TECHNICAL FIELD
[0001] The present invention relates to a process for producing an optically active,
fluorine-containing, benzyl alcohol, which is an important intermediate of medicines.
BACKGROUND OF THE INVENTION
[0002] A process for producing an optically active, fluorine-containing, benzyl alcohol
by optically resolving a phthalate half ester of racemic, fluorine-containing, benzyl
alcohol by an optically active 1-phenylethylamine and then by hydrolyzing the ester
group is publicly known (Non-patent Publication 1 and Non-patent Publication 2).
[0003] On the other hand, the following process is disclosed in Non-patent Publication
1 and Non-patent Publication 2 as a process for preparing "a phthaiate half ester of
racemic, fluorine-containing, benzyl alcohol" which is the starting compound of the
process.
[0004] That is, in Non-patent Publication 1, a process is taken (the following scheme)
in which a fluorine-containing benzaldehyde is reacted with an alkyl Grignard reagent to
obtain a magnesium alkoxide of racemic, fluorine-containing, benzyl alcohol, then the
magnesium alkoxide is converted to a racemic, fluorine-containing, benzyl alcohol, then
the racemic, fluorine-containing, benzyl alcohol is once isolated and purified, and newly
under a basic condition it is reacted with phthalic anhydride (the following scheme).
[Chemical Formula 1]
Scheme of Non-patent Publication 1 (Preparation Method of [4])

[0005] On the other hand, in Non-patent Publication 2, a process is taken
(the following scheme) in which an aliphatic aldehyde is reacted with a
fluorine-containing phenyl Grignard reagent, thereby converting it to a
magnesium alkoxide of racemic, fluorine-containing, benzyl alcohol, and
subsequently it is reacted directly with phthalic anhydride.
[Chemical Formula 2]
Scheme of Non-patent Publication 2 (Preparation Method of [4])

Non-patent Publication 1: Journal of the American Chemical Society (US),
1990, Vol. 112, No. 15, p. 5741-5747
Non-patent Publication 2: Journal of the American Chemical Society (US),
1985, Vol. 107, No. 15, p. 4513-4519
SUMMARY OF THE INVENTION
[0006] It is an object of the present invention to provide a process of an
efficient optical resolution of a fluorine-containing benzyl alcohol, which is
an important intermediate of medicines. A process, in which "a phthalate
half ester of racemic, fluorine-containing, benzyl alcohol" is optically resolved
by an optically active 1-phenylethylamine, and then the ester group is
hydrolyzed, is important as a process that is wide in substrate adaptation
range, since it provides a fluorine-containing benzyl alcohol of high optical
purity, irrespective of the substitution position of the fluorine-containing
substituent.
[0007] However, in the preparation processes mentioned in Non-patent
Publication 1 and Non-patent Publication 2, there has been a problem in
which the "phthalate half ester of racemic, fluorine-containing, benzyl
alcohol" cannot be prepared easily and with good yield. Actually, in
Non-patent Publication 1, the synthesis of "racemic, fluorine-containing,
benzyl alcohol" and the synthesis of the "phthalate half ester" were
conducted separately. Thus, the operation was very complicated in
industrial practice [the total yield based on 2-trifluoromethylbenzaldehyde
was 61% (RMgX was CH3MgBr)].
[0008] In Non-patent Publication 2, the operation is very easy, since the
magnesium alkoxide formed in the reaction system is reacted directly with
phthalic anhydride without isolation of the racemic, fluorine-containing,
benzyl alcohol. However, "a magnesium alkoxide of racemic,
fluorine-containing, benzyl alcohol" derived from an aliphatic aldehyde and a
fluorine-containing phenyl Grignard reagent did not show a good reactivity
to phthalic anhydride. Therefore, it was not possible to obtain the target
"phthalate half ester of racemic, fluorine-containing, benzyl alcohol" with
good yield [the total yield based on 3-trifluoromethylphenylmagnesium
bromide (3-trifluoromethylphenyl bromide) was 43% (the aliphatic aldehyde
was CH3CHO)].
[0009] Thus, there has been a strong demand for a process capable of
preparing a phthalate half ester of racemic, fluorine-containing, benzyl
alcohol with ease and good yield in optical resolution of the
fluorine-containing, benzyl alcohol.
[0010] As a result of an eager examination to solve the above task, the
present inventors have found that a phthalate half ester of racemic,
fluorine-containing, benzyl alcohol can be prepared very easily and with good
yield by reacting a fluorine-containing benzaldehyde with an alkyl Grignard
reagent to convert it to a magnesium alkoxide of racemic, fluorine-containing,
benzyl alcohol, and by subsequently reacting it with phthalic anhydride
(with a total yield of preferably 80% or greater, more preferably 90% or
greater, based on the fluorine-containing benzaldehyde).
[0011] The reason for good-yield preparation as compared with Non-patent
Publication 2 is considered to be no use of "aliphatic aldehyde", which tends
to cause side reactions, such as deprotonation of opposition proton and
addition to carbonyl group, by the formed magnesium alkoxide of racemic,
fluorine-containing, benzyl alcohol. In Non-patent Publication 2, the
racemic, fluorine-containing, benzyl alcohol is actually recovered in a
considerable amount (total yield: 28%), and it is considered that the
reactivity to phthalic anhydride is greatly lowered through the side
reactions.
[0012] Furthermore, the present inventors have found that the target,
optically active, fluorine-containing, benzyl alcohol can be produced with
optically and chemically very high purities by optically resolving the
obtained half ester by optically active 1-phenylethylamine and then by
hydrolyzing the ester group (the following scheme).
[Chemical Formula 3]

[0013] That is, the present invention provides a process (first process) for producing an
optically active, fluorine-containing, benzyl alcohol represented by formula [5]
[Chemical Formula 8]

[0014] [in the formula, m, n and R are the same as below, and * represents that it is an
optically active body] by reacting a fluorine-containing benzaldehyde represented by
formula [1]
[Chemical Formula 4]

[0015] [in the formula, m represents the number of substituents of fluorine
atoms and takes an integer selected from 0, 1, 2, 3, 4 or 5, n represents the
number of substituents of trifluoromethyl groups and takes an integer
selected from 0, 1, 2 or 3, m and n do not take 0 at the same time, and the
total of m and n takes 5 or less] with an alkyl Grignard reagent represented
by formula [2]
[Chemical Formula 5]

