U.S. patent application number 11/477626 was filed with the patent office on 2006-11-02 for process for producing optically active carboxylic acid substituted in 2-position.
This patent application is currently assigned to KANEKA CORPORATION. Invention is credited to Susumu Amano, Kenji Inoue, Koichi Kinoshita, Masaru Mitsuda, Yasuyoshi Ueda, Koki Yamashita.
Application Number | 20060247470 11/477626 |
Document ID | / |
Family ID | 27342123 |
Filed Date | 2006-11-02 |
United States Patent
Application |
20060247470 |
Kind Code |
A1 |
Amano; Susumu ; et
al. |
November 2, 2006 |
Process for producing optically active carboxylic acid substituted
in 2-position
Abstract
A nitrous acid salt is added at a temperature of 10 to
80.degree. C. to an aqueous solution which contains an optically
active 2-aminocarboxylic acid (4) and a protonic acid, the amount
of the latter acid being 1 to 3 equivalents to the former, and
which has a proton concentration of 0.5 to 2 mol/kg to conduct a
reaction to thereby produce an optically active 2-hydroxycarboxylic
acid (1). Thionyl chloride and a basic compound are caused to act
on the compound (1) to chlorinate it and simultaneously invert the
configuration in the 2-position. Thus, an optically active
2-chlorocarboxylic acid chloride (5) is induced. The compound (5)
is hydrolyzed to induce an optically active 2-chlorocarboxylic acid
(2). The compound (2) is reacted with a thioacetic acid salt to
incorporate an acetylthio group thereinto and simultaneously invert
the configuration in the 2-position to thereby produce an optically
active 2-acetylthiocarboxylic acid (3). ##STR1##
Inventors: |
Amano; Susumu; (Kobe,
JP) ; Mitsuda; Masaru; (Akashi, JP) ; Inoue;
Kenji; (Kakogawa, JP) ; Kinoshita; Koichi;
(Kakogawa, JP) ; Yamashita; Koki; (Kobe, JP)
; Ueda; Yasuyoshi; (Himeji, JP) |
Correspondence
Address: |
SUGHRUE MION, PLLC
2100 PENNSYLVANIA AVENUE, N.W.
SUITE 800
WASHINGTON
DC
20037
US
|
Assignee: |
KANEKA CORPORATION
|
Family ID: |
27342123 |
Appl. No.: |
11/477626 |
Filed: |
June 30, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10182260 |
Sep 25, 2002 |
7094926 |
|
|
PCT/JP01/00470 |
Jan 25, 2001 |
|
|
|
11477626 |
Jun 30, 2006 |
|
|
|
Current U.S.
Class: |
562/602 ;
562/579 |
Current CPC
Class: |
C07C 51/60 20130101;
C07C 327/32 20130101; C07C 51/367 20130101; C07C 57/58 20130101;
C07C 59/48 20130101; C07C 59/48 20130101; C07C 57/76 20130101; C07C
51/367 20130101; C07C 51/04 20130101; C07C 51/04 20130101; C07C
51/60 20130101 |
Class at
Publication: |
562/602 ;
562/579 |
International
Class: |
C07C 53/15 20060101
C07C053/15; C07C 53/16 20060101 C07C053/16 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 25, 2000 |
JP |
2000-15432 |
May 30, 2000 |
JP |
2000-160937 |
May 30, 2000 |
JP |
2000-160938 |
Claims
1. A method of producing an optically active 2-hydroxycarboxylic
acid represented by the general formula (1): ##STR15## wherein
R.sup.1 represents a substituted or unsubstituted alkyl group
containing 1 to 12 carbon atoms, a substituted or unsubstituted
aryl group containing 6 to 14 carbon atoms or a substituted or
unsubstituted aralkyl group containing 7 to 15 carbon atoms, by
reacting an optically active 2-aminocarboxylic acid represented by
the general formula (4): ##STR16## wherein R.sup.1 is as defined
above, with a nitrite salt and a protonic acid in aqueous solution,
wherein the reaction is carried out by adding the nitrite salt to
an aqueous solution containing said optically active
2-aminocarboxylic acid and 1 to 3 equivalents, relative to the
optically active 2-aminocarboxylic acid, of the protonic acid and
having a proton concentration of 0.5 to 2 mol/kg at a temperature
of 10 to 80.degree. C.
2. (canceled)
3. The method of production according to claim 1 or 2, wherein the
proton concentration is 1 to 2 mol/kg.
4. The production method according to any of claims 1 to 3, wherein
the aqueous solution contains 2 to 3 equivalents, relative to the
optically active 2-aminocarboxylic acid (4), of a protonic
acid.
5. The method of production according to any of claims 1 to 4,
wherein the temperature during nitrite salt addition and during
reaction is 15 to 60.degree. C.
6. The method of production according to any of claims 1 to 5,
wherein the protonic acid is an inorganic acid.
7. The method of production according to claim 6, wherein the
inorganic acid is sulfuric acid.
8. The method of production according to any of claims 1 to 7,
wherein the nitrite salt is used in an amount of not less than 2
moles per mole of the optically active 2-aminocarboxylic acid
(4).
9. The method of production according to any of claims 1 to 8,
wherein the addition rate of the nitrite salt per hour is 0.2 to
1.5 moles per mole of the optically active 2-aminocarboxylic acid
(4).
10. The method of production according to any of claims 1 to 9,
wherein the addition of the nitrite salt is effected by adding an
aqueous solution containing the same.
11. A method of crystallizing out an optically active
2-hydroxycarboxylic acid represented by the general formula (1):
##STR17## in which R.sup.1 represents a substituted or
unsubstituted alkyl group containing 1 to 12 carbon atoms, a
substituted or unsubstituted aryl group containing 6 to 14 carbon
atoms or a substituted or unsubstituted aralkyl group containing 7
to 15 carbon atoms, which comprises causing crystallization of the
optically active 2-hydroxycarboxylic acid by using t-butyl methyl
ether and a hydrocarbon solvent.
12. The method of crystallization according to claim 11, wherein at
least one of an .alpha.,.beta.-unsaturated carboxylic acid and an
optical isomer each corresponding to the optically active
2-hydroxycarboxylic acid (1) is removed as an impurity.
13. (canceled)
14. The method of crystallization according to any of claims 11 to
13, wherein the volume ratio of t-butyl methyl ether to the
hydrocarbon solvent is 1/20 to 1.
15. The method of crystallization according to any of claims 11 to
14, wherein the crystallization is caused by adding a hydrocarbon
solvent to t-butyl methyl ether solution containing the optically
active 2-hydroxycarboxylic acid (1) or by adding t-butyl methyl
ether solution containing the optically active 2-hydroxycarboxylic
acid (1) to a hydrocarbon solvent.
16. The method of crystallization according to claim 11 to 15,
wherein the hydrocarbon solvent is an aliphatic hydrocarbon.
17. The method of crystallization according to claim 16, wherein
the aliphatic hydrocarbon is at least one species selected from the
group consisting of hexane, heptane and methylcyclohexane.
18. (canceled)
19. The method of crystallization according to any of claims 11 to
18, wherein an extract obtained, by using t-butyl methyl ether,
from an aqueous solution containing the optically active
2-hydroxycarboxylic acid (1) produced by the method according to
any of claims 1 to 10, or a concentrate of said extract is
subjected to said method of crystallization.
20.-62. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This is a Divisional application of U.S. application Ser.
No. 10/182,260 filed on Sep. 25, 2002, which is a 371 of PCT
Application No. PCT/JP01/004704 filed on Jan. 25, 2001, which
applications are incorporated herein by reference in their
entirety.
TECHNICAL FIELD
[0002] The present invention relates to a method of producing
optically active 2-hydroxycarboxylic acids, optically active
2-chlorocarboxylic acids and optically active
2-acetylthiocarboxylic acids, which are important as intermediates
for the production of pharmaceuticals and so forth.
