Title of Invention

OPTICALLY ACTIVE AMINE DERIVATIVES AND PREPARATION PROCESS THEREFOR

Abstract A process for preparing an optically active am inoalcohol wherein an optically active 5-oxazolidinone derivative represented by a general formula (1): wherein R1 represents an unprotected or optionally protected side chain in a natural a-amino acid; and R2 represents optionally substituted aryl, optionally substituted alkyl or optionally substituted aralkyl, is reacted with an organometallic reagent represented by general formula (2): R3-M (2) wherein R3 represents optionally substituted aryl or optionally substituted heterocycle; M represents one selected from the group consisting of Li,MgX,ZnX, TiX3 and CuX; and X represents halogen, to form an optically active 5-hydroxyoxazolidine derivative represented by general formula (3): wherein R1, R2 and R3 are as defined above, which is then treated under acidic conditions to give an optically active aminoketone derivative represented by general formula (4): wherein Rl and R3 are as defined above; and R4 represents hydrogen or optionally substituted alkyloxycarbonyl, optionally substituted aryloxycarbonyl or optionally substituted aralkyloxycarbonyl as a protective group,which is then catalytically hydrogenated with a metal catalyst to stereoselectively provide an optically active amino alcohol derivative represented by general formula (5): wherein R1, R3 and R4 ire as defined above; provided (hat configuration of R1 attached to the asymmetric carbon at 4-poiition and the mbititntent represented by a nitrogen atom in the optically active 5-oxazolidinone represented by the general formula (1) is not changed throughout these reactions and relative configuration between the amino group and the hydroxy group in the optically active aminoalcohol represented by general formula (5) is an erythro configuration.
Full Text SPECIFICATION
TITLE OF THE INVENTION
Optically active amine derivatives and
preparation process therefor
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a process for
preparing an optically active aminoalcohol
derivative useful as a production intermediate
for medicines, agricultural agents and so forth;
for example, a process for preparing erythro-
(1R,2S)-p-hydroxynorephedrine. This invention
also relates to an optically active 5-
hydroxyoxazolidine derivative as an important
Intermediate for production of the above
optically active aminoalcohol derivative or a
number of other optically active amine
derivatives as well as a preparing process
therefor. For example, an optically active 5-
hydroxyoxazolidine derivative according to this
invention is also very useful as a production
Intermediate for an azole antibacterial agent. A
compound defined by general formula (1), (3) or
(4) which has an asymmetric carbon having R1 and
an amino substituent represents a R- or S-forra,
but not a racemic mixture of the R and S forms.
A compound defined by general formula (5) or (6)
having two adjacent asymmetric carbons which have
an amino and hydroxy substituents represents a R-
S or S-R form, but not an R-R or S-S form.
2. Description of the Prior Art
Recently, optically active compounds have
been increasingly needed in many applications
including medicines and agricultural agents. For
industrial applications, there has been strongly
needed for a convenient and Inexpensive process
for preparing an optically active material.
The following three processes are those
according to the prior art for preparing an
optically active aminoalcohol derivative relating
to this invention:
[1] A method, in which, after a racemic
compound of the desired compound is chemically
synthesized, it is then optically resolved via,
for example, a diastereomer salt to give the
desired optically active compound.
[2] A method, in which a technique for
chemical or biological asymmetric synthesis is
employed to give an optically active compound
from an optically inactive material.
[3] A method by a so-called "chiral pool
method", in which it starts from an optically
active material and the optical active compound
is obtained under prevention of racemization.
Regarding the process in [1] as n A method,
in which, after a racemic compound of the desired
compound is chemically synthesized, it is then
optically resolved via, for example, a
diastereomer salt to give the desired optically
active compound", an example may be a process
according to the prior art for preparing erythro-
(1R,2S)-p-hydroxynorephedrine within a category
of desired optically active aminoalcohol
derivatives in this invention, in which after a
racemate having the desired structure is first
chemically synthesized, its optical resolution is
carried out using an optically active carboxylic
acid such as D-tartaric acid (J. Med. Chem., 1977,
20, 7, 978) .
However, as long as using a preparation
process on the basis of optical resolution, it is
theoretically impossible to increase the yield
over 50 %, unless an enantiomer is recovered and
subject to a special treatment such as
racemization. Furthermore, an optically active
carboxylic acid and the other compounds required
in resolution are generally expensive, and it is
often necessary to repeat several times a process
such as recrystallization. In other words, the
optical resolution process requires an expensive
resolving agent(s) and a multiple-stage operation,
and is, therefore, industrially a high-cost
preparation process.
The process in [2] as " A method, in which a
technique for chemical or biological asymmetric
synthesis is employed to give an optically active
compound from an optically inactive material" has
been significantly advanced. As examples, there
are mentioned an asymmetric synthesis technique
based on a chemical synthesis including the uses
of asymmetric reduction catalysts or the other
agents (J. Am. Chem. Soc, 1980, 102, 7932) and
an asymmetric synthesis technique based on a
biotechnological synthesis using an enzyme or the
other agents (Japanese Patent Laid-open No. 62-
29998). Unfortunately, specificity for each
substrate is significantly involved in practical
production and thus the process cannot be applied
to all kinds of production. Furthermore, the
process cannot be always inexpensive when
requiring an expensive asymmetric catalyst. In
practice, for an optically active aminoalcohol
derivative as a desired compound in this
invention, there has been available no
industrially reasonable preparation processes on
the basis of chemical or biotechnological
technique as described above.
For the process in [3] as n A method by a so-
called "chiral pool method", in which it starts
from an optically active material and the optical
active compound is obtained under prevention of
racemization", there have been many problems to
be solved; for example, control of racemization
is difficult till now and furthermore, practical
production requires multiple steps. Regarding
the aminoalcohol derivatives as the desired
compounds in the present invention, no processes
have been reported till now, which is fully
satisfactory in the industrial viewpoint.
Regarding the prior art techniques for
production of the optically active aminoalcohol
derivatives, only the processes, which are
difficult in the industrial viewpoint and require
considerably high cost. Therefore, a novel,
inexpensive and more convenient processes for the
production are strongly desired.
Furthermore, only the following processes [4]
to [6] are known in the prior art for preparation
of an optically active 5-hydroxyoxazolidine
derivative as an important production
intermediate in the process of this invention:
[4] A method, in which (4S)-N-
(ethoxycarbonyl)-4 -(2-phenylethyl)-5-
oxazolidinone is reacted with 4-chloro-3-
methoxyphenyl magnesium bromide (WO 95/09155).
[5] A method, in which a 5-oxazolidinone
derivative is reacted with a halomethyl lithium
(WO 00/53571) .
[6] A method, in which a 5-oxazolidinone
derivative is reacted with
(trifluoromethyl)trimethylsilane (J. Org. Chem.
1998, 63 (15) , 5179) .
In the above [4], the compound as a starting
material is a special synthetic, non-naturally,
compound relating to amino-acids, which has a
phenylethyl group in its side chain. The
compound is, therefore, prepared by a multistep
reaction and it is difficult to obtain the
compound in general. In addition, it is not an
Inexpensive material in the viewpoint of its
production cost and the process maintains a
significant problem in raw material supply.
Furthermore, in the above process [4], the
process is extremely limited, as a single
production example, to that of the compound
having a 4-chloro-3-methoxyphenyl group at 5-
position in the oxazolidinone ring as a principal
structure, and the product is used only as a
starting material for a limited application to
produce a medicine (Sch39166). It cannot be said
that the preparation process as an example
described in [4] is a universal process, and that,
regarding an optically active 5-
hydroxyoxazolidine derivative, which is widely
useful, its preparation process has been fully
established.
Regarding the compounds described in above
[5] or [6], a special functional group such as a
haloalkyl group (for example, a chloromethyl
group) and a trifluoromethyl group is reacted at
the 5-position of the oxazolidine as a main
structure, but neither aryl nor hetero ring,
which are widely useful for an intermediate of a
medicine and agricultural agent are not included.
Although an optically active aminoalcohol
derivative having an aryl group or heterocycle
has been increasingly demanded in many
applications such as in the pharmaceutical and
agricultural fields, no general production
methods has been found in the prior art,
regarding the optically active 5-
hydroxyoxazolidine derivative having an aryl
group or heterocycle at the 5-position as its
important production intermediate.
As a known prior art for preparation of an
optically active aminoketone relating to this
invention, a process is known, which uses a
reaction where a carboxyl group in an N-protected
amino acid is converted into an acid chloride,
which then undergoes Friedel-Crafts reaction (J.
Am. Chem. Soc. 1981, 103, 6157). Acylation using
Friedel-Crafts reaction is, however, not
considered to be a general preparation method for
the reasons that the reaction causes racemization,
that the reaction is considerably restricted by a
structure to be acylated and that sometimes an
aminoketone produced cannot be isolated. Thus,
an industrially practical process is needed.
SUMMARY OF THE INVENTION
An objective of this invention is to provide
a stereoselectivel process for preparing an
optically active aminoalcohol derivative
represented by the general formula (5), which is
useful as a production intermediate for a
medicine or agricultural agent using a "readily
available and inexpensive natural a-amino acid"
as a starting material without racemization.
Another objective is to provide technique to
prepare the compound stably in a large scale with
an adequate optical purity and a lower cost in an
industrial viewpoint. Another objective is to
provide a novel optically active 5-
hydroxyoxazolidine derivative represented by
general formula (3) and a novel aminoketone
derivative represented by general formula (4) as
important intermediates for production of the
above optically active aminoalcohol derivative or
many optically active amine derivatives other
than the above compound as well as a novel
preparation process therefor.
After intensive investigation to achieve the
above objects, the present inventors have found a
process for preparing an optically active
aminoalcohol derivative represented by general
formula (5), as a very important production
intermediate for a medicine or agricultural agent,
from an inexpensive and easily available starting
material. Specifically, the present inventors
have newly found a process for preparing the
compound stereoselectively by a short process
while preventing racemization, using a "natural a
-L-amino acid which is industrially available
with a lower cost in a large amount" and a
"natural a-D-amino acid which is industrially
available with a lower cost in a large amount by
racemization and optical resolution of a natural
a-L-amino acid or selective assimilation
(Japanese Patent Laid-open No. 63-198997) as
starting materials.
In other words, the present inventors have
found an industrially very useful novel
preparation process for an optically active
aminoalcohol derivative, which is produced stably
even in a large scale production, as well as with
a higher optical purity and at a lower cost.
Furthermore, the present inventors have found
a novel optically active 5-hydroxyoxazolidine
derivative represented by general formula (3)
having an aryl group or heterocycle at the 5-
position in an oxazolidine ring, which is an
important intermediate for preparing the above
optically active aminoalcohol derivative and a
novel preparation process therefore; and a novel
aminoketone derivative represented by general
formula (4) and a novel preparation process
therefore.
Thus, the present invention has been
completed.
This invention includes the following
embodiments:
(I) A process for preparing an optically
active aminoalcohol derivative, wherein an
optically active 5-oxazolidinone derivative
represented by a general formula (1):

wherein R1 represents an unprotected or
optionally protected side chain in a natural a-
amino acid; and R2 represents optionally
substituted alkyl, optionally substituted aryl or
optionally substituted aralkyl;
is reacted with an organometallic reagent
represented by general formula (2):
R3-M (2)
wherein R3 represents optionally substituted
aryl or optionally substituted heterocycle; M
represents one selected from the group consisting
of Li, MgX, ZnX, TiX3 and CuX; and X represents
halogen;
to form an optically active 5-hydroxyoxazolidine
derivative represented by general formula (3):
wherein R1, R2 and R3 have the same meaning as
defined above;
which is then treated under acidic conditions to
give an optically active aminoketone derivative
represented by general formula (4):
wherein R1 and R3 have the same meanings as
defined above; and R4 represents hydrogen or
optionally substituted alkyloxycarbonyl,
optionally substituted aryloxycarbonyl or
optionally substituted aralkyloxycarbonyl as a
protective group;
which is then treated with a reducing agent or
catalytically hydrogenated with a metal catalyst
to stereoselectively provide an optically active
aminoalcohol derivative represented by general
formula (5):

