 1525, 1498 cm"1.
MS (El) m/z: [M] + = 306, 262, 136, 126, 83, 55
Example 28 a
1-propenyltriphenylphosphonium salt of phenylmethyl trans
-7-0X0-6- (sulphooxy) -1, 6-diazabicyclo [3,2,1] octane -2-
carboxylate
Stage A
phenylmethyl cis-5-hydroxy-l- (trif luoroacetyl-2-
piperidine carboxylate
6.19 g (22.77 mmoles) of .the hydrochloride of
phenylmethyl 5-hydroxy-2-piperidinecarboxylate with
molecular formula C13H18C1N03 (M = 271.746 g) (described
in Rec. Trav. Chim. (1959) , 78, 648-658) is dissolved
under an inert atmosphere in 80 ml of anhydrous
dichloromethane.
The reaction medium is cooled down to 5°C and 9.5 ml
of TEA is added then, 6.46 ml of trifluoroacetic
anhydride is added dropwise.
The reaction medium is left to react under agitation
at 5°C for one hour, then diluted with dichloromethane,
washed successively with a 10% solution of tartaric acid,
an aqueous phosphate buffer solution at pH=7 and an
aqueous solution of sodium chloride.
The organic phase is decanted and dried over
magnesium sulphate. Then the solvent is evaporated off
under reduced pressure.
10 g of a .red oil is thus obtained which is
dissolved in 100 ml of methanol. The reaction medium is
cooled: down to about 10°C, -and 6.8 g (78 mmoles) of
sodium hydrogen carbonate in solution in 100 ml of water
is added slowly, at a maximum of 20°C.
The reaction medium is left to react under agitation
at 20°C for 30 minutes, and extracted with
dichloromethane.
The organic phase is decanted, washed with a
saturated aqueous solution of sodium chloride and dried
over magnesium sulphate.
The solvent is evaporated off under reduced pressure
and 7.6 g of an orange oil is thus recovered which is
purified by chromatography on silica, eluting with a
dichloromethane/ethyl acetate mixture 95/5.
In this way 6 g of expected compound with molecular
formula C15H16F3N04 (M = 331.294 g) is recovered. The
corresponding yield is 68%.
Stage B phenylmethyl trans-5-[(2-propenyloxy)amino]-1-
(trifluoroacetyl)-2-piperidinecarboxylate,
1.74 g (5.26 mmoles) of the alcohol obtained
previously is introduced into 29 ml of acetonitrile. The
reaction medium is cooled down to -40°C and 0.61 ml of
2,6-lutidine (C5H3N (CH3) 2) then 0.91 ml of trifluoro
methanesulphonic anhydride are added at this temperature.
The reaction medium is left to react under agitation
for 30 minutes at -40°C. Then, still at -40°C, 0.7 ml
(10.52 mmoles) of O-allyl-hydroxylamine is added over one
minute.
The reaction medium is left to return to 0°C then
0.61 ml of 2,6 lutidine is added and left to react
overnight (15 hours), at .approximately 5°C, then for
another 2 hours at 20°C.
The reaction- medium- is then diluted with
dichloromethane, washed with an . aqueous solution of
sodium•hydrogen carbonate, then a 10%' aqueous solution of
tartaric acid and a saturated aqueous solution of sodium
chloride.
The organic phase is decanted, dried over magnesium
sulphate and the solvent is evaporated off under reduced
pressure.
2.1 g of a yellow oil is thus obtained which is
purified by chromatography on silica, eluting with a
toluene/ethyl acetate mixture 90/10.
1.23 g of expected, compound with molecular formula
C8H2F3N2O4 (M = 386.374 g) is recovered.
The corresponding yield is 61%.
Stage C
phenylmethyl trans-5- [(2-propenyloxy)amino] -2-
piperidinecarboxylate
1.41 g (3.65 mmoles) of compound obtained previously
is dissolved under an inert atmosphere in 25 of anhydrous
methanol.
The reaction medium is cooled down to 0-5°C, then 3
additions are made, at 45 minutes intervals, of 145 mg of
NaBH4.
The reaction medium is then acidified to pH = 2 with
a IN aqueous solution of hydrochloric acid previously
cooled to 5°C.
Extraction is carried out with ethyl acetate.
The aqueous phase is cooled down to 5°C, 100 ml of
ethyl acetate is added, followed by treatment with a
saturated solution of sodium carbonate until a pH of 8.5
The amine is then extracted with ethyl acetate. The
organic phase is washed with a saturated aqueous solution
of sodium chloride, then • dried over magnesium sulphate
and concentrated by evaporation of the solvent under
reduced pressure. '
In this way 0.628 g of expected product with
molecular formula CgHazNsOa (M = 290.364 g) is obtained.
The corresponding yield is 59%.
Stage D
phenylmethyl trans-7-oxo-6-(2-propenyloxy)-1,6-
diazabicyclo[3,2,1]octane -2-carboxylate
103 mg (0.35 mmoles) of the amine obtained
previously is dissolved under an inert atmosphere in 35
ml of anhydrous dichloromethane.
The solution is cooled down to about 0-5°C, and 0.1
ml of TEA, then 21 1 of diphosgene are added dropwise at
this temperature.
The reaction medium is left to react under agitation
for 15 minutes at 0-5°C, then the temperature is left to
rise to 20°C, and 42 mg of DMAP is added. Agitation is
continued at 20°C for approximately 5 hours.
The reaction medium is diluted with dichlorometfhane,
washed with a 10% aqueous solution of tartaric acid, then
with water.
The organic phase is dried over magnesium sulphate
and concentrated by evaporation of the solvent under
reduced pressure.
In this way 70 mg of crude product is obtained which
is purified by chromatography on 5 g of silica, eluting
with a dichloromethane/methanol mixture 98/2.
48 mg of expected product of formula C17H2oN204 (M =
316.36 g) is recovered.
The corresponding yield is 4.3%.
IR (CHC13) : 1750; 1642; 1600, 1496 cm"1.
MS (positive electrospray) m/2:. [M +. Na + CH3CN] + = 380;
M + Na]+ = 339; [M + H] + = 317. .
Stage E 1-propenyltriphenylphosphonium salt of
phenylmethyl trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo
.[3,2,1] octane -2-carboxylate
202 mg (0.638 mmoles) of the compound obtained in
stage D is dissolved under an inert atmosphere in 5.5 ml
of anhydrous dichloromethane.
73 u1 of acetic acid, then 369 mg of Pd (P (C6H5) 3) 4 is
added at 20°C to the solution obtained.
After agitation for 30 minutes at ambient
temperature, N-hydroxy-urea, formed by 5.5 ml of pyridine
and 358 mg of the SO3-pyridine complex is treated.
The reaction medium is left to react under agitation
for 18 hours at 20°C', then the reaction medium is
concentrated by evaporation of the solvent under reduced
pressure.
The reaction medium is taken up with 50 ml of
dichloromethane and washed with water. The organic phase
is dried over magnesium sulphate and the dichloromethane
is evaporated off under reduced pressure.
650 mg of crude product is thus obtained which is
purified by chromatography on silica, eluting with a
dichloromethane/acetone mixture 60/40 containing 0.1% by
volume of TEA.
In this way 280 mg of the phosphonium salt of the
expected compound, with molecular formula C35H35N207PS (M
646.705 g) is recovered.
The corresponding yield is 68%.
NMR spectrum of the proton
In CDC13, at 300 MHz, chemical shifts of the peaks
in ppm and multiplicity:
2.05 (m) , 2.22 (dm) and 2.33 (m) : N-CH-CH-CH; 2.95
(d) and 3.30 (dt) ; O=C-N-CH2,- 4.10 (m) and 4.32 (m) : 0=CN-
CH and O=C-N-CH2-CH; 5.12 (s) : COO-CH2-C6H5; 7.36: C6HS
and 2.30 (m) : CH3-CH=CH; 6.65 and 7.20 CH3-CH=CH; 7,65-
7.85 P(C6H5)3.
IR (CHC13) : 1746; 1638, 1605, 1587, 1495 cm"1.
MS (negative and positive electrospray) m/z: [Manion]" =
355; [Mcation] = 303.
Example 28b
Sodium salt of phenylmethyl trans-7-oxo-6-(sulphooxy)-
1,6-diazabicyclo [3,2,1] octane -2-carboxylate
236' mg (0.364 mmoles) of the phosphonium salt
obtained in stage E of Example 28a is dissolved in 0.8 ml
of tetrahydrofuran and 4 drops of water.
The solution obtained is passed over a column DOWEX
50WXS resin in Na+ form, eluting with water.
After lyophilization, 127 mg of the expected sodium
salt, with molecular formula C4H5N2O7SNa (M = 378.339 g)
is obtained.
The corresponding yield is 92%.
NMR spectrum of the proton
In DMSO, at 300 MHz, chemical shifts of the peaks in
ppm and multiplicity:
1.65 to 2.02: N-CH-CHa-CHs; 2.91 (d) and 3.04 (dt) :
0=C-N-CH2,- 4.00 to 4.05: O=C-N-CH and O=C-N-CH2-CH; 5,20
[AB] : COO-CH2-C6H5; 7.39 (m) : C6H5.
IR (Nujol) : 1744; 1495 cm"1.
MS (electrospray negative) m/z; [M]" = 355.
Example 28c
phenylmethyl trans-7-oxo-6-[(phenylsulphonyl)oxy]-1,6-
diazabicyclo [3,2,1] octane -2-carboxylate
48, mg (0.152 mmoles) of the derivative obtained in
stage' D of Example 28a is dissolved in 1.2 ml of
dichlorcmethane.
26 ul of acetic acid then 88 mg of Pd (PPh3)4 are
added to it at 20°C, and left to react for 2 hours at
20°C under agitation.
The reaction medium is diluted by adding toluene and
the solvents are evaporated off under reduced pressure.
1.5 ml of dichloromethane, 25 ul of pyridine and 24
p.1 of benzenesulphonyl chloride are added to the crude
product obtained.
The reaction medium is left to react at 20°C under
agitation for 1 hour then 12.5 ul of pyridine and 10 u1
of benzenesulphonyl chloride are added.
The reaction medium is agitated for 15 minutes at
20°C and diluted with dichloromethane.
The reaction medium is then washed successively with
a 10% aqueous solution of tartaric acid, a phosphate
buffer solution at pH= 7 and a saturated aqueous solution
of sodium chloride.
The aqueous phase is dried over magnesium sulphate,
and the solvent is evaporated off under reduced pressure.
180 mg of a yellow oil is obtained which is purified by
chromatography on silica, eluting with a dichloromethane/
methyl and t-butyl ether mixture 95/5.
In this way 20 mg' of the expected compound, with
molecular formula C2oH2oN2O6S (M = 416.456 g) is recovered.
The corresponding yield is 31%.
NMR spectrum of the proton
In CDC13, at 300 MHz, chemical shifts of the peaks
in ppm and multiplicity:
1.83 (m) and 2.00 to 2.25 (m) : N-CH-CHs-CHs; 3.02 (d) and
3.16 (dm): O=C-N-CH2; 4.04 (m) and 4.11 (dd) : O=C-N-CH
and -0=C-N-CH2-q; 5.21 (s) : COO-CH2-C6H5; 7.34 (m) : C6H5 ;
7.56 (m)., 7.70 (m) and 8.03 (m) : 02S-C6Hs.
IR (CHCla).; 1780, 1738; 1600, 1585, 1498; 1386, 1193 cm'1.
MS (positive electrospray) m/z: [2M + Na]+ = 855; [M + Na
+ CH3CH]+ = 480; [M+Na] + = 439; [MH] + = 417.
Example 28d
phenylmethyl trans-7~oxo-6-[(2-thienylsulphonyl)oxy]-1,6-
diazabicyclo [3,2,1] octane -2-carboxylate
Starting with 100 mg (0.316 mmoles) of the compound
obtained in stage D of Example 28a, the process is
carried out in a similar manner to the one which has just
been described, except that instead of using
benzenesulphonyl chloride, 2 thienyl sulphonyl chloride
is used.
'8 mg of expected compound, with molecular formula
C18H18N2O6S2 (M = 422.481 g) is thus recovered. The
corresponding yield is 30%.
NMR spectrum of the proton
In CDC13/ at 300 MHz, chemical shifts of the peaks
in ppm and multiplicity:
1.84 (m) and 2.10 to 2.25: N-CH-CH^-CHs; 3.02 (d) and
3.24 (dt) : 0=C-N-CH2,- 4.06 (m) : O=C-N-CH2-CH; 4.14 (dd) :
0=C-N-CH; . 5.22 (s) : COO-CH2-C6H5; 7.17 (dd) : SO3- C-SCH=
CH; 7.35 (bs) : C6Hs; 7.80 (dd) : S03-C=CH; 7.87 (m) :
SO3-C-S-CH.
IR (CHC13) : 1780, 1739; 1600, 1503, 1495 cm"1.
MS (positive electrospray) m/z: [M + Na + CH3CN]+ = 867;
[2M + Na]+ = 445; 339, 298, 91.
l E x a m p l e 28e
phenylmethyl trans-6-(2-hydroxy-2-oxoethoxy)-7-oxo-l,6-