BACKGROUND ART
[0003] Optically active 2-hydroxycarboxylic acids represented by
the general formula (1): ##STR2## (wherein R.sup.1 represents a
substituted or unsubstituted alkyl group containing 1 to 12 carbon
atoms, a substituted or unsubstituted aryl group containing 6 to 14
carbon atoms or a substituted or unsubstituted aralkyl group
containing 7 to 15 carbon atoms) are important intermediates in the
production of pharmaceuticals (for example, Biosci. Biotech.
Biochem., 60 (8), 1279-1283, 1996) and, for the production thereof,
the following methods are known, among others:
[0004] (i) L-Phenylalanine hydrochloride is prepared by treating
L-phenylalanine with concentrated hydrochloric acid in chloroform
and, then, (2S)-2-hydroxy-3-phenylpropionic acid is synthesized by
treating an aqueous solution (proton concentration 1.4 mol/kg)
containing L-phenylalanine and 4 equivalents, relative to
L-phenylalanine, of a protonic acid (hydrochloric acid and sulfuric
acid) with an aqueous solution containing 2 moles of sodium nitrite
per mole of L-phenylalanine at 0.degree. C. for 3 hours. After the
reaction, the (2S)-2-hydroxy-3-phenylpropionic acid is recovered as
crystals by ether extraction, dehydration, ether extract
concentration and treatment of the residue with benzene (isolation
yield 40%) (J. Amer. Chem. Soc., 86, 5326-5330, 1964);
[0005] (ii) (2S)-2-Hydroxy-3-phenylpropionic acid is synthesized by
adding 4 moles, per mole of L-phenylalanine, of solid sodium
nitrite to an aqueous solution (proton concentration 2.1 mol/kg)
containing L-phenylalanine and 4 equivalents, relative to
L-phenylalanine, of a protonic acid (sulfuric acid) at 0.degree. C.
over 5 hours, gradually warming the mixture to room temperature and
stirring the same overnight. After the reaction, the
(2S)-2-hydroxy-3-phenylpropionic acid is recovered as crystals by
two or more times of extraction with ethyl acetate, washing of the
extract with a saturated aqueous solution of sodium chloride,
dehydration of the same over magnesium sulfate, concentration of
the ethyl acetate solution and crystallization by addition of
hexane (isolation yield 50%) (J. Heterocyclic Chem., 29, 431-438,
1992).
[0006] However, check experiments made by the present inventors
concerning the above method (i) revealed that the method has such
problems as the use of chloroform and benzene, which are highly
toxic organic solvents, and the very low reaction yield (42%).
[0007] Checking of the above method (ii) by experiment revealed
such problems as procedure complicatedness and increased capacity
requirement, as resulting from the use of solid sodium nitrite and
of large amounts of organic solvents and inorganic salts. It was
also revealed that the reaction yield itself is low, namely 65%. In
Biosci. Biotech. Biochem., 60 (8), 1279-1283, 1996, it is noted to
the effect that the above method (ii) allows the formation, as a
byproduct, of a large amount of a related substance (cinnamic acid)
and accordingly gives a low yield, hence it is very difficult to
employ that method on a commercial scale.
[0008] Further, it was revealed that the above methods (i) and (ii)
still have another problem in that the optical purity is reduced by
the formation of a considerable amount of the optical isomer (2R)
-2-hydroxy-3-phenylpropionic acid as a byproduct as a result of
racemization.
[0009] With such a background, alternative methods of producing
optically active 2-hydroxy-3-phenylpropionic acid have been made,
for example the method comprising asymmetric reduction of racemic
2-hydroxy-3-phenylpropionitrile using a microorganism (e.g. Biosci.
Biotech, Biochem., 60 (8), 1279-1283, 1996 and JP-A 6-237789).
These method are, however, not entirely favorable since the cyano
compound to be used is highly toxic, the productivity is low and,
further, no satisfactory optical purity can be obtained.
[0010] As for the production of optically active carboxylic acids
substituted by a chlorine atom in the 2-position, which are
represented by the general formula (2): ##STR3## (wherein R.sup.1
is as defined above) the following are known in the art:
[0011] (i) The method comprising using an amino acid as a starting
material and chlorinating the same using sodium -nitrite while
retaining the configuration thereof (Liebigs Ann., 1907, 357, 1);
and
[0012] (ii) The method comprising chlorinating a
2-hydroxycarboxylic acid ester with configurational inversion (JP-A
61-57534).
[0013] However, the method (i) indeed gives a 2-chlorocarboxylic
acid whose configuration at 2-position is (S) when a naturally
occurring L-amino acid is used as the starting material but, for
producing a 2-chlorocarboxylic acid whose configuration at
2-position is (R), it requires the use of a non-natural D amino
acid, which is expensive, as the starting material, hence it has
its limit as a method of producing (R)-2-chlorocarboxylic
acids.
[0014] As for the method (ii), it is necessary to derivatize a
2-hydroxycarboxylic acid into a 2-hydroxycarboxylic acid ester,
chlorinate the same with configurational inversion and then
derivatize the chlorination product into a 2-chlorocarboxylic acid
by hydrolysis. Thus, a number of steps have to be required and the
method is not efficient.
[0015] Further, optically active 2-acetylthiocarboxylic acids
represented by the general formula (3): ##STR4## (wherein R.sup.1
is as defined above) are important intermediates in the production
of pharmaceuticals (e.g. as intermediates of antihypertensive
agents; cf. JP-A 8-337527). For the production thereof, the
following are known in the art:
[0016] (i) The method comprising thioacetylating a non-natural
D-amino acid via configuration-retaining bromination (JP-A 8-337527
etc.);
[0017] (ii) The method comprising optical resolution of a racemic
2-acetylthiocarboxylic acid (JP-A 6-56790);
[0018] (iii) The method comprising hydrolyzing a thiazoline
compound by means of a microorganism (JP-A 11-192097); and
[0019] (iv) The method comprising stereoseletively reducing a
di-substituted acrylic acid derivative by means of a microorganism
(JP-A 11-196889).
[0020] However, for producing an (S) form, the method (i) requires
the use of an expensive non-natural D-amino acid as the starting
material, hence it has its limit as a method of producing (S)
forms.
[0021] The method (ii) lies in optical resolution of racemic
2-acetylthiocarboxylic acids, hence is not so efficient but has a
problem from the industrial utilization viewpoint.
[0022] The method (iii) requires a separate procedure for
increasing the optical purity since the 2-thiocarboxylic acid
derivative obtained by hydrolysis of the thiohydantoin derivative
has an optical purity as low as 82% ee. Thus it has a problem from
the industrial utilization viewpoint.
[0023] The method (iv) is low in yield of asymmetric reduction of
mercaptoacrylic acid derivative, namely 60 to 70% and, further, the
2-thiocarboxylic acid derivative obtained has an optical purity as
low as 90% ee. Thus it has problems from the industrial utilization
viewpoint.
DISCLOSURE OF INVENTION
[0024] In view of the above-mentioned state of the art, it is an
object of the present invention to produce optically active
2-hydroxycarboxylic acids, which are important for the production
of pharmaceuticals and other compounds, with good operability and
in high yields.
[0025] In view of the above-mentioned state of the art, it is
another object of the invention to isolate or purify optically
active 2-hydroxycarboxylic acids expediently and efficiently on a
commercial scale by efficiently removing related substances and/or
undesired optical isomers coexisting with the desired optically
active 2-hydroxycarboxylic acids.
[0026] In view of the above-mentioned state of the art, it is a
further object of the invention to produce optically active
2-chlorocarboxylic acids, which are important for the production of
pharmaceuticals and other compounds, from readily available
starting materials, such as L-amino acids, efficiently and in high
optical purity.
[0027] In view of the above-mentioned state of the art, it is a
still further object of the invention to produce optically active
2-acetylthiocarboxylic acids, which are important for the
production of pharmaceuticals and other compounds, from readily
available starting materials, such as L-amino acids, efficiently
and in high optical purity.
