Title of Invention

PROCESS FOR PRODUCTION OF FLUORO DERIVATIVE FROM HYDROXY DERIVATIVE BY USING SULFURYL FLUORIDE AS A DEHYDROXYFLUORINATION AGENT

Abstract It was found that a fluoro derivative can be produced by reacting a hydroxy derivative with sulfuryl fluoride (SO2F2) in the presence of an organic base or in the presence of an organic base and "a salt or complex comprising an organic base and hydrogen fluoride". According to the present production process, it is not necessary to use perfluoroalkanesulfonyl fluoride, which is not preferable in industrial use, and it is possible to advantageously produce optically-active fluoro derivatives, which are important intermediates of medicines, agricultural chemicals and optical materials, specifically 4-fluoroproline derivatives, 2'-deoxy-2'-fluorouridine derivatives, optically-active α-fluorocarboxylate derivatives, and the like, even in a large scale.
Full Text DESCRIPTION
TECHNICAL FIELD
[0001] The present invention relates to industrial fluorination reactions,
which are suitable for large-scale productions, using sulfuryl fluoride. In
particular, it relates to production processes of optically-active fluoro
derivatives, which are important intermediates of medicines, agricultural
chemicals and optical materials, specifically 4-fluoroproline derivatives,
2'-deoxy-2'-fluorouridine derivatives, optically-active α-fluorocarboxylate
derivatives, and the like.
BACKGROUND OF THE INVENTION
[0002] The fluorination reaction, which is the target of the present
invention, is classified into a dehydroxyfluorination reaction in which a
hydroxyl group is replaced with a fluorine atom. As typical reaction
examples relating to the present invention, it is possible to cite 1) a process
(Patent Publication 1 and Patent Publication 2) in which a substrate having
a hydroxyl group is reacted with a perfluoroalkanesulfonyl fluoride, such as
perfluorobutanesulfonyl fluoride, in the presence of a special, strongly basic,
organic base, such as DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); 2) a process
(Non-patent Publication 1) in which a substrate having a hydroxyl group is
reacted with perfluorobutanesulfonyl fluoride in the presence of an organic
base, such as triethylamine, and "a salt or complex comprising an organic
base and hydrogen fluoride" such as triethylamine tris(hydrogen fluoride)
complex; and 3) a process (Patent Publication 3) in which
1-β-D-Arabinofuranosyluracil in 3',5'-hydroxyl-protected form is reacted with
a trifluoromethanesulfonylation agent, such as trifluoromethanesulfonyl
fluoride, in the presence of an organic base, such as triethylamine, to convert
it to 2'-triflate, followed by a reaction with a fluorination agent comprising "a
salt or complex comprising an organic base and hydrogen fluoride" such as


triethylamine tris(hydrogen fluoride) complex. Furthermore, there is a
report of 4) a process (Non-patent Publication 2) in which a hydroxyl group is
converted into a fluorosulfate, followed by replacement with a fluorine anion.
Patent Publication l: US Patent 5760255 specification
Patent Publication 2- US Patent 6248889 specification
Patent Publication 3: International Publication 2004/089968 Pamphlet
(Japanese Patent Application Publication 2004-323518)
Non-patent Publication 1: Organic Letters (US), 2004, Vol. 6, No. 9, p.
1465-1468
Non-patent Publication 2: Tetrahedron Letters (Great Britain), 1996, Vol. 37,
No. 1, p. 17-20
SUMMARY OF THE INVENTION
[0003] It is an object of the present invention to provide an industrial
fluorination reaction. In the processes of Patent Publication 1 and Patent
Publication 2, it was necessary to use a long-chain perfluoroalkanesulfonyl
fluoride, which is not preferable in industrial use, and a high-price, special
organic base. In the dehydroxyfluorination reaction using a
perfluoroalkanesulfonyl fluoride, a perfluoroalkanesulfonic acid is
stoichiometrically produced as a by-product in the form of a salt of an organic
base. Therefore, waste treatment of the acid was a large problem in
conducing the reaction in industrial scale. In particular, long-chain
perfluoroalkanesulfonic acid derivatives having a carbon number of 4 or
greater are pointed out to have long-term persistence in environment and
toxicity, and therefore their industrial use is limited (for example, see
FARUMASHIA Vol. 40, No. 2, 2004 with respect to perfluorooctanesulfonic
acid derivatives). Also in the process of Non-patent Publication 1, there was
a similar problem of using long-chain perfluorobutanesulfonyl fluoride. On
the other hand, the process of Patent Publication 3 is a superior process that
is capable of avoiding problems of long-term persistence in environment and
toxicity, since it uses trifluoromethanesulfonyl fluoride having a carbon
number of 1. The industrial production amount of trifluoromethanesulfonyl


fluoride is, however, limited, as compared with perfluorobutanesulfonyl
fluoride and perfluorooctanesulfonyl fluoride. Therefore, its obtainment in
large amount was not necessarily easy. The process of Non-patent
Publication 2 was not a direct fluorination reaction (see Scheme l), due to its
necessity of going through imidazole sulfate in order to convert the hydroxy
derivative to the fluorosulfate.
[0004] [Chemical Formula 1]

[0005] According to Non-patent Publication 1, it is disclosed therein that,
when the dehydroxyfluorination agent comprising trifluoromethanesulfonic
anhydride, triethylamine tris(hydrogen fluoride) complex and triethylamine
is used, gaseous trifluoromethanesulfonyl fluoride (boiling point: -21°C) is
formed in the reaction system, thereby not achieving an efficient
trifluoromethanesulfonylation of a hydroxyl group of the substrate, and that
a combination with high-boiling-point (64°C) perfluorobutanesulfonyl
fluoride (perfluorobutanesulfonyl fluoride, triethylamine tris(hydrogen
fluoride) complex and triethylamine) is preferable. This description clearly
indicates that low-boiling-point trifluoromethanesulfonyl fluoride is not
preferable as a perfluoroalkanesulfonyl fluoride of the dehydroxyfluorination
agent. Sulfuryl fluoride used in the present invention has a further lower
boiling point (-49.7°C). Thus, it has been totally unclear whether or not
that can preferably be used as the dehydroxyfluorination agent.
[0006] As mentioned hereinbefore, there has been a strong demand for a
novel fluorination reaction that is easy in industrial operation, for producing
a fluoro derivative represented by the after-mentioned formula [2].
[0007] Prior to the present application, the present applicant has filed
Japanese Patent Application 2004-130375, Japanese Patent Application

2004-184099, Japanese Patent Application 2004-215526, and Japanese
Patent Application 2004-237883. In these applications, the present
inventors have clarified that fluoro derivatives can be produced with good
yield by reacting particular hydroxy derivatives with
trifluoromethanesulfonyl fluoride in the presence of an organic base or in the
presence of an organic base and "a salt or complex comprising an organic
base and hydrogen fluoride". However, similar to the process of Patent
Publication 3, each of the processes of these applications uses
trifluoromethanesulfonyl fluoride. Therefore, there has been a demand for
developing a novel fluorination reaction in place of this, from the viewpoint
of industrial stable supply.
[0008] From the above viewpoint, the present inventors have conducted an
eager examination to find a novel fluorination reaction that is easy in
industrial operation. As a result, we have obtained a finding that sulfuryl
fluoride (SO2F2), which is widely used as a fumigant, is extremely preferable
for subjecting a hydroxy derivative, which is the target of the present
invention, to dehydroxyfluorination, thereby reaching a solution of the task.
That is, it was found that a fluoro derivative represented by the
after-mentioned formula [2] can be produced with good yield by reacting a
hydroxy derivative represented by the after-mentioned formula [l] with
sulfuryl fluoride in the presence of an organic base or in the presence of an
organic base and "a salt or complex comprising an organic base and hydrogen
fluoride". There has been no report of using sulfuryl fluoride as a
dehydroxyfluorination agent.
[0009] In the process of the present invention, it is possible to continuously
conducting a fluorosulfonylation and a fluorine substitution in one reaction
vessel without isolating a fluorosulfate that is a reaction intermediate. As
shown in Scheme 2, the characteristic of the present invention is that a
hydroxy derivative can be converted into a fluorosulfate by using sulfuryl
fluoride and that "a salt or complex comprising an organic base and
hydrogen fluoride", which has been stoichiometrically produced as a


by-product in the reaction system in the step of this fluorosulfonylation, can
be effectively used as a fluorine source of the fluorine substitution.
Furthermore, as shown in Scheme 3, the fluorosulfonylation can also be
conducted in the presence of "a salt or complex comprising an organic base
and hydrogen fluoride". As compared with the process shown in Scheme 2,
it was also found that the fluoro derivative can be obtained with high yield
and selectivity.
[0010] [Chemical Formula 2]

An example in which triethylamine (1 equivalent) has been used as the
organic base.
[0011] [Chemical Formula 3]

An example in which triethylamine (1 equivalent) has been used as the organic
base and in which a triethylamine tris(hydrogen fluoride) complex (1 equivalent)
has been used as "the salt or complex comprising an organic base and hydrogen
fluoride".
[0012] Sulfuryl fluoride, which is used as a dehydroxyfluorination agent in
the present invention, has two reaction points to the hydroxyl group.
However, in the case of using 4-hydroxyproline derivatives, which are

particularly optically active hydroxy derivatives,
1-β-D-arabinofuranosyluracil derivatives, optically active
orhydroxycarboxylate derivatives, and primary alcohol derivatives as
hydroxy derivatives, it was found that a disubstituted sulfate is almost not
given (see Scheme 4) and that the fluorine substitution proceeds well by
going through the target fluorosulfate. We have clarified that such problem
does not occur by perfluoroalkanesulfonyl fluoride and that sulfuryl fluoride
can preferably be used as a dehydroxyfluorination agent.
[0013] [Chemical Formula 4]