diazabicyclo [3,2,1]octane -2-carboxylate
Stage A
'phenylmethyl traris-7-oxo-6-[2-0x6-2-(2-propenyloxy)
ethoxy]-1,6-diazabicyclo[3,2,1]octane -2-carboxylate
48 mg (0.15 mmoles) of the compound obtained in
stage D of Example 28a is dissolved under an inert
atmosphere in 1.5 ml of anhydrous dichloromethane.
18 ul of acetic acid then 88 mg of Pd (P (CSHS) 3) 4 is
added at 20°C and left under agitation for 1 hour at
20°C.
The reaction medium is filtered over silica, eluting
with a dichloromethane/ ether t-butyl and methyl mixture
7/3.
The solvent is evaporated off under reduced pressure
and 70 mg of hydroxy urea is obtained which is taken up
in 2 ml of dichloromethane, then 85 u1 of TEA and and 64
ul of allyl bromo-acetate are added.
The reaction medium is agitated at 20°C for 3 and a
half hours.
The reaction medium is washed successively with a
10% aqueous solution of tartaric acid, an aqueous
phosphate buffer solution at pH= 7, and water.
The organic phase is dried and the solvent is
evaporated off under reduced pressure.
60 mg of crude product is thus obtained which is
chromatographed on silica eluting with a dichloromethane/
t-butyl and methyl ether mixture 90/10 containing 0.1%
TEA.
22 mg with molecular formula C9H22N2Oe, (M = 374.396
g) is recovered. The corresponding yield is 39%.
Stage B
phenylmethyl trans-6-(2-hydroxy-2-oxoethoxy) -7-oxo-l,6-
diazabicyclo [3,2,1] octane -2-carbox.ylate
22 mg (0.0587 mmoles) of the compound obtained
previously is dissolved under an•inert atmosphere in 1 ml
of anhydrous dichloromethane.
10 ul of acetic acid and 34 mg of Pd (P (C6H5) 3) 4 are
added and left to react under agitation at 20°C for 30
minutes.
The reaction medium is concentrated and taken up in
toluene in order to eliminate the acetic acid.
In this way 49 mg of crude product is obtained to
which 2 ml of phosphate buffer at pH 7 is added, then
washed twice with 1 ml of dichloromethane.
The solvent is evaporated off and 46 mg of crude
product is obtained which is purified by chromatography
on silica, eluting firstly with a dichloromethane/ tbutyl
and methyl ether mixture 90/10 then with a
dichloromethane/ethanol mixture 60/40.
In this way 4.5 mg of the expected compound, with
molecular formula C31H7N2O6P (M = 636.691 g) is obtained.
The corresponding yield is 12%.
Example 29a
(4-nitrophenyl) methyl trans-6-benzoyl-7-oxo-l,6-
diazabicyclo[3,2,1]octane -2-carboxylate
Stage A
1-(1,1-dimethylethyl) and 2-[(4-nitrophenyl)methyl] cis-
5-(methylsulphonyl)oxy-1,2- piperidinedicarboxylate
11.25 g (29.5 mmoles) of 1-(1,1-dimethylethyl) and
2- [ (4-nitrophenyl)methyl] cis-5-hydroxy-l,2-piperidine
dicarboxylate (described in Rec.Trav.Chim. (1959), 78,
648-658), with molecular formula C18H24N2O7 (M = 380.398 g)
is dissolved under an inert atmosphere in 112 ml of
dichloromethane.
The reaction medium is cooled down to 0-5°C, then 5
ml of TEA then 2.44 ml of methanesulphonyl chloride are
introduced successively.
The temperature is left to return to 20°C under
agitation and the medium is left to react for 1 hour.
The reaction medium is then diluted with dichloromethane,
washed twice with water, dried over sodium sulphate, and
the solvent is evaporated off under reduced pressure.
16 g of a crude oil is thus obtained which is
purified by chromatography on silica, eluting with
dichloromethane containing 2% ethyl acetate.
9.14 g of expected product with molecular formula
C9R26N2O9S (M . = 458.491 g) is recovered. The
corresponding yield is 67%.
Stage B 1-(1,1-dimethylethyl) and 2-[(4-nitrophenyl)
methyl]trans-5-azido-l,2-piperidinedicarboxylate
11.1 g (24.2 mmoles) of the mesylate obtained
previously is dissolved under an inert atmosphere in 111
ml of dimethylformamide.
1.73 g of sodium nitride NaN3 is then added.
The reaction medium is heated under agitation at
80°C and kept at this temperature for 18 hours. It is
left to return to 20°C, then the dimethyl formamide is
evaporated off under reduced pressure until a small
volume is obtained, then diluted with ethyl acetate and
washed with a 2 N soda solution, then with water. The
reaction medium is dried over magnesium sulphate, then
the solvents are evaporated off under reduced pressure.
The crude oil obtained is purified by chromatography
on silica eluting with dichloromethane containing 2%
ethyl acetate.
7.34 g of expected compound, with molecular formula
C18H23N506 (M = 405.413 g) is thus obtained in the form of
•a yellow oil which crystallizes.
The corresponding yield is 75%.
Stage C '
1-(1,1-dimethyl-ethyl) and 2-[(4-nitrophenyl)
methyl]trans-5-amino-l,2-piperidinedicarboxylate
7.34 g (18.1 mmoles) of the azide obtained
previously is introduced into 150 ml of tetrahydrofuran
and 30 ml of water.
7.2 g of triphenylphosphine is added, then left to
react under agitation at 20°C overnight.
The solvent is then evaporated off under reduced
pressure and two entrainments with ethyl acetate are
carried out.
In this way a dry extract is obtained which is
purified by chromatography on silica, eluting with
dichloromethane containing 5% methanol.
5,62 g of expected compound, with molecular formula
C18H25N3O6 (M = 379.416 g) is recovered. The corresponding
yield is 82%.
Stage D
1- (1,1-dimethylethyl) and 2-[(4-nitrophenyl)methyl] trans
-5- (benzoylamino)-1,2-piperidinedicarboxylate
700 mg (1.84 mmole) of the amine obtained previously
is dissolved in 8 ml of dichloromethane.
The reaction medium is cooled down to 0°C, then 257
ul of TEA then 214 u1 of benzoyl chloride is introduced.
The temperature is left to return to 20°C.
After reaction for 40 minutes, the reaction medium
is diluted with dichloromethane, washed with a saturated
solution of sodium hydrogen carbonate, then water.
Followed by drying over sodium sulphate, .and the
solvent is evaporated off under reduced pressure.. '
867 mg of expected compound, with molecular formula
C2sH29N307 (M = 483.525 g) is thus obtained. The
corresponding yield is 97 %.
Stage E
(4-nitrophenyl) methyl trans - 5 - (benzoylamino) - 2 -
piperidine carboxylate hydrochloride
861 mg (8 mmole) of the amide obtained previously, 9
ml of methanol, and 2.3 ml of a solution of gaseouc
hydrogen chloride at 8 mou1 in methanol are mixed
together.
The temperature is left to return to 20°C and left
to react over 3 hours. 1.15 ml of hydrogen chloride
solution in methanol is then added.
The reaction medium is agitated for 20 minutes at
20°C, then the solvent is evaporated off under reduced
pressure.
Two entrainments with dichloromethane, then two
entrainments with ethyl ether are carried out.
The product crystallizes from ethyl ether.
In this way 715 mg of expected compound with
molecular formula CsofClNaOs (M = 419.967 g) is'obtained.
The corresponding yield is 96%.
Stage F
(4-nitrophenyl)methyl trans-5- (benzoylatnino) -1-
(chlorocarbonyl) -2-piperidine carboxylate
1.08 g (2.58 mmole) of the hydrochloride obtained as
previously and 11 ml of dichloromethane are mixed
together.
The suspension obtained is cooled down to about 0-
5°C and 791 ul of TEA is added, then, 161 ul of
diphosgene is then added to the solution obtained.
The reaction medium is agitated for 5 minutes at 0-
5°C, then left to return to 20°C, and left under
agitation for another 30 minutes.
The reaction medium is then. diliited with
dichloromethane, washed with a 10% aqueous solution of
tartaric acid, then water.
Followed by drying over sodium sulphate and the
solvent is evaporated off under reduced pressure.
The crude product is purified by chromatography on
silica eluting with dichloromethane containing 5%
acetone.
969 mg of expected compound with molecular formula
C2H2oClN306 (M = 445.862 g) is recovered.
The corresponding yield is 84%.
Stage G
(4-nitro-phenyl) methyl trans-6-benzoyl-7-oxo-l, 6-
diazabicyclo[3,2,1]octane -2-carboxylate
928 mg (2.08 mmoles) of the compound obtained
previously and 27 ml of tetrahydrofuran are mixed
together under an inert gas.
The solution obtained is cooled down to -78°C under
agitation, then 2.1 ml of a 1M solution of lithium bis
(trimethylsilyl) amide in tetrahydrofuran is introduced.
The reaction medium is left under agitation for 10
minutes to -78°C then 130 ul of acetic acid is added and
agitation is carried out whilst leaving the temperature
to rise to 15°C.
The reaction medium is diluted with ethyl acetate
then washed successively with a 10% aqueous solution of
tartaric acid, with a phosphate buffer solution at pH=7
and water.
Followed by drying over magnesium sulphate and the
solvent is evaporated off under reduced pressure.
1.6 g of a dry extract is thus obtained which is
purified by chromatography on silica eluting with a
dichloromethane/acetone mixture 98/2.
The product is then crystallized from ethyl ether in
order to produce 204 mg' of the expected compound, with
molecular formula C2'H19N306 (M = 409.441 g) .
The corresponding yield is 24 %.
NMR spectrum of the proton
In CDC13, at 250 MHz, chemical shifts of the peaks
in ppm and multiplicity:
1.98 (m) , 2.22 (m) and 2.40 (m) : N-CH-CHa-CHa; 3.08
(d) and 3.42 (dt) : OC-N-CHs; 4.23 (dd) : O=C-N-CH; 4.53
(m) : 0=C-N-CH2-CH; 5.34 [AB] : COO-CH2-C6H5; 7.69 (m) : 8.25
(m) : 7.44 (m) and 7.56 (m) : C6Hs and CglNOa.
IR (CHC13) : 1763, 1744, 1676; 1609, 1603, 1583, 1526,
1492 cm"1.
MS (El) m/z: [M]+ = 409, 304, 273, 201, 105, 77.
Example 29b
trans-6-benzoyl-7-oxo-l,6-diazabicyclo [3,2,1]octane -2-
carboxylic acid
89 mg of the ester obtained in Example 29a, 4 ml of
acetone and 6 mg of 10% Pd/C catalyst are mixed together.
The reaction medium is left to react under
agitation, at 20°C and under a hydrogen atmosphere for 2
hours 45 minutes, then the catalyst is filtered out and
the filtrate is evaporated under reduced pressure.
In this way 88 mg of a resin is obtained which
crystallizes from 0.5 ml of ethyl ether.
In this way 54 mg of the expected compound, with
molecular formula C4:E14N2O4 (M = 274.278 -g) is obtained.
The corresponding yield is 91%.
NMR spectrum of the proton
In CDC13, at 250 MHz, chemical shifts of the peaks
in ppm and multiplicity:
1.96 (m) , 2.10 (m) and 2.37 (m) : N-CH-CH-CHs; 3.13
(d). and-.-3.41 (dm): 0=C-N-CH2; 4.10 (bd) : OC-N-CH; 4.52
.(m) : 0=C-N-CH2-CH; 7.44 (m) : 7.56 (tt) and 7.69 (dd) C6Es.
MS (El) m/z; M+ = 274, 229, 169, 105, 77.
Example 29c
methyl trans-6-benzoyl-7-oxo-1,6-diazabicyclo [3,2,1]
octane -2-carboxylate
2 ml of a solution of diazomethane at 12.7 g/1 in
dichloromethane is added under agitation to 28 mg (0.102
mmole) of the acid obtained in Example 29b.
The solvent is evaporated off under reduced pressure
and the residue is purified by chromatography on silica
eluting with a dichloromethane/ethyl acetate mixture
98/2.
18.4 mg of expected compound, with molecular formula
C5H6N204 (M = 288.305 g) is recovered. The corresponding
yield is 63%.
NMR spectrum of the proton
In CDC13, at 300 MHz, chemical shifts of the peaks
in ppm and multiplicity:
1.90 to 2.42: N-CH-CHs-CHs; 3.12 (d) and 3.44 (dt):
