TECHNICAL FIELD
[0001] The present invention relates to a process for producing an optically
active α flurocarboxylate, which is an important intermediate of medicines,
agricultural chemicals and optical materials.
BACKGROUND OF THE INVENTION
[0002] An optically active α flurocarboxylate, which is the target of the
present invention, is an important intermediate of medicines, agricultural
chemicals and optical materials. As publicly known techniques related to
the present invention, particularly as practical production processes, it is
possible to cite the undermentioned representative four examples. These
production processes are in common in that the starting raw material is an
optically active α hydroxycarboxylate having an inverse stereochemistry to
the target optically active crfluorocarboxylate and that a hydroxyl group is
converted to a leaving group (stereoretention), and a bimolecular
nucleophilic substitution (stereoinversion) is conducted with a fluorine
anion.
[0003] 1) A process (Patent Publication 1) in which an optically active
α hydroxycarboxylate is converted to a chlorosulfite by thionyl chloride, then
it is converted to a fluorosulfite by hydrogen fluoride, and finally it is
pyrolyzed using a tertiary amine as catalyst.
[0004] 2) A process (Patent Publication 2) in which an optically active
α hydroxycarboxylate is converted to methanesulfonate by methanesulfonyl
chloride in the presence of an organic base, and it is reacted with an alkali
metal fluoride.
[0005] 3) A process (Patent Publication 3) in which an optically active
α hydroxycarboxylate is converted to a trifluoromethanesulfonate by

trifluoromethanesulfonyl fluoride in the presence of an organic base, and it is
continuously reacted with a salt or complex of the organic base and hydrogen
fluoride, which has been produced as a by-product in the reaction system.
[0006] 4) A process (Patent Publication 4) in which an optically active
α hydroxycarboxylate is converted to a fluorosulfate by sulfuryl fluoride in
the presence of an organic base, and it is continuously reacted with a salt or
complex of the organic base and hydrogen fluoride, which has been produced
as a by-product in the reaction system.
Patent Publication 1: International Application Publication 2006/037887
Pamphlet
Patent Publication 2: Japanese Patent Application Publication 2006169251
Patent Publication 3: Japanese Patent Application Publication 2006-83163
Patent Publication 4- Japanese Patent Application Publication 2006-290870
SUMMARY OF THE INVENTION
[0007] It is an object of the present invention to provide an industrial
production process of an optically active α flurocarboxylate, which is an
important intermediate of medicines, agricultural chemicals and optical
materials.
[0008] In the processes of Patent Publication 1 and Patent Publication 2, it
was necessary to separately conduct at least two reaction steps. Judging
from Examples of these, they were processes in which the reaction
operations were cumbersome and furthermore waste was in large amount.
Therefore, as a result, it was hard to refer them as competitive industrial
production processes.
[0009] In the processes of Patent Publication 3 and Patent Publication 4,
they had a merit that it was possible to continuously conduct in a single
reaction container the step of converting it to a trifluoromethanesulfonate or
fluorosulfate and the step of replacing it with a fluorine anion (they can be
considered to be substantially a single reaction step). However, since the
reactions are conducted by using a reaction solvent, and since operations
such as extraction and washing are conducted in the post-treatment,

although they were industrial production processes, they were production
processes that were limited in productivity and that the amount of waste was
also larger, as compared with the production process disclosed in the present
invention, and had to be reduced.
[0010] Thus, there has been a strong demand for a process that is capable
of industrially producing an optically active α flurocarboxylate.
[0011] As a result of an eager study for solving the above-mentioned task,
the present inventors have found out that, in a process of reacting an
optically active α hydroxycarboxylate with sulfuryl fluoride,
trifluoromethanesulfonyl fluoride or nonafluorobutanesulfonyl fluoride, it is
possible to produce an optically active α flurocarboxylate with good yield
and high optical purity by conducting the reaction in the presence of organic
base and in the absence of reaction solvent. Furthermore, the present
inventors have clarified that it is possible to easily isolate the optically active
α flurocarboxylate with high purity by adding acid to the thus obtained
reaction-terminated liquid containing the optically active
α flurocarboxylate and then conducting a distillation purification.
[0012] In the present invention, even if the above dehydroxyfluorination
reaction is conducted in the absence of reaction solvent, not only there were
obtained the results that were satisfactory in yield and operability, but also
there were obtained the results that were not inferior, as compared with the
case of using reaction solvent, in terms of optical purity, too. Furthermore,
impurities that were difficult of separation were not produced as by-products
either, even if the reaction is conducted in the absence of reaction solvent.
[0013] As a result, it has become possible to greatly reduce an operation for
removing the reaction solvent and other coexisting substances after the
reaction and to very easily isolate the target substance by directly subjecting
the reaction-terminated liquid to a distillation purification.
[0014] Furthermore, the present inventors have found out that it is very
effective in producing the target substance of high purity to add acid to the
reaction-terminated liquid, prior to the distillation purification, and then