[0014] Furthermore, the present inventors have found that
stereochemistry of a fluoro derivative obtained by the reaction with sulfuryl
fluoride is inverted, in the case of using as the hydroxyl derivative an
optically active compound caused by chirality of the carbon atom that is
covalently bonded with the hydroxyl group. In the present
dehydroxyfluorination reaction, it is considered that the fluorosulfonylation
proceeds with maintenance of stereochemistry and the subsequent fluorine
substitution proceeds with inversion of stereochemistry. A
dehydroxyfluorination reaction accompanied with such inversion of
stereochemistry is also already disclosed in a process using a
perfluoroalkanesulfonyl fluoride of Patent Publication 2. However,
fluorosulfuric acid group is vastly inferior to perfluoroalkanesulfonic acid
group in leaving ability [Synthesis (Germany) 1982, Vol. 2, p. 85-126].
Therefore, it was unclear whether or not the reaction proceeds with high
asymmetry transcription percentage in a dehydroxyfluorination reaction,
using sulfuryl fluoride, of a chain substrate, which is difficult in control of
stereochemistry, particularly an optically active a-hydroxycarboxylate
derivative represented by the after-mentioned formula [9]. In contrast with

this, the present inventors have found that a dehydroxyfluorination using
sulfuryl fluoride of the present invention proceeds well under a very mild
reaction condition and that an optically active α-fluorocarboxylate derivative
represented by the after-mentioned formula [10], which is extremely high in
optical purity, is obtained by the reflection of optical purity of the optically
active crhydroxycarboxylate derivative represented by the formula [9],
which is used as the raw material substrate.
[0015] Furthermore, it was unclear whether or not fluorosulfates that are
obtained by conversion of 4-hydroxyproline derivative represented by the
after-mentioned formula [5] and 1-β-D-arabinofuranosyluracil derivative
represented by the after-mentioned formula [7] through fluorosulfonylation
and that correspond to the respective raw material substrates have sufficient
leaving abilities. In contrast with this too, the present inventors have found
that a dehydroxyfluorination reaction using sulfuryl fluoride of the present
invention can preferably be used as the process for producing 4-fluoroproline
derivative represented by the after-mentioned formula [6] and
2'-deoxy-2'-fluorouridine derivative represented by the after-mentioned
formula [8].
[0016] That is, the present invention provides a novel process of
dehydroxyfluorinating hydroxy derivatives. The process according to the
present invention may be any of the following first process to seventh
process.
[0017] The first process is a process for producing a fluoro derivative, which
is represented by the formula [2],
[Chemical Formula 6]

by reacting a hydroxy derivative, which is represented by the formula [1],
[Chemical Formula 5]


with sulfuryl fluoride (SO2F2) in the presence of an organic base,
in the formula [1] and the formula [2], each of R, R1 and R2 is
independently a hydrogen atom, alkyl group, substituted alkyl group,
aromatic ring group, or alkoxycarbonyl group.
[0018] The second process is a process for producing a fluoro derivative,
which is represented by the formula [2a],
[Chemical Formula 8]

by reacting a hydroxy derivative, which is represented by the formula [la],
[Chemical Formula 7]

with sulfuryl fluoride (SO2F2) in the presence of an organic base,
in the formula [1a] and the formula [2a], each of R, R1 and R2
independently represents a hydrogen atom, alkyl group, substituted alkyl
group, aromatic ring group, or alkoxycarbonyl group,
the alkyl group is defined as being a C1-C16 straight-chain or
branched alkyl group,
the substituted alkyl group is defined as being an alkyl group, in
which a halogen atom, lower alkoxy group, lower haloalkoxy group, lower
alkylamino group, lower alkylthio group, cyano group, aminocarbonyl group
(CONH2), unsaturated group, aromatic ring group, nucleic acid base,
aromatic-ring oxy group, aliphatic heterocyclic group, protected hydroxyl

group, protected amino group, protected thiol group, or protected carboxyl
group has been substituted therefor by any number and by any combination
on any carbon atom of the alkyl group,
any carbon atoms themselves of any two alkyl groups or substituted
alkyl groups may form a covalent bond to have an aliphatic ring, and carbon
atoms of the aliphatic ring may be partially replaced with nitrogen atom or
oxygen atom to have an aliphatic heterocyclic ring,
the aromatic ring group is defined as being an aromatic hydrocarbon
group or aromatic heterocyclic group containing oxygen atom, nitrogen atom
or sulfur atom,
the alkoxycarbonyl group is defined as being an alkoxycarbonyl
group comprising an C1-C12 straight-chain or branched alkoxy group, and
any carbon atoms themselves of the alkoxy group and of any alkyl group or
substituted alkyl group may form a covalent bond to have a lactone ring.
[0019] The third process is a process for producing an optically-active,
fluoro derivative, which is represented by the formula [4],
[Chemical Formula 10]

by reacting an optically-active, hydroxy derivative, which is represented by
the formula [3],
[Chemical Formula 9]

with sulfuryl fluoride (SO2F2) in the presence of an organic base,
in the formula [3] and the formula [4], each of R and R1 is
independently an alkyl group, substituted alkyl group, or alkoxycarbonyl

group,
* represents an asymmetric carbon (R and R' do not take the same
substituent),
the alkyl group is defined as being a C1-C16 straight-chain or
branched alkyl group,
the substituted alkyl group is defined as being an alkyl group, in
which a halogen atom, lower alkoxy group, lower haloalkoxy group, lower
alkylamino group, lower alkylthio group, cyano group, aminocarbonyl group
(CONH2), unsaturated group, aromatic ring group, nucleic acid base,
aromatic-ring oxy group, aliphatic heterocyclic group, protected hydroxyl
group, protected amino group, protected thiol group, or protected carboxyl
group has been substituted therefor by any number and by any combination
on any carbon atom of the alkyl group,
any carbon atoms themselves of two alkyl groups or substituted alkyl
groups may form a covalent bond to have an aliphatic ring, and carbon atoms
of the aliphatic ring may be partially replaced with nitrogen atom or oxygen
atom to have an aliphatic heterocyclic ring,
the alkoxycarbonyl group is defined as being an alkoxycarbonyl
group comprising an C1-C12 straight-chain or branched alkoxy group, and
any carbon atoms themselves of the alkoxy group and of any alkyl group or
substituted alkyl group may form a covalent bond to have a lactone ring,
stereochemistry of the carbon atom, to which the hydroxyl group is
covalently bonded, is inverted through the reaction.
[0020] The fourth process is a process for producing a 4-fluoroproline
derivative, which is represented by the formula [6],
[Chemical Formula 12]


by reacting a 4-hydroxyproline derivative, which is represented by the
formula [5],
[Chemical Formula 11]

with sulfuryl fluoride (SO2F2) in the presence of an organic base,
in the formula [5] and the formula [6], R3 represents a protecting
group of the secondary amino group, R4 represents a protecting group of the
carboxyl group, * represents an asymmetric carbon, and stereochemistry of
the 4-position is inverted through the reaction, and stereochemistry of the
2-position is maintained.
[0021] The fifth process is a process for producing a
2'-deoxy-2'-fluorouridine derivative, which is represented by the formula [8],
[Chemical Formula 14]

by reacting a 1-β-D-arabinofuranosyluracil derivative, which is represented
by the formula [7],
[Chemical Formula 13]


with sulfuryl fluoride (SO2F2) in the presence of an organic base,
in the formula [7] and the formula [8], each of R5 and R6
independently represents a protecting group of the hydroxyl group.
[0022] The sixth process is a process for producing an optically-active,
α-fluorocarboxylate derivative, which is represented by the formula [10],
[Chemical Formula 16]

by reacting an optically-active, orhydroxycarboxylate derivative, which is
represented by the formula [9],
[Chemical Formula 15]

with sulfuryl fluoride (SO2F2) in the presence of an organic base,
in the formula [9] and the formula [10], R7 represents a C1-C12 alkyl
group or substituted alkyl group, R8 represents a C1-C8 alkyl group, any
carbon atoms themselves of the alkyl group or of the substituted alkyl group
of R7 and R8 may form a covalent bond to have a lactone ring, * represents an
asymmetric carbon, and stereochemistry of the α-position is inverted
through the reaction.

[0023] The seventh process is a process for producing a monofluoromethyl
derivative, which is represented by the formula [12],
[Chemical Formula 18]

by reacting a primary alcohol derivative, which is represented by the formula
[11],
[Chemical Formula 17]

with sulfuryl fluoride (SO2F2) in the presence of an organic base,
in the formula [11] and the formula [12], R represents an alkyl group
or substituted alkyl group,
the alkyl group is defined as being a C1-C16 straight-chain or
branched alkyl group,
the substituted alkyl group is defined as being an alkyl group, in
which a halogen atom, lower alkoxy group, lower haloalkoxy group, lower
alkylamino group, lower alkylthio group, cyano group, aminocarbonyl group
(CONH2), unsaturated group, aromatic ring group, nucleic acid base,
aromatic-ring oxy group, aliphatic heterocyclic group, protected hydroxyl
group, protected amino group, protected thiol group, or protected carboxyl
group has been substituted therefor by any number and by any combination
on any carbon atom of the alkyl group.
[0024] In each of the above first to seventh processes, the reaction may be
conducted by making "a salt or complex comprising an organic base and
hydrogen fluoride" further present in the system.