0=C~N-CH2; 3.83 ( s ) : CH3; 4.17 (dl) : O=C-N-CH; 4.54 (m) :
0=C-N-CH2-CH; 7.44 (t) , 7.56 (t) and 7.69 (d) : C6H5.
MS (El) m/z: [M] + = 288, 229, 183, 155, 105, 77.
Example 29d
trans-6-benzoyl-7-oxo-N-(phenylmethyl)-1,6-diazabicyclo
[3,2,1] octane -2-carboxamide
30 mg (0.109 mmole) of trans-6-benzoyl-7-oxo-l,6-
diazabicyclo[3,2,1]octane -2-carboxylic acid obtained in
Example 29b, 0.5 ml of dichloromethane, 23 mg of EDCI and
13 uI of benzylamine are mixed together.
The reaction medium is left to react for 30 minutes
under agitation. It is then diluted with
dichlbromethane, washed with a 10% aqueous solution of
tartaric acid, decanted, and the organic phase is dried
over sodium sulphate.
The solvent is evaporated off under reduced pressure
in order to obtain a crude product which is purified by
chromatography on silica eluting with a
dichloromethane/acetone mixture 98/2.
In this way 19.5 mg of the expected compound, with
molecular formula C2H2N3O3 (M = 363.419 g) is obtained.
The corresponding yield is 49%.
NMR spectrum of the proton
In CDC13/ at 300 MHz, chemical shifts of the peaks
in ppm and multiplicity:
1.97 (m) , 2.34 (m) and 2.59 (m) : N-CH-CH-CHa; 2.90
(d) , 3.33 (m) , 3.99 (bd) and 4.50 (m) : 0=C-N-CH, O=C-NCH2-
CH , 0=C-N-CH2 , CO-NH-CH2-C6H5; 6.94 (bt): NH; 7.24
to 7.58 (m) and 7.68 (m) : C6Hs-Cp and CgHs-CH^.
IR (CHC13) : 3411, 1763, 1680; 1603, 1583, 1519, 1498 cm"1.
103
Example 29e
6-benzoyl-N-[methyl(phenylmethyl)3-7-oxo-l,6-diazabicyclo
[3,2,1]octane -2-carboxamide
The operation is carried out in a similar manner as
Example 29d starting with 50 mg (0.182 mmole) of the acid
obtained in Example 29b and 45 u1 of N-methylbenzylamine.
In this way 12 mg of the expected compound, with
molecular formula , C22H23N3O3 (M = 377.45 g) is recovered.
The corresponding yield is 17%.
MS (El) m/z: [M]+ = 377, 272, 105.
Example 29f
S-benzoyl-2- (hydroxymethyl) -lf 6-diazabicyclo [3,2,1] octan-
7-one
100 mg (364 mmole) of trans-6-benzoyl-7-oxo-l,6-
diazabicyclo[3,2,1]octane -2-carboxylic acid obtained in
Example 29b is dissolved under an inert atmosphere, in 3
ml of tetrahydrofuran.
The reaction medium is cooled down to -10°C and 40
ul of methylmorpholine, then 38 ul of ethyl chloroformate
are added.
The reaction medium is left to react for 15 minutes
at -10°C, then the temperature is left to rise to 0°C and
27 mg of NaBH4 is added, then 1.5 ml of methanol is added
dropwise.
The reaction medium is left under agitation at 0°C
for 2 hours then left to return to ambient temperature.
3 ml of water is added, the reaction medium is left
under agitation for 15 minutes', then a few drops of
ammmonium chloride are added. Extraction is carried out
with ethyl acetate, followed by drying over magnesium
sulphate, filtering and the solvent is evaporated off
under reduced pressure.
In this way 85 mg of a crude product is obtained
which is purified by chromatography on silica, eluting
with a dichloromethane/methanol mixture 98/2.
In this way 25 mg of expected compound, with
molecular formula C4H16N2O3 (M = 260.3 g) is recovered.
The corresponding yield is 26%.
NMR spectrum of the proton
In CDC13/ at 300 MHz, chemical shifts of the peaks
in ppm and multiplicity:
1.61 (m,lH), 2.00 (m,2H) 2.30 (m, 1H) : CH-CH2-CH2-CH;
2.19: 3.23 (d) and 3.26 (dt): N - C ; 3.60 (m): N-CH-CH2-
OH; 3.70 (m) and 3.77 (dd): CH-CHj-O; 4.56 (m):
N-CH-CH2-N.
MS (SIMS) m/z: [M + Na]+ = 283, [M + H] = 261, [M] + =
260, 229, 105.
Example 30
(4-nitrophenyl)methyl trans-6-acetyl-7-oxo-l,6-
diazabicyclo[3,2,1]octane -2-carboxylate
1 g (2.63 mmoles) of the product prepared in stage C
of Example 29 is dissolved in 12 ml of dichloromethane.
250 ul of acetic anhydride is added, the reaction medium
is left to react for 10 minutes under agitation, then
diluted with dichloromethane and washed with a saturated
aqueous solution of sodium hydrogen carbonate.
The organic phase is dried over sodium sulphate,
evaporated to dryn.ess under reduced pressure in order to
obtain 1.2 g -of 1- (1,1-dimethylethyl) and 2-[(4-
nitrophenyl)methyl] trans-5-(acetylamino)-1,2-
piperidinedicarboxylate with molecular formula
(M = 421.453 g).
This product is used without purification in stages
similar to stages E to G of Example 29 and 14 mg of
expected compound, with molecular formula C16H17N3O6 (M. =
347.330 g) is thus recovered. The corresponding yield is
17%.
NMR spectrum of the proton
In CDC13, at 300 MHz, chemical shifts of the peaks
in ppm and multiplicity:
1.87 (m) , 2.00 to 2.30 (m) : N-CH-CEb-CHs; 2.54 (s) :
N-CO-CHa; 2.95 (d) and 3.21 (m) : O=C-N-CH2; 4.26 (bd) :
0=C-N-CH; 4.55 (m) : O=C-N-CH2-GH; 5.34 [AB] : CO2-CH2-C6H4 ;
7.57 and 8.25 [AA'BB1]: CgE-NOs.
MS (El) m/z: [M] * = 347, 304, 211, 169, 125, 43.
Example 31
(4-nitrophenyl)methyl and 2-propenyl trans-7-oxo-l,6-
diazabicyclo[3,2,1]octane -2,6-dicarboxylate
1.24 g (3.278 mmoles) of the product prepared in
stage C of Example 29a is dissolved under a nitrogen
atmosphere in 8 ml of dichloromethane.
The solution is cooled down to 0°C, then 0.45 ml of
TEA then 0.35 ml of allyl chloroformate are added
dropwise.
The reaction medium is maintained at 0°C for 15
minutes, then left to react under agitation for 1 hour at
ambient temperature.
The reaction medium is then diluted with 20 ml
dichloromethane, washed with an aqueous solution of
sodium bicarbonate, and twice with water.
The reaction medium is dried over magnesium
sulphate, and the solvent is evaporated off under reduced
pressure.
1.5 g of 1- (1,1-dimethylethyl) and 2-[(4-
nitrophenyl)methyl] trans-5-[[(2-propenyloxy) carbonyl]
amino] -i,2-piperidinedicarboxylate, with molecular
formula C22H28N308, (M = 462.486 g) is thus obtained
The corresponding yield is 99%.
This product is used in stages similar to stages E
to G of Example 29a and 30.6 mg of expected compound,
with molecular formula C8H19N3O7, (M = 389.368 g) is thus
obtained in the form of a white solid. The corresponding
yield is 40%.
NMR spectrum of the proton
In CDC13, at 300 MHz, chemical shifts of the peaks
in ppm and multiplicity:
1.91 (m) , 2.00 to 2.29 (m) : N-CH-CHz-CHa; 2.98
(d) and 3.25 (bd) : O=C-N-CH2/ 4.27 (t) 0=C-N-CH; 4.37
(bs) : 0=C-N-CH2-CH; 4.77 (bd) : • COO-CIfe-CH=; 5.32 (s) :
COO-CHa-C6H4/ 5.29 to 5.46: CH2=CH; 5.98 (m) : CH2=CH; 7.96
and 8.29 [AA'BB1 ] : C6H4-N02.
IR (CHClj) : 1801, 1775, 1738, 1724; 1649; 1608, 1595,
1526 cm"1.
MS (positive electrospray) m/z: [2M + Na]+ =801, [M + Na
+ CH3CN]+ = 453, [M + Na]+ = 412
Example 31a
phenylmethyl trans-6-benzoyl-7-oxo-l,6-
diazabicyclo[3,2,1] octane -2-carboxylate
200 mg of phenylmethyl trans-5-(benzoylamino)-1-
(chlorocarbonyl) -2-pipei-idinecarboxylate, with molecular
formula C2iH2iClN2O4 (M = 400.87 g) , prepared in a similar
manner' to stages A to F of Example 29a and 6 ml of
anhydrous tetrahydrofuran are mixed together under an
inert atmosphere and cooled down to -78°C.
0.55 ml of a 1M solution of lithium bis
(trimethylsilyl) amide in tetrahydrofuran is added
dropwise.
The reaction medium is left to react under agitation
at -78°C for 10 minutes then 25 ul of acetic acid is
added.'
The temperature is left to rise to ambient
temperature, then the reaction medium is poured into 10
ml of a 10% aqueous solution of tartaric acid.
Extraction is carried out with ethyl acetate, followed by
washing with an aqueous phosphate buffer solution at pH
=7, then with water and drying over magnesium sulphate.
The reaction medium is brought to dryness by
evaporation of the solvent under reduced pressure.
158' mg of a crude product is thus obtained which is
purified by chromatography on silica, eluting with a
dichloromethane/acetone mixture 98/2.
70 mg of the expected compound, with molecular
formula C2H2oN2O4 (M = 364.40 g) is thus recovered. The
corresponding yield is 39%.
NMR spectrum of the proton
In CDC13, at 400 MHz, chemical shifts of the peaks
in ppm and multiplicity:
2.15 (m) and 2.25-(m): NCH-CH2-CH2_-CH-CO2; 1.94 (m)
and 2.36 (m) : NCH-CH2-CH2-CH-C02; 4.20 (d) N-CH-CO2; 4.50
(q) : NCH-CH2-CH2-CH-C02; 3.08 (d) and 3.40 (dt) : N-CHj;
5.25 [AB] : C02-CH2-C6H5; 7.38 (bs) : CH2-C6H5; 7.43 (bt) and
7.55 (bt) and 7.69 (bd) C6H5-CO.
IR (CHCla) : 1764, 1744, 1675; 1602, 1584, 1498 cm-i
MS (SIMS) m'/z: [M + Na] + = 387, [M + H] + = 365, 259, 257,
229, 105, 91.
Example 31b
phenylmethyl 6-benzoyl-7-oxo-l,6-diazabicyclo[3,2,1]oct-
2 -ene-2 -carboxylate
46 mg (0.126 mmoles) of the product obtained in
Example-31a and 0.5 ml of anhydrous tetrahydrofuran are
mixed together.
The reaction medium is cooled down to -70°C and 0.31
ml of 1M lithium bis (trimethylsilyl) amide iu
tetrahydrofuran is added.
The reaction medium is left to react for 2 hours at
-70°C, then the temperature is allowed to rise to -15°C
and 0.41 ml of a solution of C6H5-SeCl at 0.7 mol/1 in
THF is added at this temperature.
The reaction medium is left under agitation at -15°C
for 15 minutes,- then allowed to' return to ambient
temperature for 15 minutes and poured into a mixture of
water and ice containing a few drops of a saturated
aqueous solution of sodium bicarbonate.
The reaction medium is extracted with ethyl acetate,
washed with water, dried and the solvent is evaporated
off under reduced pressure.
The residue is purified by chromatography on silica
eluting with a dichloromethane/acetone mixture 98/2 and
15 mg of phenylmethyl 6-benzoyl-7-oxo-2-(phenylselenyl)-
1,6-diazabicyclo[3,2,1]octane -2-carboxylate, with
molecular formula C a v C S e (M= 519, 46 g) is thus
recovered. The corresponding yield is 23%.
15 mg (0.029 mmole) of the compound obtained
previously and 0.3 ml of dichloromethane are mixed
together.
The reaction medium is cooled down to 0°C and 15 mg
of meta-chloroperbenzoic acid in solution in 0.15 ml of
dichloromethane is added.
The reaction medium is left under agitation at 0°C
for 15 minutes, then left to return to ambient
temperature.
The reaction medium is poured into approximately 20
ml of water, extracted with dichloromethane and the
organic phase is washed with,.an aqueous solution of
phosphate buffer at pH=7. Followed by drying over
magnesium sulphate, filtering and the solvent is
evaporated off under reduced pressure.
In this way 15 mg of crude product is obtained which
is purified on silica eluting with a
dichloromethane/acetone mixture 98/2.
In this way 5 mg of the expected compound, with
molecular formula C2HSN2O4 (M = 362.39 g) is recovered.
The corresponding yield is 48%.
NMR spectrum of the proton'
In CDC13, at 300 MHz, chemical shifts of the peaks
in ppm and multiplicity: 2.66 (td) and 2.99 (tdd); N-CHCHs;
3,03 (d) and 3.77 (ddd) : N-CKb,. 4.76 (tt) : N-CH; 5.23
[AB] : C02-CJJ2-C6H5; 7.02 (dt) : N-C=CH; 7.30 to 7.38 (m) :
CH2-CeH5; 7.42 (tm) , 7.54 (tm) and 7.62 (dm); CgHg-CO;
Example 31c
6-benzoyl-7-oxo-l,6-diazabicyclo[3,2,1]oct-2-ene-2~
carboxylic acid
20 mg (0.055 mmole) of the product obtained in
Example 31b is mixed, 0.4 ml of acetone and 4 mg of 10%
Pd/C catalyst are added.
The reaction medium is placed under a hydrogen
atmosphere and left to react for 3 hours under vigorous