wherein R1, R3 and R4 have the same meanings
as defined above; provided that configuration of
R1 attached to the asymmetric carbon at 4-
position and the substituent represented by a
nitrogen atom in the optically active 5-
oxazolidinone derivative represented by general
formula (1) is not changed throughout these
reactions and relative configuration between the
amino group and the hydroxy group in the
optically active aminoalcohol derivative
represented by general formula (5) is an erythro
configuration.
(II) A process for preparing an aminoalcohol
derivative, wherein an optically active 5-
oxazolidinone derivative represented by a general
formula (1):

wherein R1 represents an unprotected or
optionally protected side chain in a natural a-
13
amino acid; and R represents optionally
substituted alkyl, optionally substituted aryl or
optionally substituted aralkyl;
is reacted with an organometallic reagent
represented by general formula (2):
R3-M (2)
wherein R3 represents optionally substituted
aryl or optionally substituted heterocycle; M
represents one selected from the group consisting
of Li, MgX, ZnX, TiX3 and CuX; and X represents
halogen,
to form an optically active 5-hydroxyoxazolidlne
represented derivative by general formula (3):
wherein R1, R2 and R3 have the same meanings
as defined above;
which is then treated under acidic conditions to
give an optically active aminoketone derivative
represented by general formula (4):
wherein R1 and R3 have the same meanings as
defined above; and R4 represents hydrogen or
optionally substituted alkyloxycarbonyl,
optionally substituted aryloxycarbonyl or
optionally substituted aralkyloxycarbonyl as a
protective group;
which is then treated with a reducing agent or
catalytically hydrogenated with a metal catalyst
to provide an optically active aminoalcohol
derivative represented by general formula (5):

wherein R1, R3 and R4 have the same meanings
as defined above,
and then, when R4 is a protective group, the
amino group in the product is deprotected to give
an optically active aminoalcohol derivative
represented by general formula (6):

wherein R1 and R3 have the same meanings as
defined above;
provided that configuration of R1 attached to the
asymmetric carbon at 4-position and the
substituent represented by a nitrogen atom in the
optically active 5-oxazolidinone derivative
represented by general formula (1) is not changed
throughout these reactions and relative
configuration between the amino group and the
hydroxy group in the optically active
aminoalcohol derivative represented by general
formula (6) is an erythro configuration.
(III) The process for preparing an optically
active aminoalcohol derivative as described in
(I) or (II), wherein R1 represents methyl,
isopropyl, isobutyl, benzyl, hydroxymethyl,
benzyloxymethyl, phenylthiomethyl,
methylthiomethyl, alkyloxycarbonylmethyl or
alkyloxycarbonylethyl; R2 represents benzyl,
tert-butyl, methyl, ethyl, isopropyl or 9-
fluorenylmethyl.
(IV) The process for preparing an optically
active aminoalcohol as described in (I) or (II),
wherein R3 is represented by general formula (7):
wherein Y represents halogen; or by general
formula (8):
wherein R represents hydrogen, optionally
substituted alkyl, optionally substituted
cycloalkyl. optionally substituted aralkyl,
optionally substituted phenyl, optionally
substituted heterocycle or optionally substituted
heterocyclealkyl.
(V) The process for preparing an optically
active aminoalcohol as described in (I) or (II)
wherein R1 represents methyl; and R3 is
represented by general formula (8).
(VI) An optically active 5-hydroxyoxazolidine
derivative represented by general formula (3):
wherein R1 represents an unprotected side
chain or optionally protected side chain in a
natural a-amino acid; R2 represents optionally
substituted alkyl, optionally substituted aryl or
optionally substituted aralkyl; and R3 represents
optionally substituted aryl or optionally
substituted heterocycle.
(VII) The optically active 5-
hydroxyoxazolidine derivative as described in
(VI), wherein R1 represents methyl, isopropyl,
isobutyl, benzyl, hydroxymethyl, benzyloxymethyl,
phenylthiomethyl, methylthiomethyl,
alkyloxycarbonylmethyl or alkyloxycarbonylethyl.
(VIII) The optically active 5-
hydroxyoxazolidine derivative as described in
(VI) or (VII) wherein R2 represents benzyl, tert-
butyl, methyl, ethyl, isopropyl or 9-
fluorenylmethyl.
(IX) The optically active 5-
hydroxyoxazolidine as described in (VIII) wherein
R3 is represented by general formula (7):

¦
wherein Y represents halogen; or general
formula (8):
wherein R represents hydrogen, optionally
substituted alkyl, optionally substituted
cycloalkyl, optionally substituted aralkyl,
optionally substituted phenyl, optionally
substituted heterocycle or optionally substituted
heterocyclealkyl.
(X) The optically active 5-hydroxyoxazolidine
as described in (IX) wherein R1 is methyl.
(XI) A process for preparing an optically
active 5-hydroxyoxazolidine wherein an optically
active 5-oxazolidinone derivative represented by
general formula (1):
wherein R1 represents an unprotected side
chain or optionally protected side chain in a
natural a-amino acid; R2 represents optionally
substituted alkyl, optionally substituted aryl or
optionally substituted aralkyl;
is reacted with an organometallic reagent
represented by general formula (2):
R3-M (2)
wherein R3 represents optionally substituted
aryl or optionally substituted heterocycle; M is
one selected from the group consisting of Li, MgX,
ZnX, TiX3 and CuX; and X represents halogen;
to provide an optically active 5-
hydroxyoxazolidlne derivative represented by
general formula (3):
wherein R1, R2 and R3 have the same meanings
as defined above.
(XII) The process for preparing an optically
active 5-hydroxyoxazolidine derivative as
described in (XI) wherein R1 represents methyl,
isopropyl, isobutyl, benzyl, hydroxymethyl,
benzyloxymethyl, phenylthiomethyl,
methylthiomethyl, alkyloxycarbonylmethyl or
alkyloxycarbonylethyl.
(XIII) The process for preparing an optically
active 5-hydroxyoxazolidine derivative as
described in (XI) or (XII) wherein R2 represents
benzyl, tert-butyl, methyl, ethyl, isopropyl or
9-fluorenylmethyl.
(XIV) The process for preparing an optically
active 5-hydroxyoxazolidine derivative as
described in (XIII) wherein R3 is represented by
general formula (7):
wherein Y represents halogen; or general
formula (8):
wherein R represents hydrogen, optionally
substituted alkyl, optionally substituted
cycloalkyl, optionally substituted aralkyl,
optionally substituted phenyl, optionally
substituted heterocycle or optionally substituted
heterocyclealkyl.
(XV) The process for preparing an optically
active 5-hydroxyoxazolidine derivative as
described in (XIV) wherein R1 is methyl.
(XVI) The process for preparing an optically
active 5-hydroxyoxazolidine derivative as
described in (XI) or (XII) wherein M in general
formula (2) is MgX wherein X is as defined above.
(XVII) An aminoketone represented by general
formula (4a):
wherein Rla represents methyl; R4a represents
hydrogen, benzyloxycarbonyl, tert-butoxycarbonyl
or 9-fluorenylmethoxycarbonyl; R3a represents 4-
benzyloxyphenyl, 4-methoxyphenyl, 2,4-
difluorophenyl, 2,4-dichlorophenyl or 3-indolyl.
(XVIII) A process for preparing an
aminoketone derivative wherein a 5-
hydroxyoxazolidine derivative represented by
general formula (3):
wherein R1 represents an unprotected side
chain or optionally protected side chain in a
natural a-amino acid; R2 represents optionally
substituted alkyl, optionally substituted aryl or
optionally substituted aralkyl; and R3 represents
optionally substituted aryl or optionally
substituted heterocycle;
is treated under acidic conditions to form an
aminoketone derivative represented by general
formula (4):

wherein R1 and R3 are as defined above; R4
represents hydrogen or optionally substituted
alkyloxycarbonyl, optionally substituted
aryloxycarbonyl or optionally substituted
aralkyloxycarbonyl as a protective group.
(XIX) An optically active alcohol derivative
represented by general formula (5a):
wherein Rla represents methyl; R3b represents
4-benzyloxyphenyl; R4b represents
benzyloxycarbonyl; and configuration between the
amino group and the hydroxy group is erythro.
(XX) A process for preparing an optically
active aminoalcohol derivative wherein an
optically active aminoketone represented by
general formula (4b):
wherein R1 represents an unprotected side
chain or optionally protected side chain in a
natural a-amino acid; R4 represents hydrogen or
optionally substituted alkyloxycarbonyl,
optionally substituted aryloxycarbonyl or
optionally substituted aralkyloxycarbonyl as a
protective group; R3c is represented by general
formula (8):

R5 represents hydrogen, optionally substituted
alkyl, optionally substituted cycloalkyl,
optionally substituted aralkyl, optionally
substituted phenyl, optionally substituted
heterocycle or optionally substituted
heterocyclealkyl;
is treated with a reducing agent or catalytically
hydrogenated with a metal catalyst, to
stereoselectively form an optically active
aminoalcohol derivative represented by general
formula (5b):

wherein R1, R3c and R4 are as defined above;
provided that configuration of R1 attached to the
asymmetric carbon at the 2-position and the
substituent represented by a nitrogen atom in the
optically active aminoketone derivative
represented by general formula (4b) is not
changed throughout these reactions and relative
configuration between the amino group and the
hydroxy group in the optically active
aminoalcohol derivative represented by general
formula (5b) is erythro.
(XXI) A process for preparing an optically
active aminoalcohol wherein an optically active
aminoketone derivative represented by general
formula (4b):
wherein R1 represents an unprotected side
chain or optionally protected side chain in a
natural a-amino acid; R4 represents hydrogen or
optionally substituted alkyloxycarbonyl,
optionally substituted aryloxycarbonyl or
optionally substituted aralkyloxycarbonyl as a
protective group; R3c is represented by general
formula (8):
R5 represents hydrogen, optionally substituted
alkyl, optionally substituted cycloalkyl,
optionally substituted aralkyl, optionally
substituted phenyl, optionally substituted
heterocycle or optionally substituted
heterocyclealkyl;
is treated with a reducing agent or catalytically
hydrogenated with a metal catalyst, to
stereoselectively form an optically active
aminoalcohol derivative represented by general
formula (5b):

wherein R1, R3c and R4 are as defined above,
and when R4 is a protective group, the amino
group in the product is deprotected to give an
optically active aminoalcohol derivative
represented by general formula (6a):