DETAILED DESCRIPTION
[0025] Advantageous points of the fluorination reaction of the present
invention are described in the following, as compared with prior art.
[0026] Relative to the processes of Patent Publication 1, Patent Publication
2, Non-patent Publication 1 and Patent Publication 3, it is not necessary to
use perfluoroalkanesulfonyl fluorides that are problematic in waste
treatment, long-term persistence in environment and toxicity, and it is
possible in the present invention to use sulfuryl fluoride, which is widely
used as a fumigant.
[0027] In the present invention, fluorosulfuric acid is stoichiometrically
produced as a salt of an organic base. It is, however, possible to easily treat
the acid into fluorite (CaF2) as a final waste. It is thus extremely preferable
for a fluorination reaction in industrial scale.
[0028] Furthermore, the perfluoroalkyl moiety of perfluoroalkanesulfonyl
fluoride is at last not incorporated into the target product. One having a
less fluorine content is industrially advantageous, as long as it has sufficient
sulfonylation ability and leaving ability. From such a viewpoint too,
sulfuryl fluoride is vastly superior.
[0029] It is not necessary to use a high-price, special organic base such as
DBU. In the present invention, it is possible to use a low-price organic base,
such as triethylamine, that is common in industrial use.
[0030] Relative to the process of Non-patent Publication 2, it is not
necessary to go through imidazole sulfate. In the present invention, it is
possible to directly convert a hydroxy derivative to a fluorosulfate by using
sulfuryl fluoride.
[0031] Furthermore, a new advantageous effect of the invention has been
found by using sulfuryl fluoride. In a dehydroxyfluorination reaction using
a perfluoroalkanesulfonyl fluoride, a salt of a perfluoroalkanesulfonic acid
and an organic base is stoichiometrically contained in the
reaction-terminated liquid. The salt, particularly a salt derived from a
perfluoroalkanesulfonic acid having a carbon number of 4 or greater, has an


extremely high solubility in organic solvent. We thus have found that there
is a problem that it is not possible to effectively remove the salt and thereby
it imposes a burden on the purification operation, even if conducting a
post-treatment operation that is generally used in organic syntheses, such as
washing of organic layer with water or alkali aqueous solution.
Furthermore, a salt of perfluoroalkanesulfonic acid and organic base may act
as an acid catalyst in some cases. Thus, it was necessary to efficiently
remove the salt in order to produce a compound having an acid-labile
functional group. Actually, if a large amount of a salt of
perfluorobutanesulfonic acid and organic base is contained in a distillation
purification of a crude product of 4-fluoroproline derivative represented by
the formula [6], in which the protecting group of the secondary amino group
is a tert'butoxycarbonyl (Boc) group, debutoxycarbonylation reaction is
found considerably. Thus, it was not possible to recover the target product
with good yield. On the other hand, a salt of fluorosulfuric acid and organic
base, which is produced as a by-product in the present invention, is
extremely high in solubility in water. Therefore, it can perfectly be removed
by washing the organic layer with water or alkali aqueous solution. Since it
does almost not impose a burden on the purification operation, it was found
to be extremely preferable for an industrial fluorination reaction.
[0032] A fluorination reaction having characteristics disclosed in the
present invention has not been disclosed at all in related technical fields. It
is extremely useful as an industrial fluorination reaction, since it is very
high in selectivity and does almost not produce as by-products impurities
that are difficult in separation. In particular, it can extremely preferably be
used for an industrial production process of optically active fluoro derivatives,
which are important intermediates of medicines, agricultural chemicals and
optical materials, specifically 4-fluoroproline derivatives,
2'-deoxy-2'-fluorouridine derivatives, and optically active orfluorocarboxylate
derivatives. It is capable of remarkably efficiently producing them, as
compared with conventional production processes.


[0033] In the following, a fluorination reaction using sulfuryl fluoride of the
present invention is described in detail.
[0034] The present invention is conducted by reacting a hydroxy derivative
represented by the formula [1] with sulfuryl fluoride in the presence of an
organic base or in the presence of an organic base and "a salt or complex
comprising an organic base and hydrogen fluoride". It is possible to
continuously conduct the fluorosulfonylation and the fluorine substitution in
one reaction vessel without isolating a fluorosulfate that is the reaction
intermediate. In the fluorosulfonylation, stereochemistry of the hydroxyl
group is maintained, and stereochemistry is inverted in the subsequent
fluorine substitution. Therefore, 4-fluoroproline derivative represented by
the formula [6] in 4S/2R configuration is obtained from 4-hydroxyproline
derivative represented by the formula [5] in 4R/2R configuration. Similarly,
4R/2R configuration from 4S/2R configuration, 4S/2S configuration from
4R/2S configuration, and 4R/2S configuration from 4S/2S configuration.
Optically active orfluorocarboxylate derivative represented by the formula
[10] in S configuration at opposition is obtained from optically active
orhydroxycarboxylate derivative represented by the formula [9] in R
configuration at opposition. Similarly, R configuration at opposition is
obtained from S configuration at opposition.
[0035] Each of R, R1 and R2 of the hydroxyl derivative represented by the
formula [1] is independently a hydrogen atom, alkyl group, substituted alkyl
group, aromatic ring group, or alkoxycarbonyl group.
[0036] When R, R1 and R2 of the hydroxyl derivative represented by the
formula [1] are alkyl groups, substituted alkyl groups, aromatic ring groups
or alkoxycarbonyl groups other than hydrogen atoms, they also can have an
optically active moiety caused by chirality of carbon atom, axis and the like.
In these cases, stereochemistry of the optically active moiety is maintained
through the fluorination reaction of the present invention.
[0037] The alkyl group of R, R1 and R2 of the hydroxy derivative
represented by the formula [la] is defined as being "a C1-C16 straight-chain
1?

or branched alkyl group".
[0038] The substituted alkyl group of R, R1 and R2 of the hydroxy derivative
represented by the formula [1a] is defined as being "an alkyl group, in which
a halogen atom of fluorine, chlorine, bromine and iodine; lower alkoxy group
such as methoxy group, ethoxy group and propoxy group; lower haloalkoxy
group such as fluoromethoxy group, chloromethoxy group and
bromomethoxy group; lower alkylamino group such as dimethylamino group,
diethylamino group and dipropylamino group; lower alkylthio group such as
methylthio group, ethylthio group and propylthio group; cyano group,'
aminocarbonyl group (CONH2); unsaturated group such as alkenyl group
and alkynyl group,' aromatic ring group such as phenyl group and naphthyl
group," nucleic acid base such as adenine residue, guanine residue,
hypoxanthine residue, xanthine residue, uracil residue, thymine residue and
cytosine residue; aromaticring oxy group such as phenoxy group and
naphthoxy group; aliphatic heterocyclic group such as piperidyl group,
piperidino group and morpholyl group; protected hydroxyl group, protected
amino group, protected thiol group, protected carboxyl group, or the like has
been substituted therefor by any number and by any combination on any
carbon atom of the alkyl group".
[0039] In the present specification, each of the following terms is used as
having the following meaning. "Lower" means C1-C6 straight-chain or
branched. In case that "unsaturated group" is a double bond, it can be in a
geometrical isomerism of either E configuration or Z configuration.
"Aromatic ring group" also can be an aromatic heterocyclic group (containing
a condensed skeleton) containing oxygen atom, nitrogen atom, sulfur atom
and the like, such as furyl group, pyrrolyl group and thienyl group, other
than aromatic hydrocarbon groups. "Nucleic acid base" can be protected
with a protecting group that is generally used in the field of syntheses of
nucleic acid related substances (For example, as a protecting group of
hydroxyl group, it is possible to mention acyl groups such as acetyl group and
benzoyl group; alkyl groups such as methoxymethyl group and allyl group;


and aralkyl groups such as benzyl group and triphenylmethyl group. As a
protecting group of amino group, it is possible to mention acyl groups such as
acetyl group and benzoyl group and aralkyl groups such as benzyl group.
Furthermore, halogen atom, lower alkyl group, lower alkoxy group and the
like can be substituted in these protecting groups.). Furthermore, hydrogen
atom, hydroxyl group and amino group of "nucleic acid base" can be replaced
with hydrogen atom, amino group, halogen atom, lower alkyl group, lower
alkenyl group nitro group and the like. As "protecting groups of hydroxyl
group, amino group, thiol group and carboxyl group", it is possible to use
protecting groups and the like described in Protective Groups in Organic
Synthesis, Third Edition, 1999, John Wiley & Songs, Inc. In "unsaturated
group", "aromatic ring group", "aromatic ring oxy group" and "aliphatic
heterocyclic group", it is possible to substitute lower alkyl group, halogen
atom, lower haloalkyl group, lower alkoxy group, lower haloalkoxy group,
lower alkylamino group, lower alkylthio group, cyano group, aminocarbonyl
group, protected hydroxyl group, protected amino group, protected thiol
group, protected carboxyl group, and the like.
[0040] Alkyl group and substituted alkyl group of R, R1 and R2 of the
hydroxy derivative represented by the formula [la] also can be an aliphatic
ring, such as cyclopentane ring and cyclohexane ring, by the formation of a
covalent bond by any carbon atoms of any two alkyl groups or substituted
alkyl groups. They also can be an aliphatic heterocyclic ring, such as
pyrrolidine ring (also containing a protected secondary amino group),
piperidine ring (also containing a protected secondary amino group), oxolane
ring and oxane ring, in which carbon atoms of the aliphatic ring have been
partially replaced with nitrogen atoms or oxygen atoms.
[0041] Aromatic ring group of R, R1 and R2 of the hydroxy derivative
represented by the formula [la] is defined as being "an aromatic hydrocarbon
group, such as phenyl group, naphthyl group and anthryl group, or aromatic
heterocyclic group containing oxygen atom, nitrogen atom, sulfur atom or the
like, such as furyl group, pyrrolyl group, thienyl group, benzofuryl group,