agitation.
The catalyst is filtered out and washed with acetone
then with methanol. The filtrate is evaporated off under
reduced pressure.
In this way 14 mg of expected compound, with
molecular formula C14H12N2O4 (M = 272.4 g) is obtained.
The corresponding yield is 93%.
MS (El) m/z: [M]+: 272, 105.
Example 32 a
2-propenyl trans-7-oxo-6-(2-phenylmethoxy)-1,6-diazabicyclo[
3,2,1] octane -2-carboxylate
Stage A
2-propenyl cis-5-hydoxy-l-[(trifluoroacetyl)-2-piperidine
carboxylate
17 g (0.059 mole) of 1-(1,1-dimethylethyl) and 2-(2-
propenyl) cis-5-hydroxy-1,2-piperidinedicarboxylate
(described in Rec. Trav. Chim. (1959), 78, 648-658), with
molecular formula C14H23NO5 (M = 285.3431 g) is dissolved
in 17 ml of ethyl acetate.
A solution of 51 ml of hydrogen chloride in ethyl
acetate at 150 u1 is added at 0°C.
The reaction medium is left to return to ambient
temperature and left to react under agitation for 1 hour
and 30 minutes.
The ethyl acetate is evaporated off under reduced
pressure, followed by taking up in ethyl ether, which is
eliminated in turn under reduced pressure.
In this way 12 g of a pale yellow solid is obtained
which is mixed with 200 ml of tetrahydrofuran. The
reaction medium is cooled down to 0°C, then 37.6 ml of
TEA is added.
The temperature is maintained at 0°C/ then 16.8 ml
of trifluoroacetic anhydride is slowly added.
The temperature is allowed to rise to 20°C and the
reaction medium is left to react for another 20 minutes
under agitation.
20 ml of water is then added.
The solution obtained is agitated for 1 hour at
ambient temperature and poured into 300 ml of water. The
solution is extracted with ethyl acetate, washed with
water, dried over sodium sulphate, and the solvent is
evaporated off under reduced pressure.
15.7 g of crude product is obtained which is
purified by chromatography on silica eluting with a.
dichloromethane/ethyl acetate mixture 90/10.
12.3 g of expected compound, with molecular formula
CiiHi4F3NO4 (M - 281.23 g) , is thus obtained in the form of
a yellow oil. The corresponding yield is 73%.
Stage B
2-propenyl trans-5-[(phenylmethoxy)amino]-1-
(trifluoroacetyl)-2-piperidinecarboxylate
10.9 g (38.7 mmoles) of the compound obtained in
stage A, and 150 ml of acetonitrile are mixed together.
The pale yellow solution obtained is cooled down to
-30°C, then 4.94 ml of 2.6-lutidine and 6.7 ml of
trifluoromethanesulphonic anhydride are added. The
reaction medium is agitated for 15 minutes, then, still
at -30°C, 9.57 g of 0-benzylhydroxylamine is added.
At the end of the addition, the temperature is left
to rise to 0°C and the reaction medium is left to react
for 1 hour at this temperature. 4.9 ml of 2,6-lutidine
is then added and left in contact for 3 days at 0°C.
The reaction mixture is then poured into 500 ml of
water and extracted with ethyl acetate. The reaction
medium is washed successively with water, with an aqueous
soliation of phosphate buffer at pH=7.0, with a saturated
aqueous solution of sodium chloride, then again with
water.
Drying is carried out over sodium sulphate and the
solvent is evaporated off under reduced pressure.
23 g of crude product is thus obtained which is
dissolved in- 150 ml of dichloromethane, followed by
washing with a 10% aqueous solution of tartaric acid,
then drying over sodium sulphate and the solvent is
evaporated off under reduced pressure.
16.1 g of a yellow oil is thus recovered which is
purified by chromatography on silica.
4
12.1 g of expected compound, with molecular formula
Ci8H2iF3N2O4 (M = 386.37 g) is recovered in cristallized
form. The corresponding yield is 72%.
Stage C •
2-propenyl trans-5-[(phenylmethoxy)amino]-2-piperidine
carboxylate
80 ml of methanol is cooled down to -10°C, then 4.15
g (37.8 mmoles) of NaBH4 is added.
A solution of 10.6 g (27.4 mmoles) of the compound
obtained previously in 80 ml of methanol is slowly added,
under agitation, to this mixture for a duration of 30
minutes, whilst maintaining the temperature at -10°C.
The temperature is then left to rise to 0°C, then
this temperature is maintained for 3 hours.
The reaction mixture is poured into 450 ml of ice
and water and 150 ml of ethyl acetate, followed by
decanting, washing with water then the organic' phase is
dried over sodium sulphate and then the solvent is
evaporated off under reduced pressure.
8.2 g of a yellow oil is thus obtained which is
dissolved in 80 ml of tetrahydrofuran, a solution of 2.43
g of oxalic acid in 25 ml of THF is added. The oxalate
which crystallizes is filtered out and washed with a
little THF then dried under reduced pressure and
dissolved in a saturated solution of sodium bicarbonate.
Extraction is carried out with ethyl acetate, the organic
phase is washed with water, dried over sodium sulphate
and the solvent is evaporated off under reduced pressure.
4.39 g of expected compound, with molecular formula
C6H22N203 (M = 290.36 g) is thus obtained, in the form of
an oil which crystallizes when the temperature is below
20 C°. The corresponding yield is 55%.
Stage D
2-propenyl trans-7-oxo-6- (2-phenylmethoxy) -1, 6-diazabicyclo[
3,2,1]-octane-2-carboxylate
3.2 g (1-1 mmoles) of the •• oil obtained previously is
dissolved under a nitrogen atmosphere in 500 ml of
acetonitrile. '
The solution obtained is cooled down to 0°C using an
ice bath and 3.37 ml of TEA, then 0.796 ml of diphosgene,
and 1.48 g of DMA.P are added.
The temperature is left to rise to 20°C and the
medium is left to react for 2 hours under agitation.
The reaction mixture is then poured into 200 ml of a
0. IN aqueous solution of hydrochloric acid, 400 ml of
water is added, followed by extracting with
dichloromethane, washing with water and drying over
sodium sulphate.
The solvent is then evaporated off under reduced
pressure in order to obtain 3.1 g of expected compound,
with molecular formula C17H20N2O4 (M = 316.36 g) , in the
form of crystals'. The corresponding yield is 89%.
NMR spectrum of the proton
1.66 (m) and 2.00 to 2.16 (m) O=C-CH-CH2-CH2; 2.94 (d) and
3.07 (dt) N-CH2; 3.31 (m) N-CH2-CH; 4.14 (dd) 0=C-CH, 4.68
(dt) CH2-CH=CH2; 4.90 and 5.06 [AB] CH2-C6H5; 5.26 (dq) and
5.34 (dq) CH2-CH = CH,; 5.92 (m) CH2-CH=CH2; 7.37 to 7.42
(m) C6Hs.
IR (CHC13) : 1748; 1646; 1496 cm"1.
MS (positive electrospray) m/z: [2M + Na] + = 655, [M + Na
+ CH3CN]+ = 380, [M + Na] + = 339, [M + H] + = 317, 289, 91.
Example 32b
trans-7-oxo-6-(phenylmethoxy)-1,6-diazabicyclo [3,2,1]
octane-2-carbdxylic acid and its cyclohexylamine salt.
2.21 g (6.98 mmoles) of the compound obtained in
*
Example 32a is dissolved under a nitrogen atmosphere, in
44 ml of dichloromethane.
A 0.5 M solution of sodium ethyl-hex.ano.ate in ethyl
acetate is added.
Then 242 mg of tetrakistriphenylphosphine palladium
is added in one go, then the medium is maintained under
agitation for 1 hour, followed by diluting with.22 ml of
ethyl acetate and pouring into 75 ml of a saturated
solution of NaH2PO4.
Extraction is then carried out with ethyl acetate
and the organic phase is dried over sodium sulphate. The
solvent is evaporated off under reduced pressure in order
to obtain 3.5 g of a yellow residue which is dissolved in
a mixture of 11 ml of ethyl acetate and 0.8 ml of
cyclohexylamine.
The crystallized cyclohexylamine salt is separated
by filtration and washed with ethyl ether, then the
solvent is evaporated off under reduced pressure. In
this way a total of 2.51 g of crystallized salt is
obtained which is dissolved in 25 ml of a saturated
aqueous .solution of NaH2P04. After extracting with ethyl
acetate, the organic phases are combined and dried over
sodium sulphate, then the solvent is evaporated off under
reduced pressure.
1.82 g of expected compound with molecular formula
C14H6N204 (M = 276.29 g) is thus recovered, in
crystallized form. The corresponding yield is 94 %.
NMR spectrum of the proton
In CDC13, at 300 MHz, chemical shifts of the peaks
in ppm and multiplicity-:
1.68 (m) and of 2.20 to 2.22 (m) : CH-CHs-CH-CH;
2.89 (d) and 3.11' (ddd) : N-CHz; 3.34 (dd) N-CH2-CH, 4.13
(bd) : N~CH-C=0; 4.90 and 5.05 [AB] : CHa-O; 7.32 to 7.43:
C6Hs.
MS (SIMS) m/z; [M + Na] * = 299, [M + H]* = 277.91.
Example 33 a
Pyridinium salt of trans-7-0x0-6-(sulphooxyj-1,6-
diazabicyclo [3,2,1] octane-2-carboxamide
Stage A
trans-7-oxo-6-(phenylmethoxy)-1, 6-diazabicyclo [3,2,1]
octane-2-carboxamide
1.1 g (4 mmole) of the compound obtained in Example
32b is dissolved in 30 ml of dichloromethane.
0.67 ml of TEA is added to this solution.
The solution is cooled down to 5°C and 0.57 ml of
isobutyl chloroformate is added quite rapidly.
Agitation is maintained for 20 minutes at 5°C, then
3 ml of concentrated ammonia is added, slowly, under
vigorous agitation..
Agitation is maintained for one hour at ambient
temperature,-the reaction medium is diluted with 30 ml of
water, followed by extracting with dichloromethane,
washing with water, drying over sodium sulphate and
concentrating under reduced pressure.
In this way 1.1 g of expected product with molecular
formula C4H17N3O3 (M = 275.31 g) is obtained.
The yield is quantitative.
Stage B
trans-6-hydroxy-7-oxo-l,6-diazabicyclo[3,2,1]octane-2-
carboxamide
1.1 g of the compound obtained in stage A, 30 ml of
methanol and 300 mg of 10% Pd/C are mixed together.
The reaction medium is placed under a hydrogen
atmosphere then the mixture is agitated vigorously for 45
minutes.
The catalyst is then filtered out, washed with
methanol then with a dichloromethane/methanol mixture.
The filtrate is evaporated under reduced pressure.
800 mg of expected product with molecular formula
C7HnN3O3 • (M = 185.18 g) is thus obtained, in the form of
a colourless foam.
Stage C
Pyridinium salt of trans-7-oxo--6-(sulphooxy)-1, 6-
diazabicyclo [3,2,1] octane~2-carboxamide
800 mg of the compound obtained previously and 20 ml
of anhydrous pyridine are .mixed together under a nitrogen
atmosphere.
Then 1.91 g of SO3-pyridine complex is added.
The mixture is agitated for 20 hours at ambient
temperature.
The reaction medium is then filtered and the solvent
evaporated off under reduced pressure.
The expected product with molecular . formula
C12H16N406S, C5H5N (M = 344,35 g) is thus obtained in the
form of a yellow product.
Example 33b
Tetrabutylammonium salt of trans-7-oxo-6- (sulphooxy) -1, 6
diazabicyclo [3,2,1] octane-2-carboxamide
The product obtained previously is introduced into
40 ml of a concentrated aqueous solution of NaH2PO4 so as
to obtain a pH of 4.
Extraction is carried out with ethyl acetate then
1.01 g of tetrabutyl ammonium hydrogen sulphate is added
to the aqueous phase.
Agitation is carried out for 10 minutes at ambient
temperature, followed by extracting 4 times with 300 ml
of ethyl acetate, drying the organic phase over sodium
sulphate and concentrating under reduced pressure.
1.530 g of a colourless foam is thus obtained which
is purified by chromatography on silica, eluting with an
acetone/dichloromethane/TEA solvent 50/48/2.
In this way 1.02 g of expected product with