wherein R1 and R3c are as defined above;
provided that configuration of R1 attached to the
asymmetric carbon at the 2-posltion and the
substituent represented by a nitrogen atom in the
optically active aminoketone derivative
represented by general formula (4b) is not
changed throughout these reactions and relative
configuration between the amino group and the
hydroxy group in the optically active
aminoalcohol derivative represented by general
formula (6a) is erythro.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
This invention will be detailed.
The term "unprotected side chain or
optionally protected side chain in a natural a-
amino acid" as used herein refers to a side chain
on an a-carbon such as alanine, valine, leucine,
isoleucine, serine, threonine, aspartic acid,
glutamic acid, asparagine, glutamine, lysine.
hydroxylysine, arginine, cysteine, cystine,
methionine, phenylalanine, tyrosine, tryptophan,
histidine and ornithine for, for example, an
"unprotected side chain in a natural a-amino
acid".
An "optionally protected side chain" may be a
side chain on an a-carbon in any of the above
natural a-amino acid in which a given functional
group is protected by a protective group. The
protective group may be any of those commonly
used in a process known by those skilled in the
art. For example, it may be a protective group
for an amino, thiol, hydroxy, phenol or carboxyl
group used in common preparation of an amino acid.
An "optionally substituted alkyl" means a
substituted alkyl at an optional position(s).
Examples of the alkyl group include methyl, ethyl,
isopropyl, tert-butyl, pentyl, hexyl, octyl,
decyl and allyl. Examples of the substituents
used include hydroxy; alkoxys such as methoxy,
benzyloxy and methoxyethoxy; phenoxy; nitro;
amino; amide; carboxyl; alkoxycarbonyl;
phenoxycarbonyl; and halogens such as fluorine,
chlorine, bromine and iodine.
An "optionally substituted aryl" means a
substituted aryl at an optional position(s).
Examples of the aryl group include phenyl,
naphthyl, anthracenyl, fluorenyl and
phenanthrenyl. Examples of a substituent(s) used
include alkyls such as methyl, tert-butyl and
benzyl; cycloalkyls such as cyclopropyl,
cyclopentyl and cyclohexyl; phenyl; hydroxy;
alkoxys such as methoxy, benzyloxy and
methoxyethoxy; phenoxy; nitro; amino; amide;
carboxyl; alkoxycarbonyl; phenoxycarbonyl; and
halogens such as fluorine, chlorine, bromine and
iodine.
An "optionally substituted aralkyl" means a
substituted aralkyl at an optional position(s).
Examples of the aralkyl group include benzyl,
naphthylmethyl, phenylethyl and 9-fluorenylmethyl.
Examples of a substituent(s) used include alkyls
such as methyl, tert-butyl and benzyl;
cycloalkyls such as cyclopropyl, cyclopentyl and
cyclohexyl; phenyl; hydroxy; alkoxys such as
methoxy, benzyloxy and methoxyethoxy; phenoxy;
nitro; amino; amide; carboxyl; alkoxycarbonyl;
phenoxycarbonyl; and halogens such as fluorine,
chlorine, bromine and iodine.
An "optionally substituted heterocycle" means
an substituted heterocycle at an optional
position(s) .
Examples of the heterocycle include
tetrahydropyranyl, tetrahydrofuranyl,
tetrahydrothienyl, piperidyl, morpholinyl,
piperazinyl, pyrrolyl, furyl, thienyl, pyridyl,
furfuryl, thenyl, pyridylmethyl, pyrimidyl,
pyrazyl, imidazoyl, imidazoylmethyl, indolyl,
indolylmethyl, isoquinolyl, quinolyl and
thiazolyl. Examples of a substituent used
Include alkyls such as methyl, tert-butyl and
benzyl; cycloalkyls such as cyclopropyl,
cyclopentyl and cyclohexyl; phenyl; hydroxy;
alkoxys such as methoxy, benzyloxy and
methoxyethoxy; phenoxy; nitro; amino; amide;
carboxyl; alkoxycarbonyl; phenoxycarbonyl; and
halogens such as fluorine, chlorine, bromine and
iodine.
A "heterocyclealkyl" in an optionally
substituted heterocyclealkyl means an alkyl
substituted with one or more heterocycles at one
or more positions, and the "heterocyclealkyl"
Itself is optionally substituted. Examples of
the heterocycle, the alkyl and the substituent
therefor may be those described above for an
"optionally substituted alkyl" and an "optionally
substituted heterocycle".
An "optionally substituted alkyloxycarbonyl"
means an optionally substituted alkyloxycarbonyl
at given one or more positions. Examples of the
alkyloxycarbonyl include methoxycarbonyl,
ethoxycarbonyl, isopropoxycarbonyl, tert-
butoxycarbonyl, pentyloxycarbonyl,
hexyloxycarbonyl, octyloxycarbonyl,
decyloxycarbonyl and allyloxycarbonyl. Examples
of the substituent(s) used include hydroxy;
alkoxys such as methoxy, benzyloxy and
methoxyethoxy; phenoxy; nitro; amino; amide;
carboxyl; alkoxycarbonyl; phenoxycarbonyl; and
halogens such as fluorine, chlorine, bromine and
iodine.
An "optionally substituted aryloxycarbonyl"
means an optionally substituted aryloxycarbonyl
at given one or more positions. Examples of the
aryloxycarbonyl include phenoxycarbonyl,
naphthyloxycarbonyl, anthracenyloxycarbonyl,
fluorenyloxycarbonyl and phenanthrenyloxycarbonyl.
Examples of the substituent(s) used include
alkyls and aralkyls such as methyl, tert-butyl
and benzyl; cycloalkyls derived from cyclopropane,
cyclopentane and cyclohexane (for example,
cyclopropyl, cyclopentyl and cyclohexyl); phenyl;
hydroxy; alkoxys such as methoxy, benzyloxy and
methoxyethoxy; phenoxy; nitro; amino; amide;
carboxyl; alkoxycarbonyl; phenoxycarbonyl; and
halogens such as fluorine, chlorine, bromine and
iodine.
An "optionally substituted
aralkyloxycarbonyl" means an optionally
substituted aralkyloxycarbonyl at given one or
more positions. Examples of the
aralkyloxycarbonyl include benzyloxycarbonyl,
naphthylmethyloxycarbonyl, phenylethyloxycarbonyl
and 9-fluorenylmethyloxycarbonyl. Examples of
the substituent(s) used include alkyls and
aralkyls; such as methyl, tert-butyl and benzyl;
cycloalkyls derived from cyclopropane,
cyclopentane and cyclohexane (for example,
cyclopropyl, cyclopentyl and cyclohexyl); phenyl;
hydroxy; alkoxys such as methoxy, benzyloxy and
methoxyethoxy; phenoxy; nitro; amino; amide;
carboxyl; alkoxycarbonyl; phenoxycarbonyl; and
halogens such as fluorine, chlorine, bromine and
iodine.
Each of the above optionally substituted
groups may have one or more substituents. When
it has a plurality of substituents, each
substituent may be independently selected from
those described above.
A "halogen" may be fluorine, chlorine,
bromine or iodine. Two "Ys" in general formula
(7) may be the same or different.
A "reducing agent" means a reagent which can
reduce a ketone moiety in the aminoketone
derivative represented by general formula (4)
into an alcohol moiety, including borane reagents
such as borane-tetrahydrofuran complex;
borohydride reagents such as sodium borohydride,
zinc borohydride and sodium trimethoxy
borohydride; alkylaluminum reagents such as
diisopropylaluminum hydride; aluminum hydride
reagents such as lithium aluminum hydride and
lithium trialkoxyaluminum hydride; silane
reagents such as trichlorosllane and
triethylsilane; sodium metal in liquid ammonia;
and magnesium metal in an alcohol.
"Catalytic hydrogenation with a metal
catalyst" means reduction of a ketone moiety in
the aminoketone derivative represented by general
formula (4) into an alcohol moiety by catalytic
hydrogenation in the presence of a metal catalyst.
Examples of the metal catalyst include nickel
catalysts such as Raney nickel, platinum
catalysts such as platinum oxide, palladium
catalysts such as palladium-carbon or rhodium
catalysts such as
chlorotris(triphenylphosphine)rhodium which is
also known as a Wilkinson catalyst.
"Erythro configuration" is a term indicating
a relative configuration of two adjacent
asymmetric carbons. For a compound represented
by general formula (5) or (6), when the amino and
the hydroxy groups as substituents are in the
same side in a Ficher projection formula, they
have erythro configuration.
Tables 1 to 21 show representative optically
active 5-hydroxyoxazolidine derivatives within
general formula (3); Tables 22 to 27 show
representative optically active aminoketone
derivatives within general formula (4); and
Tables 28 to 39 show representative optically
active aminoalcohol derivatives within general
formula (5) or (6), but this invention is not
limited to these exemplified compounds. In these
Tables, Ph is phenyl or phenylene; Me is methyl;
Boc is tert-butoxycarbonyl as a protective group.
There will be described representative
preparation processes according to this invention.
In a process for preparing a compound
represented by general formula (5) or (6) from a
compound represented by general formula (1) as a
starting material in this invention, the meaning
of the phrase "configuration of R1 attached to
the carbon at 4-position and the substituent
represented by a nitrogen atom in the optically
active 5-oxazolidinone is not changed throughout
these reactions and relative configuration
between the amino group and the hydroxy group in
the optically active aminoalcohol represented by
general formula (5) is erythro" may be described
in the following reaction equations 1 and 2 in
detail:
Reaction equation 1


General formula (12)
General formula (11) General formula (13)
Reaction equation 2

General formula (2)
ranAT.ai ^«^m„i= iia\ General formula (15)
General formula (14)