conduct the distillation. In the present invention, it is inevitable that a
small amount of fluoride ions remains in the reaction-terminated liquid. It
has been found that separation between this fluoride ion and the target
substance is relatively difficult, and its removal from the target substance is
difficult, even if a normal distillation treatment is conducted. The present
inventors, however, prior to this distillation treatment, added acid to the
reaction-terminated liquid and then conducted the distillation. With this, it
has become clear that fluoride ions are greatly reduced, and an excessive
organic base remaining in the system can also significantly be reduced, and
the target substance of a still higher purity can be produced.
[0015] Thus, the following two are mentioned as characteristics of the
present invention.
1) The target reaction proceeds well under neat condition that reaction
solvent is never used, and an optically active α flurocarboxylate is obtained
with an extremely high optical purity (99%ee or greater in a preferable case)
and good yield (Example 1, Example 2, and Example 3).
2) Furthermore, the reaction-terminated liquid is directly subjected to a
distillation purification. With this, it is possible to extremely easily recover
the optically active α flurocarboxylate. Furthermore, upon this, acid is
added and then a distillation purification is conducted. With this, it is
possible to effectively reduce the organic base content and the fluoride ion
concentration in the optically active α flurocarboxylate to be recovered (a
comparison between Example 2, and Example 1 and Example 3).
[0016] According to the present invention, there is provided a process (first
process) for producing an optically active α flurocarboxylate represented by
formula [2]
[Chemical Formula 2]


wherein R1 represents a C1-6 alkyl group, R2 represents a C1-4 alkyl group,
and * represents an asymmetric carbon, the process including
reacting an optically active α hydroxycarboxylate represented by formula [1]
[Chemical Formula 1]

wherein R1, R2 and * are defined as above, with sulfuryl fluoride (SO2F2),
trifluoromethanesulfonyl fluoride (CF:sSO2F) or nonafluorobutanesulfonyl
fluoride (C4F9SO2F), in the presence of organic base and in the absence of
reaction solvent,
wherein stereochemistry of the asymmetric carbon in formula [1] is
inverted by the reaction.
[0017] The first process may be a process (second process) for producing an
optically active 2-fluoropropionate represented by formula [4]
[Chemical Formula 4]

wherein R represents a methyl group or ethyl group, and * represents an
asymmetric carbon, the process including reacting an optically active lactate
represented by formula [3]


wherein R and * are defined as above, with sulfuryl fluoride (SO2F2) or
trifluoromethanesulfonyl fluoride (CFKSC^F), in the presence of an organic
base selected from the group consisting of triethylamine,
diisopropylethylamine, tri-n-propylamine, tri-n-butylamine,
tri-n-pentylamine, tri-n-hexylamine, pyridine, 2,3-lutidine, 2,4-lutidine,
2,61utidine, 3,4-lutidine, 3,5-lutidine, 2,4,6-collidine, and 3,5,6-collidine, and
in the absence of reaction solvent,
wherein stereochemistry of the asymmetric carbon in formula [3] is
inverted by the reaction.
[0018] The first or second process may be a process (third process) for
producing methyl (R)-2-fluoropropionate represented by formula [6]
[Chemical Formula 6]

the process including reacting methyl (S)-lactate represented by formula [5]