[0028] Thus, the present invention relates to a method of producing
optically active 2-hydroxycarboxylic acids represented by the
general formula (1): ##STR5##
[0029] in which R.sup.1 represents a substituted or unsubstituted
alkyl group containing 1 to 12 carbon atoms, a substituted or
unsubstituted aryl group containing 6 to 14 carbon atoms or a
substituted or unsubstituted aralkyl group containing 7 to 15
carbon atoms,
[0030] by reacting an optically active 2-aminocarboxylic acid
represented by the general formula (4): ##STR6##
[0031] in which R.sup.1 is as defined above,
[0032] with a nitrite salt and a protonic acid in aqueous
solution,
[0033] which method comprises carrying out the reaction by adding
the nitrite salt to an aqueous solution containing said optically
active 2-aminocarboxylic acid and 1 to 3 equivalents, relative to
the optically active 2-aminocarboxylic acid, of the protonic acid
and having a proton concentration of 0.5 to 2 mol/kg at a
temperature of 10 to 80.degree. C.
[0034] The invention also relates to a method of crystallizing out
optically active 2-hydroxycarboxylic acids
[0035] which comprises causing crystallization of an optically
active 2-hydroxycarboxylic acid represented by the above general
formula (1) by using t-butyl methyl ether and a hydrocarbon
solvent.
[0036] Further, the invention relates to a method of producing
optically active 2-chlorocarboxylic acid chlorides represented by
the general formula (5): ##STR7##
[0037] in which R.sup.1 is as defined above,
[0038] which comprises reacting an optically active
2-hydroxycarboxylic acid represented by the above general formula
(1) with thionyl chloride and a basic compound for chlorination
with inversion of the configuration at 2-position.
[0039] The invention also relates to a method of producing
optically active 2-chlorocarboxylic acids represented by the
general formula (2): ##STR8##
[0040] in which R.sup.1 is as defined above,
[0041] which comprises reacting an optically active
2-hydroxycarboxylic acid represented by the above general formula
(1) by reaction with thionyl chloride and a basic compound for
chlorination with inversion of the configuration at 2-position
and
[0042] hydrolyzing the thus-obtained optically active
2-chlorocarboxylic acid chloride represented by the general formula
(5).
[0043] Furthermore, the present invention relates to a method of
producing optically active 2-acetylthiocarboxylic acids represented
by the general formula (3) ##STR9##
[0044] in which R.sup.1 is as defined above,
[0045] which comprises reacting an optically active
2-chlorocarboxylic acid represented by the general formula (2) with
a thioacetate salt for substitution by acetylthio group with
inversion of the configuration at 2-position.
[0046] In the following, the present invention is described in
detail.
[0047] In the present specification, the following reactions (a) to
(c) are included:
[0048] (a) The reaction which converts an optically active
2-aminocarboxylic acid of general formula (4) to the corresponding
optically active 2-hydroxycarboxylic acid of general formula
(1);
[0049] (b) The reaction which converts the optically active
2-hydroxycarboxylic acid (1) to the corresponding optically active
2-chlorocarboxylic acid chloride of general formula (5) and the
reaction which converts the optically active 2-chlorocarboxylic
acid chloride (5) to the corresponding optically active
2-chlorocarboxylic acid of general formula (2); and, further,
[0050] (c) The reaction which converts the optically active
2-chlorocarboxylic acid (2) to the corresponding optically active
2-acetylthiocarboxylic acid of general formula (3). ##STR10##
[0051] In addition, in the present specification, there is included
a method of crystallizing out an optically active
2-hydroxycarboxylic acid represented by the general formula
(1).
[0052] In the following, these reactions and method are described
in detail one by one.
1. Reaction (a)
[0053] In the step of reaction (a) according to the invention, an
optically active 2-hydroxycarboxylic acid (1) is synthesized by
reacting an optically active 2-aminocarboxylic acid (4) with a
nitrite salt and a protonic acid.
[0054] In the above general formula (4) or (1), R.sup.1 represents
a substituted or unsubstituted alkyl group containing 1 to 12
carbon atoms, a substituted or unsubstituted aryl group containing
6 to 14 carbon atoms or a substituted or unsubstituted aralkyl
group containing 7 to 15 carbon atoms. Specifically, it includes,
but is not limited to, methyl, ethyl, isopropyl, tert-butyl,
n-octyl, hydroxymethyl,-phenyl, p-hydroxyphenyl, benzyl,
p-chlorobenzyl, p-fluorobenzyl and naphthyl group. Substituted or
unsubstituted aralkyl groups containing 7 to 15 carbon atoms are
preferred, and a benzyl group is more preferred.
[0055] As the substituent which the group R.sup.1 may have, there
may be mentioned alkoxy groups containing 1 to 12 carbon atoms,
such as methoxy, ethoxy, t-butyloxy and n-octyloxy group, aryloxy
groups containing 6 to 14 carbon atoms, such as phenyloxy and
p-hydroxyphenyloxy group, aralkyloxy groups containing 7 to 15
carbon atoms, such as benzyloxy, p-chlorobenzyloxy and
p-fluorobenzyloxy group, acyl groups containing 1 to 15 carbon
atoms, such as acetyl and benzoyl group, a halogen atom and a
hydroxyl group.
[0056] In cases where R.sup.1 is an aryl or aralkyl group, the
substituent on the phenyl group thereof is not particularly
restricted but, as such, there may be mentioned, among others,
halogen atoms such as fluorine and chlorine atoms, hydroxyl group,
alkyl groups containing 1 to 12 carbon atoms, such as methyl and
isopropyl group, aralkyl groups containing 7 to 15 carbon atoms,
such as benzyl group, aryl groups containing 6 to 14 carbon atoms,
such as phenyl group, alkoxy groups containing 1 to 12 carbon
atoms, such as methoxy and isopropyloxy group, aralkyloxy groups
containing 7 to 15 carbon atoms, such as benzyloxy group, aryloxy
groups containing 6 to 14 carbon atoms, such as phenyloxy group,
and acyl groups containing 1 to 15 carbon atoms, such as acetyl and
benzoyl group. Among them, halogen atoms are preferably used. The
position of such a substituent is not particularly restricted but
the para position is usual. Although the phenyl group may have a
plurality of such substituents as mentioned above, the phenyl
group, when substituted, usually has one substituent.
[0057] When the optically active 2-aminocarboxylic acid (4)
subjected to reaction (a) according to the invention is in (S)
form, the (S) form of the optically active 2-hydroxycarboxylic acid
(1) is predominant in the product obtained. When the optically
active 2-aminocarboxylic acid (4) is in (R) form, the (R) form of
the optically active 2-hydroxycarboxylic acid (1) is predominant in
the product obtained.
[0058] The reaction (a) according to the invention is carried out
in aqueous solution. While it is generally suitable to carry out
the reaction in water, an organic solvent may coexist in an amount
not producing any adverse effect.
[0059] The nitrite salt to be used in the reaction (a) according to
the invention is not particularly restricted but includes, among
others, alkali metal nitrites such as sodium nitrite, potassium
nitrite, lithium nitrite and cesium nitrite. Sodium nitrite is
preferred, however. It is particularly preferred to use the nitrite
salt in the form of an aqueous solution (e.g. 20 to 40% (by weight)
aqueous solution of sodium nitrite).
[0060] As the protonic acid to be used in the reaction (a)
according to the invention, there maybe mentioned, among others,
inorganic acids, such as sulfuric acid, hydrochloric acid and
nitric acid, and organic acids, such as acetic acid and citric
acid. Generally, the use of inorganic acids is expedient and
preferred and, for suppressing byproduct formation and attaining a
high reaction yield, sulfuric acid is most preferred among others.
The protonic acid can be used in the form of an aqueous
solution.
[0061] The reaction (a) according to the invention is carried out
by adding the above nitrite salt to an aqueous solution containing
an optically active 2-aminocarboxylic acid (4) and a protonic
acid.
[0062] On that occasion, the protonic acid is used in an amount of
1 to 3 equivalents, preferably 2 to 3 equivalents, relative to the
optically active 2-aminocarboxylic acid (4). The proton
concentration (normality) of the aqueous solution containing the
optically active 2-aminocarboxylic acid (4) and the protonic acid
is 0.5 to2 mol/kg, preferably 1 to 2 mol/kg. When the amount and
concentration of the protonic acid are insufficient, the optical
purity of the desired product tends to decrease. When the amount
and concentration of the protonic acid are excessive, the yield
tends to decrease.