General formula (17)
General formula (16) General formula (18)
Specifically, as shown in reaction equation 1,
S-form optically active 5-oxazolidinone
derivative represented by general formula (9)
selectively gives a 1R,2S-optically active
aminoalcohol derivative of erythro configuration
represented by general formula (12) or (13).
Furthermore, as shown in reaction formula 2, an
R-form optically active 5-oxazolidinone
derivative represented by general formula (14)
can provide a IS,2R-optically active aminoalcohol
derivative of erythro configuration represented
by general formula (17) or (18).
Each preparation step will be detailed.
Preparation of an optically active 5-
oxazolldinone derivative represented by general
formula (1)
An optically active 5-oxazolidinone
derivative represented by general formula (1) can
be provided according to a well-known process
where an N-urethane protected compound derived
from a readily available and inexpensive natural
a-amino acid is reacted with paraformaldehyde in
the presence of a catalytic amount of an acid (J.
Am. Chem. Soc. 1957, 79, 5736).
Preparation of an organometallic reagent
represented by general formula (2)
An organometallic reagent represented by
general formula (2) may be easily prepared by a
well-known process; for example, oxidative
addition of a metal to a corresponding
halogenated compound or transmetallation with an
organometallic reagent.
In preparation of an organometallic reagent,
there is no limitation of the solvent, as long as
it is inert to the reaction, and, for example,
ethers such as tetrahydrofuran, diethyl ether,
dioxane and diglyme; toluene; and xylenes can be
used. Among these, preferred is tetrahydrofuran
alone or a mixture of tetrahydrofuran and another
solvent in the light of solubility of a substrate.
A reaction temperature may be generally -78 °C to
a boiling point of the solvent used. Furthermore,
an organometallic reagent, particularly a
Grignard reagent can be used to give good results
in a preparation process according to this
invention.
A Grignard reagent may be easily prepared by,
for example, adding dropwise a halogenated
compound represented by R3X where X is as defined
above, after initiating the reaction by adding a
catalytic amount of an initiator such as 1,2-
dibromoethane, ethyl bromide and iodine to
magnesium dispersed in a solvent.
Preparation of an optically active 5-
hydroxyoxazolidlne derivative represented by
general formula (3)
In a reaction of an optically active 5-
oxazolidinone derivative represented by general
formula (1) with an organometallic reagent
represented by general formula (2), a reaction
solvent may be, but not limited to, the same
solvent as that used in preparing the
organometallic reagent or a solvent mixture which
does not significantly affect the reaction. The
amount of the organometallic reagent is
preferably, but not limited to, an equal to a
five-fold moles, more preferably 1.0 to 2-fold
moles per one mole of the 5-oxazolidinone
derivative as a substrate. A reaction
temperature may be preferably, but not limited to,
an ambient temperature, room temperature, to -78°C.
In this reaction, there are no restrictions to
the order of adding the optically active 5-
oxazolidinone derivative and the organometallic
reagent. That is, the organometallic reagent may
be added to the optically active 5-oxazolidinone
derivative or vice versa. At the end of the
reaction, for obtaining the optically active 5-
hydroxyoxazolidine derivative produced, the
excessive organometallic reagent in the reaction
solution is decomposed using, for example, an
aqueous diluted hydrochloric acid, diluted
sulfuric acid, acetic acid, ammonium chloride,
citric acid or potassium hydrogen sulfate
solution and then the product can be isolated
from the resulting mixture by a common
separation/purification process such as
extraction, concentration, neutralization,
filtration, recrystallization and column
chromatography.
Furthermore, as described above, a Grignard
reagent can be used as an organometallic reagent
to give particularly good results in this
reaction. When using a Grignard reagent as an
organometallic reagent, the conditions including
a reaction solvent, the amount of the materials
used, a reaction temperature, the order of adding
the reagents, work-up of the reaction and
isolation and purification of the product are as
described for the above general preparation
process when using an organometallic reagent.
The optically active 5-oxazolidine derivative
prepared as described above is generally obtained
as a mixture of two diastereomers because both R-
and S-forras are formed for configuration at the
5-position in the oxazolidine. Depending on the
conditions, high performance liquid
chromatography or nuclear magnetic spectrometry
may be performed to determine a diastereomer
ratio. A diastereomer ratio may vary depending
on the reaction conditions and properties of the
product, and the diastereomers may be
individually isolated or may be obtained as a
mixture. However, a diastereomer mixture may be
converted into an optically active aminoketone
derivative represented by the same general
formula (4) by, for example, treatment with an
acid described below. It is, therefore, not
necessary to separate the diastereomers as
production intermediates in the light of a
production cost.
Preparation of an optically active aminoketone
derivative represented by general formula (4)
A process for converting an optically active
5-hydroxyoxazolldine derivative into an optically
active aminoketone derivative represented by
general formula (4) under an acidic condition can
be generally conducted in a solvent. Examples of
a solvent which can be used include, but not
limited to, alcohols such as methanol and
ethanol; acetonitrile; tetrahydrofuran; benzene;
toluene; and water. These solvents may be used
alone or in combination of two or more in a given
mixing ratio. Examples of an acid which can be
used include, but not limited to, inorganic acids
such as hydrochloric acid, sulfuric acid and
perchloric acid; organic acids such as p-
toluenesulfonic acid and methanesulfonic acid;
acidic resins such as Amberlite IR-120 and
Amberlist; and Lewis acids such as boron
trifluoride and zinc chloride. The amount of an
acid used is an equal to 30-fold moles,
preferably 1.5- to 10-fold moles per one mole of
the optically active 5-hydroxyoxazolidine
derivative. When using a resin, its amount is 5
to 200 % by weight, preferably 10 to 100 % by
weight. A reaction temperature may be -30 °C to a
boiling point of a solvent, particularly 0 CC to
100 °C. An aminoketone derivative may be easily
isolated from a reaction mixture by a common
separation/purification method such as extraction,
concentration, neutralization, filtration,
recrystallization and column chromatography.
Preparation of an optically active amlnoalcohol
derivative represented by general formula (5)
A process for reducing an aminoketone
derivative represented by general formula (4)
with a reducing agent to give an optically active
alcohol derivative represented by general formula
(5) is generally conducted in a solvent.
Examples of the solvent, which can be used
include, but not limited to, methanol, ethanol,
2-propanol, tetrahydrofuran and water. These
solvents may be used alone or in combination of
two or more in a given mixing ratio.
Examples of the reducing agent include borane
reagents such as borane-tetrahydrofuran complex;
borohydride reagents such as sodium borohydride,
zinc borohydride and sodium
trimethoxyborohydride; alkylaluminum reagents
such as diisopropylaluminum hydride; aluminum
hydride reagents such as lithium aluminum hydride
and lithium trialkoxyaluminum hydride; silane
reagents such as trichlorosilane and
triethylsilane; sodium metal in liquid ammonia;
and magnesium metal in an alcohol. In particular,
borohydride reagents such as sodium borohydride,
zinc borohydride and sodium trimethoxyborohydride
are suitable.
The amount of the reducing agent may be an
equal to 10-fold moles per one mole of a material
to be reduced. A reaction temperature is
appropriately selected within the range of -78 °C
to a boiling point of the solvent, preferably -40
°C to 80 °C.
Alternatively, an aminoketone derivative
represented by general formula (4) may be
catalytically hydrogenated in the presence of an
appropriate metal catalyst in an appropriate
solvent under an atmosphere of hydrogen, to give
an optically active aminoalcohol derivative
represented by general formula (5). A hydrogen
pressure may be, but not limited to, an ambient
pressure to 3 MPa, preferably 0.3 MPa to 1 MPa.
Any solvent may be used as long as it does not
adversely affect the reaction; for example,
methanol, ethanol, n-propanol, 2-propanol, n-
butanol and water. These solvents may be used
alone or in combination of two or more in a given
mixing ratio. The amount of a solvent is 1 to 50
parts (wt/wt), preferably 3 to 20 parts per one
part of the compounds.
Examples of the metal catalyst which can be
used include nickel catalysts such as Raney
nickel; platinum catalysts such as platinum-
alumina, platinum-carbon and platinum oxide;
palladium catalysts such as palladium-alumina,
palladium-carbon and palladium hydroxide-carbon;
ruthenium catalysts such as ruthenium oxide; and
rhodium catalysts such as
chlorotrls(triphenylphosphine)rhodium which is
also known as a Wilkinson catalyst, more suitably
palladium catalysts. A reaction temperature may
be, but not limited to, -20 to 200 °C, preferably
0 to 60 °C.
A process for deprotecting a compound
represented by general formula (5) having a
protected amino group as appropriate to give a
free amine derivative represented by general
formula (6) may be conducted by, for example,
hydrolysis using an acid or base. Examples of an
acid, which can be used include, but not limited
to, inorganic acids such as hydrochloric acid,
sulfuric acid and hydrobromic acid; and organic
acids such as trifluoromethanesulfonic acid,
trifluoroacetic acid, p-toluenesulfonic acid and
acetic acid. Examples of a base, which can be
used, include inorganic bases such as sodium
hydrogen carbonate, potassium carbonate, lithium
hydroxide and sodium hydroxide; and organic bases
such as triethylamine, morpholine,
tetrabutylammonium fluoride and
tetraethylammonium hydroxide.
An optically active aminoalcohol derivative
represented by general formula (5) or (6) thus
obtained may be isolated as crystals of the free
amine or as a salt by adding, if necessary, an
appropriate acid. A diastereomeric purity or
optical purity of the compound may be improved by
recrystallization.
When the compound is obtained as crystals of
a free amine, any solvent which is suitable to
such purification can be used for crystallization.
Examples of such a solvent include alcohols such
as methanol, ethanol, n-propanol and 2-propanol;
esters such as ethyl acetate and butyl acetate;
halogenated solvents such as chloroform and
methylene chloride; ethers such as 1,4-dioxane
and tetrahydrofuran; water; acetonitrile; 2-
butanone; and toluene, which can be used alone or
in combination of two or more.
Any acid which can form a crystalline salt
suitable for purification may be used for salt
formation. Examples of such an acid include
inorganic acids such as hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid,
sulfuric acid and phosphoric acid; and organic
acids such as acetic acid, tartaric acid, citric
acid, fumaric acid, methanesulfonate and p-
toluenesulfonate.
Any solvent which is suitable for
purification may be used for recrystallization.
Examples of such solvent include alcohols such as
methanol, ethanol, n-propanol and 2-propanol;
esters such as ethyl acetate and butyl acetate;
halogenated solvents such as chloroform and
methylene chloride; ethers such as 1,4-dioxane
and tetrahydrofuran; water; acetonitrile; 2-
butanone; and toluene, which may be used alone or
in combination of two or more.
A salt purified by recrystallization may be
treated with an alkaline solution by a common
procedure to be isolated as a free amine.
Examples
This invention will be more specifically
described with reference to, but not limited to.
Reference Examples and Examples.
Reference Example 1
Preparation of (4S)-N-benzyloxycarbonyl-4-methyl-
5-oxazolidinone
Benzyloxycarbonyl-L-alanine (19.3 g),
paraformaldehyde (6.56 g) and p-toluenesulfonic
acid monohydrate (0.17 g) were suspended in
toluene (190 mL), and the mixture was heated at
reflux while removing water produced. At the end
of the reaction, the reaction mixture was cooled
to room temperature, washed with saturated
aqueous sodium hydrogen carbonate solution and
then saturated saline. The toluene solution was
dried over anhydrous sodium sulfate. The solvent
was evaporated under a reduced pressure, the
resulting crystals were filtrated to give the
title compound (19.0 g) as white crystals in an
yield of 93 %.
Melting point: 91-93T:
lK NMR (CDC13, 400 MHz) 6 ppm: 1.54 (d, 3H, J=6.4
Hz), 4.29-4.31 (m, 1H), 5.18 (s, 2H), 5.28-5.29
(m, 1H), 5.47 (br, 1H), 7.33-7.41 (m, 5H);
IR (KBr) vmax 1778, 1685 cm"1.