with sulfuryl fluoride (SO2F2), in the presence of triethylamine or
trrirbutylamine and in the absence of reaction solvent.
DETAILED DESCRIPTION
[0019] By the process of the present invention, it is possible to produce an
optically active α flurocarboxylate on a large-amount scale. Advantageous
points of the present invention as compared with conventional techniques
are put together in the following.
[0020] As compared with the processes of Patent Publication 1 and Patent
Publication 2, the number of reaction steps is smaller, the reaction operation
is also easier, and furthermore there is less waste.
[0021] As compared with the processes of Patent Publications 3 and Patent
Publication 4, it is not necessary at all to use reaction solvent, and the
post-treatment operation is extremely easy in a preferable example.
[0022] Therefore, in the process of the present invention, it is possible to
produce an optically active α flurocarboxylate with high productivity and
little waste. Thus, it is very useful as an industrial process.
[0023] The process for producing an optically active α flurocarboxylate of
the present invention is explained in detail.
[0024] (1) REACTION STEP
Firstly, there is explained a reaction step for producing an optically
active α flurocarboxylate represented by formula [2] by reacting an
optically active α hydroxycarboxylate represented by formula [1] with
sulfuryl fluoride, trifluoromethanesulfonyl fluoride or
nonafluorobutanesulfonyl fluoride in the presence of organic base and in the
absence of reaction solvent.
[0025] Regarding stereochemistry of asymmetric carbon of the starting raw
material and the target product of the reaction, a step of converting the
hydroxyl group to a leaving group proceeds with stereoretention, and a step
of conducting a bimolecular nucleophilic substitution reaction with fluorine
anion proceeds with stereoinversion. Therefore, S configuration at a

position of an optically active α flurocarboxylate represented by formula [2]
is obtained from R configuration at a position of an optically active
α hydroxycarboxylate represented by formula [1], and similarly R
configuration at a position is obtained from S configuration at a position.
[0026] As R1 of an optically active α hydroxycarboxylate represented by
formula [1], it is possible to cite methyl group, ethyl group, propyl group,
butyl group, amyl group, and hexyl group, and an alkyl group having a
carbon number of 3 or more can take a straight-chain or branch. In a
preferable example, it is possible to recover an optically active α flurocarboxylate represented by formula [2] by directly distilling the
reaction-terminated liquid. Upon this, one having a lower boiling point is
more easily recovered. Therefore, of those, methyl group, ethyl group, and
propyl group are preferable, and particularly methyl group and ethyl group
are more preferable.
[0027] As R2 of an optically active α hydroxycarboxylate represented by
formula [1], it is possible to cite methyl group, ethyl group, propyl group and
butyl group, and an alkyl group having a carbon number of 3 or more can
take a straight-chain or branch. Similar to the above, one having a lower
boiling point is more easily recovered. Therefore, of those, methyl group
and ethyl group are preferable, and particularly methyl group is more
preferable. Furthermore, alkyl groups of R1 and R2 can also form a lactone
ring by a covalent bond.
[0028] Regarding stereochemistry of asymmetric carbon of an optically
active α hydroxycarboxylate represented by formula [1], it can take R
configuration or S configuration. Enantiomeric excess (%ee) is not
particularly limited. It suffices to use one having 90%ee or greater.
Normally, 95%ee or greater is preferable, and particularly 97%ee or greater
is more preferable.
[0029] An optically active α hydroxycarboxylate represented by formula [1]
can be produced similarly from various optically active cramino acids on the
market, with reference to Synthetic Communications (US), 1991, Volume 21,