[0016] [in the formula, R represents an alkyl group of a carbon number of
1-6, and X represents a halogen atom selected from chlorine, bromine and
iodine], to convert it to a magnesium alkoxide of racemic, fluorine-containing,
benzyl alcohol represented by formula [3]
[Chemical Formula 6]

[0017] [in the formula, m, n, R and X are the same as above, and the wavy
line represents that it is a racemate], and subsequently by reacting the
magnesium alkoxide with phthalic anhydride to obtain a phthalate half ester
of racemic, fluorine-containing, benzyl alcohol represented by formula [4]
[Chemical Formula 7]

[0018] [in the formula, m, n, R and the wavy line are the same as above], by
optically resolving the half ester by optically active 1-phenylethylamine, and
then by hydrolyzing the ester group.
[0019] The above first process may be a process (second process) for
producing an optically active, fluorine-containing, benzyl alcohol represented
by formula [10]
[Chemical Formula 13]

[0020] [in the formula, * represents that it is an optically active body] by
reacting a fluorine-containing benzaldehyde represented by formula [6]
[Chemical Formula 9]

[0021] with an alkyl Grignard reagent represented by formula [7]
[Chemical Formula 10]

[0022] to convert it to a magnesium alkoxide of racemic, fluorine-containing,
benzyl alcohol represented by formula [8]
[Chemical Formula 11]

[0023] [in the formula, the wavy line represents that it is a racemate] and
subsequently by reacting the magnesium alkoxide with phthalic anhydride
to obtain a phthalate half ester of racemic, fluorine-containing, benzyl
alcohol represented by formula [9]
[Chemical Formula 12]

[0024] [in the formula, the wavy line is the same as above], by optically
resolving the half ester by optically active 1-phenylethylamine, and then by
hydrolyzing the ester group.
[0025] The above first process may a process (third process) for producing
an optically active, fluorine-containing, benzyl alcohol represented by
formula [14]
[Chemical Formula 18]

[0026] [in the formula, * represents that it is an optically active body] by
reacting a fluorine-containing benzaldehyde represented by formula [11]
[Chemical Formula 14]

[0027] with an alkyl Grignard reagent represented by formula [7]
[Chemical Formula 15]

[0028] to convert it to a magnesium alkoxide of racemic, fluorine-containing,
benzyl alcohol represented by formula [12]
[Chemical Formula 16]

[0029] [in the formula, the wavy line represents that it is a racemate] and
subsequently by reacting the magnesium alkoxide with phthalic anhydride
to obtain a phthalate half ester of racemic, fluorine-containing, benzyl
alcohol represented by formula [13]
[Chemical Formula 17]