Reference Example 2
Preparation of 4-benzyloxybromobenzene
p-Bromophenol (25.0 g) and anhydrous
potassium carbonate (20.0 g) were suspended in
N,N-dimethylformamide (250 mL). To the
suspension was added dropwise benzyl chloride
(20.2 g) at room temperature. After heating at
95 to 100 °C for one hour, the reaction mixture
was cooled to room temperature and water (400 mL)
was added. After extraction with ethyl acetate,
the organic layer was washed with saturated
saline and dried over anhydrous sodium sulfate.
The solvent was evaporated under a reduced
pressure to give the title compound (34.3 g) as
milk-white crystals in a yield of 90%.
Melting point: 55-57 °C ;
XH-NMR (CDC13, 400 MHz) 6 ppm: 5.04 (s, 2H), 6.83-
6.87 (m, 2H), 7.31-7.43 (m, 2H).
Example 1
Preparation of (4S)-N-benzyloxycarbonyl-5-(4-
benzyloxyphenyl)-4-methyl-5-
hydroxyoxazolidlne(Compound No.: 1001)
Preparation of a Grignard reagent
To magnesium metal (1.16 g) in anhydrous
tetrahydrofuran (20 mL) was added ethyl bromide
(0.26 g) under nitrogen atmosphere, and the
mixture was stirred at room temperature for 1
hour. At reflux of the solvent, a solution of 4-
benzyloxybromobenzene (10.5 g) prepared in
Reference Example 2 dissolved in anhydrous
tetrahydrofuran (20 mL) was added dropwise over
about 1 hour. At the end of addition, the
mixture was stirred at reflux for further 40 min
to prepare a Grignard reagent.
Grignard reaction
In anhydrous tetrahydrofuran (40 mL) was
dissolved (4S)-N-benzyloxycarbonyl-4-methyl-5-
oxazolidinone (7.84 g) prepared in Reference
Example 1 and the solution was cooled to -20 °C.
To the solution under nitrogen atmosphere was
added dropwise the Grignard reagent prepared
above while maintaining the internal temperature
at -20 °C. At the end of addition, the mixture
was stirred for further 1 hour at that
temperature, and then treated with an aqueous 5 %
hydrochloric acid solution. The solution was
warmed to room temperature and extracted with
ethyl acetate. The organic layer was dried over
anhydrous sodium sulfate. The solution was
concentrated in vacuo. The residue was purified
by silica column chromatography (eluent:
chloroform) to give the title compound (9.85 g)
as a diastereomer mixture as white crystals in a
yield of 71 %.
Melting point: 83-86^.
^-NMR (CDC13, 400 MHz) indicated that a
diastereomer ratio was about 2:1.
Major diastereomer product
XH-NMR (CDCI3, 400 MHz) 5 ppm: 1.47 (d, 3H, J=7.3
Hz), 3.81-3.84 (m, 1H), 4.79-5.07 (m, 2H), 5.14
(s, 2H), 5.14 (d, 1H, J=8.4 Hz), 5.20 (d, 1H,
J=8.4 Hz), 5.87 (q, 1H, J=7.3 Hz), 7.02 (d, 2H,
J=8.8 Hz), 7.23-7.44 (m, 10H), 8.01 (d, 2H, J=8.8
Hz)
Sub diastereomer product
XH-NMR (CDCI3, 400 MHz) 6 ppm: 1.49 (d, 3H, J=7.3
Hz), 3.60-3.70 (m, 1H), 4.79-5.15 (m, 4H), 5.13
(S, 2H), 5.57 (q, 1H, J=7.3 Hz), 6.91 (d, 2H,
J=8.8 Hz), 7.23-7.44 (m, 10H), 7.83 (d, 2H, J=8.8
Hz) ;
IR(neat) vraax 3436, 3033, 1671, 1603, 1508 cm"1.
Example 2
Preparation of (2S)- 2-(benzyloxycarbonyl)amino-l-
(4-benzyloxyphenyl)-1-propanone (Compound No.:
22001)
In toluene (50 mL) was dissolved (4S)-N-
benzyloxycarbonyl-5-(4-benzyloxyphenyl)-4-methyl-
5-hydroxyoxazolldine (3.8 g) prepared in Example
1. After adding Amberlist (300 mg), the mixture
was reacted at room temperature. At the end of
the reaction, Amberlist was filtered off, the
filtrate was concentrated in vacuo. The residue
was purified by silica column chromatography
(eluent: chloroform) to give the title compound
(3.1 g) as pale yellow crystals in a yield of
88 % .
Melting point: 89-91 °C ;
^-NMR (CDC13, 400 MHz) 6ppm: 1.43 (d, 3H, J=6.83
Hz), 5.13 (s, 2H), 5.15 (s, 2H), 5.28-5.31 (m,
1H), 5.88 (br, 1H), 7.03 (d, 2H, J=9.0 Hz), 7.31-
7.44 (m, 10H), 7.96 (d, 2H, J=9.0 Hz);
IR (KBr) vmax 3374, 1712, 1690 cm"1;
Optical purity: 93 %ee
HPLC analysis conditions;
Column: Daicel Chiral-Pak AD-RH (4.6 mm(J) x
150 mm);
Mobile phase: methanol;
Flow rate: 0.5 mL/min;
Wavelength: 2 54 nm;
Temperature: room temperature;
tR: (2S-form); 19.8 rain;
(2R-form); 24.3 min.
Example 3
Preparation of (2S)-2-(benzyloxycarbonyl)amino-1
(4-benzyloxyphenyl)-1-propanone (Compound No.:
22001)
Preparation of a Grlgnard reagent
To anhydrous tetrahydrofuran (15 mL) under
nitrogen atmosphere were added magnesium metal
(1.16 g) and ethyl bromide (0.05 g), and the
mixture was stirred at room temperature for 30
min. To the mixture at reflux of the solvent was
added dropwise a solution of 4-
benzyloxybromobenzene (10.92 g) prepared in
Reference Example 2 dissolved in anhydrous
tetrahydrofuran (10 mL) over about 1 hour. At
the end of addition, the mixture was stirred at
reflux for further 30 min to prepare a Grignard
reagent.
Grignard reaction
In anhydrous tetrahydrofuran (26 mL) was
dissolved (4S)-N-benzyloxycarbonyl-4-methyl-5 -
oxazolidinone (6*. 97 g) prepared in Reference
Example 1 and the mixture was cooled to -20 °C.
To the solution under nitrogen atmosphere was
added dropwise the Grignard reagent prepared
above while maintaining the internal temperature
at -20 °C. At the end of addition, the mixture
was stirred for further 1 hour at that
temperature.
Deformylation
To the mixture was added a 6.5 % aqueous
hydrochloric acid solution, and the reaction was
stirred at 35 to 40 °C for 6 hours. The aqueous
layer was discarded after separation. Then to
the organic layer was added a 5 % aqueous
hydrochloric acid solution, and the mixture was
stirred at 45 to 50 °C for 4 hours. The reaction
mixture was extracted with toluene and the
organic layer was washed with water. The
solution was concentrated in vacuo, 2-propanol
(70 g) was added, and then the mixture was
stirred at room temperature for 6 hours. The
reaction mixture was cooled to 0 to 5 °C to
precipitate crystals, which were then filtered to
give the title compound (8.61 g) as pale yellow
crystals in a yield of 80 %.
Melting point: 89-91 °C;
XH-NMR (CDC13, 400 MHz) 6 ppm: 1.43 (d, 3H, J=6.8
Hz), 5.13 (s, 2H), 5.15 (s, 2H), 5.28-5.31 (m,
1H), 5.88 (br, 1H), 7.03 (d, 2H, J=9.0 Hz), 7.31-
7.44 (m, 10H), 7.96 (d, 2H, J=9.3 Hz);
IR (KBr) vraax 3374, 1712, 1690 cm"1;
Specific rotation: [a]D24 = + 26° (01.00, CHC13)
Optical purity: 99 %ee (analytical conditions are
as described in Example 2).
Example 4
Preparation of erythro-(IR,2S)-p-
hydroxynorephedrine (Compound No.: 28001)
A mixture of (2S)-2-(benzyloxycarbonyl)amino-
1-(4-benzyloxyphenyl)-1-propanone (4.8 g)
prepared in Example 2 or 3, methanol (100 mL) ,
water (50 mL) and 5% Pd/C (50% water-containing)
(1.0 g) was stirred below 20 °C under hydrogen
atmosphere (0.5 MPa) for 28 hours. The catalyst
was filtered off, the filtrate was concentrated
in vacuo, and the residue was slushed with 2-
propanol to give the title compound (1.44 g) as
white crystals in a yield of 70 %.
Melting point: 163-165 °C ;
XH-NMR (DMSO-d6, 400 MHz) 5 ppm: 0.85 (d, 3H,
J=6.3 Hz), 2.77-2.83 (m, 1H), 4.17 (d, 1H, J = 5.3
Hz), 4.96 (brs, 1H), 6.70 (d, 2H, J=8.3 Hz), 7.09
(d, 2H, J=8.3 Hz), 8.31 (s, 1H);
IR (KBr) Vmax 3470, 1593, 1484, 1242 cm"1;
Specific rotation: [a]D24 = -18 • (C=0.2, MeOH);
Erythro : threo = 99.5 : 0.5;
HPLC analysis conditions:
Column: YMC TMS A-102 (6 mm x 150 mm)
Mobile phase: acetonitrile : water = 3 : 97
(each of NaH2P04 and Na2HP04 is 10 mM, pH 6.9);
Detection wavelength: 275 nm;
Flow rate: 0.5 mL/min;
Column temperature: 40 °C;
tR: erythro form; 6.9 min;
threo form; 7.1 min;
Optical purity: 99 %ee
HPLC analysis conditions:
Column: Daicel Crown-Pak CR(-) (4 mm x 150
mm) ;
Mobile phase: HC104 aq (pH 3.5);
Detection wavelength: 275 nm;
Flow rate: 0.1 mL/min;
Column temperature: 2 5*0.
Example 5
Preparation of erythro-(1R,2S)-2-
(benzyloxycarbonyl)amino-1-(4-benzyloxyphenyl)-1-
propanol (Compound No.: 36002)
To methanol (25 mL) was added sodium
borohydride (0.32 g), and the mixture was cooled
to 0 to 5 °C. To the solution was added (2S)-2-
(benzyloxycarbony1)amino-1-(4 -benzyloxyphenyl)-1-
propanone (2.00 g) prepared in Example 2 or 3,
and the mixture was stirred at room temperature.
Precipitated crystals were filtered, washed with
methanol and then dried to give the title
compound (1.39 g) as white crystals in a yield of
69 %.
Melting point: 85-91 °C ;
*H-NMR (DMSO-d6, 400 MHz) 6 ppm: 0.99 (d, 3H,
J=6.59 Hz), 3.61-3.62 (m, 1H), 4.46-4.49 (m, 1H),
4.95 (s, 2H), 5.07 (s, 2H), 5.23 (m, 1H), 6.93 (d,
2H, J=7.08), 7.19-7.40 (m, 10H), 7.44 (d, 2H,
J=7.08), 8.30 (s, 1H);
IR (KBr) vraax 3334, 1690 cm"1.
Example 6
Preparation of erythro-(IR,2S)-p-
hydroxynorephedrine (Compound No.; 28001)
In methanol was dissolved erythro-(1R,2S)-2-
(benzyloxycarbony1)amino-1-(4-benzyloxyphenyl) -1-
propanol (1.39 g) prepared in Example 5, and the
solution was stirred with 5 % Pd/C (50% water-
containing) (0.03 g) under hydrogen atmosphere
(ambient pressure) at room temperature for 2
hours. After removing the catalyst by filtration,
the filtrate was concentrated in vacuo. The
residue was crystallized with 2-propanol to give
the title compound (0.65 g) as white crystals in
a yield of 75 %.
Melting point: 163-165 °C ;
XH-NMR (DMSO-d6, 400 MHz) 6 ppm: 0.85 (d, 3H,
J=6.3 Hz), 2.77-2.83 (m, 1H), 4.17 (d, 1H, J=5.3
Hz), 4.96 (brs, 1H), 6.70 (d, 2H, J=8.3 Hz), 7.09
(d, 2H, J=8.3 Hz), 8.31 (s, 1H);
IR (KBr) vmax 3470, 1593, 1484, 1242 cm"1;
Specific rotation: [a]D24 = -18 ° (C=0.2, MeOH);
Erythro : threo = 97.5 : 2.5 (analysis conditions
are as described in Example 4);
Optical purity: 99 %ee (analysis conditions are
as described in Example 4).
Reference Example 3
Preparation of (4S)-N-tert-butoxycarbonyl-4-
methyl-5-oxazolldinone
In toluene (250 mL) were suspended tert-
butoxycarbonyl-L-alanine (18.9g),
paraformaldehyde (6.70 g) and p-toluenesulfonic
acid monohydrate (0.19 g), and the suspension was
heated at reflux while removing water produced.
At the end of the reaction, the mixture was
cooled to room temperature, washed with saturated
aqueous sodium hydrogen carbonate solution and
saturated saline. The toluene solution was dried
over anhydrous sodium sulfate. The solvent was
evaporated under a reduced pressure, and the
crystals obtained were filtered to give the title
compound (14.2 g) white crystals in a yield of
71 %.
Melting point: 66-68 °C ;
1H NMR (CDCI3, 400 MHz) 5 ppm: 1.49 (s, 9H), 1.52
(d, 2H, J=7.1 Hz), 4.23 (br, 1H), 5.23 (br, 1H),
5.41 (br, 1H);
IR (KBr) vraax 1798, 1698 cm"1.
Example 7
Preparation of (4S)- 5-(4-benzyloxyphenyl)-N-tert
butoxycarbonyl-4-methyl-5-hydroxyoxazolidlne
(Compound No.: 1015)
In anhydrous tetrahydrofuran (40 mL) was
dissolved (4S)-N-tert-butoxycarbonyl-4-methyl-5-
oxazolidinone (6.64 g) prepared in Reference
Example 3, and the solution was cooled to -20 °C.
To the solution under nitrogen atmosphere was
added dropwise a Grignard reagent prepared as
described in Example 1 while maintaining the
internal temperature at -20 °C. At the end of
addition, the mixture was stirred at that
temperature for 1 hour and then treated with a
5 % aqueous hydrochloric acid solution. The
solution was warmed to room temperature and
extracted with ethyl acetate. The organic layer
was dried over anhydrous sodium sulfate. The
solution was concentrated in vacuo and the
residue was purified by silica column
chromatography (eluent: chloroform) to give the
title compound (10.2 g) as a diastereomer mixture
as a pale yellow syrup in an yield of 80 %.
^-NMR (CDC13, 400 MHz) 6 ppm: 1.35-1.38 (m, 3H),
1.44-1.49 (m. 9H), 4.90-5.85 (m, 5H), 6.99-7.03
(m, 2H), 7.35-7.44 (m, 5H), 7.80-8.00 (m, 2H);
IR (KBr) vraax 3422, 1683 cm"1.
Reference Example 4
Preparation of (4S)-N-benzyloxycarbonyl-4 -
isopropyl-5-oxazolldlnone
In toluene (250 mL) were suspended
benzyloxycarbonyl-L-valine (25.1 g),
paraformaldehyde (6.70 g) and p-toluenesulfonic
acid monohydrate (0.19 g), and the suspension was
heated at reflux while removing water produced.
At the end of the reaction, the mixture was
cooled to room temperature, washed with saturated
aqueous sodium hydrogen carbonate solution and
saturated saline. The toluene solution was dried
over anhydrous sodium sulfate. The solvent was
evaporated under a reduced pressure to give the
title compound (23.7 g) as colorless transparent
syrup in an yield of 90 %.
1H-NMR (CDC13, 400 MHz) 5 ppm: 1.00 (d, 3H, J=6.6
Hz), 1.07 (d, 3H, J=6.6 Hz), 2.30-2.40 (m, 1H),
4.22 (bs, 1H), 5.15-5.22 (m, 3H), 5.56 (bs, 1H),
7.15-7.40 (m, 5H);
IR (KBr) vmnx 1798, 1698 cm"1.
Example 8
Preparation of (4S)- 5-(4-benzyloxyphenyl)-N-
benzyloxycarbonyl-4-isopropyl-5-
hydroxyoxazolidine (Compound No.; 2001)
In anhydrous tetrahydrofuran (22 mL) was
dissolved (4S)-benzyloxycarbonyl-4-isopropyl-5-
oxazolidinone (5.20 g) prepared in Reference
Example 4, and the solution was cooled to -20 °C.
To the solution under nitrogen atmosphere was
added dropwise a Grignard reagent prepared as
described in Example 1 while maintaining the
internal temperature at -10 to 20 °C. At the end
of addition, the mixture was stirred at that
temperature for 1 hour and then treated with a
12.5 % aqueous hydrochloric acid solution. The
solution was warmed to room temperature,
extracted with toluene. The organic layer was
dried over anhydrous magnesium sulfate. The
solution was concentrated in vacuo. The residue