No. 21, p. 2165-2170. A commercial product was used as methyl (SMactate
used in Examples.
[0030] As a reagent for converting the hydroxyl group to a leaving group, it
is possible to cite sulfuryl fluoride, trifluoromethanesulfonyl fluoride, or
nonafluorobutanesulfonyl fluoride. Of these, in view of atom economy of
fluorine, industrial availability, the post-treatment operation, and waste
treatment, sulfuryl fluoride and trifluoromethanesulfonyl fluoride are
preferable, and particularly sulfuryl fluoride is more preferable.
[0031] Usage of sulfuryl fluoride, trifluoromethanesulfonyl fluoride, or
nonafluorobutanesulfonyl fluoride is not particularly limited. It suffices to
use 0.7-7 moles relative to 1 mole of an optically active α hydroxycarboxylate represented by formula [1]. Normally, 0.8-5 moles is preferable, and
particularly 0.9-3 moles is more preferable.
[0032] The organic base is not particularly limited. As representative
ones, it is possible to cite tertiary amines and pyridines. As such organic
bases, it is possible to cite trimethylamine, triethylamine,
diisopropylethylamine, tri-n-propylamine, tri-n-butylamine,
tri-n-pentylamine, tri-n-hexylamine, 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-coUidine, 2,4,6-collidine, 3,4,5-collidine, 3,5;6-collidine,
and the like. Of these, preferable are triethylamine, diisopropylethylamine,
tri-n-propylamine, tri-n-butylamine, tri-n-pentylamine, tri-n-hexylamine,
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.
[0033] In the present invention, the reaction is conducted in the absence of
reaction solvent. Therefore, it is important that a salt or complex of the
organic base and hydrogen fluoride or a salt or complex of the organic base
and RfSOaH [in the formula, Rf represents a fluorine atom, trifluoromethyl
group, or nonafluorobutyl group] has a suitable flow property to make it
possible to stir well. As such organic base, particularly triethylamine and
tri-n-butylamine are more preferable [Flow property was better in the case of

using triethylamine or tri-n-butylamine as the organic base than in the case
of using diisopropylethylamine or tri-n-propylamine, as a result of a study on
flow property of the obtained reaction-terminated liquid at room
temperature by conducting the reaction similar to Examples using methyl
(S)-lactate (l.Oeq), sulfuryl fluoride (l.2eq) and organic base (l.2eq). See
Table-1].
[0034] Furthermore, in the distillation operation, it suffices to use one that
is different in boiling point at atmospheric pressure from the target
compound, optically active cc-fluorocarboxylate, by 30°C or more. Normally
40°C or more is preferable, and particularly 50°C or more is more preferable.
Furthermore, it is important to select an organic base of which recovery and
reuse can easily be conducted. In view of these viewpoints,
tri-n-butylamine is extremely preferable in producing methyl
(R)-2-fluoropropionate, which is a preferable target compound of the present
invention.

[0035] Usage of the organic base is not particularly limited. Relative to
lmole of optically active α hydroxycarboxylate represented by formula [1], it
suffices to use 0.7-7 moles. Normally 0.8-5 moles is preferable, and
particularly 0.9-3 moles is more preferable.
[0036] To conduct the reaction in the absence of reaction solvent, which is
an important mode of the present invention, refers to that the reaction is
conducted by making reaction solvent (liquid such as organic solvent or
water) substantially nonexistent in the system, except the above-mentioned
reaction reagents. Specifically, it refers to a condition of less than 0.1L

(liter) relative to 1 mole of optically active α hydroxycarboxylate represented
by formula [1]. Normally less than 0.07L is preferable, and particularly less
than 0.05L is more preferable. A mode of conducting the reaction by not
intentionally adding reaction solvent to the system is a representative of
conducting the reaction in the absence of reaction solvent and is extremely
preferable. By conducting the reaction in the absence of reaction solvent, it
is possible to produce optically active α flurocarboxylate represented by
formula [2] with high productivity and little waste.
[0037] Regarding the reaction temperature, since the reaction is conducted
in the absence of reaction solvent in the present invention, it is important
that a salt or complex of the organic base and hydrogen fluoride or a salt or
complex of the organic base and RJESO3H [in the formula, Rf represents a
fluorine atom, trifluoromethyl group or nonafluorobutyl group], which is
produced as a by-product in the reaction system, has a suitable flow property
and can be stirred well. As such reaction temperature, normally -20 to
+70°C is preferable, and particularly -10 to +50°C is more preferable. In
the case of conducting the reaction at a reaction temperature that is boiling
point or higher of sulfuryl fluoride, trifluoromethanesulfonyl fluoride or
nonafluorobutanesulfonyl fluoride, it is possible to use a pressure-proof
reaction container.
[0038] The reaction pressure is not particularly limited. It suffices to
conduct that in a range of atmospheric pressure (O.lMPa) to 2MPa.
Normally atmospheric pressure to 1.5MPa is preferable, and particularly
atmospheric pressure to lMPa is more preferable. Therefore, it is
preferable to conduct the reaction by using a pressure-proof reaction
container made of a material such as stainless steel (SUS) or glass (glass
lining).
[0039] The reaction time is not particularly limited. It suffices to conduct
that in a range of 24 hours or less. It depends on the starting material, the
organic base, the reactant for converting the hydroxyl group to a leaving
group, the reaction conditions, etc. Therefore, it is preferable to monitor the