[0063] The proton concentration (normality) is expressed by the
following formula 1: Proton concentration (normality)=(Number of
moles of protonic acid.times.number of ionic valency)/(amount of
water existing in reaction system) (mol/kg) The number of ionic
valency is the absolute value of the ionic valency of the protonic
acid anion. Therefore, according to the above formula 1, the proton
concentration (normality) of a solution containing 98 g (1 mol) of
sulfuric acid per kg of water, for instance, is 2 mol/kg.
[0064] The nitrite salt is used in an amount of not less than 1
mole, preferably not less than 2 moles, judiciously 2 to 4 moles,
per mole of the optically active 2-aminocarboxylic acid (4). The
addition of the nitrite salt is preferably carried out continuously
or in divided portions. In this case, the addition rate of the
nitrite salt per hour is 0.2 to 1.5 moles, preferably 0.25 to 1.0
mole, more preferably 0.3 to 0.7 moles, per mole of the optically
active 2-aminocarboxylic acid (4). Excessively high or low addition
rates tend to result in decreased yields.
[0065] The nitrite salt addition and the subsequent reaction are
carried out at 10 to 80.degree. C., preferably 15 to 60.degree. C.,
more preferably 20 to 50.degree. C. At excessively low
temperatures, the yield tends to decrease and/or the reaction
mixture tends to solidify. At excessively high temperatures, the
yield and optical purity tend to decrease.
[0066] The reactant concentrations depend on the optical active
2-aminocaboxylic acid (4) species and other factors, hence cannot
be specified in all cases. As for the amount (weight) of the
optically active 2-aminocarboxylic acid (4) used relative to the
volume of the reaction mixture at the time of completion of the
reaction, for instance, the lower limit is not less than 1% (w/v),
preferably not less than 3% (w/v), and the upper limit is not more
than 30% (w/v), preferably 20% (w/v). Generally, for example, 3 to
20% (w/v), more preferably 5 to 15% (w/v), in particular about
8.+-.2% (w/v) is appropriate for carrying out the reaction.
[0067] The progress of the reaction can be followed by HPLC, for
instance. Generally, the reaction will be complete in 24 hours
after completion of the nitrite salt addition.
[0068] After completion of the reaction, the product can be
recovered from the reaction mixture by ordinary work-up. For
example, the reaction mixture after completion of the reaction is
extracted with an ordinary extracting solvent, such as ethyl
acetate, diethyl ether, methylene chloride, toluene or hexane. The
desired product can be recovered from the thus-obtained extract by
distilling off the reaction solvent and extracting solvent by such
a procedure as heating under reduced pressure. Although the
thus-obtained product is nearly pure, the purity may further be
increased by ordinary purification procedures such as purification
by crystallization, fractional distillation, column chromatography,
etc.
[0069] By using the reaction (a) according to the present
invention, it becomes possible to produce the desired product in
very high reaction yield and optical purity.
2. Method of Crystallizing Out Optically Active 2-hydroxycarboxylic
Acids (1)
[0070] In the process of producing the optically active
2-hydroxycarboxylic acid (1) by reacting the optically active
2-aminocarboxylic acid (4) with a nitrite salt and a protonic acid
in aqueous solution, impurities, such as the corresponding
.alpha.,.beta.-unsaturated carboxylic acid (e.g. cinnamic acid, the
phenyl group of which may be substituted) and like related
substances as well as the undesired optical isomer are formed in
many instances in addition to the desired 2-hydroxycarboxylic acid
(1).
[0071] For removing these impurities and thereby-isolating or
purifying the above optically active 2-hydroxycarboxylic acid (1)
expediently and efficiently, the crystallization method according
to the invention is carried out using t-butyl methyl ether and a
hydrocarbon solvent. The use of t-butyl methyl ether greatly
contributes to improvements in yield and quality.
[0072] The above-mentioned hydrocarbon solvent may be an aliphatic
hydrocarbon or an aromatic hydrocarbon. The aliphatic hydrocarbon
is not particularly restricted but, for example, linear or cyclic
aliphatic hydrocarbons containing 5 to 12 carbon atoms can suitably
be used. As specific examples, there may be mentioned hexane,
heptane, octane, decane, cyclohexane, methylcyclohexane,
ethylcyclohexane and the like. Among them, hexane, heptane and
methylcyclohexane are preferred. The aromatic hydrocarbon is not
particularly restricted but monocyclic aromatic hydrocarbons
containing 6 to 12 carbon atoms, for instance, can suitably be
used. Specifically, there may be mentioned benzene, toluene, xylene
and ethylbenzene. Among them, toluene is preferred. Form the
crystallization yield viewpoint, aliphatic hydrocarbons are more
preferably used. The hydrocarbon solvent may comprise either one
single species or a combination of two or more species.
[0073] As for the quantity ratio between the above-mentioned
hydrocarbon solvent and t-butyl methyl ether, the volume ratio of
t-butyl methyl ether, relative to hydrocarbon solvent, is generally
not more than 1, preferably not more than 2/3, still more
preferably not more than 1/2, and generally not lower than 1/30,
preferably not less than 1/20, still more preferably not less than
1/10. The ratio can appropriately be varied taking into
consideration the solubility and treatment concentration of
optically active 2-hydroxycarboxylic acid (1), the purification
effect (impurity removing effect) and the physical properties of
crystals to be recovered.
[0074] The technique of crystallization to be employed in carrying
out the present invention is not particularly restricted but may
comprise crystallization by-cooling, crystallization by
concentration, crystallization by solvent replacement (e.g.
conversion of the solution comprising t-butyl methyl ether to a
solution comprising the above hydrocarbon solvent), crystallization
by addition of the above hydrocarbon solvent to the solution
comprising t-butyl methyl ether, or crystallization by addition of
the solution comprising t-butyl methyl ether to the above
hydrocarbon solvent, for instance. Such techniques to be used in
combination are also preferable.
[0075] Preferred among others are the technique comprising
effecting crystallization by adding a hydrocarbon solvent to
t-butyl methyl ether solution containing an optically active
2-hydroxycarboxylic acid (1), and the technique comprising
effecting crystallization by adding t-butyl methyl ether solution
containing an optically active 2-hydroxycarboxylic acid (1) to a
hydrocarbon solvent. In particular, the technique comprising adding
a hydrocarbon solvent to a t-butyl methyl ether solution containing
an optically active 2-hydroxycarboxylic acid (1) for
crystallization thereof is more preferably used.
[0076] Preferred as the optically active 2-hydroxycarboxylic acid
(1) are those in which R.sup.1 is a benzyl group, which may
optionally have a substituent on the aromatic ring. Most preferred
among others are optically active 2-hydroxy-3-phenylpropionic acid
and optically active 2-hydroxy-3-(p-halophenyl)propionic acids.
[0077] The crystallization according to the present invention is
judiciously carried out using the extract (inclusive of the one
after washing) obtained, by using t-butyl methyl ether, from an
aqueous solution containing the optically active
2-hydroxycarboxylic acid produced by the reaction mentioned above,
or a concentrate of such extract.
[0078] The crystallization concentration is not particularly
restricted but generally is 2 to 30% (w/v), preferably 5 to 20%
(w/v), as expressed in terms of weight of optically active
2-hydroxycarboxylic acid (1) relative to volume of solvent.
[0079] The crystallization temperature is not particularly
restricted but preferably is not lower than 30.degree. C. from the
viewpoint of physical properties and quality features of crystals
to be obtained.
[0080] In carrying out the crystallization, seed crystals may be
added according to need.