molecular formula C23H46N4O6S (M = 506.71 g) is recovered,
in the form of a colourless foam. The corresponding
overall yield is 50%.
Example 33 c
Sodium salt of trans-7~oxo-6-(sulphooxy)-1,6-diazabicyclo
[3,2,1] octane-2-carboxamide
The product obtained in Example 33b is dissolved in
7 ml of an acetone/water mixture 1/1 then deposited on a
column of 180 g of DOWEX 50WX8 resin in Na+ form and
eluted with water. After evaporation of the water under
reduced pressure, the product crystallizes.
542 mg of expected compound, -of formula C7HioN3NaO6S
(M = 287.23 g) is thus obtained. The corresponding yield
is 94%.
NMR spectrum of the proton
118
In DMSO, at 300 MHz, chemical shifts of the peaks in
ppm and multiplicity:
1.55 to 2.10 (3H) : CH-CHs-CBb-CH; 2.91 (d) and 3.02
' (bd)-: N-CH2; 3.38 (bs) : N-CH2-CH; 3.68 (d) : N-CH-C-0;
7.23 and 7 .44 : NH2.
MS (negative electrospray) m/z: [M]" = 264
Examples 34 to 47
The following carboxamides were prepared following
an operating method similar to that which is used in
Example 33 starting from 110 mg of the acid obtained in
Example 32b.
The only difference is that in Stage 1, the reagent
used, i.e. the ammonia solution, is replaced by a
solution of the corresponding amine.
Thus, only the Rl group as' defined in formula 1
varies.
Example 34
Starting from 49 p,I of benzylamine, 64 mg of the sodium
salt of trans-7-oxo-N~(phenylmethyl)-6-(sulphooxy)-1,6-
diazabicyclo[3,2,1]octane-2-carboxamide is obtained i.e.
an overall yield of 38 %.
MS (positive electrospray) m/z: [M + Na]+ =400, [M + H] +
= 378
Example 35
Starting from 43 /zl of 2-pyridinemethanamine, 37 mg of
the sodium salt of trans-7-oxo-N-(2-pyridinylmethyl)-6-
(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
is obtained i.e. an overall yield of 14 %.
MS (positive electrospray) m/z: [M + H]+ = 379
Example 36
Starting from 51.3 mg of 3-pyridineethanamine, 42 mg of
the sodium salt of trans-7-oxo-N-[2-(3-pyridinyl)ethyl]-
6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
is obtained i.e. an overall yield of 20 %.
MS (positive electrospray) m/z: [M + H] + = 393
Example 37
Starting from 51.3 mg of 4-pyridineethanamine, 40 mg of
the sodium salt of trans-7-oxo-N-[2-(4-pyridinyl) ethyl] -
6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
is obtained i.e. a yield of 20 %.
MS (positive electrospray) m/z-. [M + Na] + =415, [M + H]+
= 333
Example 38
Starting from 50.2 mg of 2-pyridineethanamine, 45 mg of
the sodium salt of trans-7-oxo-N-[2-(2-pyridinyl)ethyl]-
6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
is obtained i.e. a yield of 23 %.
MS (positive electrospray) m/z: [M + H]+ = 393
Example 39
Starting from 58.3 mg of 3-amino-benzamide, 43 mg of the
sodium salt of trans-N-[3-(aminocarbonyl)phenyl]-7-oxo-6-
(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
is obtained i.e. a yield of 22 %.
MS (negative electrospray) m/z: [M]" = 383
Example 40
Starting from 58.3 mg of 4-dimethylamino-benzenamine,
65.3 mg the sodium salt of trans-N- [4-
(dimethylamino)phenyl]-7-oxo-6-(sulphooxy)-1,6-
diazabicyclo[3,2,1]octane-2-carboxamide is obtained i.e.
a yield of 40 %.
MS (negative electrospray) m/z: [M] ~ = 383
Example 41
Starting from 58.3 mg of 3-dimethylamino-benzenamine, 91
mg of the sodium salt of trans-N- [3-
(dimethylamino)phenyl]-7-oxo-6-(sulphooxy)-1,6-
diazabicyclo[3,2 ,1]octane-2-carboxamide is obtained i.e.
a yield of 54 %.
MS (negative electrospray) m/z: [M]" = 383
Example 42
Starting from 43 /tl of 4-pyridinemethanamine, 24.6 mg of
the sodium salt of trans-7-oxo-N-[(4-pyridinyl)methyl] -6-
(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
is obtained i.e. a yield of 15 %.
MS (negative electrospray) m/z: [M]" = 355
Example 43
Starting from 44 ul of 3-pyridinemethanamine, 44.7 mg of
the sodium salt of trans-7-oxo-N-(3-pyridinylmethyl) -6-
(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
is obtained i.e. a yield of 26 %.
MS (negative electrospray) m/z: [M]" = 355
Example 44
Starting from 84 mg (.+-.)-.alpha.-amino-benzene
propanamide, 55 mg of the sodium salt of trans-N- (1-
amino-l-oxo-3-phenyl-2-propyl)-7-oxo-6-(sulphooxy)-1,6-
diazabicyclo[3,2,1]octane-2-carboxamide is obtained i.e.
a yield of 27 %.
MS (negative electrospray) m/z: [M]" = 411, 321
Example 45
Starting from 46 mg of 2-amino-acetamide hydrochloride
and 61 p.1 of TEA, 25 mg of the sodium salt of trans-N- (2-
amino-2-oxoethyl)-7-oxo-6-(sulphooxy)-1,6-diazabicyclo
[3,2,1] octane-2-carboxainide is obtained i.e. ,a yield of
13 %.
MS (negative electrospray) m/z: [M] = 321, 249
Example 46
Starting from 64 mg of (3-aminophenyl)-urea, 43 mg of the
sodium salt of trans-N-[3-[(aminocarbonyl)amino]phenyl]-
7-oxo-6-(sulphooxy)-1, 6-diazabicyclo[3,2,1]octane-2-
carboxamide is obtained i.e. a yield of 24 %.
MS (negative electrospray) m/z: [M]". = 398, 153, 111
Example 47
Starting from 63 mg of (.+-.)-.alpha.-aminobenzeneacetamide,
64 mg of the sodium salt of trans-N-(2-
amino-2-oxo-l-phenylethyl)-7-oxo-6-(sulphooxy)-1,6-
diazabicyclo [3,2,1] octane-2-carboxamide is obtained
i.e. a yield of 38 %
MS (negative electrospray) m/z: [M] " = 397
Examples 48 to 51
The following compounds were prepared starting from 110
mg of compound obtained in stage E of Example 32,-which
is esterified each time with the appropriate alcohol in
order to produce the final product.
Then, the operation is carried out in a similar
manner to that described in stages B to E of Example 33.
Example 48
Starting from 31.5 tng of 2-hydroxy-acetamide, 54 mg of
the sodium salt of 2-amino-2-oxoethyl trans-7-oxo-6-
(sulphooxy)-1,6-diazabicyclo [3,2,1] octane-2-carboxylate
is obtained i.e. a yield of 32 %.'•
MS (negative electrospray) m/z: [M]" = 322
Example 49
Starting from 51.7 mg of 4-pyridineethanol, 20 mg of the
sodium salt of 2- (4-pyridinyl)ethyl trans-7-oxo-6-
(sulphooxy)-1,6-diazabicyclo [3,2,1] octane-2-carboxylate
is obtained i.e. a yield of 8.5 %.
MS (negative electrospray) m/z: [M]" = 370
Example _50
Starting from 47.3 mg' of 2-pyridineethanol, 47 mg of the
sodium salt of 2-(2-pyridinyl)ethyl trans-7-oxo-6-
(sulphooxy)-1,6-diazabicyclo [3,2,1] octane-2-carboxylate
is obtained i.e. a yield-of 23.4 %.
MS (negative electrospray) m/z: [M]" = 370
Example 51
Starting from 57.7 mg of 3-pyridineethanol 50 mg of the
sodium salt of 2-(3-pyridinyl)ethyl trans-7-oxo-6-
(sulphooxy)-1,6-diazabicyclo[3,2,1] octane-2-carboxylate
is obtained i.e. a yield of 26 %.
MS (negative electrospray) m/z: [M]" = 370
PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION
In vitro activity, method of dilution in liquid medium
A series of tubes are prepared in which the same
quantity of sterile nutritive medium is distributed.
Increasing quantities of the product to be studied are
distributed into each tube, then each tube is sown with a
bacterial strain. After incubation for twenty-four hours
in a heating chamber at 37°C, the growth inhibition is
evaluated by transillumination, which allows the minimal
inhibitory concentrations (M.I.C.) to be determined,
expressed in jog/cml.
The tests were carried out with the following
products of the invention:
Test A: Sodium salt of trans-N-(2-amino-2-oxoethyl) -
7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-
carboxamide, the preparation of which is described in
Example 45
Test B: Sodium salt of trans-7-oxo-6-(sulphooxy) -
1,6-diazabicyclo[3,2,1]octane-2-carboxamide, the
preparation of which is described in Example 33c
Test C: Sodium salt of trans-7-oxo-N- (3-
pyridinylmethyl)-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]
octane-2-carboxamide, the preparation of which is
described in Example 43
Test D: Sodium salt of trans-7-oxo-N-[(4-
pyridinyl)methyl] -6-(sulphooxy)-1,6-diazabicyclo[3,2,1]
octane-2-carboxamide, the preparation of which is
described in Example 42
•Test E: Sodium salt of trans-7-oxo-N-(phenylmethyl)-
6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-
carboxamide, the preparation of which is described in
Example ,34
Test F: Sodium salt of phenylmethyl trans-7-oxo-6-
(sulphooxy)-1,6-diazabicyclo[3,2,1] octane-2-carboxylate,
the preparation of which is described in Example 28b.
The results are set out in the following table:
Strains
(Figure Removed)
The- compounds according to the invention therefore
show an anti-bacterial activity.
Example 52
Sodium salt of 3-methoxy-6-(sulphooxy)-1,6-
diazabicyclo [3,2,1] oct-3-en-7-one
Stage A
lOg (50 mmoles) of 1,1-dimethylethyl 3,5-dioxo-lpiperidinecarboxylate
is dissolved in 10 ml of methanol,
then 6g (54 mmoles) of 0-allylhydroxylamineamine
hydrochloride is added.
The reaction medium is left under agitation for 3
hours, then the solvent is evaporated off under reduced
pressure.
The residue is taken up in water, followed by
extraction with dichloromethane. The organic phase is
washed with water, then dried over sodium sulphate.
After filtration and evaporation of the solvent
under reduced pressure, 10.6 g of 1,1-dimethylethyl 5-
methoxy-3-[(2-propenyloxy)iminoJ-3,6-dihydro-l(2H)-
pyridinecarboxylate is obtained with a molecular formula
C14H22N204 (M = 282.342 g) .
The corresponding yield is 75%.
Stage B
10.6g (37.6 mmoles) of the product obtained in Stage
A and 212 ml of methanol are placed in a flask.
The solution is cooled down to -5°C, 3"7.8g of sodium
cyanoborohydride then 58.2 ml of boron fluoride etherate
is added.
The reaction medium is then- diluted with
dichloromethane, poured into a mixture of water and 2N
soda, extraction is carried out with dichloromethane, the
organic phase is washed with water, followed by drying
over sodium sulphate, filtering and evaporation of the
solvent under reduced pressure.
The product obtained is purified by chromatography
on silica eluting with an AcOEt/dichloromethane mixture
10/90.
In this way 5.5g of 1,1-dimethylethyl 5-methoxy-3-
[(2-propenyloxy)amino]-3,6-dihydro-l(2H)-
pyridinecarboxylate of molecular formula C14H24N202 (M
284.36 g) is obtained. The corresponding yield is 51%.
Stage c
5. 5g (19.3 mmoles) of the product obtained in Stage
B, 27.5 ml of dichloromethane and 4.2 ml of anisole are
introduced into a flask.
27.5 ml of trifluoroacetic acid is then added.
The TFA and the dichloromethane are eliminated under
reduced pressure.
The residue is taken up in water followed by
extraction 3 times with AcOEt. The aqueous phase is
rendered basic by the addition of ammonium hydroxide,
then extraction with AcOEt is carried out.
The organic phases are washed with water, then dried
over sodium sulphate* followed by filtering then
evaporation of the solvent under reduced pressure.
In this way 2.45g of 5-methoxy-N-(2-propenyloxy)-
1,2,3,6- tetrahydro-3-pyridinamine of molecular formula
C9H16N202 (M = 184.24 g) is obtained.
The corresponding yield is 69%.
Stage D
2.45g (0.0133 mmole) of the product obtained in
Stage C is dissolved under an inert atmosphere in 826 ml
of acetonitrile and the solution is cooled down to 0°C.
0.778 ml of diphosgene is added.
The temperature is allowed to return to ambient