condition of the reaction progress by an analytical means such as gas
chromatography, thin-layer chromatography, liquid chromatography, or
nuclear magnetic resonance (NMR) and judge the time when the starting
raw material has almost disappeared as being end point.
[0040] (2) DISTILLATION STEP
An optically active α flurocarboxylate obtained by the
above-mentioned reaction step can be isolated by subsequently subjecting it
to purification step (post-treatment). This purification means is not
particularly limited. In the present invention, however, reaction solvent is
not used. Therefore, it is possible to distill the reaction-terminated liquid
directly (as it is without conducting a particular purification operation).
That is particularly preferable. As mentioned above, in the reaction of the
present invention, impurities that are difficult of separation are almost not
produced even under a condition in the absence of reaction solvent.
Therefore, even if the reaction-terminated liquid is directly subjected to
distillation step, it is possible to recover the target optically active
α flurocarboxylate represented by formula {2] with high purity and high
optical purity. In the following, this distillation step is explained.
[0041] As the conditions of the distillation, in view of the boiling point, a
person skilled in the art can suitably set pressure and bath temperature
(tank temperature). Distillation under reduced pressure is preferable since
it is possible to moderately reduce the distillation temperature. In the case
of conducting distillation under reduced pressure, the degree of pressure
reduction (It refers to absolute pressure in the system upon distillation. It
is the same hereinafter) is not particularly limited. It suffices to conduct
that in a range of less than atmospheric pressure. Normally 50kPa or less
is preferable, and particularly 25kPa or less is more preferable. If it is
lower than O.lkPa, separation efficiency of the distillation lowers, and it
becomes rather disadvantageous in operation in some cases. Therefore, it is
not preferable. Therefore, it is a preferable mode to conduct the distillation
in a range of, for example, 0.5kPa to 25kPa.

[0042] Furthermore, the column top temperature in the distillation
depends on the above-mentioned degree of pressure reduction. Of course,
the bath temperature is set at a temperature that is higher than this column
top temperature. The bath temperature also gets to depend on the degree of
pressure reduction. This temperature is in a range of 200°C or lower.
Normally 175°C or lower is preferable, and particularly 150°C or lower is
more preferable. The bath temperature does not have the lower limit.
However, when the distillation is conducted at a bath temperature of 20°C or
higher, more preferably 40°C or higher, the distillation tends to become
stable. It is therefore advantageous. Accordingly, a bath temperature of
20-175°C is taken as a preferable temperature, and 40-150°C is a still more
preferable temperature.
[0043] According to need, the recovered distillate is subjected to a fractional
distillation. With this, it is possible to obtain the target product with higher
purity.
[0044] In the present invention, it is possible to recover and reuse the
organic base used in the reaction. If the reaction and the distillation are
conducted under preferable operation conditions, it is possible to recover
from the tank residue (distillation residue) the organic base after use in the
form of a salt or complex with RfSOsH [in the formula, Rf represents a
fluorine atom, trifluoromethyl group or nonafLuorobutyl group] (a mixture
with RfSOsH) or a salt or complex with hydrogen fluoride (a mixture with
hydrogen fluoride) (mostly in the form of the former). The tank residue is
neutralized with an alkaline aqueous solution prepared from sodium
hydroxide, potassium hydroxide, calcium hydroxide, or the like. The
Liberated organic base is separated. According to need, washing with water
or dehydration operation is conducted, followed by distillation. With this, it
is possible to recover the organic base with high chemical purity and good
yield. The recovered organic base can be reused without lowering of the
reactivity. In the case of conducting the recovery and the reuse by such
method, an organic base that is high in fat-solubility and easy in dehydration