was purified by silica column chromatography
(eluent: hexane/ethyl acetate = 2/1) to give the
title compound (4.72 g) as a diastereomer mixture
as a pale yellow syrup in an yield of 53 %.
XH-NMR (CDCI3, 400 MHz) indicated that a
diastereomer ratio was about 1.9 : 1.
Major diastereomer product
XH-NMR (CDCI3, 400 MHz) 5 ppm: 0.85 (d, 3H, J = 6.6
Hz), 0.98 (d, 2H, J=6.6). 2.29-2.40 (m, 1H), 3.29
(m, 1H), 4.79 (m, 1H), 5.10-5.50 (m, 6H), 7.02 (d,
2H, J = 8.7 Hz), 7.28-7.45 (m, 10H), 8.11 (d, 2H,
J=8.7 Hz);
Sub diastereomer product
XH-NMR (CDCI3. 400 MHz) 6 ppm: 0.83 (d, 3H, J=6.2
Hz), 1.00 (d, 2H, J=6.2), 2.29-2.40 (m, 1H), 3.55
(m, 1H), 4.79 (m, 1H), 5.10-5.50 (m, 6H), 6.81 (d,
2H, J=9.0 Hz), 7.28-7.45 (m, 10H), 7.85 (d, 2H,
J=9.0 Hz);
IR (KBr) vnax 3422, 1683 cm"1.
Example 9
Preparation of (2S)-2-(benzyloxycarbonyl)amino-1-
(4-benzyloxyphenyl)-3-methyl-l-butanone (Compound
No.: 23001)
In tetrahydrofuran (4 mL) was dissolved (4S)-
N-benzyloxycarbonyl-5-(4-benzyloxyphenyl)-4-
isopropyl-5-hydroxyoxazolidine (1.38 g) prepared
in Example 8, and to the solution were added
water (5 mL) and cone, hydrochloric acid (2 mL).
The mixture was stirred at room temperature for
24 hours. The reaction was diluted with toluene
and the aqueous layer was discarded. The organic
layer was washed with water three times. The
organic layer was dried over anhydrous magnesium
sulfate and then concentrated in vacuo. The
residue was purified by silica column
chromatography (eluent: hexane/ethyl acetate =
2/1) to give the title compound (466 mg) as pale
yellow crystals in a yield of 36 %.
Melting point: 75-77 °C;
^-NMR (CDC13. 400 MHz) 6 ppm: 0.76 (d, 3H. J=6.8
Hz), 1.04 (d, 3H, J=6.8 Hz), 2.16 (m, 1H), 5.11
(s, 1H), 5.14 (s, 1H), 5.24 (dd, 1H, J=8.8,4 Hz),
5.70 (d, 1H, J=8.8 Hz), 7.03 (d, 2H, J=8.8 Hz),
7.30-7.45 (m, 10H), 7.96 (d, 2H, J=8.8 Hz);
IR (KBr) vmax 3422, 1683 cm"1.
Example 10
Preparation of (4S)-N-benzyloxycarbonyl-5 -(4-
methoxyphenyl)- 4-methyl-5-hydroxyoxazolidine
(Compound No.: 1020)
Preparation of a Grignard reagent
To anhydrous tetrahydrofuran(20 mL) under
nitrogen atmosphere were added magnesium metal
(756 mg) and ethyl bromide (0.1 g), and the
mixture was stirred at room temperature for 1
hour. To the mixture at reflux of the solvent
was added dropwise a solution of 4-bromoanisole
(3.76 g) dissolved in anhydrous tetrahydrofuran
(20 mL) over 1 hour. At the end of addition, the
mixture was stirred at reflux for further 40 min
to prepare a Grignard reagent.
Grignard reaction
In anhydrous tetrahydrofuran (30 mL) was
dissolved (4S)-N-benzyloxycarbonyl-4-methyl-5-
oxazolidinone (7.70 g) prepared in Reference
Example 1, and the solution was cooled to -20 °C.
To the solution under nitrogen atmosphere was
added dropwise the Grignard reagent while
maintaining the internal temperature at -20 °C.
At the end of addition, the mixture was stirred
for 1 hour at that temperature and then treated
with a 5 % aqueous hydrochloric acid solution.
The solution was warmed to room temperature and
extracted with ethyl acetate. The organic layer
was dried over anhydrous sodium sulfate. The
solution was concentrated in vacuo. The residue
was purified by silica column chromatography
(eluent: hexane/ethyl acetate = 2/1 to 3/2), to
give the title compound (4.56 g) as a
diastereomer mixture as a colorless transparent
syrup in a yield of 66 %.
XH-NMR (CDC13, 400 MHz) indicated that a
diastereomer ratio was about 2:1.
Major diastereomer product
XH-NMR (CDCI3, 400 MHz) 6 ppm: 1.47 (d, 3H, J=7
Hz), 3.70-3.75 (m, 1H), 3.87 (s, 3H), 4.80-5.20
(m, 2H), 5.16 (d, 1H, J=12.4 Hz), 5.25 (d, 1H,
J=12.4 Hz), 5.88 (q, 1H, J=7 Hz), 6.95 (d, 2H,
J=9.0 Hz), 7.23-7.36 (m, 5H), 8.02 (d, 2H, J=9.0
Hz) ;
Minor diastereomer product
^-NMR (CDCI3, 400 MHz) 5 ppm: 1.48 (d, 3H, J = 7
Hz), 3.70-3.75 (m, 1H), 3.86 (s, 3H), 4.80-5.20
(m, 2H), 5.16 (d, 1H, J=12.4 Hz), 5.25 (d, 1H,
J=12.4 Hz), 5.57 (q, 1H, J=7 Hz), 6.83 (d, 2H,
J=8.8 Hz), 7.23-7.36 (m, 5H), 8.83 (d, 2H, J=8.8
Hz) ;
IR (neat) vmax 3443, 1697, 1601 cm"1.
Example 11
Preparation of (2S)-2-(benzyloxycarbonyl)amino-1
(4-methoxyphenyl)-1-propanone (Compound No.;
22020)
In tetrahydrofuran (4 mL) was dissolved (4S)-
N-benzyloxycarbonyl-5-(4-methoxyphenyl)-4-methyl-
5-hydroxyoxazolidlne (1.72 g) prepared in Example
10 and then water (5 mL) and cone, hydrochloric
acid (2 mL) were added. The mixture was stirred
at room temperature for 24 hours. The reaction
was diluted with toluene, the aqueous layer was
discarded, and then the organic layer was dried
over anhydrous magnesium sulfate. After
concentration under a reduced pressure, the
residue was purified by silica column
chromatography (eluent: hexane/ethyl acetate =
3/1) to give the title compound (1.40 mg) as
white crystals in a yield of 89 %.
Melting point: 46-48 °C ;
^-NMR (CDC13, 400 MHz) 6 ppm: 1.43 (d, 3H, J = 6.8
Hz), 3.88 (s, 3H), 5.13 (s, 2H), 5.30 (dq, 1H,
J=7.1, 6.8 Hz), 5.91 (d, 1H, J = 7 . 1 Hz), 6.96 (d,
2H, J=8.8 Hz), 7.29-7.37 (m, 5H), 7.96 (d, 2H,
J=8.8 Hz);
IR (KBr) vmax 3458, 2958, 1714, 1676, 1597, 1527
cm"1.
Example 12
Preparation of (4S)-N-benzyloxycarbonyl-5-(2,4-
difluorophenyl)-4-methyl-5-hydroxyoxazolidine
(Compound No.; 1030)
Preparation of a Grignard reagent
To anhydrous tetrahydrofuran (20 mL) under
nitrogen atmosphere were added magnesium metal
(2.56 g) and iodine (30 mg). To the mixture at
room temperature was added one-fifth of a
solution of 2,4-difluorobromobenzene (19.3 g)
dissolved in anhydrous tetrahydrofuran (60 mL) in
one portion. Five minutes after addition,
Grignard reagent formation was initiated as
indicated by temperature rising of the reaction.
While maintaining a reaction temperature below 45
°C, the remaining four-fifths of the reagent was
added dropwise over about 30 min. At the end of
addition, the mixture was stirred at 25 to 40 °C
for 30 min to give a Grignard reagent.
Grignard reaction
In anhydrous tetrahydrofuran (68 mL) was
dissolved (4S)-N-benzyloxycarbony1-4-methyl-5 -
oxazolidinone (21.2 g) prepared in Reference
Example 1, and the solution was cooled to -20 °C.
To the solution under nitrogen atmosphere was
added dropwise the Grignard reagent prepared
while maintaining the internal temperature at -20
°C. At the end of addition, the mixture was
stirred at that temperature for one hour and
treated with a 5 % aqueous hydrochloric acid
solution. The solution was warmed to room
temperature and extracted with toluene. The
organic layer was dried over anhydrous magnesium
sulfate. The solution was concentrated in vacuo.
The residue was purified by silica column
chromatography (eluent: hexane/ethyl acetate =
2/1) to give the title compound (21.4g) as a
diastereomer mixture as a pale yellow syrup in a
yield of 68 %.
^-NMR (CDC13, 400 MHz) 6 ppm: 1.52 and 1.51 (2d,
3H, J=6.8 Hz), 3.20-3.45 (m, 1H), 4.30-4.50 (m,
1H), 4.70-5.45 (m, 4H), 6.55-6.90 (m, 2H), 7.30-
7.40 (m, 5H), 7.50-7.90 (m, 1H);
IR (KBr) vmax 3402, 1803, 1701, 1614 cm"1.
Example 13
Preparation of (2S)-2-(benzyloxycarbonyl)amino-1
(2,4-dlfluorophenyl)-1-propanone (Compound No.;
22030)
In tetrahydrofuran (70 mL) was dissolved
(4S)-2-(benzyloxycarbonyl)amino-5-(2,4-
difluorophenyl)-4-methyl-5-hydroxyoxazolidine
(14.0 g) prepared in Example 12, and water (50
mL) and cone, hydrochloric acid (20 mL) were
added. The mixture was stirred at room
temperature for 24 hours. The reaction mixture
was diluted with toluene, the aqueous layer was
discarded, and the organic layer was washed with
water three times. The organic layer was dried
over anhydrous magnesium sulfate and concentrated
in vacuo. The residue was purified by silica
column chromatography (eluent: hexane/ethyl
acetate = 3/1) to give the title compound (11.7
g) as a pale yellow syrup in a yield of 92 %.
^-NMR (CDC13, 400 MHz) 5 ppm: 1.40 (d, 3H, J=7.0
Hz), 5.10 (s, 2H), 5.05-5.20 (m, 1H), 5.75-5.80
(m, 1H), 6.88-6.94 (m, 1H), 6.98-7.02 (m, 1H),
7.30-7.37 (m, 5H), 7.95-8.01 (m, 1H);
IR (neat) vraax 3358, 1718, 1681, 1611, 1532 cm'1;
Optical purity: 90 tee;
HPLC analysis conditions
Column: Daicel Chiral-Pak AD-RH (4.6 mm(j) x
150 mm);
Mobile phase: methanol;
Flow rate: 0.5 mL/mln;
Wavelength: 254 nm;
Temperature: room temperature;
tR: (2R-form); 6.5 min
(2S-form); 7.5 min.
Reference Example 5
Preparation of (4R)-N-benzyloxycarbonyl-4-methyl-
5-oxazolidinone
In toluene (190 mL) were suspended
benzyloxycarbonyl-D-alanine (19.3 g),
paraformaldehyde (6.56 g) and p-toluenesulfonic
acid monohydrate (0.17 g), and the mixture was
heated at reflux while removing water produced.
At the end of the reaction, the mixture was
cooled to room temperature, and washed with
saturated aqueous sodium hydrogen carbonate
solution and saturated saline. The toluene
solution was dried over anhydrous sodium sulfate
The solvent was evaporated under a reduced
pressure. The precipitated crystals were
filtered to give the title compound (17.4 g) as
white crystals in a yield of 85 %.
Melting point: 89-91 °C ;
lH NMR (CDC13, 400 MHz) 6 ppm: 1.54 (d, 3H, J=6.4
Hz), 4.29-4.31 (m, 1H), 5.18 (s, 2H), 5.28-5.29
(m, 1H), 5.47 (br, 1H), 7.33-7.41 (m, 5H);
IR (KBr) vmax 1778, 1685 cm"1.
Example 14
Preparation of (4R)-N-benzyloxycarbonyl-5-(4 -
benzyloxyphenyl)-4-methyl-5-hydroxyoxazolldine
(Compound No.; 19001)
(4R)-N-Benzyloxycarbonyl-4-methyl-5-
oxazolidinone (2.61 g) prepared in Reference
Example 5 was processed as described in Example 1
to give the title compound (9.0 g) as a
diastereomer mixture as white crystals in an
yield of 65 %.
Melting point: 82-86 °C.
^-NMR (CDC13, 400 MHz) indicated that a
diastereomer ratio was about 2:1.
Major diastereomer product
^-NMR (CDCI3, 400 MHz) 5 ppm: 1.47 (d, 3H, J=7.3
Hz), 3.81-3.84 (m, 1H), 4.79-5.07 (m, 2H), 5.14
(s, 2H), 5.14 (d, 1H, J=8.4 Hz), 5.20 (d, 1H,
J=8.4 Hz), 5.87 (q, 1H, J=7.3 Hz), 7.02 (d, 2H.
J = 8.8 Hz), 7.23-7.44 (m, 10H), 8.01 (d, 2H, J = 8.8
HZ) ;
Sub dlastereomer product
^-NMR (CDC13, 400 MHz) 6 ppm: 1.49 (d, 3H, J=7.3
Hz), 3.60-3.70 (m, 1H), 4.79-5.15 (m, 4H), 5.13
(S, 2H), 5.57 (q, 1H, J=7.3 Hz), 6.91 (d, 2H,
J-8.8 Hz), 7.23-7.44 (m. 10H), 7.83 (d, 2H, J=8.8
Hz) ;
IR (neat) vmax 3436, 3033, 1671, 1603, 1508 cm"1.
Example 15
Preparation of (2R)-2-(benzyloxycarbonyl)amino-1-
(4-benzyloxyphenyl)-1-propanone (Compound No.:
25001)
(4R)-N-Benzyloxycarbonyl-5-(4 -
benzyloxyphenyl)-4-methyl-5-hydroxyoxazolidine
(2.1 g) prepared in Example 14 was processed as
described in Example 9 to give the title compound
(1.85 g) as pale yellow crystals in an yield of
95 %.
Melting point: 88-90 °C ;
*H-NMR (CDC13, 400 MHz) 5 ppm: 1.43 (d, 3H, J = 6.83
Hz), 5.13 (s, 2H), 5.15 (s, 2H), 5.28-5.31 (m,
1H), 5.88 (br, 1H), 7.03 (d, 2H, J=9.0 Hz), 7.31-
7.44 (m, 10H), 7.96 (d, 2H, J=9.0 Hz);
IR (KBr) vmax 3374, 1712, 1690 cm"1;
Specific rotation: [a]D24 = -25 • (Ol.OO, CHC13);
Optical purity: 98 %ee (analysis conditions are
as described in Example 3).
Example 16
Preparation of (4R)-N-benzyloxycarbonyl-5-(2,4-
dlfluorophenyl)-4-methyl-5-hydroxyoxazolidlne
(Compound No.: 19030)
Preparation of a Grignard reagent
To anhydrous tetrahydrofuran (10 mL) under
nitrogen atmosphere were added magnesium metal
(1.28 g) and iodine (20 mg). A solution of 2,4-
difluorobromobenzene (9.65 g) in anhydrous
tetrahydrofuran (30 mL) at room temperature was
used as described in Example 12 to give a
Grignard reagent.
Grignard reaction
In anhydrous tetrahydrofuran (34 mL) was
dissolved (4R)-N-benzyloxycarbonyl-4-methyl-5-
oxazolidinone (10.6g). The mixture was processed
as described in Example 12 to give the title
compound (10.7 g) as a diastereomer mixture as a
pale yellow syrup in a yield of 68 %.
^-NMR (CDC13, 400 MHz) 6 ppm: 1.52 and 1.51 (2d,
3H, J=6.8 Hz), 3.20-3.45 (m, 1H), 4.30-4.50 (m,
1H), 4.70-5.45 (m, 4H), 6.55-6.90 (m, 2H), 7.30-
7.40 (m, 5H), 7.50-7.90 (m, 1H);
IR (KBr) vmax 3402, 1803, 1701, 1614 cm"1.
Example 17
Preparation of (2R)-2-(benzyloxycarbonyl)amino-1-
(2,4-difluorophenyl)-1-propanone (Compound No.;
25030)
In tetrahydrofuran (35 mL) was dissolved
(4R)-2-(benzyloxycarbony1)amino-5-(2,4-
difluorophenyl)-4-methyl-5-hydroxyoxazolidine
(6.98 g) prepared in Example 16, and water (25
mL) and cone, hydrochloric acid (10 mL) were
added. The mixture was processed as described in
Example 13 to give the title compound (5.87 g) as
pale yellow syrup in a yield of 92 %.
XH-NMR (CDC13, 400 MHz) 6 ppm: 1.40 (d, 3H, J=7.0
Hz), 5.10 (s, 2H), 5.05-5.20 (m, 1H), 5.75-5.80
(m, 1H), 6.88-6.94 (m, 1H), 6.98-7.02 (m, 1H),
7.30-7.37 (m, 5H), 7.95-8.01 (m, 1H);
IR (neat) vmax 3358. 1718, 1681, 1611, 1532 cm"1;
Optical purity: 90 %ee (analysis conditions are
as described in Example 12).
Industrial applicability
According to the present invention, an
optically active aminoalcohol derivative
represented by general formula (5) or (6), which
is useful as a production intermediate for a
medicine or agricultural agent, can be produced
stably in a large scale with an industrially
adequate optical purity and a lower cost. This
invention also provides an optically active 5-
WE CLAIM:
NevRfeFSf=cf5ffTf5
1. A process for preparing an optically active aminoalcohol wherein
an optically active 5-oxazolidinone derivative represented by a general formula
(1):