temperature/ then 5.56 ml of TEA is added.
Agitation is carried out overnight at ambient
temperature, then the solvent is evaporated off under
reduced pressure.
The residue is taken up in water, followed by
extraction with AcOEt, the organic phase is washed with
water, then dried over sodium sulphate, followed by
filtration then evaporation of the solvent under reduced
pressure.
The residue is purified by chromatography on silica
eluting with an AcOEt/dichloromethane mixture 1/9.
In this way 1.13g of 3-methoxy-6-(2-propenyloxy)-
1,6- diazabicyclo[3,2,1]oct-3-en-7-one of molecular
formula CoHMN203 is obtained (M = 210.23 g) .
The corresponding yield is 40.3%.
Stage E
105 mg (0.5 mmole) of the product obtained in Stage
D, is dissolved in a flask placed under an inert
atmosphere in 1.1 ml of dichloromethane, 57^1 of acetic
acid, then 317 mg of Pd [P (C6Hs)3] 4 are added.
After reaction for 1 hour, 1.1 ml of pyridine, then
238 mg of S03-pyridine complex are added.
Agitation is carried out overnight, then the solvent
is evaporated off under reduced pressure.
The residue is taken up in water, followed by
extraction with dichloromethane and washing with water.
The organic phase is dried over sodium sulphate, followed
by filtering and evaporating the solvent under reduced
pressure.
The residue is purified by chromatography on silica,
eluting with a trichloromethane/acetonitrile mixture
50/50.
In this way 148 mg of the 1-
propenyltriphenylphosphonium salt of 3-methoxy-6-
(sulphooxy)-1,S-diazabicyclo[3,2,1]oct-3-en-7- one of
molecular formula C28H29N206PS is obtained. The
corresponding yield is 53%.
Stage F
148 mg of the product obtained in Stage E is
dissolved in water containing 10% THF.
The solution obtained is passed over a column of
DOWEX 50WX8 resin in Na+ form, eluting with water
containing 10% THF.
The product collected is lyophilized in order to
obtain 51 mg of the expected sodium salt, of molecular
formula C7H9N20«SNa (M = 272.21 g) .
The corresponding yield is 70%.
NMR spectrum of the proton
3.04 (d) and 3.25 (dd) : C=CH-CH-CH2-N; 3.41 (d) and
3.71 (dd) : N-CH2-C=CH; -3.47 (s): CH3-0; 4.20 (dd) : C=CHCg-
CH2-N; 5.19 (bd) : C=CH-CH-CH2-N
MS (negative electrospray) m/z: [M]" = 249, [M -
CH3] - = 235
Example 53
Sodium salt of 3-methoxy-6-(sulphooxy)-1, 6-
diazabicyclo [3,2,1]oct-3-en-7-one
Stage A
l.OSg (5.2 mrnoles) of 1,1-dimethylethyl 3,6-dihydro-
3-oxo- 1(2H)-pyridinecarboxylate of molecular formula
C10H15N03 is dissolved in 15 ml of ethanol. 572 mg (5.2
mmoles) of 0-allylhydroxylamineamine, then 1.3 ml of
pyridine are added.
The reaction mixture is left under agitation for 15
minutes, then 100 ml of dichloromethane is added,
followed by washing with a 10% aqueous solution of
tartaric acid, then the organic phase is dried over
magnesium sulphate.
Filtration is carried out and the solvent is
evaporated off under reduced pressure.
In this way 1.36 g of 1,1-dimethylethyl 3,6-dihydro-
3- [ (2-propenyloxy)iminoj-1(2H)-pyridinecarboxylate of
molecular formula C3H20N203 (M = 252.32 g) is obtained.
The corresponding yield is quantitative.
Stage B
The operation is carried out as indicated in Stage A
of Example 52 starting from 1.38g of the product obtained
in Stage A, 15.lg of sodium cyanoborohydride and 8.3 ml
of baron trifluoride etherate.
0.99g of a mixture of 2/3 1,1-dimethylethyl 3-[(2-
propenyloxy)amino]-1-piperidinecarboxylate and 1/3 1,1-
dimethylethyl 3,6-dihydro-3- [ (2-propenyloxy)amino]-1(2H)-
pyridinecarboxylate of molecular formula CuHNzO (M =
254.33 g) are obtained in this way after purification.
The corresponding yield is 71%.
Stage C
1.07g (4.26 mmoles) of the mixture obtained in Stage
B is dissolved in 2 ml of AcOEt. The reaction medium is
cooled down to 0°C/ then 5.8 ml of a 7.3 M solution of
hydrogen chloride in AcOEt is added. The reaction medium
is left to react for 2 hours 30 minutes at 0°C.
The solvent is evaporated off under reduced
pressure, then the residue is taken up in ether, the
precipitate is filtered and dried under reduced pressure.
In this way 560 mg of N- (2-propenyloxy) -1, 2 , 3 , 6-
tetrahydro-3- pyridinamine dihydrochloride of molecular
formula C8HSCl2N20 (M = 227.14 g) is obtained.
The corresponding yield is 57%.
Stage D
560 mg (2.46 mmoles) of the product obtained in
Stage C is dissolved in 6 ml of dichloromethane, then 2.5
ml of 2N soda is added.
The reaction medium is decanted and the aqueous
phase is extracted with AcOEt.
The organic phases are combined then dried over
magnesium sulphate, followed by filtering and evaporation
of the solvent under reduced pressure.
In this way 278 mg of N-(2-propenyloxy)-I,2,3,6-
tetrahydro-3- pyridinamine of molecular formula CaHi4N20
(M = 154.21 g) is obtained.
The corresponding yield is 73%.
Stage E
270 mg (1.75 mmoles) of the product obtained in
Stage D is dissolved under an argon atmosphere in 45 ml
of acetonitrile, then 760ui of TEA and 105 /zl of
diphosgene are added.
The reaction medium is reacted for 15 minutes at
0°C, then allowed to •return to ambient temperature and
also allowed to react for 2 hours.
213 mg of DMAP is added then the reaction medium is
left to react overnight.
AcOEt is added, followed by washing with a 10%
aqueous solution of tartaric acid and with water.
The organic phase is dried over magnesium sulphate
followed by filtration and the solvent is evaporated off
under reduced pressure.
The crude product obtained is purified on silica,
eluting with a dichloromethane/acetone 95/5 mixture
containing 0.1% TEA.
In this way 36 mg of 6-(2-propenyloxy)-I,6-
diazabicyclo(3,2,I]oct-3-en-7~one of molecular formula
C9H12N202 is obtained (M = 180.21 g).
The corresponding yield is 11%.
Stage F
The operation is carried out in a similar way to
that described in Stage E of Example 52 starting from 51
mg (0.27 mmole) of the product obtained in Stage E, 33 pi
of acetic acid, 165 mg of Pd [P (C6H5) 3] 4 and 132 mg of S03-
pyridine complex.
In this way 29.6 mg of the 1-
propenyltriphenylphosphonium salt, of 6- (sulphooxy) -1,6-
diazabicyclo[3,2,1]oct-3-en-7-one is obtained.
This salt is passed over a column of DOWEX 50WX8
resin in Na+ form, eluting with water containing 10% THF.
The product collected is lyophilized in order to
obtain 13 mg of the expected sodium salt, of molecular
formula CfiH7N205SNa (M = 242.19 g) .
The corresponding yield is 20%.
MS (necfative electrospray) m/z: [M] ' = 219
Example 54
Sodium salt of 6-(sulphooxy)-1,6-
diazabicyclo[3,2,1]octan-7- one
Stage A
The operation is carried out as indicated in Stage A
of Example 53 starting from 12g (0.061 mole) of 1,1-
dimethylethyl 3,6-dihydro-3-oxo-l(2H)-pyridinecarboxylate
of molecular formula C0HSN03, 9. 7g of 0-
benzylhydroxylamine hydrochloride and 15 ml of pyridine.
In this way 19.4g of 1,1-dimethylethyl 3,6-dihydro-
3- [(phenylmethoxy)imino]-1(2H)-pyridinecarboxylate of
molecular formula C7H22N203 is obtained (M = 302.38 g) .
The corresponding yield is quantitative.
Stage B
The operation is carried out as indicated in Stage B
of Example 53 starting from 14.9g (0.0496 mole) of the
product obtained in Stage A, 12g of sodium
cyanoborohydride and 30 ml of boron trifluoride etherate.
After purification, 8.2g of a mixture of 2/3 of 1,1-
dimethylethyl 3,6-dihydro-3-[(phenylmethoxy)amino]-1(2H)-
pyridinecarboxylate and 1/3 of 1,1-dimethylethyl 3-
[(phenylmethoxy)amino]-1-piperidinecarboxylate of
molecular formula C7H22N203 is obtained in this way (M =
304.39 g). The corresponding yield is 55%.
Stage C
The operation is carried out as indicated in Stage C
of Example 53 starting from 9.3g (0.0306 mole) of the
mixture obtained in Stage B and 106 ml of a 7 mol/1
solution of hydrogen chloride in AcOEt.
8.39g of a mixture of 2/3 of N- (phenylmethoxy) -
1/2,3,6- tetrahydro-3-pyridinamine dihydrochloride and
1/3 of N-(phenylmethoxy)-3-piperidinamine dihydrochloride
of molecular formula CuHiaCl^O is obtained in this way
(M = 277.20 g). The corresponding yield is 98%.
Stage D
The operation is carried out as indicated in Stage D
of Example 53 starting from 8.30g (0.0299 mole) of the
mixture obtained in Stage C and 30 ml of 2N soda.
5.95g of a mixture of 2/3 of N-(phenylmethoxy)-
1,2,3,6-tetrahydro-3-pyridinamine and 1/3 of N-
(phenylmethoxy)-3- piperidinamine of molecular formula
C N O (M = 204.27 g) is obtained in this way.
The corresponding yield is 98%.
Stage E
The operation is carried out as indicated in Stage E
of Example 53 starting from 5.02g (0.0246 mole) of the
mixture obtained in Stage D, 2.43 ml of diphosgene, 7.4
ml of TEA and 3g of DMAP.
5.020g (0.0246 mole) of the product obtained in
Stage D and 1.2 ml of I,2-dichloroethane are introduced,
at 0°C and under argon into a flask equipped with a
magnetic Btirrer. 2.43g of diphosgene is added.
In this way 2.4g of 6-(phenylmethoxy)-1,6-
diazabicyclo[3,2,1J oct-3-en-7-one of molecular formula
is collected after purification (M = 230.27 g) .
The corresponding yield is 42%.
512 mg of 6-(phenylmethoxy)-I, 6-
diazabicyclo [3,2,1]octan-7-one of molecular formula
C3H16N2O2 is also collected (M = 232.27 g)
The corresponding yield is 9%.
Stage F
0.128g (0.551 mmole) of 6-(phenylmethoxY)-1,6-
diazabicyclo[3,2,l]octan-7-one obtained in Stage E is
dissolved in 1 ml of methanol.
0.035g of Pd/C •catalyst is added and the reaction
medium is placed under a hydrogen atmosphere at normal
pressure.
At the end of the reaction, the reaction medium is
filtered, rinsed with methanol and the solvent is
evaporated off under reduced pressure.
In this way 76 mg of 6-nydroxy-l, 6-
diazabicyclo[3,2,1)octan-7- one of molecular formula
CsHoNO;, ia obtained (M = 142.16 g) . The corresponding
yield is quantitative.
Stage G
75 mg (0.528 mmole) of the product obtained in Stage
F in 2 ml of pyridine is introduced into a flask placed
under an inert atmosphere.
235 mg of SOa-pyridine complex is added and the
mixture is left to react for 2 hours.
A few drops of water are then added and the solvent
is evaporated off under reduced pressure.
In this way 361 mg of crude product is obtained,
which is purified by chromatography on silica eluting
with a dichloromet.hane/ethanol mixture 6/4 containing
0.1% by weight of TEA.
In this way 32 mg of purified triethylammonium salt
of 6- (sulphoxy)-1,6-diazabicyclo[3,2,1]octan-7-one of
molecular formula CiiH15N3OsS is collected (M = 301.32 g) .
The corresponding yield is 17%.
Stage H
31 mg of the product obtained in Stage G is
dissolved in 0.5 ml of water containing 10% THF.
The solution obtained is passed over a column of
DOWEX 50WX8 resin in form Na+, eluting with water
containing 10% THF.
The product obtained is lyophilized in order to
obtain 20 mg of the expected sodium salt, of molecular
formula CgH9N205SNa (M = 221 g) .
The corresponding yield is 77%.
MS (negative electrospray) m/z: [M-H]' = 221
Example of pharmaceutical composition
A pharmaceutical composition for injection is
prepared containing:
Compound of Example 33c - 500 mg
Sterile aqueous excipient g.s.f. 5cm3