is preferable. Naturally, the method of the recovery and the reuse is not
limited to the above-mentioned technique.
[0045] The above distillation step can still more preferably be conducted by
conducting it after adding acid to the reaction-terminated liquid. That is,
acid is added to the reaction-terminated liquid, and the resulting liquid is
subjected to the distillation step. With this, it was found that the organic
base used in the reaction and the remaining fluoride ions are effectively
removed, and optically active α flurocarboxylate represented by formula [2]
can be produced with higher purity, high productivity and less waste.
[0046] As such acid, it is possible to use inorganic acid or organic acid. In
particular, an acid that does not exist as aqueous solution and is low in
volatility is still more preferable. As such inorganic acid, it is possible to
cite sulfuric acid, phosphoric acid, boric acid, etc. As the organic acid, it is
possible to cite formic acid, methanesulfonic acid, trifluoromethanesulfonic
acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, oxalic acid,
propionic acid, acrylic acid, malonic acid, butyric acid, methacrylic acid,
succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, valeric acid,
hexanoic acid, benzoic acid, o-, m- or p-fluorobenzoic acid, o-, nr or
p-chlorobenzoic acid, o-, nr or p-hydroxybenzoic acid, p-toluenesulfonie acid,
o-, m- or p-toluic acid, o-, nr or p-anisic acid, o-, nr or p-benzenedicarboxylic
acid (phthalic acid, isophthalic acid or terephthalic acid), etc. Of these,
organic acid is preferable due to its high capability for removing fluoride ions.
Particularly, benzoic acid is more preferable.
[0047] Usage of the acid is not particularly limited. It suffices to use 0.7-9
moles relative to lmole of the organic base used excessively. Normally,
0.8-7 moles is preferable, and particularly 0.9-5 moles is more preferable (for
example, in Example 2, the organic base used excessively is in 0.27mol, and
the acid has been used in 0.62mol, meaning that it has been used in 2.30eq).
[0048] In the present invention, it is a particularly preferable mode to add
the organic acid to the reaction-terminated liquid and then conduct a

distillation purification under reduced pressure, in producing the optically
active 2-fluoropropionate.
[0049] Furthermore, in the present invention, particularly preferable
modes are a method in which optically active lactate represented by formula
[3] is reacted with sulfuryl fluoride (SO2F2) or trifluoromethanesulfonyl
fluoride (CF3SO2F), in the presence of an organic base selected from
trie thy lamine, diisopropylethylamine, trrn-propylamine, tri-n-butylamine,
tri-n-pentylamine, tri-n-hexylamine, 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, and
in the absence of reaction solvent, thereby obtaining optically active
2-fluoropropionate represented by formula [4], and a method in which an
organic acid is added to the reaction-terminated liquid containing optically
active 2-fluoropropionate represented by formula [4] and obtained by the
above method, followed by conducting a distillation purification under
reduced pressure, since usefulness of the product is conspicuous and since
advantageous effect of the present invention is conspicuous.
[0050] Furthermore, extremely preferable modes are a method in which
methyl (S)-lactate represented by formula [5] is reacted with sulfuryl
fluoride (SO2F2) in the presence of an organic base selected from
triethylamine and tri-n-butylamine and in the absence of reaction solvent to
obtain methyl (R)-2-fluoropropionate represented by formula [6], and a
method in which benzoic acid is added to the reaction-terminated liquid
containing methyl (R)-2-fluoropropionate represented by formula [6] and
obtained by the above method, followed by conducting a distillation
purification under reduced pressure, due to that usefulness of the product is
conspicuous, that getting hold of the raw material compound is particularly
easy, that advantageous effect of the present invention is conspicuous, etc.
[0051] Embodiments of the present invention are specifically explained by
the following examples, but the present invention is not limited to these
examples.
[0052] [EXAMPLE 1]