indolyl and benzothienyl group. In these aromatic hydrocarbon groups and
aromatic heterocyclic groups, it also possible to substitute lower alkyl group,
halogen atom, lower haloalkyl group, lower alkoxy group, lower haloalkoxy
group, lower alkylamino group, lower alkylthio group, cyano group,
aminocarbonyl group, unsaturated group, aromatic ring group, aromatic ring
oxy group, aliphatic heterocyclic group, protected hydroxyl group, protected
amino group, protected thiol group, protected carboxyl group, and the like.
[0042] Alkoxycarbonyl group of R, R1 and R2 of the hydroxy derivative
represented by the formula [1a] is defined as being "an alkoxycarbonyl group
comprising an C1-C12 straight-chain or branched alkoxy group". Any carbon
atoms of the alkoxy group and of any alkyl group or substituted alkyl group
may form a covalent bond to have a lactone ring.
[0043] Each of R and R1 of the optically active hydroxy derivative
represented by the formula [3] is independently an alkyl group, substituted
alkyl group, or alkoxycarbonyl group. * represents an asymmetric carbon
(R and R' do not take the same substituent). The alkyl group is defined as
being a C1-C16 straight-chain or branched alkyl group. The substituted
alkyl group is defined as being an alkyl group, in which a halogen atom,
lower alkoxy group, lower haloalkoxy group, lower alkylamino group, lower
alkylthio group, cyano group, aminocarbonyl group (CONH2), unsaturated
group, aromatic ring group, nucleic acid base, aromatic-ring oxy group,
aliphatic heterocyclic group, protected hydroxyl group, protected amino
group, protected thiol group, or protected carboxyl group has been
substituted therefor by any number and by any combination on any carbon
atom of the alkyl group. Any carbon atoms themselves of two alkyl groups
or substituted alkyl groups may form a covalent bond to have an aliphatic
ring, and carbon atoms of the aliphatic ring may be partially replaced with
nitrogen atom or oxygen atom to have an aliphatic heterocyclic ring. The
alkoxycarbonyl group is defined as being an alkoxycarbonyl group
comprising an C1-C12 straight-chain or branched alkoxy group, and any
carbon atoms themselves of the alkoxy group and of any alkyl group or


substituted alkyl group may form a covalent bond to have a lactone ring.
[0044] As to the alkyl group or substituted alkyl group of R of the primary
alcohol derivative represented by the formula [11], the alkyl group is defined
as being a C1-C16 straight-chain or branched alkyl group. The substituted
alkyl group is defined as being an alkyl group, in which a halogen atom,
lower alkoxy group, lower haloalkoxy group, lower alkylamino group, lower
alkylthio group, cyano group, aminocarbonyl group (CONH2), unsaturated
group, aromatic ring group, nucleic acid base, aromatic-ring oxy group,
aliphatic heterocyclic group, protected hydroxyl group, protected amino
group, protected thiol group, or protected carboxyl group has been
substituted therefor by any number and by any combination on any carbon
atom of the alkyl group.
[0045] The dehydroxyfluorination reaction of the present invention
becomes particularly effective for the production of high-optical-purity fluoro
derivatives, which are required for important intermediates of medicines,
agricultural chemicals and optical materials. In order to maximize this
effect, the selection of the raw material substrate is important. Specifically,
although it can be applied to optically active tertiary alcohol derivatives,
which are sterically bulky, optically active secondary alcohol derivatives
(corresponding to optically active hydroxy derivatives represented by the
formula [3]), which can be expected to have a high asymmetry transcription
percentage, are still more preferable. Furthermore, the substituents of the
optically active secondary alcohol derivative (corresponding to R and R' of
the optically active hydroxy derivative represented by the formula [3]) are
preferably alkyl group, substituted alkyl group and alkoxycarbonyl group, as
compared with aromatic ring groups, which are expected to be accompanied
with a partial racemization by going through a transition state, such as the
benzyl-position carbonium ion, in the course of the fluorine substitution of
the fluorosulfate as the reaction intermediate.
[0046] Due to the usefulness of the product to be obtained, the carbon
number of the alkyl group is generally preferably 1 to 14, particularly more


preferably 1 to 12. The substituents of the substituted alkyl group are
preferably nucleic acid base, protected hydroxyl group, protected amino
group, and protected carboxyl group. It is preferable that two alkyl groups
or substituted alkyl groups take an aliphatic heterocyclic ring. The carbon
number of the alkoxy group of the alkoxycarbonyl group is generally
preferably 1 to 10, particularly more preferably 1 to 8.
[0047] Furthermore, stereochemistry of the asymmetric carbon of the
optically active secondary alcohol derivative (corresponding to the optically
active hydroxy derivative represented by the formula [3]) can be R
configuration or S configuration. Enantiomer excess ratio (%ee) is not
particularly limited. It suffices to use one having 90%ee or greater. In
general, 95%ee or greater is preferable, and particularly 97%ee is more
preferable.
[0048] In the development of medicines having new effectiveness,
"monofluoromethyl group" is recognized as being an important motif. Thus,
primary alcohol derivatives (corresponding to the primary alcohol derivative
represented by the formula [11]), which can efficiently produce
monofluoromethyl derivatives (corresponding to the monofluoromethyl
derivative represented by the formula [12]), are also preferable substrates.
[0049] Specifically, the optically active hydroxy derivative represented by
the formula [3], the 4-hydroxyproline derivative represented by the formula
[5], 1-β-D-arabinofuranosyluracil derivative represented by the formula [7],
the optically active crhydroxycarboxylate derivative represented by the
formula [9], and the primary alcohol derivative represented by the formula
[11 are particularly preferable as the hydroxy derivative represented by the
formula [1]. These are respectively converted into the optically active fluoro
derivative represented by the formula [4], the 4-fluoroproline derivative
represented by the formula [6], the 2'-deoxy-2'-fluorouridine derivative
represented by the formula [8], the optically active α-fluorocarboxylate
derivative represented by the formula [10], and the monofluoromethyl
derivative represented by the formula [12], through the fluorination reaction


of the present invention.
[0050] As the protecting group R3 of the secondary amino group of the
4-hydroxyproline derivative represented by the formula [5], it is possible to
mention benzyloxycarbonyl (Z) group, tert-butoxycarbonyl (Boc) group,
9-fluorenylmethoxycarbonyl (Fmoc) group, 3-nitro-2-pyridinesulfenyl (Npys)
group, p-methoxybenzyloxycarbonyl [Z(MeO)] group, and the like. Of these,
benzyloxycarbonyl (Z) group and tert-butoxycarbonyl (Boc) group are
preferable, and particularly tert-butoxycarbonyl (Boc) group is more
preferable.
[0051] As the protecting group R4 of the carboxyl group of the
4-hydroxyproline derivative represented by the formula [5], it is possible to
mention methyl (Me) group, ethyl (Et) group, tert_butyl (t-Bu) group,
trichloroethyl (Tce) group, phenacyl (Pac) group, benzyl (Bzl) group,
4-nitrobenzyl [Bzl(4-NO2)] group, 4-methoxybenzyl [Bzl(4-MeO)] group, and
the like. Of these, methyl (Me) group, ethyl (Et) group and benzyl (Bzl)
group are preferable, and particularly methyl (Me) group and ethyl (Et)
group are more preferable.
[0052] It is possible to produce the 4-hydroxyproline derivative represented
by the formula [5] from a commercial optically active 4-hydroxyproline by
referring to 4th Edition Jikken Kagaku Koza 22 Organic Synthesis IV Acid,
Amino acid, Peptide (Maruzen, 1992, p. 193-309). Depending on a
combination of the protecting group R3 of the secondary amino group and the
protecting group R4 of the carboxyl group, there are commercial products,
and it is also possible to use these. Of the 4-hydroxyproline derivative
represented by the formula [5], it is possible to easily convert a hydrochloride
of optically active 4-hydroxyproline methyl ester into one in which the
protecting group R3 of the secondary amino group is a tert-butoxycarbonyl
(Boc) group and in which the protecting group R4 of the carboxyl group is a
methyl (Me) group, in accordance with Tetrahedron Letters (United
Kingdom), 1988, Vol. 39, No. 10, p. 1169-1172.
[0053] As stereochemistry of the asymmetric carbon of the


4-hydroxyproline derivative represented by the formula [5], each of
2-position and 4-position can independently take R configuration or S
configuration. As a combination of stereochemistry, there is 4R/2R form,
4S/2R form, 4R/2S form or 4S/2S form. Enantiomer excess ratio (%ee) or
diastereomer excess ratio (%de) of each stereoisomer is not particularly
limited. It suffices to use 90%ee or 90%de or greater, normally preferably
95%ee or 95%de or greater, particularly more preferably 97%ee or 97%de or
greater.
[0054] As the protecting groups R5 and R6 of the hydroxyl groups of the
1-β-D-arabinofuranosyluracil derivative represented by the formula [7], it is
possible to mention trithyl group (triphenylmethyl group), tetrahydropyranil
group (THP group), and tetrahydrofuranyl group (THF group). Of these,
tetrahydropyranil group (THP group), and tetrahydrofuranyl group (THF
group) are preferable, and particularly tetrahydropyranil group (THP group)
is more preferable. It is possible to produce 1-β-D-arabinofuranosyluracil
derivative represented by the formula [7] by referring to Chem. Pharm. Bull.
(Japan), 1994, Vol. 42, No. 3, p. 595-598 and Khim. Geterotsikl. Soedin.
(Russia), 1996, No. 7, p. 975-977. It is possible to obtain one, in which
hydroxyl groups of 3'-position and 5'-position are selective protected, by
following the processes of these publications.
[0055] As R7 of the optically active α-hydroxycarboxylate derivative
represented by the formula [9], it is possible to mention methyl group, ethyl
group, propyl group, butyl group, amyl group, hexyl group, heptyl group,
octyl group, nonyl group, decyl group, undecyl group, and lauryl group. The
alkyl group having a carbon number of 3 or greater can be straight-chain or
branched. On any carbon atom of the alkyl group, it is possible to
substitute one or any combination of two of aromatic hydrocarbon groups
such as phenyl group and naphthyl group, unsaturated hydrocarbon groups
such as vinyl group, C1-C6 straight-chain or branched alkoxy groups, aryloxy
groups such as phenoxy group, halogen atoms (fluorine, chlorine, bromine
and iodine), protected carboxyl groups, protected amino groups, or protected