[0030] [in the formula, the wavy line is the same as above], by optically
resolving the half ester by optically active 1-phenylethylamine, and then by
hydrolyzing the ester group.
DETAILED DESCRIPTION
[0031] The present invention is characterized in the preparation process of
a phthalate half ester of racemic, fluorine-containing benzyl alcohol, and it is
possible to prepare the half ester from a fluorine-containing benzaldehyde
easily and with a total yield of 80% or greater (more preferably 90% or
greater). As a result of this, it is possible to efficiently produce an optically
active, fluorine-containing, benzyl alcohol.
[0032] Advantageous points of the production process of the present
invention as compared with the conventional production techniques are
described in the following. As compared with the preparation process
written in Non-patent Publication 1, it is not necessary to isolate the racemic,
fluorine-containing, benzyl alcohol, and it is possible to continuously conduct
the two reactions as one-pot reaction. Therefore, the operation is very easy
in industrial practice. As compared with the preparation process written in
Non-patent Publication 2, a magnesium alkoxide of racemic,
fluorine-containing, benzyl alcohol, which is derived from a
fluorine-containing benzaldehyde and an alkyl Grignard reagent, shows a
very good reactivity to phthalic anhydride. Therefore, the target phthalate
half ester of racemic, fluorine-containing, benzyl alcohol can be obtained
with an extremely good yield.
[0033] In the following, the production process (the above first process) of
the present invention is explained in detail.
[0034] Firstly, the step (step I) of reacting a fluorine-containing
benzaldehyde represented by formula [1] with an alkyl Grignard reagent
represented by formula [2] is described.
[0035] The fluorine atoms or trifluoromethyl groups of the
fluorine-containing benzaldehyde represented by formula [1] can take
arbitrary substitution positions. Specifically, it is possible to cite
2-fluorobenzaldehyde, 3-fluorobenzaldehyde, 4-fluorobenzaldehyde,
2,4-difluorobenzaldehyde, 2,6-difluorobenzaldehyde,
3,5-difluorobenzaldehyde, 3,4,5-trifluorobenzaldehyde,
2,3,4,5,6-pentafluorobenzaldehyde, 2-trifluoromethylbenzaldehyde,
3-trifluoromethylbenzaldehyde, 4-trifluoromethylbenzaldehyde,
3,5-bis(trifluoromethyl)benzaldehyde,
2-fluoro-3-trifluoromethylbenzaldehyde,
2-fluoro-4-trifluoromethylbenzaldehyde,
2-fluoro-5-trifluoromethylbenzaldehyde,
2-fluoro-6-trifluoromethylbenzaldehyde,
3-fluoro-2-trifluoromethylbenzaldehyde,
3-fluoro-4-trifluoromethylbenzaldehyde,
3-fluoro-5-trifluoromethylbenzaldehyde,
3-fluoro-6-trifluoromethylbenzaldehyde,
4-fluoro-2-trifluoromethylbenzaldehyde,
4-fluoro-3-trifluoromethylbenzaldehyde, and the like.
[0036] The optically active, fluorine-containing, benzyl alcohol represented
by formula [5], which is the target in the present invention, can also be
synthesized by an asymmetric reduction of the corresponding
fluorine-containing, phenylalkyl ketone. Effectiveness of the present
invention can be obtained to the maximum, in case that the ketone has an
extremely high price as compared with the fluorine-containing benzaldehyde,
which is the raw material substrate of the present invention and that the
reaction between the aldehyde and the alkyl Grignard reagent represented
by formula [2] proceeds well without by-production of a reduced body
[ArCH2OMgX (Ar represents a fluorine-containing phenyl group, and X
represents a halogen atom selected from chlorine, bromine and iodine] and
the like.
[0037] As a fluorine-containing benzaldehyde satisfying such requirements,
it is possible to cite one having a fluorine-containing substituent at
ortho-position. Therefore, of the above specific examples, preferable ones
are 2-fluorobenzaldehyde, 2,4-difluorobenzaldehyde,
2,6-difluorobenzaldehyde, 2,3,4,5,6-pentafluorobenzaldehyde,
2-trifluoromethylbenzaldehyde, 2-fluoro-3-trifluoromethylbenzaldehyde,
2-fluoro-4-trifluoromethylbenzaldehyde,
2-fluoro-5-trifluoromethylbenzaldehyde,
2-fluoro-6-trifluoromethylbenzaldehyde,
3-fluoro-2-trifluoromethylbenzaldehyde,
3-fluoro-6-trifluorometb.ylbenzaldeb.yde, and
4-fluoro-2-trifluorometb.ylbenzaldehyde. In particular,
2-fluorobenzaldehyde and 2-trifluoromethylbenzaldehyde are more
preferable.
[0038] As R of the alkyl Grignard reagent represented by formula [2], it is
possible to cite methyl, ethyl, propyl, butyl, pentyl and hexyl. One having a
carbon number of 3 or greater can take a straight-chain or branched form.
[0039] X of the alkyl Grignard reagent represented by formula [2] is
selected from chlorine, bromine and iodine. In the present invention, it is
particularly important to conduct a good reaction between a magnesium
alkoxide of racemic, fluorine-containing, benzyl alcohol represented by
formula [3], which is derived from the fluorine-containing benzaldehyde
represented by formula [1] and the alkyl Grignard reagent, and phthalic
anhydride. This reactivity is influenced by the type of X. Therefore, of the
above halogen atoms, chlorine and bromine, with which nucleophilicity of the
magnesium alkoxide becomes higher, are preferable, and in particular
chlorine is more preferable.
[0040] The alkyl Grignard reagent represented by formula [2] can be
prepared with reference to publicly known methods, for example, "Jikken
Kagaku Koza" 18 Synthesis of Organic Compounds VI -Organic Syntheses
Using Metals- p. 59-76, 5th Ed., Edited by The Chemical Society of Japan.
Furthermore, various constant concentration ether solutions are on the
market, and it is easy to use these.
[0041] The amount of the alkyl Grignard reagent represented by formula
[2] to be used is not particularly limited. Generally, it suffices to use it in
0.7 moles or greater relative to 1mol of the fluorine-containing benzaldehyde
represented by formula [1]. It is preferably 0.8-1.2 moles, particularly more
preferably 0.9-1.1 moles. Although even the use in less than 0.7 moles is
not particularly problematic, the fluorine "containing benzaldehyde remains
unreacted, and yield of the phthalate half ester of racemic,
fluorine-containing, benzyl alcohol represented by formula [4] shows a
tendency of decrease. Although even the use in 1.3 moles or greater is not
particularly problematic, the alkyl Grignard reagent remains in excess and
reacts with phthalic anhydride to consume it. Therefore, it is necessary to
use phthalic anhydride in excess. Thus, a range of 0.7-1.2 moles is
preferable to produce the phthalate half ester of racemic, fluorine-containing,
benzyl alcohol with good yield and economically.
[0042] The reaction solvent is not particularly limited. Generally,
ether-series solvents are preferable. Of them, diethyl ether,
tetrahydrofuran, tert-butyl methyl ether, dri-propyl ether, cyclopentyl
methyl ether, and 1,4-dioxane are preferable. In particular, diethyl ether,
tetrahydrofuran, tert-butyl methyl ether, and di-rpropyl ether are more
preferable. These reaction solvents can be used singly or in combination.
[0043] The amount of the reaction solvent used is not particularly limited.
Generally, it suffices to use it in 0.1L (liters) or greater relative to 1mol of the
fluorine-containing benzaldehyde represented by formula [1]. It is
preferably 0.15-5 L, particularly more preferably 0.2-3 L. In the case of
using a constant-concentration ether solution as the alkyl Grignard reagent
represented by formula [2], it is also possible to conduct the reaction only
with the part of the solvent contained in the ether solution without newly
using a reaction solvent.
[0044] The method of reacting the fluorine-containing benzaldehyde
represented by formula [1] with the alkyl Grignard reagent represented by
formula [2] is not particularly limited. It is preferable that an ether
solution of the alkyl Grignard reagent is cooled normally under an inert gas
atmosphere, and under stirring the fluorine-containing benzaldehyde (or a
solution diluted with the reaction solvent) is gradually added, thereby
conducting the reaction with stirring under a further cooled condition.
Although even a method of adding the alkyl Grignard reagent to the
fluorine-containing benzaldehyde is not particularly problematic, the former
method is more preferable to prevent by-production of the above reduced
body and the like and to industrially safely handle the alkyl Grignard
reagent.
[0045] The temperature condition is not particularly limited. Generally, it
suffices to conduct it in a range of-100 to +100°C, preferably -80 to +80°C,
particularly more preferably -60 to +60°C.
[0046] The reaction time is not particularly limited. Generally, it suffices
to conduct it in a range of 24 hours or shorter. It depends on a combination
of the fluorine-containing benzaldehyde represented by formula [1] and the
alkyl Grignard reagent represented by formula [2], the reaction conditions
and the like. Therefore, it is preferable to trace the fluorine-containing
benzaldehyde remaining unreacted by an analytical means such as gas
chromatography, liquid chromatography, NMR or the like and to determine
a point at which the aldehyde has almost disappeared, as the end point.
[0047] Since the magnesium alkoxide of racemic, fluorine-containing,
benzyl alcohol represented by formula [3] is reacted directly with phthalic
anhydride in the present invention, a post-treatment of the
reaction-terminated liquid is not conducted. It is also possible to stably
keep the reaction-terminated liquid for a long time under an inert gas
atmosphere.
[0048] Next, the step (step II) of reacting the magnesium alkoxide of
racemic, fluorine-containing, benzyl alcohol represented by formula [3] with
phthalic anhydride is described.
[0049] The amount of phthalic anhydride used is not particularly limited.
Generally, it suffices to use 0.9 moles or greater, preferably 0.95-1.05 moles,
particularly more preferably an equimolar amount, relative to lmol of the
amount of the alkyl Grignard reagent represented by formula [2] to be used.
[0050] The reaction solvent is not particularly limited. Generally, the
above ether solvents are preferable.
[0051] The amount of the reaction solvent used is not particularly limited.
Generally, it is preferable to conduct the reaction only with the part of the
solvent contained in the reaction-terminated liquid, in which it has been
converted to the racemic, fluorine-containing, benzyl alcohol represented by
formula [3], without newly using a reaction solvent.
[0052] The method of reacting the magnesium alkoxide of racemic,
fluorine-containing, benzyl alcohol represented by formula [3] with phthalic
anhydride is not particularly limited. It is preferable that the
reaction-terminated liquid, in which it has been converted to the magnesium
alkoxide of racemic, fluorine-containing, benzyl alcohol, is cooled normally
under an inert gas atmosphere, and under stirring phthalic anhydride (or a
solution diluted with the reaction solvent) is gradually added, thereby
conducting the reaction with stirring at room temperature. Although even
a method of adding the alkoxide to phthalic anhydride is not particularly
problematic, the former method capable of adopting a one-pot reaction,
which is industrially easy, is more preferable.
[0053] The temperature condition is not particularly limited. Generally, it
suffices to conduct it in a range of-100 to +100°C, preferably -80 to +80°C,
particularly more preferably -60 to +60°C.
[0054] The reaction time is not particularly limited. Generally, it suffices
to conduct it in a range of 24 hours or shorter. It depends on the type of the
magnesium alkoxide of racemic, fluorine-containing, benzyl alcohol
represented by formula [3], the reaction conditions and the like. Therefore,
it is preferable to trace the magnesium alkoxide of racemic,
fluorine-containing, benzyl alcohol (or the corresponding racemic,
fluorine-containing, benzyl alcohol in the reaction check after hydrolysis)
remaining unreacted by an analytical means such as gas chromatography,
liquid chromatography, NMR or the like and to determine a point at which
the alkoxide (or the alcohol) has almost disappeared, as the end point.
[0055] The post-treatment is not particularly limited. Generally, it is
possible to obtain the target phthalate half ester of racemic,
fluorine-containing, benzyl alcohol represented by formula [4] by adding a
mineral acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, and the like) to the reaction-terminated liquid, followed by extraction
with an organic solvent (e.g., toluene, methylene chloride, ethyl acetate, and
the like). Furthermore, according to need, it can be purified to have a
higher chemical purity by activated carbon treatment, recrystallization,
distillation or column chromatography or the like.
[0056] Finally, the step (step III) of optically resolving the phthalate half
ester of racemic, fluorine-containing, benzyl alcohol represented by formula
[4] and then hydrolyzing the ester group.
[0057] The present step is publicly known, and it can be conducted with
reference to Organic Reactions (US), Vol. II, Chapter 9, p. 376-414,
Non-patent Publication 1 and Non-patent Publication 2. Therefore, it is not
limited to the following typical production method.
[0058] The present step is formed of (step IIPA) bringing the phthalate half
ester of racemic, fluorine-containing, benzyl alcohol represented by formula
[4] into contact with optically active 1-phenylethylamine to obtain a
diastereomer salt formed of the phthalate half ester of racemic,
fluorine-containing, benzyl alcohol and the optically active
1-phenylethylamine, which is represented by formula [15]
[Chemical Formula 19]