A stainless steel (SUS), pressure-proof, reaction container was
charged with 12.0g (ll5mmol, l.OOeq, optical purity 99.0%ee or higher) of
methyl (S)-lactate represented by the following formula
[Chemical Formula 7]

and 13.Og (l28mmol, l.lleq) of triethylamine, followed by cooling in a
refrigerant bath of -20°C and then bubbling from a cylinder 13.5g (l32mmol,
1.15eq) of sulfuryl fluoride (SO2F2). The inside temperature was gradually
increased to room temperature, followed by stirring at the same temperature
for 2 hours and 30 minutes. Conversion of the reaction was found to be 95%
or higher by determination by gas chromatography.
[0053] Then, the reaction-terminated liquid was directly subjected to a
distillation under reduced pressure (degree of pressure reduction; 15kPa,
bath temperature; 70°C), thereby obtaining 10.3g of a distillate of methyl
(R)-2-fluoropropionate represented by the following formula.
[Chemical Formula 8]

Recovery percentage was 84%. Chemical purity (calculated by gas
chromatography), optical purity [calculated by gas chromatography; the
ester group is subjected to hydride reduction to convert that to
(R)-2-fluoropropanol, and its Mosher ester is analyzed], triethylamine
content (calculated by XH-NMR), and fluoride ion concentration of the
-... distillate were respectively 94.2%, 99.0%ee or higher, 3.8mol%,-and 342ppm.

[0054] XH and 19F"NMR spectrums of methyl (R)-2-fluoropropionate are
shown in the following.
iH-NMR [standard substance,' (CH^Si, deuterated solvent; CDCI3], 8 ppm;
1.59 (dd, 23.6Hz, 6.8Hz, 3H), 3.81 (s, 3H), 5.03 (dq, 48.6Hz, 6.9Hz, 1H).
19F-NMR (standard substance.' CeF6, deuterated solvent; CDCI3), 8 ppm;
-22.77 (dq, 47.2Hz, 23.8Hz, IF).
[0055] [EXAMPLE 2]
A stainless steel (SUS), pressure-proof, reaction container was
charged with 258g (2.48mol, l.OOeq, optical purity 99.0%ee or higher) of
methyl (S) -lactate represented by the following formula
[Chemical Formula 9]

and 278g (2.75mol, l.lleq) of triethylamine, followed by bubbling from a
cylinder 280g (2.74mol, l.lOeq) of sulfuryl fluoride (SO2F2) while controUing
the inside temperature in 0-ll°C. The inside temperature was gradually
increased to room temperature, followed by stirring at the same temperature
for all night. Conversion of the reaction was found to be 92% by
determination by gas chromatography.
[0056] Then, 76g (0.62mol, 2.30eq relative to triethylamine used
excessively) of benzoic acid was added to the reaction-terminated liquid, and
it was subjected to a distillation under reduce pressure (degree of pressure
reduction; 1.5kPa, bath temperature; 70°C), thereby obtaining 193g of a
distillate of methyl (R)-2-fluoropropionate represented by the following
formula.
[Chemical Formula 10]


Recovery percentage was 73%. Chemical purity (calculated by gas
chromatography), optical purity [calculated by gas chromatography," the
ester group is subjected to hydride reduction to convert that to
(R)-2-fluoropropanol, and its Mosher ester is analyzed], triethylamine
content (calculated by 1H-NMR), and fluoride ion concentration of the
distillate were respectively 97.3%, 99.5%ee, a trace amount (less than
0.2mol%), and 89ppm.
[0057] *H and 19F-NMR spectrums of methyl (R)-2-fluoropropionate were
the same as those of Example 1.
[0058] In such a manner, it was possible in Example 2 to further greatly
reduce triethylamine content and fluoride ion content by conducting the
distillation after adding acid to the reaction-terminated liquid, as compared
with Example 1.
[0059] [EXAMPLE 3]
A stainless steel (SUS), pressure-proof, reaction container was
charged with 106.8kg (l.026kmol, l.OOeq, optical purity 99.0%ee) of methyl
(SMactate represented by the following formula
[Chemical Formula 11]

and 190.1kg (l.026kmol, l.OOeq) of tri-n-butylamine, followed by cooling with
a circulation-type refrigerant of-10°C and bubbling from a cylinder 105.1kg
(l.030kmol, l.OOeq) of sulfuryl fluoride (SO2F2). The inside temperature