wherein R1 represents an unprotected or optionally protected side
chain in a natural a-amino acid; and R2 represents optionally substituted aryl,
optionaljy substituted alky) or optionally substituted aralkyl^ is reacted with an
organometallic reagent represented by general formula (2):
R3-M (2)
wherein R3 represents optionally substituted aryl or optionally
substituted heterocycle; M represents one selected from the group consisting of
Li, MgX, ZnX, TiX3 and CuX; and X represents halogen,
to form an optically active 5-hydroxyoxazolidine derivative represented by
general formula (3):

wherein R1, R2 and R3 are as defined above,
which is then treated under acidic conditions to give an optically active
aminoketone derivative represented by general formula (4):

wherein R1 and R3 are as defined above; and R4 represents
hydrogen or optionally substituted alkyloxycarbonyl, optionally substituted
aryloxycarbonyl or optionally substituted aralkyloxycarbonyl as a protective
group,
which is then catalyticaljyj^rc^enated with a metal catalyst to stereoselective^
provide an optically active aminoalcohol derivative represented by general
formula (5):

wherein R1, R3 and R4 are as defined above;
provided that configuration of R1 attached to the asymmetric carbon at 4-position
and the substituent represented by a nitrogen atom in the optically active
5-oxazolidinone represented by general formula (1) is not changed throughout
these reactions and relative configuration between the amino group and the
hydroxy group in the optically active aminoalcohol represented by general
formula (5) is an erythro configuration.
2. A process for preparing an aminoalcohol wherein an optically
active 5-oxazolidinone derivative represented by a general formula (1):
wherein R1 represents an unprotected or optionally protected side
chain in a natural a-amino acid; and R2 represents optionally substituted aryl,
optionally substituted alky!-01" optionally substituted aralkyl,
is reacted with an organometallic reagent represented by general formula (2):
R3-M (2)
wherein R3 represents optionally substituted aryl or optionally
substituted heterocycle; M represents one selected from the group consisting of
Li, MgX, ZnX, TIX3 and CuX; and X represents halogen,
to form an optically active 5-hydroxyoxazolidine derivative represented by
general formula (3):
wherein R1, R2 and R3 are as defined above,
which is then treated under acidic conditions to give an optically active
aminoketone derivative represented by general formula (4):