hydroxyl groups. As the protecting groups of the carboxyl group, amino
group and hydroxyl group, similar to the above, it is possible to use
protecting groups described in Protective Groups in Organic Synthesis,
Third Edition, 1999, John Wiley & Sons, Inc. Specifically, it is possible to
mention ester group and the like as the protecting group of the carboxyl
group. It is possible to mention benzyl group, acyl groups (acetyl group,
chloroacetyl group, benzoyl group, 4-methylbenzoyl group and the like), and
phthaloyl group, and the like as the protecting group of the amino group. It
is possible to mention benzyl group, 2-tetrapyranil group, acyl groups (acetyl
group, chloroacetyl group, benzoyl group, 4-methylbenzoyl group and the
like), silyl groups (trialkylsilyl group, alkylarylsilyl group and the like), and
the like. In particular, it is possible to mention a protecting group or the
like that forms 2,2-dimethyM,3-dioxolane, as the protecting group of the
1,2-dihydroxy group.
[0056] Although the production process, which is the target of the present
invention, can be used even in case that R7 of the optically active
crhydroxycarboxylate derivative represented by the formula [9] is an
aromatic hydrocarbon group, optical purity of the target product, optically
active orfluorocarboxylate derivative (R7 = an aromatic hydrocarbon group)
represented by the formula [10], lowers significantly, as compared with a
case that R7 is an alkyl group or substituted alkyl group. Therefore, an
alkyl group or substituted alkyl group is preferable as R7 of the optically
active crhydroxycarboxylate derivative represented by the formula [9].
[0057] As R8 of the optically active crhydroxycarboxylate derivative
represented by the formula [9], it is possible to mention methyl group, ethyl
group, propyl group, butyl group, amyl group, hexyl group, heptyl group, and
octyl group. The alkyl group having a carbon number of 3 or greater can be
straight-chain or branched. Furthermore, any carbon atoms themselves of
the alkyl group or of the substituted alkyl group of R7 and R8 of the optically
active crhydroxycarboxylate derivative represented by the formula [9] may
form a covalent bond to have a lactone ring.


[0058] Stereochemistry of the asymmetric carbon of the optically active
orhydroxycarboxylate derivative represented by the formula [9] can be R
configuration or S configuration. Enantiomer excess ratio (%ee) is not
particularly limited. It suffices to use one having 90%ee or greater. In
general, 95%ee or greater is preferable, and particularly 97%ee is more
preferable.
[0059] The optically active orhydroxycarboxylate derivative represented by
the formula [9] can be produced similarly from various, commercial,
optically-active, α-ramino acids by referring to Synthetic Communications
(US), 1991, Vol. 21, No. 21, p. 2165-2170. A commercial product was used as
(S)-ethyl lactate used in the Examples.
[0060] It is possible to achieve the reaction in the present invention by
bringing any of the above-mentioned hydroxy derivatives into contact with
sulfuryl fluoride in the presence of organic base or in the presence of organic
base and "a salt or complex comprising organic base and hydrogen fluoride",
followed by a sufficient mixing with the after-mentioned predetermined
temperature and pressure.
[0061] The amount of sulfuryl fluoride (SO2F2) used is not particularly
limited. It suffices to use 1 mole or greater, normally preferably 1-10 moles,
particularly more preferably 1-5 moles, relative to 1 mole of the hydroxy
derivative represented by the formula [1].
[0062] As the organic base, it is possible to mention trimethylamine,
triethylamine, diisopropylethylamine, tri-n-propylamine, pyridine,
2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine,
2,3,4-collidine, 2,4,5-collidine, 2,5,6-collidine, 2,4,6-collidine, 3,4,5-collidine,
3,5,6-collidine, and the like. Of these, triethylamine, diisopropylethylamine,
tri-n-propylamine, pyridine, 2,3-lutidine, 2,4-lutidine, 2,6-lutidine,
3,4-lutidine, 3,5-lutidine, 2,4,6-collidine, and 3,5,6-collidine are preferable.
In particular, triethylamine, diisopropylethylamine, pyridine, 2,4-lutidine,
2,6-lutidine, 3,5-lutidine, and 2,4,6-collidine are more preferable.
[0063] The amount of the organic base used is not particularly limited. It


suffices to use 1 mole or greater, normally preferably 1-20 moles, particularly
more preferably 1-10 moles, relative to 1 mole of the hydroxy derivative
represented by the formula [l].
[0064] Next, "a salt or complex comprising an organic base and hydrogen
fluoride", which is usable in the first to seventh processes, is explained in
detail.
[0065] As the organic base of "the salt or complex comprising an organic
base and hydrogen fluoride", it is possible to mention trimethylamine,
triethylamine, diisopropylethylamine, tri-n-propylamine, pyridine,
2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine,
2,3,4-collidine, 2,4,5-collidine, 2,5,6-collidine, 2,4,6-collidine, 3,4,5-collidine,
3,5,6-collidine, and the like. Of these, triethylamine, diisopropylethylamine,
tri-n-propylamine, pyridine, 2,3-lutidine, 2,4-lutidine, 2,6-lutidine,
3,4-lutidine, 3,5-lutidine, 2,4,6-collidine, and 3,5,6-collidine are preferable.
In particular, triethylamine, diisopropylethylamine, pyridine, 2,4-lutidine,
2,6-lutidine, 3,5-lutidine, and 2,4,6-collidine are more preferable.
[0066] The molar ratio of organic base to hydrogen fluoride of "the salt or
complex comprising organic base and hydrogen fluoride" is in a range of
100:1 to 1:100, normally preferably 50:1 to 1:50, particularly more preferably
25:1 to 1:25. Furthermore, it is very convenient to use "a complex
comprising 1 mole of triethylamine and 3 moles of hydrogen fluoride" and "a
complex comprising ~30% (~10 mol%) of pyridine and ~70% (~90 mol%) of
hydrogen fluoride", which are on the market from Aldrich (Aldrich,
2003-2004 overall catalogue).
[0067] The amount of "the salt or complex comprising organic base and
hydrogen fluoride" used is not particularly limited. It suffices to use 0.3
moles or greater, normally preferably 0.5-50 moles, particularly more
preferably 0.7-25 moles, in terms of fluorine anion (F-), relative to 1 mole of
the hydroxy derivative represented by the formula [1].
[0068] As the reaction solvent, it is possible to mention aliphatic
hydrocarbon series such as n-hexane, cyclohexane and n-heptane; aromatic


hydrocarbon series such as benzene, toluene, xylene and mesitylene;
halogenated hydrocarbon series such as methylene chloride, chloroform and
1,2-dichloroethane; ether series such as diethyl ether, tetrahydrofuran and
tert-butyl methyl ether; ester series such as ethyl acetate and n-butyl
acetate; amide series such as N,N-dimethylformamide,
N,N-dimethylacetamide and N-methylpyrrolidone; nitrile series such as
acetonitrile and propionitrile; dimethylsulfoxide; and the like. Of these,
n-heptane, toluene, mesitylene, methylene chloride, tetrahydrofuran, ethyl
acetate, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile,
propionitrile, and dimethylsulfoxide are preferable. In particular, toluene,
mesitylene, methylene chloride, tetrahydrofuran, N,N-diemethylformamide,
and acetonitrile are more preferable. It is possible to use these reaction
solvents alone or in combination.
[0069] The amount of the reaction solvent used is not particularly limited.
It suffices to use 0.1L (liter) or greater, normally preferably 0.1-20L,
particularly more preferably 0.1-10L, relative to 1 mole of the hydroxy
derivative represented by the formula [1].
[0070] The temperature condition is not particularly limited. It suffices to
conduct it in a range of-100 to +100°C, normally preferably -80 to +80°C,
particularly preferably -60 to +60°C. In the case of conducting the reaction
under a temperature condition that is not lower than boiling point (-49.7°C)
of sulfuryl fluoride, it is possible to use a pressure-proof reaction vessel.
[0071] The pressure condition is not particularly limited. It suffices to
conduct it in a range of atmospheric pressure to 2MPa, normally preferably
atmospheric pressure to 1.5MPa, particularly more preferably atmospheric
pressure to IMPa. Therefore, it is preferable to conduct the reaction using a
pressure-proof reaction vessel made of a material such as stainless steel
(SUS) or glass (glass lining).
[0072] The reaction time is not particularly limited. It suffices to conduct
it in a range of 0.1 to 72 hours. Since it depends on substrate and the
reaction conditions, it is preferable to determine the time, at which the raw


material has almost disappeared, as the end point, while tracing the
progress of the reaction by an analytical means such as gas chromatography,
liquid chromatography, or NMR.
[0073] The post-treatment is not particularly limited. Normally, it is
possible to obtain a crude product by pouring the reaction-terminated liquid
into water or an aqueous solution of inorganic base (for example, sodium
hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate or
potassium carbonate) of alkali metal, followed by extraction with an organic
solvent (for example, toluene, mesitylene, methylene chloride or ethyl
acetate). A salt formed of fluorosulfuric acid and organic base or an alkali
metal salt of fluorosulfuric acid, which is produced as a by-product from
sulfuryl fluoride, is remarkably high in distribution to water. Therefore, it
is possible to efficiently remove these salts by an easy operation such as
washing with water and to obtain the target fluoro derivative represented by
the formula [2] with high chemical purity. According to need, it can be
purified to have a higher chemical purity by activated carbon treatment,
distillation, recrystallization and the like.
EXAMPLES
[0074] In the following, embodiments of the present invention are
specifically explained by examples. The present invention is, however, not
limited to these examples.
[EXAMPLE 1]
A pressure-proof reaction vessel made of stainless steel (SUS) was
charged with 2.45g (9.99mmol, l.OOeq) of 4-hydroxyproline derivative
represented by the following formula,
[Chemical Formula 19]