was gradually increased to room temperature, and stirring was conducted at
the same temperature for 4 hours. Conversion of the reaction was found to
be 95% by determination by ^-NMR.
[0060] Then, the reaction-terminated liquid was directly subjected to a
distillation under reduced pressure (degree of pressure reduction; l.OkPa,
bath temperature." 75°C).
[0061] With this, 95.4kg of a distillate of methyl (R)-2-fluoropropionate
represented by the following formula
[Chemical Formula 12]

was obtained. Recovery percentage was 84%. Chemical purity (calculated
by gas chromatography), optical purity [calculated by chiral gas
chromatography], tri-n-butylamine content (calculated by gas
chromatography), fluoride ion concentration and water content of the
distillate were respectively 96.5%, 97.4%ee, 1.5%, 543ppm, and 317ppm.
[0062] XB. and 19F-NMR spectrums of methyl (R)-2-fluoropropionate were
the same as those of Example 1.
[0063] 560kg of water was added to the tank residue (distillation residue),
followed by cooling with a circulation-type refrigerant of 0°C. 48% sodium
hydroxide aqueous solution was added until pH became 12. The liberated
organic layer was subjected to a two-layer separation. The recovered
organic layer was washed with 105kg of water. Then, a fractional
distillation (column top temperature 79-82°C, degree of pressure reduction
14-16hPa) was conducted by using a distillation apparatus made of glass (the
number of theoretical plates: 15), thereby recovering 156kg of a main
distillate (chemical purity: 99.9% or higher, water content: less than 0.1%)

(recovery percentage- 82%). It was possible to reuse the recovered
trrn-butylamine without lowering of reactivity.

WE CLAIM
1. A process for producing an optically active 2-fluoropropionate
represented by formula [4]

wherein R represents a methyl group or ethyl group, and * represents an
asymmetric carbon, the process comprising reacting an optically active
lactate represented by formula [3]

wherein R and * are defined as above, with sulfuryl fluoride (SO2F2) or
trifluoromethanesulfonyl fluoride (CF3SO2F), in the presence of an organic
base selected from the group consisting of triethylamine,
diisopropylethylamine, trin-propylamine, tri-n-butylamine,
tri-n-pentylamine, tri-n-hexylamine, 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, and
in the absence of reaction solvent
wherein stereochemistry of the asymmetric carbon in formula [3] is
inverted by the reaction.
2. A process as claimed in claim 1, wherein a distillation purification
under reduced pressure is conducted after adding an organic acid to a
reaction-terminated liquid that has been obtained by the reaction according
to claim 1 and that contains the optically active 2-fluoropropionate.

3. A process as claimed in claim 1, for producing methyl
(R)-2 fluoropropionate represented by formula [6]

the process comprising reacting methyl (S)lactate represented by formula
[5]

with sulfuryl fluoride (SO2F2), in the presence of triethylamine or
tri-n-butylamine and in the absence of reaction solvent.
4. A process as claimed in claim 3, wherein a distillation purification
under reduced pressure is conducted after adding benzoic acid to a
reaction-terminated liquid that has been obtained by the reaction according
to claim 3 and that contains the methyl (R)-2-fluoropropionate.
5. A process as claimed in claim 2, wherein the organic acid is benzoic
acid.

ABSTRACT

Title: PROCESS FOR PRODUCING OPTICALLY ACTIVE
α-FLUOROCARBOXYLATE
An optically active α flurocarboxylate is produced by reacting an
optically active α hydroxycarboxylate with sulfuryl fluoride (SO2F2),
trifluoromethanesulfonyl fluoride (CF3SO2F) or nonafluorobutanesulfonyl
fluoride (C4F9SO2F) in the presence of organic base and in the absence of
reaction solvent. More preferably, a distillation purification is conducted
after adding acid to the reaction-terminated liquid. With this, it is possible
to produce an optically active α flurocarboxylate of a still higher purity. It
is possible by this process to advantageously produce an optically active
α flurocarboxylate on a large-amount scale.