wherein R1 and R3 are as defined above; and R4 represents
hydrogen or optionally substituted alkyloxycarbonyl, optionally substituted
aryloxycarbonyl or optionally substituted aralkyloxycarbonyl as a protective
group,
which is then catalvticallv hvdroqenated with a metal catalyst to provide an
optically active aminoalcohol derivative represented by general formula (5):

wherein R\ R3 and R4 are as defined above,
and then, when R4 is a protective group, the amino group in the product is
deprotected to give an optically active aminoalcohol derivative represented by
general formula (6):
wherein R1 and R3 are as defined above;
provided that configuration of R1 attached to the asymmetric carbon at 4-position
and the substituent represented by a nitrogen atom in the optically active
5-oxazolidinone represented by general formula (1) is not changed throughout
these reactions and relative configuration between the amino group and the
hydroxy group in the optically active aminoalcohol represented by general
formula (6) is an erythro configuration.
3. The process for preparing an optically active aminoalcohol as
claimed in Claim 1 or 2 wherein R1 represents methyl, isopropyl, isobutyl, benzyl,
hydroxymethyl, benzyloxymethyl, phenylthiomethyl, methylthiomethyl,
alkyloxycarbonylmethyl or alkyloxycarbonylethyl; R2 represents benzyl, tert-butyl,
methyl, ethyl, isopropyl or 9-fluorenylmethyl.
4. The process for preparing an optically active aminoalcohol as
claimed in Claim 1 or 2 wherein R3 is represented by general formula (7):

wherein Y represents halogen; or by general formula (8):
wherein R" represents hydrogen, optionally substituted alkyl,
optionally substituted cycloalkyl, optionally substituted aralkyl, optionally
substituted phenyl, optionally substituted heterocycle or optionally substituted
heterocycipalkyi.
5. The process for preparing an optically active aminoalcohol
derivative as claimed in Claim 1 or 2 wherein R1 represents methyl; and R3 is
represented by general formula (8):

wherein R5 represents hydrogen, optionally substituted akyl, optionally
substituted cyctoakyl, optionally substituted arafcyl, optionally substituted
phenyl, optionally substituted heterocycle or optionally substituted
heterocycloalcyl.
6. An optionally active 5-hydroxyoxazolkJine derivetive represented by
general formula (3):

Wherein R1 represents an unprotected side chain or optionally protected side
chain in a natural ct-emino acid; R2 represents benzyl, tert-butyl, methyl, ethyl,
isopropyl or 9-fkiorenylmethyl; and R3 represents optionally substituted aryl or
optionally substituted heterocycle.
7. The optically active 5-hydroxyoxazolidine derivative as claimed in claim 6
wherein R3 is represented by general formula (7):

wherein Y represents halogen; or general formula (8):

wherein R5 represents hydrogen, optionally substituted akyl/jpbonalfy
substituted cycloalokyl, optionaily substituted arakyl, optionally substituted
phenyl, optionally substituted heterocyclt or optionally substituted
heterocycloalcyl.
8. The optically active 5-hydroxyoxazolidine derivative as claimed in claim
7 wherein R1 is methyl.
9. A process for preparing an optically active 5-hydroxyoxazolidine
derivative wherein an optically active 5-oxazolidinone derivative represented
by general formula (1):

Wherein R1 represents an unprotected side chain or optionally protected side
chain in a natural a-amino acid;and R2 represents benzyl,tert-butyl, methyl,
ethyl, isopropyl or 9-fluorenylmethyl, is reacted with an organometalHc
reagent represented by general formula (2):
R3-M (2)
Wherein R3 represents optionally substituted aryi or optionally substituted
heterocycle; M is one selected from the group consisting of Li, MgX, ZnX, TiX3
and CuX; and X represents halogen, to provide an optically active 5-hydroxy-
oxazolidine derivative represented by general formula (3):
-127-

wherein R1, R2 and R3 are as defined above.
10. The process for preparing an optically active 5-hydroxyoxazolidine
derivative as claimed in claim 9 wherein R3 is represented by general formula
(7):
wherein Y represents halogen; or general formula (8):

wherein R5 represents hydrogen, optionally substituted akyl, optionally
substituted cycloalkyl, optionally substituted aralcyl, optionally substituted
phenyl, optionally substituted heterocycle or optionally substituted
heterocycloalkyl.
11. The process for preparing an optically active 5-hydroxyoxazolidine
derivative as claimed in claim 10 wherein R1 is methyl.
-128-
12. The process for preparing an optically active 5-hydroxyoxazolidine
derivative as claimed in Claim 9 wherein M in general formula (2) is MgX
wherein X is as defined above.
13. An aminoketone derivative represented by general formula (4a):

wherein R1a represents methyl; R4a represents benzyloxycarbonyl,
tert-butoxycarbonyl or 9-fluorenylmethoxycarbonyl; R3a represents
4-benzyloxyphenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl or
3-indolyl.
14. A process for preparing an aminoketone derivative wherein a
5-hydroxyoxazolidine derivative represented by general formula (3):

wherein R1 represents an unprotected side chain or optionally
protected side chain in a natural a-amino acid; R2 represents optionally
substituted alkyl, optionally substituted aryl or optionally substituted aralkyl; and
R3 represents optionally substituted aryl or optionally substituted heterocycle,
is treated under acidic conditions to form an aminoketone derivative represented
by general formula (4):

wherein R1 and R3 are as defined above; R4 represents hydrogen
or optionally substituted alkyloxycarbonyl, optionally substituted aryloxycarbonyl
or optionally substituted aralkyloxycarbonyl as a protective group.
15. An optically active alcohol derivative represented by general
formula (5a):

wherein R1a represents methyl; R3b represents 4-benzyloxyphenyl;
R4b represents benzyloxycarbonyl; and configuration between the amino group
and the hydroxy group is an erythro configuration.
10
16. A process for preparing an optically active aminoakohol derivative
wherein an optically active aminoketone derivative represented by general
formula (4b):
wherein R1 represents an unprotected side chain or optionally protected side
chain in a natural a-amino acid; R4 represents hydrogen or optionally
substituted alkyloxycarbonyl, optionally substituted aryloxycarbonyl or
optionally substituted arakyloxycarbonyl as a protective group; R* is
represented by general formula (8):

wherein R5 represents hydrogen, optionally substituted akyl, optionally
substituted cycbakyl, optionally substituted aralkyl, optionally substituted p
henyl, optionally substituted heterocycle or optionally substituted
heterocycloalcyl is catatically hydrogenated with a metal catalyst, to stereo-
selective ly form an optically active am'moatcoho! derivative represented by
gpeneral formula (5b):
wherein R1, R3c and R4 are as defined above;
provided that configuration of R1 attached to the asymmetric carbon at 2-position
and the substituent represented by a nitrogen atom in the optically active
aminoketone derivative represented by general formula (4b) is not changed
throughout these reactions and relative configuration between the amino group
and the hydroxy group in the optically active aminoalcohol derivative
represented by general formula (5b) is an erythro configuration.
17. A process for preparing an optically active aminoalcohol derivative
wherein an optically active aminoketone derivative represented by general
formula (4b):
wherein R1 represents an unprotected side chain or optionally
protected side chain in a natural cc-amino acid; R4 represents hydrogen or
optionally substituted alkyloxycarbonyl, optionally substituted aryloxycarbonyl or
optionally substituted aralkyloxycarbonyl as a protective group; R30 is
represented by general formula (8):
wherein R5 represents hydrogen, optionally substituted alkyl,
optionally substituted cycloalkyl, optionally substituted aralkyl, optionally
substituted phenyl, optionally substituted heterocycle or optionally substituted
heterocycloalkvl,
is catalvtically hvdrogenated with a metal catalyst, to stereoselectively form an
optically active aminoalcohol represented by general formula (5b):
wherein R1, R3c and R4 are as defined above,
and when R4 is a protective group, the amino group in the product is deprotected
to give an optically active aminoalcohol derivative represented by general
formula (6a):

wherein R1 and R30 are as defined above;
provided that configuration of R1 attached to the asymmetric carbon at 2-position
and the substituent represented by a nitrogen atom in the optically active
aminoketone derivative represented by general formula (4b) is not changed
throughout these reactions and relative configuration between the amino group
and the hydroxy group in the optically active aminoalcohol derivative
represented by general formula (6a) is an erythro configuration.


A process for preparing an optically active am inoalcohol wherein an
optically active 5-oxazolidinone derivative represented by a general formula
(1):

wherein R1 represents an unprotected or optionally protected side chain in a
natural a-amino acid; and R2 represents optionally substituted aryl,
optionally substituted alkyl or optionally substituted aralkyl, is reacted with
an organometallic reagent represented by general formula (2):
R3-M (2)
wherein R3 represents optionally substituted aryl or optionally substituted
heterocycle; M represents one selected from the group consisting of
Li,MgX,ZnX, TiX3 and CuX; and X represents halogen, to form an optically
active 5-hydroxyoxazolidine derivative represented by general formula (3):
wherein R1, R2 and R3 are as defined above, which is then treated under
acidic conditions to give an optically active aminoketone derivative
represented by general formula (4):

wherein Rl and R3 are as defined above; and R4 represents hydrogen or
optionally substituted alkyloxycarbonyl, optionally substituted
aryloxycarbonyl or optionally substituted aralkyloxycarbonyl as a protective
group,which is then catalytically hydrogenated with a metal catalyst to
stereoselectively provide an optically active amino alcohol derivative
represented by general formula (5):
wherein R1, R3 and R4 ire as defined above; provided (hat configuration of
R1 attached to the asymmetric carbon at 4-poiition and the mbititntent
represented by a nitrogen atom in the optically active 5-oxazolidinone
represented by the general formula (1) is not changed throughout these
reactions and relative configuration between the amino group and the
hydroxy group in the optically active aminoalcohol represented by general
formula (5) is an erythro configuration.

Documents:

570-kolnp-2003-correspondence.pdf

570-kolnp-2003-examination report.pdf

570-kolnp-2003-form 18.pdf

570-kolnp-2003-form 3.pdf

570-kolnp-2003-form 5.pdf

570-kolnp-2003-gpa.pdf

570-kolnp-2003-granted-abstract.pdf

570-kolnp-2003-granted-claims.pdf

570-kolnp-2003-granted-description (complete).pdf

570-kolnp-2003-granted-form 1.pdf

570-kolnp-2003-granted-form 2.pdf

570-kolnp-2003-granted-specification.pdf

570-kolnp-2003-priority document.pdf

570-kolnp-2003-reply to examination report.pdf

570-kolnp-2003-translated copy of priority document.pdf


Patent Number 240609
Indian Patent Application Number 570/KOLNP/2003
PG Journal Number 21/2010
Publication Date 21-May-2010
Grant Date 19-May-2010
Date of Filing 05-May-2003
Name of Patentee MITSUI CHEMICALS, INC.
Applicant Address 2-5, KASUMIGASEKI 3-CHOME, CHIYODA-KU, TOKYO
Inventors:
# Inventor's Name Inventor's Address
1 OKUMURA KUNIO C/O MITSUI CHEMICALS, INC., 580-32, NAGAURA, SODEGAURA-SHI, CHIBA 299-0265
2 TSUNODA HIDETOSHI C/O MITSUI CHEMICALS, INC., 1144, TOGO, MOBARA-SHI, CHIBA 297-0017
3 OTSUKA KENGO C/O MITSUI CHEMICALS, INC., 1144, TOGO, MOBARA-SHI, CHIBA 297-0017
PCT International Classification Number C07C 215/30
PCT International Application Number PCT/JP2001/09830
PCT International Filing date 2001-11-09
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2000-341906 2000-11-09 Japan
2 2000-341767 2000-11-09 Japan