[0059] [in the formula, m represents the number of substituents of fluorine
atoms and takes an integer selected from 0, 1, 2, 3, 4 or 5, n represents the
number of substituents of trifluoromethyl groups and takes an integer
selected from 0, 1, 2 or 3, m and n do not take 0 at the same time, the total of
m and n takes 5 or less, R represents an alkyl group of a carbon number of
1-6, each of* independently represents that it is an optically active body, and
• represents that a salt is formed between the carboxyl group and amino
group], (step IIPB) conducting a recrystallization purification according to
need, and (step III-C) subsequently bringing the diastereomer salt into
contact with a strong acid, thereby recovering a phthalate half ester of
optically active, fluorine-containing, benzyl alcohol represented by formula
[16]
[Chemical Formula 20]

[0060] [in the formula, m, n, R and * are the same as above], and (step
III-D) finally under basic condition hydrolyzing the ester group, thereby
producing an optically active, fluorine-containing, benzyl alcohol represented
by formula [5].
[0061] The step III-A is described.
[0062] As the method of bringing the phthalate half ester of racemic,
fluorine-containing benzyl alcohol represented by formula [4] into contact
with optically active 1-phenylethylamine, it is possible to obtain a
diastereomer salt, which is represented by formula [15] and is formed of the
phthalate half ester of optically active, fluorine-containing, benzyl alcohol
and optically active 1-phenylethylamine, by adding the half ester and the
amine to a crystal precipitating solvent, by dissolving them through heating
at a temperature around boiling point of the solvent, by gradually decreasing
the temperature under standing still or stirring to sufficiently precipitate
crystals in a range of-30 to +30°C by spending 1 to 48 hours, and by filtering
the precipitated crystals.
[0063] As mentioned from the industrial viewpoint, a method is more
preferable in which the crystals are precipitated by adding optically active
1-phenylethylamine (or a solution diluted with the crystal precipitating
solvent) to the recovering organic layer, with which the phthalate half ester
of racemic, fluorine-containing, benzyl alcohol represented by formula [4] has
been extracted.
[0064] Furthermore, a phthalate half ester of fluorine-containing benzyl
alcohol (or a diastereomer salt formed of the half ester and optically active
1-phenylethylamine) having the inverse stereochemistry is contained in
excess in the filtrate. Therefore, it is possible to recover a phthalate half
ester of optically active, fluorine-containing, benzyl alcohol represented by
formula [16], which has the inverse stereochemistry, by conducting an
operation similar to that of the step IIPC on the concentration residue of the
filtrate.
[0065] Furthermore, it is also possible to produce an optically active,
fluorine-containing, benzyl alcohol represented by formula [5], which has the
inverse stereochemistry, by conducting a similar operation in the order of
step III-A ? step III-B ? step III-C ? step III-D using an optically active
1-phenylethylamine having the inverse stereochemistry relative to the half
ester.
[0066] As stereochemistry of the optically active 1-phenylethylamine, it
suffices to suitably use R configuration or S configuration in accordance with
the target stereochemistry of the optically active, fluorine-containing, benzyl
alcohol represented by formula [5].
[0067] As optical purity of the optically active 1-phenylethylamine, it
suffices to use one having 95% enantiomeric excess (ee) or greater. One
having 97%ee or greater is preferable, and particularly one having 99%ee or
greater is more preferable.
[0068] As the amount of the optically active 1-phenylethylamine used, it
suffices to use 0.2 moles or greater, preferably 0.3-3 moles, particularly more
preferably 0.4-1.5 moles, relative to 1 mole of the phthalate half ester of
racemic, fluorine-containing, benzyl alcohol represented by formula [4].
[0069] As the crystal precipitating solvent, it is possible to cite aliphatic
hydrocarbon series such as n-pentane, n-hexane, cyclohexane and n-heptane;
aromatic hydrocarbon series such as benzene, toluene, ethylbenzene, xylene
and mesitylene; halogenated hydrocarbon series such as methylene chloride,
chloroform and 1,2-dichloroethane; ether series such as diethyl ether,
tetrahydrofuran, tert-butyl methyl ether, dri-propyl ether, cyclopentyl
methyl ether and 1,4-dioxane,' ketone series such as acetone, methyl ethyl
ketone and methyl i'butyl ketone! ester series such as ethyl acetate and
n-butyl acetate; nitrile series such as acetonitrile and propionitrile; alcohol
series such as methanol, ethanol, n-propanol, i-propanol and n-butanol;
water and the like. Of these, n-hexane, cyclohexane, n-heptane, toluene,
xylene, mesitylene, methylene chloride, diethyl ether, tetrahydrofuran,
tert-butyl methyl ether, dri-propyl ether, acetone, ethyl acetate, acetonitrile,
methanol, ethanol, and i-propanol are preferable. In particular, n-hexane,
n-heptane, toluene, xylene, tetrahydrofuran, ter-butyl methyl ether, acetone,
ethyl acetate, acetonitrile, methanol, and i-propanol are more preferable. It
is possible to use these crystal-precipitating solvents singly or in
combination.
[0070] As the amount of the crystal precipitating solvent used, it suffices to
use 0.1L or greater, preferably 0.2-10L, particularly preferably 0.3-7L,
relative to lmol of the phthalate half ester of racemic, fluorine-containing,
benzyl alcohol, which is represented by formula [4].
[0071] The step III-B is described.
[0072] As a method of a recrystallization purification of the diastereomer
salt formed of the phthalate half ester of optically active, fluorine-containing,
benzyl alcohol and optically active 1-phenylethylamine, which is represented
by formula [15], it is possible to purify the diastereomer salt to have a higher
optical purity by adding the diastereomer salt, which has been obtained by
the step III-A, to a recrystallizing solvent, and, similar to the operation of the
step III-A, by dissolving it through heating at a temperature around boiling
point of the recrystallizing solvent, by gradually decreasing the temperature
under standing still or stirring to sufficiently precipitate crystals in a range
of-30 to +30°C by spending 1 to 48 hours, and by filtering the precipitated
crystals. By repeating this step, it can also be purified to have a further
high optical purity. The recrystallization mother liquor can also be
recovered in accordance with a usual way and reused.
[0073] As the recrystallizing solvent, it is possible to use the crystal
precipitating solvent of the step III-A.
[0074] The amount of the recrystallizing solvent used is the same as the
amount of the crystal precipitating solvent of the step IIP A.
[0075] In the present step, according to need, it is also possible to more
efficiently precipitate crystals by adding seed crystals.
[0076] The step III-C is described.
[0077] As a method for bringing the diastereomer salt formed of phthalate
half ester of optically active, fluorine-containing, benzyl alcohol and optically
active 1-phenylethylamine, which is represented by formula [15], into
contact with a strong acid, it is possible to recover a phthalate half ester of
optically active, fluorine-containing, benzyl alcohol, which is represented by
formula [16], by adding the diastereomer salt to an aqueous solution of
inorganic acid, followed by a sufficient shaking and an extraction with
organic solvent.
[0078] As the inorganic acid, it is possible to cite hydrogen chloride,
hydrogen bromide, sulfuric acid, nitric acid, and the like. Of these,
hydrogen chloride and sulfuric acid are preferable, and particularly
hydrogen chloride is more preferable.
[0079] As the amount of the inorganic acid used, it suffices to use 0.7moles
or greater, preferably 0.8-7moles, particularly more preferably 0.9-5moles,
relative to 1mol of the diastereomer salt formed of the phthalate half ester of
optically active, fluorine-containing, benzyl alcohol and the optically active
1-phenylethylamine, which is represented by formula [15].
[0080] As the concentration of the inorganic acid aqueous solution, it
suffices to use 0.3 normality (N) or greater, preferably 0.4-7N, particularly
more preferably 0.5-5N.