We Claim:
1. Azabicyclic heterocyclic compound of general formula (I), or one of its salts with a base or an acid:
(Formula Removed)
in which:
R1 represents a hydrogen atom, a COOH, CN, COOR, CONR6, R7, (CH2) n'R5 or
(Formula Removed)
R is chosen from the group constituted by an alkyl radical containing from 1 to 6 carbon atoms, optionally substituted by a pyridyl or carbamoyl radical, a -CH2-alkenyl radical containing at the most 3 to 9 carbon atoms, aryl containing from 6 to 10 carbon atoms or aralkyl containing from 7 to 11 carbon atoms, the ring of the aryl or aralkyl radical being optionally substituted by an OH, NH2, NO2, alkyl radical containing from 1 to 6 carbon atoms, an alkoxy radical containing from 1 to 6 carbon atoms or by one or more halogen atoms,
R6 and R7 being identical or different, are chosen from the group constituted by a hydrogen atom, an alkyl radical containing from 1 to 6 carbon atoms, an aryl radical containing from 6 to 10 carbon atoms and an aralkyl radical containing from 7 to 11 carbon atoms, optionally substituted by a carbamoyl, ureido or dimethylamino radical, and an alkyl radical containing from 1 to 6 carbon atoms substituted by a pyridyl radical, n' is equal to 1 or 2,
R5 is chosen from the group constituted by a COOH, CN, OH, NH2, CO-NR6R7, COOR, OR, OCOH, OCOR, OCOOR, OCONHR, OCONH2, NHR, NHCOH, NHCOR, NHSO2R, NH-COOR, NH-CO-NHR or NHCONH2, R, R6 and R7 being as defined above;
R2 represents a hydrogen atom or a (CH2) n'1R5 group, n'1 being equal to 0, 1 or 2 and R5 being as defined above;
R3 represents a hydrogen atom or an alkyl radical containing from 1 to 6 carbon atoms; A represents a bond between the two carbon carriers of R1 and R2 or a
(Formula Removed)
group, R4 representing a hydrogen atom or a (CH2)n'1R5 group, n'1
and R5 being as defined above, the dotted line representing an optional bond with one or
other of the carbon carriers of the substituents R1 and R2;
n is equal to 1 or 2;
X represents a divalent -C (O)-B- group attached to the nitrogen atom by the carbon
atom,
B represents a divalent -O- (CH2) n" - group attached to the carbonyl by the oxygen atom,
an -NR8 - (CH2) n" - or -NR8- 0- group attached to the carbonyl by the nitrogen atom, n"
is equal to 0 or 1 and Rs is chosen from the group constituted by a hydrogen atom, an OH,
R, OR, Y, OY, Y1, OY1, Y2, OY2, Y3, OCH2CH2SOmR, OSiRaRbRc radical, Ra, Rb and Rc
individually representing a linear or branched alkyl radical containing from 1 to 6 carbon
atoms or an aryl radical containing from 6 to 10 carbon atoms, R being as defined above
and m being equal to 0,1 or 2;
Y is chosen from the group constituted by the COH, COR, COOR, CONH2, CONHR,
CONHOH, CONHSO2R, CH2COOH, CH2COOR, CH2CONHOH, CH2CONHCN,
CH2tetrazole, protected CH2tetrazole, CH2SO3H, CH2SO2R, CH2PO(OR)2, CH2PO(OR)
(OH), CH2PO(R) (OH) and CH2PO(OH)2 radicals,
Y1 is chosen from the group constituted by the SO2R, SO2NHCOH, SO2NHCOR,
SO2NHCOOR, SO2NHCONHR, SO2NHCONH2 and SO3H radicals,
Y2 is chosen from the group constituted by the PO (OH)2, PO(OR)2, PO (OH) (OR) and
PO (OH) (R) radicals,
Y3 is chosen from the group constituted by the tetrazole radicals, tetrazole substituted by
the R radical, squarate, NH or NR tetrazole, NH or NR tetrazole substituted by the R
radical, NHSO2R and NRSO2R, R being as defined above;
it being understood that when n is equal to 1 and A represents
(Formula Removed)
group
in which R4 is a hydrogen atom and
either X represents the -C (O)-O-(CH2) n" group in which n" is 0 or 1,
- or X represents the -CO-NR8-(CH2) n" group in which n" is 1 and R8 is the isopropyl
group,
- or X represents the -CO-NR8-(CH2) n" group in which n" is 0 and R8 is hydrogen or
phenyl,
so all three of R1, R2 and R3 cannot represent a hydrogen atom at the same time.
2. Compound as claimed in claim 1, wherein that n is equal to 1.
3. Compound as claimed in claim 1 or claim 2, wherein A represents a
(Formula Removed)
group as defined in claim 1.
4. Compound as claimed in claim 3, wherein R4 represents a hydrogen atom.
5. Compound as claimed in one of claims 1 to 4, wherein X represents a divalent -CO-B-
group in which B represents a -NR8-(CH2) n" group - as defined in claim 1.
6. Compound as claimed in one of claims 1 to 5, wherein the R8 group is a Y1 or OY1 group,
in which Y1 is chosen from the SO2R, SO2NHCOR, SO2NHCOOR, SO2NHCONHR and
SO3H groups and R is as defined in claim 1.
7. The compounds of formula (I), as claimed in claim 1, the names of which follow:
trans-7-oxo-6-(sulphooxy)-l,6-diazabicyclo [3,2,1] octane-2-carboxamide and its base
salts, in particular sodium, trans-7-oxo-N-(phenylmethyl)-6-(sulphooxy)-l,6-diazabicyclo
[3,2,1] octane-2-carboxamide and its base salts, in particular sodium,
trans-7-oxo-N-(4-pyridinylmethyl)-6-(sulphooxy)-1,6-diazabicyclo [3,2,1 ] octane-2-
carboxamide and its base salts, in particular sodium,
trans-7-oxo-N-(3-pyridinylmethyl)-6-(sulphooxy)-1,6-diazabicyclo [3,2,1 ] octane-2-carboxamide and its base salts, in particular sodium,
trans-7-oxo-N-(2-amino 2-oxo ethyl)-6-(sulphooxy)-l ,6-diazabicyclo[3,2,1 ]octane-2-
carboxamide and its base salts, in particular sodium,
phenylmethyl trans-7-oxo-6-(sulphooxy)-l,6-diazabicyclo [3,2,1] octane-2-carboxylate.
8. Compound of general formula (I) as claimed in any of the preceding claims as and when
used for the preparation of medicaments as antibacterials.
9. Pharmaceutical compositions containing compound of general formula (I) as claimed in any of the preceding claims as active ingredient along with the excipients, sterile vehicle, wherein said composition comprises 1 to 70% by weight of the active ingredient.