10.0mL of acetonitrile, and 1.10g (l0.87mmol, 1.09eq) of triethylamine,
followed by lowering the inside temperature to -40°C and then bubbling
2.00g (l9.60mmol, 1.96eq) of sulfuryl fluoride from a cylinder. The inside
temperature was returned to room temperature, and stirring was conducted
for 20 hours and 20 minutes. Conversion of the reaction was found by gas
chromatography measurement to be 100%. The reaction-terminated liquid
was poured into a potassium carbonate aqueous solution [prepared from
2.80g (20.26mmol, 2.03eq) of potassium carbonate and 50.0mL of water],
followed by extraction two times with 50.0mL of ethyl acetate. The
recovered organic layer was concentrated under reduced pressure, followed
by vacuum drying, thereby obtaining a crude product of 4-fluoroproline
derivative represented by the following formula,
[Chemical Formula 20]

as a brown-color, oil-like substance. The recovered amount of the crude
product was slightly greater than the weight of the theoretical yield.
Selectivity of the crude product was found by gas chromatography
measurement to be 82.4% (As major three kinds of impurities were named
Impurities A-C, Impurity A, Impurity B and Impurity C were respectively
contained by 8.2%, 3.3% and 4.9%.) Instrument data of the crude product of
the obtained 4-fluoroproline derivative are shown in the following (assigned
as a mixture of E/Z isomers resulting from the NBoc group). It was found
by 19F-NMR spectrum that the crude product did not contain at all a salt
(FSO3H Et3N or FSO3K) derived from fluorosulfuric acid.
1H-NMR (standard substance: Me4Si, heavy solvent: CDCl3), δppm:
1.43&1.49 (sx2, total 9H), 1.95-2.55 (total 2H), 3.51-3.94 (total 2H), 3.75 (S,
3H), 4.36-4.58 (total 1H), 5.10-5.31 (total 1H).

19F-NMR (standard substance: C6F6, heavy solvent: CDCl3), δppm: -11.27
(total 1F).
[EXAMPLE 2]
A pressure-proof reaction vessel made of stainless steel (SUS) was
charged with 2.45g (9.99mmol, 1.00eq) of 4-hydroxyproline derivative
represented by the following formula,
[Chemical Formula 21]

13.0mLof acetonitrile, 3.50g (34.59mmol, 3.46eq) of triethylamine, and 1.60g
(9.92mmol, 0.99eq) of triethylamine tris(hydrogen fluoride) complex,
followed by lowering the inside temperature to -40°C and then bubbling
2.00g (l9.60mmol, 1.96eq) of sulfuryl fluoride from a cylinder. The inside
temperature was returned to room temperature, and stirring was conducted
for 20 hours. Conversion of the reaction was found by gas chromatography
measurement to be 100%. The reaction-terminated liquid was poured into a
potassium carbonate aqueous solution [prepared from 6.30g (45.58mmol,
4.56eq) of potassium carbonate and 100.0mL of water], followed by
extraction two times with 100.0mL of ethyl acetate. The recovered organic
layer was concentrated under reduced pressure, followed by vacuum drying,
thereby obtaining a crude product of 4-fluoroproline derivative represented
by the following formula,
[Chemical Formula 22]

as a brown-color, oil-like substance. The recovered amount of the crude

product was slightly greater than the weight of the theoretical yield.
Selectivity of the crude product was found by gas chromatography
measurement to be 91.0% (As major three kinds of impurities were named
Impurities A-C, Impurity A, Impurity B and Impurity C were respectively
contained by 6.4%, 2.4% and 0.1%.) Instrument data of the crude product of
the obtained 4-fluoroproline derivative were similar to those of Example 1.
[EXAMPLE 3]
A pressure-proof reaction vessel made of stainless steel (SUS) was
charged with 12.30g (29.82mmol, 1.00eq) of 1-β-D-arabinofuranosyluracil
derivative represented by the following formula,
[Chemical Formula 23]

38.0mL of acetonitrile, 18.15g (l79.37mmol, 6.02eq) of triethylamine, and
19.30g (ll9.71mmol, 4.01eq) of triethylamine tris(hydrogen fluoride)
complex, followed by lowering the inside temperature to -40°C and then
bubbling 10.00g (97.98mmol, 3.29eq) of sulfuryl fluoride from a cylinder.
The inside temperature was returned to room temperature, and stirring was
conducted for 16 hours and 30 minutes and then at 40°C for 5 hours and 30
minutes. Conversion of the reaction was found by liquid chromatography
measurement to be not lower than 99%. The reaction-terminated liquid
was poured into a potassium carbonate aqueous solution [prepared from
58.00g (419.65mmol, 14.07eq) of potassium carbonate and 300.0mL of water],
followed by extraction two times with 300.0mL of ethyl acetate. The
recovered organic layer was washed with 200.0mL of 10% brine, followed by

concentration under reduced pressure and vacuum drying, thereby obtaining
12.83g of a crude product of 2'-deoxy2'-fluorouridine derivative represented
by the following formula,
[Chemical Formula 24]

as a brown-color, oil-like substance. The recovered amount of the crude
product was slightly greater than the weight of the theoretical yield.
Selectivity of the crude product was found by liquid chromatography
measurement to be 83.2%. Instrument data of the crude product of the
obtained 2'-deoxy-2'-fluorouridine derivative are shown in the following (four
kinds of diastereomers resulting from two THP groups were observed).
19F-NMR (standard substance: C6F6, heavy solvent: CDC13), δppm: -43.13 (dt,
51.9Hz, 15.4Hz), -42.50 (dt, 51.5Hz, 15.4Hz), -37.62 (dt, 51.5Hz, 15.0Hz),
-37.55 (dt, 51.9Hz, 15.0Hz)/total 1F.
[EXAMPLE 4]
A pressure-proof reaction vessel made of stainless steel (SUS) was
charged with 9.60g (81.27mmol, 1.00eq, optical purity: 98.4%ee) of an
optically-active, a-hydroxycarboxylate derivative represented by the
following formula,
[Chemical Formula 25]


27.0mL of mesitylene, and 8.50g (84.00mmol, 1.03eq) of triethylamine,
followed by lowering the inside temperature to -40°C and then bubbling
11.50 g (ll2.68mmol, 1.39eq) of sulfuryl fluoride from a cylinder. The
inside temperature was returned to room temperature, and stirring was
conducted for 22 hours and 10 minutes. Conversion of the reaction was
found by gas chromatography measurement to be 100%. The
reaction-terminated liquid was poured into a potassium carbonate aqueous
solution [prepared from 7.90g (57.16mmol, 0.70eq) of potassium carbonate
and 100.0mL of water], followed by extraction two times with 45.0mL of
mesitylene. The recovered organic layer was washed with a hydrochloric
acid brine (prepared from 95.0mL of 1N hydrochloric acid and 10.00g of
common salt), thereby obtaining 110.63g of a mesitylene solution of a crude
product of an optically-active, α-fluorocarboxylate derivative represented by
the following formula.
[Chemical Formula 26]

Selectivity of the crude product was found by gas chromatography
measurement to be not less than 99.0% (except mesitylene). The
mesitylene solution of the crude product was subjected to a fractional
distillation (81-90°C/20000Pa), thereby recovering 26.82g of a main fraction.
The main fraction was found by 1H-NMR spectrum to contain 46.90mmol of
the optically-active, α-fluorocarboxylate derivative, and the main fraction
concentration was 21.0wt%. The total yield was 58%. Optical purity and
instrument data of the main fraction of the obtained optically-active,
crfluorocarboxylate derivative are shown in the following.
Optical purity: 97.7%ee (It was determined by conducting a hydride
reduction using excessive aluminum lithium hydride in tetrahydrofuran,
then by leading the obtained (R)-2-fluoro-1-propanol into Mosher ester, and

then by conducting gas chromatography. Asymmetry transcription
percentage was 99.3%.)
1H-NMR (standard substance: Me4Si, heavy solvent: CDCl3), δppm: 1.32 (t,
7.2Hz, 3H), 1.58 (dd, 23.6Hz, 6.9Hz, 3H), 4.26 (q, 7.2Hz, 2H), 5.00 (dq,
49.0Hz, 6.9Hz, 1H).
19F-NMR (standard substance: C6F6, heavy solvent: CDCl3), δppm: -21.88 (dq,
48.9Hz, 24.4Hz, 1F)
[EXAMPLE 5]
A pressure-proof reaction vessel made of stainless steel (SUS) was
charged with 3.50g (15.00mmol, 1.00eq) of a primary alcohol derivative
represented by the following formula,
[Chemical Formula 27]