[0081] As the organic solvent, it is possible to cite toluene, methylene
chloride, ethyl acetate, and the like. Of these, toluene and ethyl acetate are
preferable, and particularly toluene is more preferable. It is possible to use
these organic solvents singly or in combination.
[0082] As the amount of the organic solvent used, it suffices to use 0.1L or
greater, preferably 0.2-7L, particularly more preferably 0.3-5L, relative to
lmol of the diastereomer salt formed of the phthalate half ester of optically
active, fluorine-containing, benzyl alcohol and the optically active
1-phenylethylamine, which is represented by formula [15].
[0083] As the post-treatment, according to need, it is also possible to
subject the recovering organic layer, with which the phthalate half ester of
optically active, fluorine-containing, benzyl alcohol represented by formula
[16] has been extracted, to water washing, drying, and concentration, to
isolate the half ester. As mentioned from the industrial viewpoint, a
method is more preferable in which an aqueous solution of an inorganic base
of the step III-D is directly added to the recovering organic layer to hydrolyze
the ester group. It is also possible to recover the optically active
1-phenylethylamine contained in the acidic water layer side in accordance
with a neutralization extraction of usual method to reuse it as the amine of
the step III-A.
[0084] The step III-D is described.
[0085] As a method for hydrolyzing the ester group of the phthalate half
ester of optically active, fluorine-containing, benzyl alcohol represented by
formula [16] under a basic condition, it is possible to produce the optically
active, fluorine-containing, benzyl alcohol represented by formula [5] by
reacting the half ester with an aqueous solution of an inorganic base.
[0086] As the phthalate half ester of optically active, fluorine-containing,
benzyl alcohol represented by formula [16], it is possible to use the isolated
product as mentioned above or the recovering organic layer obtained by the
extraction. It is also possible to conduct the reaction of the present step in a
two-phase system. In such a case, according to need, it is also possible to
accelerate the reaction rate by using a phase transfer catalyst such as a
halide of quaternary ammonium or phosphonium. It is, however, possible
to obtain a good reactivity by employing preferable reaction conditions of the
present step, even if the catalyst is not necessarily used.
[0087] As the inorganic base, it is possible to cite lithium carbonate, sodium
carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide,
potassium hydroxide, and the like. Of these, lithium hydroxide, sodium
hydroxide, and potassium hydroxide are preferable, and particularly sodium
hydroxide and potassium hydroxide are more preferable.
[0088] As the amount of the inorganic base used, it suffices to use 1.7moles
or greater, preferably 1.8-15moles, particularly more preferably 1.9-10moles,
relative to lmol of the phthalate half ester of optically active,
fluorine-containing, benzyl alcohol represented by formula [16].
[0089] As the concentration of an aqueous solution of the inorganic base, it
suffices to use 0.5N or greater, preferably 0.7-15N, particularly more
preferably 1-10N.
[0090] As the reaction solvent, it is possible to cite aromatic hydrocarbon
series such as benzene, toluene, ethylbenzene, xylene and mesitylene;
halogenated hydrocarbon series such as methylene chloride, chloroform and
1,2-dichloroethane; ether series such as diethyl ether, tetrahydrofuran,
ter-butyl methyl ether, di-i-propyl ether, cyclopentyl methyl ether and
1,4-dioxane; nitrile series such as acetonitrile and propionitrile; alcohol
series such as methanol, ethanol, n-propanol, i-propanol and n-butanol;
water; and the like. Of these, toluene, xylene, mesitylene, methylene
chloride, tetrahydrofuran, tert-butyl methyl ether, dri-propyl ether,
acetonitrile, methanol, ethanol and i-propanol are preferable. In particular,
toluene, xylene, methylene chloride, tetrahydrofuran, tert-butyl methyl
ether, acetonitrile, methanol and i-propanol are more preferable. It is
possible to use these solvents singly or in combination. In the case of
directly using the recovering organic layer, with which the phthalate half
ester of optically active, fluorine-containing, benzyl alcohol represented by
formula [16] has been extracted, it is also possible to conduct the reaction
only with the part of the solvent contained in the recovering organic layer
without newly using the reaction solvent.
[0091] As the amount of the reaction solvent used, it suffices to use 0.1L or
greater, preferably 0.2-7L, particularly more preferably 0.3-5L, relative to
1mol of the phthalate half ester of optically active, fluorine-containing,
benzyl alcohol represented by formula [16].
[0092] As the temperature condition, it suffices to conduct it in a range of
-30 to +150°C, preferably -20 to +125°C, particularly more preferably -10 to
+100°C.
[0093] As the reaction time, it suffices to conduct it in a range of 24 hours
or shorter. It depends on a combination of the phthalate half ester of
optically active, fluorine-containing, benzyl alcohol and an aqueous solution
of the inorganic base, the reaction conditions and the like. Therefore, it is
preferable to trace the phthalate half ester of optically active,
fluorine-containing, benzyl alcohol remaining unreacted by an analytical
means such as gas chromatography, liquid chromatography, NMR or the like
and to determine a point at which the half ester has almost disappeared, as
the end point.
[0094] As the post-treatment, it is possible to produce the target, optically
active, fluorine-containing, benzyl alcohol represented by formula [5] by
directly separating the reaction-terminated liquid or, according to need, by
extraction through adding an organic solvent, such as toluene, methylene
chloride or ethyl acetate, or water to concentrate the recovered organic layer.
Furthermore, according to need, it can be purified to have a higher chemical
purity and optical purity by activated carbon treatment, recrystallization,
distillation or column chromatography or the like.
[0095] [Examples]
In the following, embodiments of the present invention are
specifically explained by examples. The present invention is, however, not
limited to these examples. The structural formulas and the compound
names of examples are expressed as R configuration or S configuration.
This means not only an optically pure R configuration or S configuration, but
also an optically active condition [for example, R configuration is in 90%ee (R
configuration : S configuration = 95:5] in which R configuration or S
configuration is contained in excess in the course of optical resolution.
Optical purity of the moiety of the phthalate half ester of optically active,
fluorine-containing, benzyl alcohol of the diastereomer salt formed of the
phthalate half ester of optically active, fluorine-containing, benzyl alcohol
and the optically active 1-phenylethylamine, which is represented by
formula [15], was determined by chiral gas chromatography of the optically
active, fluorine-containing, benzyl alcohol obtained by conducting the
operation of the step III-D.
EXAMPLE 1
[0096] Under nitrogen atmosphere, 1300mL (2.60mol, 1.00eq) of 2.0M
methylmagnesium chloride-tetrahydrofuran solution was cooled, and 322.7g
(2.60mol, 1.00eq) of 2-fluorobenzaldehyde was added while adjusting the
inside temperature to -20 to +2°C, followed by stirring for 30 minutes under
a cooled condition in iced water. Conversion of methylation was 99.9% by
determination by gas chromatography. Subsequently, while adjusting the
inside temperature to -22 to 0°C, 385.1g (2.60mol, 1.00eq) of phthalic
anhydride was added, followed by stirring at room temperature through the
night. Conversion of acylation was 99% or greater by determination by
1H-NMR. 1300mL (2.60mol, 1.00eq) of 2.0N hydrochloric acid was added to
the reaction-terminated liquid, followed by extraction with 650mL of toluene.
The recovered organic layer was washed with 650mL of brine, dried with
anhydrous sodium sulfate, concentrated under reduced pressure, and
vacuum dried, thereby obtaining 706.1g of racemic 1-(2-fluorophenyl)ethyl
alcohol phthalate half ester represented by the following formula,
[Chemical Formula 21]