[0081] The crystal of optically active 2-hydroxycarboxylic acid (1)
as formed by the crystallization method of the invention can be
recovered by an ordinary solid-liquid separation technique such as
centrifugation, pressure filtration or vacuum filtration. In the
step of collecting crystal, the amount of crystal to be obtained
can be maximized by cooling the solution for crystallization
finally to a temperature of not higher than 10.degree. C. The
crystal obtained can further be dried according to need, for
example by reduced pressure (vacuum) drying, to give dry
crystals.
[0082] The crystallization method of the invention can also be
utilized as a method of recrystallization or a method of isolation
from the reaction mixture.
[0083] By using the crystallization method of the invention, it is
possible to obtain the desired product in very high crystallization
yield and with high quality.
3. Reaction (b)
[0084] The reaction (b) according to the invention includes the
step of converting the optically active 2-hydroxycarboxylic acid
represented by the above general formula (1) to the optically
active 2-chlorocarboxylic acid chloride represented by the above
general formula (5) by treatment with thionyl chloride and a basic
compound for chlorination with inversion of the configuration at
2-position, and the step of converting, by hydrolysis, the
optically active 2-chlorocarboxylic acid chloride (5) to the
optically active 2-chlorocarboxylic acid represented by the above
general formula (2).
[0085] In the general formula (1), (5) or (2) mentioned above,
R.sup.1 is as defined above. Benzyl is preferred, however.
[0086] In the reaction (b) according to the invention, inversion
occurs of the configuration at 2-position in general formula (1).
Thus, when the 2-position in the above general formula (1) has the
configuration (S), the configuration at 2-position in the general
formulas (5) and (2) is (R) and, when the 2-position in the general
formula (1) has the configuration (R), the configuration at
2-position in the general formulas (5) and (2) is (S). The
configuration at 2-position in general formula (1) may be either
(R) or (S). The configuration (S) is preferred, however.
[0087] The rate of inversion of configuration in the inverting
chlorination reaction (b) according to the invention should
preferably be not less than 95%. The rate of configurational
inversion so referred to herein is expressed in terms of the ratio
of the percentage of enantiomeric excess (% ee) of the product with
inversed configuration [2-chlorocarboxylic acid chloride (5) or
2-chlorocarboxylic acid (2)] to the enantiomeric excess (% ee) of
the starting material [2-hydroxycarboxylic acid (1)].
[0088] In the reaction (b) according to the invention, thionyl
chloride is generally used in an amount of not less than 2 moles
per mole of the optically active 2-hydroxycarboxylic acid (1). For
suppressing the starting material or product from being decomposed
or racemized and attaining a maximum yield, thionyl chloride is
preferably used in further excess. Therefore, the amount of thionyl
chloride to be used in the reaction (b) according to the invention
is generally not less than 2 moles and, for maximizing the effects
of the present invention, it is not less than 2.5 moles, preferably
not less than 3 moles, per mole of the optically active
2-hydroxycarboxylic acid of general formula (1).
[0089] The basic compound to be used in the reaction (b) according
to the invention is not particularly restricted but preferably is
an organic base, an amide group-containing compound or a quaternary
ammonium halide.
[0090] The above organic base includes alkylamines, aralkylamines,
aryl amines and aromatic amines and, specifically, it includes, but
is not limited to, triethylamine, tributylamine,
ethyldiisopropylamine, N-methyl-2-pyrrolidine, dimethylaniline,
imidazole, pyridine and lutidine. Preferred are triethylamine,
diisopropylethylamine and pyridine.
[0091] The above amide group-containing compound specifically
includes, but is not limited to, dimethylformamide,
dimethylacetamide, tetramethylurea, N-methyl-2-pyrrolidone and
hexamethylphosphoric triamide. Preferred are dimethylformamide and
N-methyl-2-pyrrolidone.
[0092] The above quaternary ammonium halide specifically includes,
but is not limited to, tetramethylammonium chloride,
tetraethylammonium chloride, tetra-n-butylammonium chloride,
benzyltrimethylammonium chloride, benzyltri-n-butylammonium
chloride, tetramethylammonium bromide, tetraethylammonium bromide,
tetra-n-butylammonium bromide, benzyltrimethylammonium bromide and
benzyltri-n-butylammonium bromide. Preferred is
tetra-n-butylammonium chloride.
[0093] Among the basic compounds mentioned above, amide
group-containing compounds are generally preferred.
Dimethylformamide, N-methyl-2-pyrrolidone and the like are
particularly preferred.
[0094] In the reaction (b) according to the invention, the above
basic compound may be used in a stoichiometric amount or in a
larger amount relative to the optically active 2-hydroxycarboxylic
acid of general formula (1) but, preferably, it is used in an
amount not more than 0.5 mole per mole of acid (1). Usually, an
amount of about 0.1 to 0.5 mole per mole of acid (1) is appropriate
to the reaction.
[0095] The reaction solvent to be used in the reaction (b)
according to the invention is preferably an aprotic organic
solvent. The aprotic organic solvent is not particularly restricted
but includes, among others, aliphatic hydrocarbon solvents such as
n-hexane and methylcyclohexane; aromatic hydrocarbon solvents such
as benzene, toluene and xylene; ether solvents such as diethyl
ether, tetrahydrofuran, 1,4-dioxane, t-butyl methyl ether,
dimethoxyethane and ethylene glycol dimethyl ether; halogenated
hydrocarbon solvents such as methylene chloride, chloroform and
1,1,1-trichloroethane; and nitrogen-containing solvents such as
acetonitrile, dimethylformamide, dimethylacetamide,
diethylacetamide, dimethylbutyramide, N-methyl-2-pyrrolidone and
hexamethylphosphoric triamide. These may be used singly or two or
more of them may be used in combination.
[0096] Particularly when an ether solvent such as diethyl ether,
tetrahydrofuran, 1,4-dioxane, t-butyl methyl ether, dimethoxyethane
or ethylene glycol dimethyl ether or an aromatic hydrocarbon
solvent such as benzene, toluene or xylene is used, the reaction
can proceed with high configurational inversion rate and high yield
to give the optically active 2-chlorocarboxylic acid chloride (5)
of high purity from the optically active 2-hydroxycarboxylic acid
(1). Tetrahydrofuran, dimethoxyethane, 1,4-dioxane and toluene are
preferred among others, and tetrahydrofuran and toluene are
particularly preferred.
[0097] The reaction temperature is preferably -20.degree. C. to
120.degree. C., more preferably 0.degree. C. to 80.degree. C., most
preferably 20.degree. C. to 60.degree. C.
[0098] The reaction concentration is not particularly restricted
but is not less than 5% (w/v), preferably not less than 10% (W/v),
as expressed in terms of the amount of the optically active
2-hydroxycarboxylic acid of general formula (1) relative to the
amount of the solvent.
[0099] The procedure for carrying out the reaction (b) according to
the invention is not particularly restricted. For example, thionyl
chloride is added to a solution of the optically active
2-hydoxycarboxylic acid (1), and the mixture is stirred for several
hours. Thereafter, the above-mentioned basic compound is added and,
then, the resulting mixture is stirred for several hours, whereby
the optically active 2-chlorocarboxylic acid chloride (5) can be
obtained. The optically active 2-chlorocarboxylic acid chloride (5)
can be isolated, for example, by evaporating the solvent from the
reaction mixture and then distilling the concentrate under reduced
pressure.
[0100] Further, the optically active 2-chlorocarboxylic acid
chloride (5) can be converted to the optically active
2-chlorocarboxylic acid (2) by hydrolysis.
[0101] Generally, the above hydrolysis reaction can be carried out
by adding water at room temperature or at lower temperature to the
reaction mixture containing, or a solution of, the optically active
2-chlorocarboxylic acid chloride (5) and stirring the mixture for
several minutes to several hours.
[0102] The product can be recovered from this reaction mixture by
ordinary work-up procedure. For example, the reaction mixture after
completion of the hydrolysis reaction is extracted with an ordinary
extracting solvent, such as ethyl acetate, diethyl ether, methylene
chloride, toluene or hexane. The reaction solvent and extracting
solvent are distilled off from the extract obtained by such a
procedure as heating under reduced pressure, whereby the optically
active 2-chlorocarboxylic acid (2) can be obtained.