30.0mL of acetonitrile, 8.35g (82.52mmol, 5.50eq) of triethylamine, and 4.84g
(30.02mmol, 2.00eq) of triethylamine tris(hydrogen fluoride) complex,
followed by lowering the inside temperature to -40°C and then bubbling
7.86g (77.01mmol, 5.13eq) of sulfuryl fluoride from a cylinder. The inside
temperature was returned to room temperature, and stirring was conducted
for 1 hr and 10 minutes. Stirring was further conducted at 60°C for 39
hours and 30 minutes. Conversion of the reaction was found by gas
chromatography measurement to be 100%. 50.0mL of water were added to
the reaction-terminated liquid, followed by concentration under reduced
pressure, then adding 50.0mL of water to the concentrated residue, and then
conducting an extraction one time with 100.0mL of ethyl acetate. The
recovered organic layer was dried with anhydrous sodium sulfate, followed
by concentration under reduced pressure and vacuum drying, thereby
obtaining 2.72g of a crude product of a monofluoromethyl derivative

represented by the following formula,
[Chemical Formula 28]

as a dark brown color, oil-like substance. Selectivity of the crude product
was found by gas chromatography measurement to be 69.4%. The crude
product was found by internal standard method (internal standard
substance: C6F6) of 19F-NMR to contain 3.45mmol of the monofluoromethyl
derivative. The yield was 23%. Instrument data of the crude product of
the obtained monofluoromethyl derivative are shown in the following.
1H-NMR (standard substance: Me4Si, heavy solvent: CDCl3), δppm: 0.90 (d,
6.8Hz, 3H), 1.08 (d, 6.8Hz, 3H), 2.44 (m, 1H), 4.24 (m, 1H), 4.76 (ddd, 46.6Hz,
9.5Hz, 4.8Hz, 1H), 5.01 (dt, 46.6Hz, 9.5Hz, 1H), 7.74 (Ar-H, 2H), 7.86 (Ar-H,
2H).
19F-NMR (standard substance: C6F6, heavy solvent: CDCl3), δppm: -62.12 (dt,
13.3Hz, 46.6Hz, 1F).
It is possible to produce the primary alcohol derivative of the raw
material substrate from a commercial optically active valinol by referring to
Protective Groups in Organic Synthesis, Third Edition, 1999, John Wiley &
Sons, Inc. The obtained monofluoromethyl derivative can be converted to
optically active l-isopropyl-2-fluoroethylamine without damaging optical
purity by referring to the same book.
[EXAMPLE 6]
A pressure-proof reaction vessel made of stainless steel (SUS) was
charged with 1.39g (7.98mmol, 1.00eq) of a primary alcohol derivative
represented by the following formula,
[Chemical Formula 29]


16.0mL of acetonitrile, 4.45g (43.98mmol, 5.51eq) of triethylamine, and 2.58g
(16.00mmol, 2.01eq) of triethylamine tris(hydrogen fluoride) complex,
followed by lowering the inside temperature to -40°C and then bubbling
3.00g (29.39mmol, 3.68eq) of sulfuryl fluoride from a cylinder. The inside
temperature was returned to room temperature, and stirring was conducted
for 19 hr and 15 minutes. Conversion of the reaction was found by gas
chromatography measurement to be 100%. 10.0mL of water were added to
the reaction-terminated liquid, followed by concentrating acetonitrile under
reduced pressure and then conducting an extraction of the concentrated
residue one time with 30.0mL of ethyl acetate. The recovered organic layer
was washed with 10.0mL of saturated brine, followed by drying with
anhydrous sodium sulfate, concentration under reduced pressure and
vacuum drying, thereby obtaining 0.36g of a crude product of a
monofluoromethyl derivative represented by the following formula,
[Chemical Formula 30]

as a brown color, oil-like substance. Selectivity of the crude product was
found by gas chromatography measurement to be 98.6%. The yield was
26%. Instrument data of the crude product of the obtained
monofluoromethyl derivative are shown in the following.
1H-NMR (standard substance: Me4Si, heavy solvent: CDCl3), δppm: 1.42-1.88
(m, 10H), 3.35-3.52 (m, 2H), 3.70-3.88 (m, 2H), 4.45 (dt, 46.8Hz, 6.1Hz, 2H),
4.56 (m, 1H).
19F-NMR (standard substance: C6F6, heavy solvent: CDCl3), δppm: -56.37
(septet, 23.4Hz, 1F).
It is possible to produce the primary alcohol derivative of the raw
material substrate from a commercial optically active 1,4-butanediol by
referring to Protective Groups in Organic Synthesis, Third Edition, 1999,

John Wiley & Sons, Inc. The obtained monofluoromethyl derivative can be
converted to 4-fluoro-1-butanol by referring to the same book.
[EXAMPLE 7]
A pressure-proof reaction vessel made of stainless steel (SUS) was
charged with 1.58g (9.98mmol, 1.00eq) of a primary alcohol derivative
represented by the following formula,
[Chemical Formula 31]

20.0mL of acetonitrile, 5.57g (55.04mmol, 5.52eq) of triethylamine, and 3.22g
(l9.97mmol, 2.00eq) of triethylamine tris(hydrogen fluoride) complex,
followed by lowering the inside temperature to -40°C and then bubbling
2.04g (l9.99mmol, 2.00eq) of sulfuryl fluoride from a cylinder. The inside
temperature was returned to room temperature, and stirring was conducted
for 22 hr and 20 minutes. Conversion of the reaction was found by gas
chromatography measurement to be 100%. 20.0mL of water were added to
the reaction-terminated liquid, followed by conducting an extraction one
time with 20.0mL of ethyl acetate. The recovered organic layer was washed
with 20.0mL of water and then with 20.0mL of saturated brine, followed by
drying with anhydrous sodium sulfate and concentration under reduced
pressure, thereby obtaining a crude product of a monofluoromethyl
derivative represented by the following formula,
[Chemical Formula 32]

as a brown color, oil-like substance. Selectivity of the crude product was
found by gas chromatography measurement to be 94.2%. The crude product
was found by internal standard method (internal standard substance: C6F6)
of 19F-NMR to contain 2.10mmol of the monofluoromethyl derivative. The
yield was 21%. Instrument data of the crude product of the obtained
monofluoromethyl derivative are shown in the following.

1H-NMR (standard substance: Me4Si, heavy solvent: CDCl3), δppm: 0.89 (t,
6.8Hz, 3H), 1.20-1.45 (m, 14H), 1.60-1.70 (m, 2H), 4.44 (dt, 47.6Hz, 6.2Hz,
2H).
19F-NMR (standard substance: C6F6, heavy solvent: CDCl3), δppm: -55.97
(septet, 23.8Hz, 1F).
A commercial product was used as the primary alcohol derivative of
the raw material substrate.

We Claim:
1. A process for producing a fluoro derivative, which is represented by the
formula [2],

by reacting a hydroxy derivative, which is represented by the formula [1],

with sulfuryl fluoride (SO2F2) in the presence of an organic base,
wherein in formula [1] and formula [2], each of R, R1 and R2 is
independently a hydrogen atom, an alkyl group, a substituted alkyl group, an
aromatic ring group, or an alkoxycarbonyl group.
2. A process for producing a fluoro derivative according to claim 1, wherein
the reaction is conducted by making a salt or complex comprising an organic
base and hydrogen fluoride further present in the system.
3. A process for producing a fluoro derivative, which is represented by the
formula [2a],

by reacting a hydroxy derivative, which is represented by the formula [1a],


with sulfuryl fluoride (SO2F2) in the presence of an organic base,
wherein
in formula [1a] and formula [2a], each of R, R1 and R2 independently
represents a hydrogen atom, an alkyl group, a substituted alkyl group, an
aromatic ring group, or an alkoxycarbonyl group,
the alkyl group is defined as being a C1-C16 straight-chain or branched
alkyl group,
the substituted alkyl group is defined as being an alkyl group, in which a
halogen atom, lower alkoxy group, lower haloalkoxy group, lower alkylamino
group, lower alkylthio group, cyano group, aminocarbonyl group (CONH2),
unsaturated group, aromatic ring group, nucleic acid base, aromatic-ring oxy
group, aliphatic heterocyclic group, protected hydroxyl group, protected amino
group, protected thiol group, or protected carboxyl group has been substituted
therefor by any number and by any combination on any carbon atom of the
alkyl group,
any carbon atoms themselves of any two alkyl groups or substituted
alkyl groups may form a covalent bond to have an aliphatic ring, and carbon
atoms of the aliphatic ring may be partially replaced with a nitrogen atom or
oxygen atom to have an aliphatic heterocyclic ring,
the aromatic ring group is defined as being an aromatic hydrocarbon
group or aromatic heterocyclic group containing oxygen atom, nitrogen atom or
sulfur atom, and
the alkoxycarbonyl group is defined as being an alkoxycarbonyl group
comprising an (C1-C12 straight-chain or branched alkoxy group, and any carbon
atoms themselves of the alkoxy group and of any alkyl group or substituted
alkyl group may form a covalent bond to have a lactone ring.