[0097] The total yield from 2-fluorobenzaldehyde was 94.2%.
2-fluorobenzyl alcohol phthalate half ester, the reduced body, was not
produced as a byproduct (less than 1.0% by determination by 1H-NMR).
1H-NMR and 19F-NMR spectrums of the obtained racemic
1-(2-fluorophenyl)ethyl alcohol phthalate half ester are shown in the
following.
[0098] 1H-NMR (standard substance: (CH3)4Si, deuterated solvent: CDCl3),
d ppm: 1.67 (d, 6.4Hz, 3H), 6.40 (q, 6.4Hz, 1H), 7.00-7.95 (Ar-H, 8H), and
assignment to carboxyl group was not possible.
19F-NMR (standard substance: C6F6, deuterated solvent: CDCl3), d ppm:
43.56 (m, 1F).
[0099] 706.1g (2.45mol, 1.00eq) of the half ester and 148.4g (1.22mol,
0.50eq) of (S)-1-phenylethylamine were added to a mixed solution of 5000mL
of i-propanol and 480mL of methanol, followed by dissolving them by heating
at 52°C, gradual cooling to room temperature, filtering the precipitated
crystals, and vacuum drying, thereby obtaining 323.8g of a diastereomer salt
of (S)-1-(2-fluorophenyl)ethyl alcohol phthalate half
ester (S)-1-phenylethylamine, which is represented by the following formula
[Chemical Formula 22]