Documents:

3239-DELNP-2005-Abstract-(10-12-2010).pdf

3239-DELNP-2005-Abstract-(18-03-2011).pdf

3239-delnp-2005-abstract.pdf

3239-DELNP-2005-Assignment-(13-09-2009).pdf

3239-DELNP-2005-Claims-(10-12-2010).pdf

3239-DELNP-2005-Claims-(18-03-2011).pdf

3239-delnp-2005-claims.pdf

3239-DELNP-2005-Correspondence Others-(01-06-2011).pdf

3239-DELNP-2005-Correspondence Others-(02-09-2011).pdf

3239-DELNP-2005-Correspondence Others-(15-11-2011).pdf

3239-DELNP-2005-Correspondence-Others-(04-01-2011).pdf

3239-DELNP-2005-Correspondence-Others-(10-12-2010).pdf

3239-DELNP-2005-Correspondence-Others-(13-09-2009).pdf

3239-DELNP-2005-Correspondence-Others-(18-03-2011).pdf

3239-delnp-2005-correspondence-others.pdf

3239-DELNP-2005-Description (Complete)-(10-12-2010).pdf

3239-delnp-2005-description (complete).pdf

3239-DELNP-2005-Form-1-(01-06-2011).pdf

3239-DELNP-2005-Form-1-(02-09-2011).pdf

3239-DELNP-2005-Form-1-(10-12-2010).pdf

3239-DELNP-2005-Form-1-(15-11-2011).pdf

3239-delnp-2005-form-1.pdf

3239-delnp-2005-form-18.pdf

3239-DELNP-2005-Form-2-(01-06-2011).pdf

3239-DELNP-2005-Form-2-(10-12-2010).pdf

3239-delnp-2005-form-2.pdf

3239-DELNP-2005-Form-3-(04-01-2011).pdf

3239-DELNP-2005-Form-3-(10-12-2010).pdf

3239-DELNP-2005-Form-3-(18-03-2011).pdf

3239-delnp-2005-form-3.pdf

3239-DELNP-2005-Form-5-(01-06-2011).pdf

3239-delnp-2005-form-5.pdf

3239-DELNP-2005-GPA-(10-12-2010).pdf

3239-DELNP-2005-GPA-(13-09-2009).pdf

3239-delnp-2005-gpa.pdf

3239-DELNP-2005-Petition 137-(10-12-2010).pdf


Patent Number 248632
Indian Patent Application Number 3239/DELNP/2005
PG Journal Number 30/2011
Publication Date 29-Jul-2011
Grant Date 29-Jul-2011
Date of Filing 21-Jul-2005
Name of Patentee NOVEXEL
Applicant Address 102,ROUTE DE NOISY,93230 ROMAINVILLE,FRANCE,
Inventors:
# Inventor's Name Inventor's Address
1 MAXIME LAMPILAS 60 RUE VEUVE AUBLET, 93230 ROAMINVILLE, FRANCE.
2 JOZSEF ASZODI 6470 N SILVERSMITH PI, 85750 TUCSON, ARIZONA, U.S.A.
3 DAVID ALAN ROWLANDS 8 ILE DE MIGNEAUX, 78300 POISSY, FRANCE.
4 CLAUDE FROMENTIN 16 AVENUE DE FLANDRE, 75019 PARIS, FRANCE.
PCT International Classification Number N/A
PCT International Application Number PCT/FR01/02418
PCT International Filing date 2001-07-28
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 00/10121 2000-08-01 France