[0103] It is also possible to once isolate the optically active
2-chlorocarboxylic acid chloride (5) by such a procedure as
concentration or distillation without hydrolysis and then
subjecting the chloride (5) to the hydrolysis reaction and
subsequent procedure.
[0104] Furthermore, in extracting the optically active
2-chlorocarboxylic acid (2), a procedure may also be performed at
least once which comprises distributing the optically active
2-chlorocarboxylic acid (2) in an aqueous phase under neutral to
basic conditions to thereby remove impurities into an organic
solvent. Moreover, a procedure may be performed which comprises
distributing the optically active 2-chlorocarboxylic acid (2) into
an organic solvent finally under acidic conditions to thereby
remove impurities, inclusive of salts resulting from
neutralization, into an aqueous phase. Although the thus-obtained
product is nearly pure, the product can further be purified by an
ordinary technique, such as purification by crystallization,
fractional distillation or column chromatography, to further
increase the purity.
4. Reaction (c)
[0105] In the step of reaction (c) according to the invention, the
optically active 2-chlorocarboxylic acid represented by the above
general formula (2) is reacted with a thioacetate salt for
substitution by acetylthio group with inversion of the
configuration at 2-position. Thus is prepared the corresponding
optically active 2-acetylthiocarboxylic acid represented by the
general formula (3).
[0106] In the general formula (2) or (3) mentioned above, R.sup.1
is as defined hereinabove. Preferred is a benzyl group.
[0107] In the reaction (c) according to the invention, the
configuration at 2-position in the general formula (2) is inverted.
Namely, when the 2-position configuration in the above general
formula (2) is (S), the 2-position configuration in general formula
(3) is (R) and, when the 2-position configuration in general
formula (2) is (R), the 2-position configuration in general formula
(3) is (S). The 2-position configuration in general formula (2) may
be either of (R) and (S) but preferably is (R).
[0108] In the reaction (c) according to the invention, the rate of
configurational inversion is preferably not less than 95%. The rate
of configurational inversion so referred to herein is expressed in
terms of the ratio of the percentage of enantiomeric excess (% ee)
of the product with inversed configuration [2-acetylthiocarboxylic
acid (3)] to the enantiomeric excess (% ee) of the starting
material [2-chlorocarboxylic acid (2)].
[0109] In the reaction (c) according to the invention, the
thioacetate salt is not particularly restricted but includes salts
of thioacetic acid with bases, preferably alkali metal thioacetates
such as sodium thioacetate, potassium thioacetate, lithium
thioacetate and cesium thioacetate. Among them, potassium
thioacetate is preferably used.
[0110] Alternatively, the reaction may be carried out using
thioacetic acid and a base (e.g. the hydroxide, hydride or alkoxide
of an alkali metal) so as to prepare the corresponding thioacetate
salt in the reaction system. The alkali metal hydroxide mentioned
above includes, but is not limited to, lithium hydroxide, sodium
hydroxide and potassium hydroxide. Among them, potassium hydroxide
is preferred. The alkali metal hydride mentioned above includes,
but is not limited to, lithium hydride, sodium hydride and
potassium hydride. Among them, potassium hydride is preferred. The
alkali metal alkoxide mentioned above includes, but is not limited
to, lithium methoxide, sodium methoxide and potassium methoxide.
Potassium methoxide is preferred, however.
[0111] In the reaction (c) according to the invention, the
thioacetate salt is used in an amount of 1 to 5 equivalents,
preferably 1 to 2 equivalents, relative to the optically active
2-chlorocarboxylic acid of general formula (2).
[0112] The reaction (c) according to the invention is preferably
carried out in the presence of an aprotic polar solvent. The
aprotic polar solvent is not particularly restricted but includes,
among others, water-soluble ether compounds such as
tetrahydrofuran, 1,4-dioxane, dimethoxyethane and ethylene glycol
dimethyl ether; ester compounds such as ethyl acetate and butyl
acetate; ketone compounds such as acetone and methyl ethyl ketone;
halogenated compounds such as methylene chloride, chloroform and
1,1,1-trichloroethane; sulfur-containing compounds such as dimethyl
sulfoxide; and nitrogen-containing compounds such as acetonitrile,
dimethylformamide, dimethylacetamide, diethylacetamide,
dimethylbutyramide, N-methyl-2-pyrrolidone and hexamethylphosphoric
triamide. These may be used singly or two or more of them may be
used in combination. Among them, water-soluble ether compounds,
ester compounds, ketone compounds, sulfur-containing compounds and
nitrogen-containing compounds are preferably used. More
specifically, aprotic polar compounds having a dielectric constant
of not less than 15 and a dipole moment of not less than 2.5 D are
preferred. Suited for use among them are those nitrogen-containing
compounds mentioned above which are liquid. From the viewpoint of
reaction yield and rate of configurational inversion, amide
group-containing liquid compounds are particularly preferred and,
specifically, dimethylformamide, dimethylacetamide,
diethylacetamide, dimethylbutyramide and N-methyl-2-pyrrolidone are
preferred.
[0113] For causing such aprotic polar compounds to exist in the
reaction system, one of such compounds which exists as a liquid may
be used as the reaction solvent in the step of thioacetylation or
one of such compounds which is a solid may be used in the form of a
solution in water and/or another solvent such as mentioned below.
Among the alternatives, the use as the reaction solvent is
expedient. In cases where an aprotic polar solvent is used as the
reaction solvent, the reaction solvent may comprise the aprotic
polar compound alone or a mixed solvent composed of it and water
and/or another organic solvent to be mentioned below.
[0114] The reaction solvent to be used in carrying out the reaction
(c) according to the invention is generally water, an organic
solvent or a mixture thereof. While the organic solvent includes
the above-mentioned aprotic polar compounds, the other organic
solvents are not particularly restricted but include, among others,
alcohol solvents such as methanol, ethanol, butanol, isopropanol,
ethylene glycol and methoxyalcohol; hydrocarbon solvents such as
benzene, toluene, n-hexane and cyclohexane; and water-insoluble
ether solvents such as diethyl ether, diisopropyl ether, dibutyl
ether and t-butyl methyl ether. These may be used singly or two or
more of them may be used in combination.
[0115] When the reaction yield is low with the solvent employed, a
phase transfer catalyst may be used for improving the yield. The
phase transfer catalyst to be used is not particularly restricted
but includes, among others, crown ethers such as 12-crown-4,
15-crown-5, 18-crown-6, 24-crown-8, dibenzo-18-crown-6,
dibenzo-24-crown-8, dicyclohexyl-18-crown-6 and
dicyclohexyl-24-crown-8; cryptands such as cryptand[2,2],
cryptand[2,1,1], cryptand[2,2,1], cryptand[2,2,2] and
cryptand[2B,2,2]; and quaternary ammonium salts such as
trioctylmethylammonium chloride (trade name: ALIQUAT 336),
trioctylmethylammonium bromide and methyltrialkyl (C.sub.8 to
C.sub.10)ammonium chloride (trade name: Adogen 464). Among the
phase transfer catalysts mentioned above, quaternary ammonium salts
are generally preferred and, among them, trioctylmethylammonium
chloride is judiciously used.
[0116] The level of addition of the phase transfer catalyst is not
particularly restricted but, in general, it is preferably 0.05 to 5
mole percent, more preferably 0.3 to 1 mole percent, relative to
the optically active 2-chlorocarboxylic acid of general formula
(2).
[0117] The reaction temperature is preferably -20.degree. C. to
120.degree. C., more preferably 0.degree. C. to 50.degree. C.
[0118] After completion of the reaction, the product can be
recovered from the reaction mixture by ordinary work-up. For
example, water is added to the reaction mixture after completion of
the reaction and an extraction procedure is performed using an
ordinary extracting solvent such as ethyl acetate, diethyl ether,
methylene chloride, toluene or hexane. The reaction solvent and
extracting solvent are distilled off, for example by heating under
reduced pressure, whereby the product can be recovered. It is also
possible to distill off the reaction solvent by heating under
pressure, for instance, directly after completion of the reaction
and then perform the same procedure as mentioned above. Although
the thus-obtained product is nearly pure, the purity can be further
increased by an ordinary purification procedure such as
purification by crystallization, fractional distillation or column
chromatography.