[0100] Optical purity of the diastereomer salt was 74.8%ee by
determination by chiral gas chromatography. Recovery of the diastereomer
salt was 56.4%.
[0101] 323.8g of the diastereomer salt was added to a mixed solution of
1650mL of i-propanol and 920mL of methanol, followed by dissolving it by
heating at 63°C, gradual cooling to 5°C, and filtering the precipitated
crystals, thereby obtaining 255.7g (a product not yet dried) of a recrystallized
product of the diastereomer salt of (S)-1-(2-fluorophenyl)ethyl alcohol
phthalate half ester (S)-1-phenylethylamine represented by the above
formula. Optical purity of the recrystallized product was 99.2%ee by
determination by chiral chromatography.
[0102] 780mL (l.56mol, 2.50eq) of 2.0N hydrochloric acid was added to
255.7g (set at 0.624mol, 1.00eq) of the recrystallized product, followed by
extraction with 1000mL of toluene, thereby obtaining a toluene solution of
(S)-1-(2-fluorophenyl)ethyl alcohol phthalate half ester represented by the
following formula.
[Chemical Formula 23]

[0103]
[0104] 520mL (3.12mol, 5.00eq) of 6.0N sodium hydroxide was added to the
toluene solution, followed by stirring at 60°C for 1hr. Conversion of the
hydrolysis was 100% by determination by 19F-NMR. The organic layer of
the reaction-terminated liquid was separated. The recovered organic layer
was washed with 500mL of 1.0N sodium hydroxide, followed by washing
with 500mL of 10% brine, drying with anhydrous sodium sulfate,
concentration under reduced pressure, and vacuum drying, thereby
obtaining (S)-1-(2-fluorophenyl)ethyl alcohol represented by the following
formula
[Chemical Formula 24]

[0105] The alcohol was subjected to a fractional distillation (58°C/530Pa),
thereby obtaining 63.5g of a distillation purified product of
(S)-1-(2-fluorophenyl)ethyl alcohol represented by the above formula.
Optical purity of the purified product was 99.3%ee by determination by
chiral chromatography. Chemical purity of the purified product was 99.9%
by determination by gas chromatography. The total yield from the
recrystallization purification of the diastereomer salt of
(S)-1-(2-fluorophenyl)ethyl alcohol phthalate half
ester (S)-1-phenylethylamine was 65.3%. 1H-NMR and 19F-NMR spectrums
of the obtained (S)-1-(2-fluorophneyl)ethyl alcohol are shown in the
following.
[0106] 1H-NMR (standard substance: (CH3)4Si, deuterated solvent: CDCl3),
d ppm: 1.53 (d, 6.8Hz, 3H), 1.80 (br, 1H), 5.21 (q, 6.8Hz, 1H), 6.95-7.55 (Ar-H,
4H).
19F-NMR (standard substance: C6F6, deuterated solvent: CDCl3), d ppm:
41.67 (m, 1F).
EXAMPLE 2
[0107] Under nitrogen atmosphere, 500mL (1.00mol, 1.00eq) of 2.0M
methylmagnesium chloride-tetrahydrofuran solution was cooled, and 174.1g
(1.00mol, 1.00eq) of 2-trifluoromethylbenzaldehyde was added while
adjusting the inside temperature to 4 to 21°C, followed by stirring for 15
minutes under a cooled condition in iced water. Conversion of methylation
was 99.9% or greater by determination by gas chromatography.
Subsequently, while adjusting the inside temperature to 9 to 37°C, 148.1g
(1.00mol, 1.00eq) of phthalic anhydride was added, followed by stirring at
room temperature through the night. Conversion of acylation was 99% or
greater by determination by 1H-NMR. 500mL (1.00mol, 1.00eq) of 2.0N
hydrochloric acid was added to the reaction-terminated liquid, followed by
extraction with 250mL of toluene. The recovered organic layer was washed
with 250mL of brine, thereby obtaining 952g of a toluene solution
(containing tetrahydrofuran, too) of racemic l-(2-trifluoromethylphenyl)ethyl
alcohol phthalate half ester represented by the following formula,
[Chemical Formula 25]

[0108] 2-trifluoromethylbenzyl alcohol phthalate half ester, the reduced
body, was not produced as a by-product (less than 1.0% by determination by
1H-NMR).
[0109] Under room temperature, while adjusting the inside temperature to
25 to 34°C, a n-heptane solution (the amount of n-heptane used: 500mL) of
(S)-1-phenylethylamine in 60.6g (0.50mol, 0.50eq) was added to 952g (set at
1.00mol, 1.00eq) of the toluene solution, followed by filtering the precipitated
crystals, washing with 200mL of n-heptane, and vacuum drying, thereby
obtaining 170.0g of a diastereomer salt of
(S)-1-(2-trifluoromethylphenyl)ethyl alcohol phthalate half
ester-(S)-1-phenylethylamine, which is represented by the following formula
[Chemical Formula 26]