4. A process for producing a fluoro derivative according to claim 3, wherein
the reaction is conducted by making a salt or complex comprising an organic
base and hydrogen fluoride further present in the system.
5. A process for producing an optically-active, fluoro derivative, which is
represented by the formula [4],

by reacting an optically-active, hydroxy derivative, which is represented by the
formula [3],

with sulfuryl fluoride (SO2F2) in the presence of an organic base,
wherein
in formula [3] and formula [4], each of R and R1 is independently an alkyl
group, a substituted alkyl group, or an alkoxycarbonyl group,
* indicates an asymmetric carbon,
the alkyl group is defined as being a C1-C16 straight-chain or branched
alkyl group,
the substituted alkyl group is defined as being an alkyl group, in which a
halogen atom, lower alkoxy group, lower haloalkoxy group, lower alkylamino
group, lower alkylthio group, cyano group, aminocarbonyl group (CONH2),
unsaturated group, aromatic ring group, nucleic acid base, aromatic-ring oxy
group, aliphatic heterocyclic group, protected hydroxyl group, protected amino
group, protected thiol group, or protected carboxyl group has been substituted
therefor by any number and by any combination on any carbon atom of the

alkyl group,
any carbon atoms themselves of two alkyl groups or substituted alkyl
groups may form a covalent bond to have an aliphatic ring, and carbon atoms of
the aliphatic ring may be partially replaced with a nitrogen atom or oxygen
atom to have an aliphatic heterocyclic ring,
the alkoxycarbonyl group is defined as being an alkoxycarbonyl group
comprising an C1-C12 straight-chain or branched alkoxy group, and any carbon
atoms themselves of the alkoxy group and of any alkyl group or substituted
alkyl group may form a covalent bond to have a lactone ring, and
stereochemistry of the carbon atom, to which the hydroxyl group is
covalently bonded, is inverted through the reaction.
6. A process for producing an optically-active, fluoro derivative according to
claim 5, wherein the reaction is conducted by making a salt or complex
comprising an organic base and hydrogen fluoride further present in the
system.
7. A process for producing a 4-fluoroproline derivative, which is represented
by the formula [6],

by reacting a 4-hydroxyproline derivative, which is represented by the formula
[5],


with sulfuryl fluoride (SO2F2) in the presence of an organic base,
wherein in formula [5] and formula [6], R3 represents a protecting group
of the secondary amino group, R4 represents a protecting group of the carboxyl
group, * indicates an asymmetric carbon, and stereochemistry of the 4-position
is inverted through the reaction, and stereochemistry of the 2-position is
maintained.
8. A process for producing a 4-fluoroproline derivative according to claim 7,
wherein the reaction is conducted by making a salt or complex comprising an
organic base and hydrogen fluoride further present in the system.
9. A process for producing a 2'-deoxy-2'-fluorouridine derivative, which is
represented by the formula [8],

by reacting a 1-β-D-arabinofuranosyluracil derivative, which is represented by
the formula [7],


with sulfuryl fluoride (SO2F2) in the presence of an organic base,
wherein in formula [7] and formula [8], each of R5 and R6 independently
represents a protecting group of the hydroxyl group.
10. A process for producing a 2'-deoxy2'-fluorouridine derivative according to
claim 9, wherein the reaction is conducted by making a salt or complex
comprising an organic base and hydrogen fluoride further present in the
system.
11. A process for producing an optically-active, orfluorocarboxylate
derivative, which is represented by the formula [10],

by reacting an optically-active, α-rhydroxycarboxylate derivative, which is
represented by the formula [9],

with sulfuryl fluoride (SO2F2) in the presence of an organic base,
wherein in formula [9] and formula [10], R7 represents a C1-C12 alkyl
group or substituted alkyl group, R8 represents a C1-C8 alkyl group, any carbon
atoms themselves of the alkyl group or of the substituted alkyl group of R7 and
R8 may form a covalent bond to have a lactone ring, * indicates an asymmetric
carbon, and stereochemistry of the α-position is inverted through the reaction.
12. A process for producing an optically-active, orfluorocarboxylate
derivative according to claim 11, wherein the reaction is conducted by making a
salt or complex comprising an organic base and hydrogen fluoride further
present in the system.

13. A process for producing a monofluoromethyl derivative, which is
represented by the formula [12],

by reacting a primary alcohol derivative, which is represented by the formula
[11],

with sulfuryl fluoride (SO2F2) in the presence of an organic base,
wherein in formula [11] and formula [12], R represents an alkyl group or
substituted alkyl group,
the alkyl group is defined as being a C1-C16 straight-chain or branched
alkyl group,
the substituted alkyl group is defined as being an alkyl group, in which a
halogen atom, lower alkoxy group, lower haloalkoxy group, lower alkylamino
group, lower alkylthio group, cyano group, aminocarbonyl group (CONH2),
unsaturated group, aromatic ring group, nucleic acid base, aromatic-ring oxy
group, aliphatic heterocyclic group, protected hydroxyl group, protected amino
group, protected thiol group, or protected carboxyl group has been substituted
therefor by any number and by any combination on any carbon atom of the
alkyl group.

14. A process for producing a monofluoromethyl derivative according to claim
13, wherein the reaction is conducted by making a salt or complex comprising
an organic base and hydrogen fluoride further present in the system.


It was found that a fluoro derivative can be produced by reacting
a hydroxy derivative with sulfuryl fluoride (SO2F2) in the presence of an
organic base or in the presence of an organic base and "a salt or
complex comprising an organic base and hydrogen fluoride".
According to the present production process, it is not necessary to use
perfluoroalkanesulfonyl fluoride, which is not preferable in industrial use,
and it is possible to advantageously produce optically-active fluoro
derivatives, which are important intermediates of medicines, agricultural
chemicals and optical materials, specifically 4-fluoroproline derivatives,
2'-deoxy-2'-fluorouridine derivatives, optically-active α-fluorocarboxylate
derivatives, and the like, even in a large scale.

Documents:

02802-kolnp-2007-abstract.pdf

02802-kolnp-2007-claims.pdf

02802-kolnp-2007-correspondence others 1.1.pdf

02802-kolnp-2007-correspondence others.pdf

02802-kolnp-2007-description complete.pdf

02802-kolnp-2007-form 1.pdf

02802-kolnp-2007-form 2.pdf

02802-kolnp-2007-form 3 1.1.pdf

02802-kolnp-2007-form 3.pdf

02802-kolnp-2007-form 5.pdf

02802-kolnp-2007-gpa.pdf

02802-kolnp-2007-international search report.pdf

02802-kolnp-2007-others.pdf

02802-kolnp-2007-priority document.pdf

2802-KOLNP-2007-ABSTRACT.pdf

2802-KOLNP-2007-AMANDED CLAIMS-1.1.pdf

2802-KOLNP-2007-AMANDED CLAIMS.pdf

2802-KOLNP-2007-CORRESPONDENCE-1.1.pdf

2802-KOLNP-2007-CORRESPONDENCE.pdf

2802-kolnp-2007-correspondence1.2.pdf

2802-KOLNP-2007-DESCRIPTION (COMPLETE).pdf

2802-KOLNP-2007-ENGLISH TRANSLATION.pdf

2802-kolnp-2007-examination report.pdf

2802-KOLNP-2007-FORM 1.pdf

2802-kolnp-2007-form 18.1.pdf

2802-kolnp-2007-form 18.pdf

2802-KOLNP-2007-FORM 2.pdf

2802-kolnp-2007-form 26.pdf

2802-KOLNP-2007-FORM 3-1.2.pdf

2802-kolnp-2007-form 3.pdf

2802-kolnp-2007-form 5.pdf

2802-KOLNP-2007-FORM-27.pdf

2802-kolnp-2007-granted-abstract.pdf

2802-kolnp-2007-granted-claims.pdf

2802-kolnp-2007-granted-description (complete).pdf

2802-kolnp-2007-granted-form 1.pdf

2802-kolnp-2007-granted-form 2.pdf

2802-kolnp-2007-granted-specification.pdf

2802-KOLNP-2007-INTERNATIONAL SEARCH REPORT.1.1.pdf

2802-KOLNP-2007-OTHERS-1.1.pdf

2802-KOLNP-2007-OTHERS.pdf

2802-kolnp-2007-others1.2.pdf

2802-KOLNP-2007-PETITION UNDER RULE 137.pdf

2802-KOLNP-2007-REPLY TO EXAMINATION REPORT.pdf

2802-kolnp-2007-reply to examination report1.1.pdf

2802-kolnp-2007-translated copy of priority document.pdf


Patent Number 248219
Indian Patent Application Number 2802/KOLNP/2007
PG Journal Number 26/2011
Publication Date 01-Jul-2011
Grant Date 28-Jun-2011
Date of Filing 01-Aug-2007
Name of Patentee CENTRAL GLASS COMPANY, LIMITED
Applicant Address 5253, OAZA OKIUBE, UBE-SHI, YAMAGUCHI
Inventors:
# Inventor's Name Inventor's Address
1 TAKASHI OOTSUKA C/O CHEMICAL RESEARCH CENTER OF CENTRAL GLASS COMPANY, LIMITED 2805, IMAFUKUNAKADAI, KAWAGOE-SHI, SAITAMA 350-1151
2 MANABU YUSUMOTO C/O CHEMICAL RESEARCH CENTER OF CENTRAL GLASS COMPANY, LIMITED 2805, IMAFUKUNAKADAI, KAWAGOE-SHI, SAITAMA 350-1151
3 HIDEYUKI TSURUTA C/O CHEMICAL RESEARCH CENTER OF CENTRAL GLASS COMPANY, LIMITED 2805, IMAFUKUNAKADAI, KAWAGOE-SHI, SAITAMA 350-1151
4 KENJIN INOMIYA C/O CHEMICAL RESEARCH CENTER OF CENTRAL GLASS COMPANY, LIMITED 2805, IMAFUKUNAKADAI, KAWAGOE-SHI, SAITAMA 350-1151
5 KOJI UEDA C/O CHEMICAL RESEARCH CENTER OF CENTRAL GLASS COMPANY, LIMITED 2805, IMAFUKUNAKADAI, KAWAGOE-SHI, SAITAMA 350-1151
6 KAORI MOGI C/O CHEMICAL RESEARCH CENTER OF CENTRAL GLASS COMPANY, LIMITED 2805, IMAFUKUNAKADAI, KAWAGOE-SHI, SAITAMA 350-1151
7 AKIHIRO ISHII C/O CHEMICAL RESEARCH CENTER OF CENTRAL GLASS COMPANY, LIMITED 2805, IMAFUKUNAKADAI, KAWAGOE-SHI, SAITAMA 350-1151
PCT International Classification Number C07C 17/16
PCT International Application Number PCT/JP2006/305435
PCT International Filing date 2006-03-17
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2005-379257 2005-12-28 Japan
2 2005-079641 2005-03-18 Japan