BEST MODES FOR CARRYING OUT THE INVENTION
[0119] The following examples illustrate the present invention in
further detail. These examples are, however, by no means limitative
of the scope of the present invention.
[0120] In the following, the assay of 2-hydroxy-3-phenylpropionic
acid and the measurement of the apparent purity of
2-hydroxy-3-(p-fluorophenyl)propionic acid were carried out using
the following analytical system. [Column: Develosil ODS-HG-3
(product of Nomura Chemical), 150 mm.times.4.6 mm I.D., mobile
phase: 0.1% (wt/v) phosphoric acid water/acetonitrile=75/25, flow
rate: 1.0 ml/min, detection: UV 210 nm, column temperature:
40.degree. C., retention time: 2-hydroxy-3-phenylpropionic acid 3.9
min, 2-hydroxy-3-(p-fluorophenyl)propionic acid 5.1 min].
[0121] The above-mentioned apparent purity is expressed by the
formula 2: Apparent purity=(integrated area value for
2-hydroxy-3-(p-fluorophenyl)propionic acid/total integrated area
value for all compounds detected).times.100 (%)
[0122] The optical purity evaluation of 2-hydroxy-3-phenylpropionic
acid and 2-hydroxy-3-(p-fluorophenyl)propionic acid was made by
derivatization into the corresponding methyl ester respectively by
the method mentioned below.
Optical Purity Evaluation of 2-hydroxy-3-phenylpropionic Acid
[0123] The product (20 mg, 0.12 mmol) was dissolved in a mixed
solvent composed of 1 ml of methanol and 3.5 ml of toluene, 166 mg
(0.15 mmol) of a 10% solution of trimethylsilyldiazomethane was
added dropwise, the reaction was allowed to proceed at room
temperature for 30 minutes, the solvent was then distilled off
under reduced pressure, and the concentrate was purified on a
silica gel (hexane/ethyl acetate=4/1) to give methyl
2-hydroxy-3-phenylpropionate. This methyl ester was analyzed by
HPLC [column: Chiralcel OD-H (product of Daicel Chemical
Industries), mobile phase: hexane/isopropanol=98/2, flow rate: 1.0
ml/min, detection: UV 210 nm, column temperature: 5.degree. C.,
retention time: S form 32 min, R form 30 min].
Optical Purity Evaluation of 2-hydroxy-3-(p-fluorophenyl)propionic
Acid
[0124] The product (20 mg, 0.11 mmol) was dissolved in a mixed
solvent composed of 1 ml of methanol and 3.5 ml of toluene, 166 mg
(0.15 mmol) of a 10% solution of trimethylsilyldiazomethane was
added dropwise, the reaction was allowed to proceed at room
temperature for 30 minutes, the solvent was then distilled off
under reduced pressure, and the concentrate was purified on a
silica gel (hexane/ethyl acetate=4/1) to give methyl
2-hydroxy-3-(p-fluorophenyl)propionate. This methyl ester was
analyzed by HPLC [column: Chiralcel OJ (product of Daicel Chemical
Industries), mobile phase: hexane/ethanol=95/5, flow rate: 1.0
ml/min, detection: UV 210 nm, column temperature: 20.degree. C.,
retention time: R form 15 min, S form 16 min].
EXAMPLE 1
Production of (2S)-2-hydroxy-3-phenylpropionic acid
[0125] ##STR11##
[0126] L-Phenylalanine (10.00 g, 60.5 mmol) was added to a dilution
of 8.88 g (90.5 mmol) of concentrated sulfuric acid in 110 g of
water and then, at an inside temperature of 20.degree. C., a
mixture of 10.45 g (151.5 mmol) of sodium nitrite and 20 g of water
was added over 5 hours. After addition, the mixture was stirred at
20.degree. C. for 20 hours, 100 ml of t-butyl methyl ether was then
added and, after 30 minutes of stirring at 20.degree. C., the
organic phase was separated (extract 1). Further, 50 ml of t-butyl
methyl ether was added to the aqueous phase, the mixture was
stirred at 20.degree. C. for 30 minutes, and the-organic phase was
separated (extract 2). The extracts 1 and2 were combined. The
combined extract (116.5 g) contained 8.6 g of
(2S)-2-hydroxy-3-phenylpropionic acid (yield 86%, optical purity
95.9% ee). The proton concentration (normality) in the reaction of
this example was 1.7 mol/kg, the amount of the protonic acid was
3.0 equivalents (relative to L-phenylalanine), and the reaction
temperature was 20.degree. C.
EXAMPLE 2
Production of (2S)-2-hydroxy-3-phenylpropionic acid
[0127] L-Phenylalanine (10.00 g, 60.5 mmol) was added to a dilution
of 5.93 g (60.5 mmol) of concentrated sulfuric acid in 110 g of
water and then, at an inside temperature of 20.degree. C., a
mixture of 10.45 g (151.5 mmol) of sodium nitrite and 20 g of water
was added over 5 hours. After addition, the mixture was further
stirred at 20.degree. C. for 20 hours and, thereafter, the same
work-up procedure as in Example 1 was followed. The combined
extract (116.1 g) obtained contained 8.7 g of
(2S)-2-hydroxy-3-phenylpropionic acid (yield 87%, optical purity
95.2% ee). The proton concentration (normality) in the reaction of
this example was 1.1 mol/kg, the amount of the protonic acid was
2.0 equivalents (relative to L-phenylalanine), and the reaction
temperature was 20.degree. C.
EXAMPLE 3
Production of (2S)-2-hydroxy-3-phenylpropionic acid
[0128] L-Phenylalanine (10.00 g, 60.5 mmol) was added to a dilution
of 4.15 g (42.4 mmol) of concentrated sulfuric acid in 110 g of
water and then, at an inside temperature of 20.degree. C., a
mixture of 10.45 g (151.5 mmol) of sodium nitrite and 20 g of water
was added over 5 hours. After addition, the mixture was further
stirred at 20.degree. C. for 20 hours and, thereafter, the same
work-up procedure as in Example 1 was followed. The combined
extract (115.8 g) obtained contained 8.7 g of
(2S)-2-hydroxy-3-phenylpropionic acid (yield 87%, optical purity
92.0% ee). The proton concentration (normality) in the reaction of
this example was 0.8 mol/kg, the amount of the protonic acid was
1.4 equivalents (relative to L-phenylalanine), and the reaction
temperature was 20.degree. C.
COMPARATIVE EXAMPLE 1
[0129] L-Phenylalanine (10.00 g, 60.5 mmol) was added to a dilution
of 14.83 g (151.3 mmol) of concentrated sulfuric acid in 110 g of
water and then, at an inside temperature of 20.degree. C., a
mixture of 10.45 g (151.5 mmol) of sodium nitrite and 20 g of water
was added over 5 hours. After addition, the mixture was further
stirred at 20.degree. C. for 20 hours and, thereafter, the same
work-up procedure as in Example 1 was followed. The combined
extract (114.4 g) obtained contained 6.9 g of
(2S)-2-hydroxy-3-phenylpropionic acid (yield 69%, optical purity
96.5% ee). The proton concentration (normality) in the reaction of
this comparative example was 2.7 mol/kg, the amount of the protonic
acid was 5.0 equivalents (relative to L-phenylalanine), and the
reaction temperature was 20.degree. C.
COMPARATIVE EXAMPLE 2
[0130] L-Phenylalanine (10.00 g, 60.5 mmol) was added to a dilution
of 8.88 g (90.5 mmol) of concentrated sulfuric acid in 110 g of
water and then, at an inside temperature of 0.degree. C., a mixture
of 10.45 g (151.5 mmol) of sodium nitrite and 20 g of water was
added over 5 hours. After addition, the mixture was further stirred
at 0.degree. C. for 20 hours and, thereafter, the same work-up
procedure as in Example 1 was followed. The combined extract (113.7
g) obtained contained 7.0 g of (2S)-2-hydroxy-3-phenylpropionic
acid (yield 70%, optical purity 96.6% ee). The proton concentration
(normality) in the reaction of this example was 1.7 mol/kg, the
amount of the protonic acid was 3.0 equivalents (relative to
L-phenylalanine), and the reaction temperature was 0.degree. C.