[0110] Optical purity of the diastereomer salt was 90.6%ee by
determination by chiral gas chromatography. The total yield from
2-trifluoromethylbenzaldehyde was 70.5%.
[0111] 170.0g of the diastereomer salt was added to 510mL of methanol,
followed by dissolving it by heating at 60°C, gradual cooling to 5°C, filtering
the precipitated crystals, and vacuum drying, thereby obtaining 99.4g of a
recrystallized product of the diastereomer salt of
(S)-1-(2-trifluoromethylphenyl)ethyl alcohol phthalate half
ester (S)-1-phenylethylamine represented by the above formula. Optical
purity of the recrystallized product was 98.9%ee by determination by chiral
chromatography. Recovery of the recrystallized product was 61.0%.
1H-NMR and 19F-NMR spectrums of the obtained diastereomer salt of
(S)-1-(2-trifluoromethylphenyl)ethyl alcohol phthalate half
ester (S)-1-phenylethylamine are shown in the following.
[0112] 1H-NMR (standard substance: (CH3)4Si, deuterated solvent: CDCl3),
d ppm: 1.51 (d, 6.8Hz, 3H), 1.61 (d, 6.8Hz, 3H), 3.68 (br, 3H), 4.26 (q, 6.8Hz,
1H), 6.37 (q, 6.8Hz, 1H), 7.24-7.82 (Ar-H, 13H).
19F-NMR (standard substance: C6F6, deuterated solvent: CDCl3), d ppm:
103.20 (S, 3F).
[0113] 185mL (0.370mol, 2.00eq) of 2.0N hydrochloric acid was added to
85.0g (0.185mol, 1.00eq) of the recrystallized product, followed by extraction
with 185mL of toluene. The recovered organic layer was washed with
100mL of water, thereby obtaining a toluene solution of
(S)-1-(2-trifluoromethylphenyl)ethyl alcohol phthalate half ester represented
by the following formula.
[Chemical Formula 27]

[0114]
[0115] 150mL (0.555mol, 3.00eq) of 3.7N potassium hydroxide was added to
the toluene solution, followed by stirring at 50°C for 1 hour and 30 minutes.
Conversion of the hydrolysis was 100% by determination by 19F-NMR. The
organic layer of the reaction-terminated liquid was separated, followed by
concentration under reduced pressure and vacuum drying, thereby obtaining
34.3g of (S)-1-(2-trifluoromethylphenyl)ethyl alcohol represented by the
following formula
[Chemical Formula 28]

[0116] The alcohol was subjected to a fractional distillation (84°C/1330Pa),
thereby obtaining 31.5g of a distillation purified product of
(S)-1-(2-trifluoromethylphenyl)ethyl alcohol represented by the above
formula. Optical purity of the purified product was 99.0%ee by
determination by chiral chromatography. Chemical purity of the purified
product was 99.9% by determination by gas chromatography. The total
yield from the recrystallized product of the diastereomer salt of
(S)-1-(2-trifluoromethylphenyl)ethyl alcohol phthalate half
ester (S)-1-phenylethylamine was 89.6%. 1H-NMR and 19F-NMR spectrums
of the obtained (S)-1-(2-trifluoromethylphneyl)ethyl alcohol are shown in the
following.
[0117] 1H-NMR (standard substance: (CH3)4Si, deuterated solvent: CDCl3),
d ppm: 1.49 (d, 6.4Hz, 3H), 1.99 (br, 1H), 5.33 (q, 6.4Hz, 1H), 7.35-7.84 (Ar-H,
4H).
19F-NMR (standard substance: C6F6, deuterated solvent: CDCl3), d ppm:
103.43 (s, 3F).
We Claim:
1. A process for producing an optically active, fluorine-containing,
benzyl alcohol represented by formula [5]

wherein m represents the number of substituents of fluorine atoms and takes
an integer selected from 0, 1, 2, 3, 4 or 5,
n represents the number of substituents of trifluoromethyl groups
and takes an integer selected from 0, 1, 2 or 3,
m and n do not take 0 at the same time,
the total of m and n takes 5 or less,
R represents an alkyl group of a carbon number of 1-6, and
* represents that the benzyl alcohol is an optically active body,
comprising the steps of:
(a) reacting a fluorine-containing benzaldehyde represented by
formula [1]

wherein m and n are defined as above, with an alkyl Grignard reagent
represented by formula [2l

wherein R is defined as above, and X represents a halogen atom selected
from chlorine, bromine and iodine,
to convert the benzaldehyde to a magnesium alkoxide of racemic, fluorine-
containing, benzyl alcohol represented by formula [3]

wherein m, n, R and X are the same as above, and the wavy line represents
that the magnesium alkoxide is a racemate;
(b) reacting the magnesium alkoxide with phthalic anhydride to
obtain a phthalate half ester of racemic, fluorine-containing, benzyl alcohol
represented by formula [4]

wherein m, n, R and the wavy line are the same as above;
(c) optically resolving the half ester by optically active 1-
phenylethylamine; and
(d) hydrolyzing an ester group of the half ester obtained by the step
(c), thereby obtaining the optically active, fluorine-containing, benzyl alcohol.
2. A process according to claim 1 for producing an optically active,
fluorine-containing, benzyl alcohol represented by formula [10]

wherein * is as defined in claim 1,
wherein in step (a) a fluorine-containing benzaldehyde represented by
formula [6]

is reacted with an alkyl Grignard reagent represented by formula [7]

to convert the benzaldehyde to a magnesium alkoxide of racemic, fluorine-
containing, benzyl alcohol represented by formula [8]

wherein the wavy line is as defined in claim 1; and
wherein in step (b) the magnesium alkoxide is reacted with phthalic
anhydride to obtain a phthalate half ester of racemic, fluorine-containing,
benzyl alcohol represented by formula [9]

wherein the wavy line is the same as above.
3. A process according to claim 1, for producing an optically active,
fluorine-containing, benzyl alcohol represented by formula [14]

wherein * is as defined in claim 1,
wherein in step (a) a fluorine-containing benzaldehyde represented by
formula [11]

is reacted with an alkyl Grignard reagent represented by formula [7]

to convert the benzaldehyde to a magnesium alkoxide of racemic, fluorine-
containing, benzyl alcohol represented by formula [12]

wherein the wavy line is as defined in claim 1; and
wherein in step (b) the magnesium alkoxide is reacted with phthalic
anhydride to obtain a phthalate half ester of racemic, fluorine-containing,
benzyl alcohol represented by formula [13]

wherein the wavy line is the same as above.

A fluorine-containing benzaldehyde is reacted with an alkyl Grignard reagent
to convert it to a magnesium alkoxide of racemic, fluorine-containing, benzyl alcohol,
and subsequently the magnesium alkoxide is reacted with phthalic anhydride to obtain a
phthalate half ester of racemic, fluorine-containing, benzyl alcohol, and the half ester is
optically resolved by optically active 1-phenylethyiamine, and then the ester group is
hydrolyzed, thereby producing an optically active, fluorine-containing, benzyl alcohol.