COMPARATIVE EXAMPLE 3
[0131] A solution of 14 g (217 mmol) of sodium nitrite in 20 ml of
water was added dropwise to a solution of 14 g (85 mmol) of
L-phenylalanine in 100 ml of 1 N sulfuric acid at 0.degree. C. over
3 hours, and the mixture was stirred overnight at room temperature.
After extraction with three 100-ml portions of ethyl acetate, the
organic phase was dried over sodium sulfate. The optical purity of
(2S)-2-hydroxy-3-phenylpropionic acid in this extract was 93.0% ee.
The solvent was distilled off under reduced pressure to give 12 g
of crude (2S)-2-hydroxy-3-pheylpropionic acid. Further, this crude
product was purified by recrystallization using 35 ml of ethyl
acetate to give 7.5 g (yield 53%) of the desired
(2S)-2-hydroxy-3-phenylpropionic acid. The proton concentration
(normality) in the reaction of this comparative example was 1.0
mol/kg, the amount of the protonic acid was 1.2 equivalents
(relative to L-phenylalanine), and the reaction temperature was
0.degree. C. to room temperature.
[0132] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 7.34-7.25
(5H, m), 4.51 (1H, dd, J=7.3 Hz, 4.4 Hz), 3.21 (1H, dd, J=14.2 Hz,
4.4 Hz), 3.00 (1H, dd, J=13.7 Hz, 7.4 Hz).
EXAMPLE 4
Production of (2S)-2-hydroxy-3-phenylpropionic acid
[0133] L-Phenylalanine (10.00 g, 60.5 mmol) was added to a dilution
of 8.88 g (90.5 mmol) of concentrated sulfuric acid in 110 g of
water and then, at an inside temperature of 40.degree. C., a
mixture of 10.45 g (151.5 mmol) of sodium nitrite and 20 g of water
was added over 5 hours. After addition, the mixture was further
stirred at 40.degree. C. and, thereafter, the same work-up
procedure as in Example 1 was followed. The combined extract (146.9
g) obtained contained 8.9 g of (2S)-2-hydroxy-3-phenylpropionic
acid (yield 89%, optical purity 94.3% ee). The proton concentration
(normality) in the reaction of this example was 1.7 mol/kg, the
amount of the protonic acid was 3.0 equivalents (relative to
L-phenylalanine), and the reaction temperature was 40.degree.
C.
EXAMPLE 5
Production of (2S)-2-hydroxy-3-phenylpropionic acid
[0134] L-Phenylalanine (10.00 g, 60.5 mmol) was added to a dilution
of 8.88 g (90.5 mmol) of concentrated sulfuric acid in 110 g of
water and then, at an inside temperature of 70.degree. C., a
mixture of 10.45 g (151.5 mmol) of sodium nitrite and 20 g of water
was added over 5 hours. After addition, the mixture was further
stirred at 70.degree. C. for 20 hours and, thereafter, the same
work-up procedure as in Example 1 was followed. The combined
extract (147.3 g) obtained contained 8.5 g of
(2S)-2-hydroxy-3-phenylpropionic acid (yield 85%, optical purity
92.0% ee). The proton concentration (normality) in the reaction of
this example was 1.7 mol/kg. The amount of the protonic acid was
3.0 equivalents (relative to L-phenylalanine) and the reaction
temperature was 70.degree. C.
EXAMPLE 6
Production of (2S)-2-hydroxy-3-phenylpropionic acid
[0135] L-Phenylalanine (10.00 g, 60.5 mmol) was added to a dilution
of 8.88 g (90.5 mmol) of concentrated sulfuric acid in 110 g of
water and then, at an inside temperature of 20.degree. C., a
mixture of 10.45 g (151.5 mmol) of sodium nitrite and 20 g of water
was added over 2 hours. After addition, the mixture was stirred at
20.degree. C. for 20 hours and, thereafter, the same work-up
procedure as in Example 1 was followed. The combined extract (116.3
g) obtained contained 8.5 g of (2S)-2-hydroxy-3-phenylpropionic
acid (yield 85%, optical purity 94.0% ee). The proton concentration
(normality) in the reaction of this example was 1.7 mol/kg. The
amount of the protonic acid was 3.0 equivalents (relative to
L-phenylalanine) and the reaction temperature was 20.degree. C.
COMPARATIVE EXAMPLE 4
[0136] L-Phenylalanine (10.00 g, 60.5 mmol) was added to a dilution
of 8.88 g (90.5 mmol) of concentrated sulfuric acid in 55 g of
water and then, at an inside temperature of 20.degree. C., a
mixture of 10.45 g (151.5 mmol) of sodium nitrite and 20 g of water
was added over 5 hours. After addition, the mixture was further
stirred at 20.degree. C. for 20 hours and, thereafter, the same
work-up procedure as in Example 1 was followed. The combined
extract (116.5 g) obtained contained 6.4 g of
(2S)-2-hydroxy-3-phenylpropionic acid (yield 64%; optical purity
96.6% ee). The proton concentration (normality) in the reaction of
this example was 3.3 mol/kg, the amount of the protonic acid was
3.0 equivalents (relative to L-phenylalanine), and the reaction
temperature was 20.degree. C.
COMPARATIVE EXAMPLE 5
[0137] This comparative example was to confirm the reaction results
of the method described in J. Amer. Chem. Soc., 86, 5326-5330,
1964.
[0138] L-Phenylalanine hydrochloride (12.2 g, 60.5 mmol) was added
to 183 ml of 5% sulfuric acid (sulfuric acid: 96.0 mmol) and the
solution was treated with a mixture of 8.35 g (121 mmol) of sodium
nitrite and 44.5 g of water at 0.degree. C. for 3 hours.
Thereafter, 100 ml of diethyl ether was added to the reaction
mixture and, after stirring, the organic phase was separated
(extract 1). Further, 50 ml of diethyl ether was added to the
aqueous phase and, after stirring, the organic-phase was separated
(extract 2). The extracts 1 and 2 were combined. The combined
extract (95.0 g) contained 4.2 g of
(2S)-2-hydroxy-3-phenylpropionic acid (yield 42%, optical purity
92.6% ee). The proton concentration (normality) in the reaction of
this comparative example was 1.4 mol/kg, the amount of the protonic
acid was 4.0 equivalents (relative to L-phenylalanine), and the
reaction temperature was 0.degree. C.
COMPARATIVE EXAMPLE 6
[0139] This comparative example was to confirm the reaction results
of the method described in J. Heterocyclic Chem., 29, 431-438,
1992.
[0140] Crystalline sodium nitrite (16.6 g, 241 mmol) was added to a
mixture of 120 ml of 1 M sulfuric acid (sulfuric acid: 120 mmol)
and 10.0 g (60.5 mmol) of L-phenylalanine at 0.degree. C. over 5
hours. After addition, the temperature was raised to room
temperature (15.degree. C.), and the mixture was stirred overnight.
Ethyl acetate (40 ml) was added to this reaction mixture and, after
stirring, the organic phase was separated. The above procedure was
further repeated twice. The organic phases were combined. The total
extract (115.2 g) contained 6.6 g of
(2S)-2-hydroxy-3-phenylpropionic acid (yield 66%, optical purity
96.2% ee). The proton concentration (normality) in the reaction of
this comparative example was 2.1 mol/kg, the amount of the protonic
acid was 4.0 equivalents (relative to L-phenylalanine), and the
reaction temperature was 0.degree. C. during the addition of sodium
nitrite and room temperature (15.degree. C.) after completion of
the addition.
EXAMPLE 7
Crystallization of (2S)-2-hydroxy-3-phenylpropionic acid
[0141] A portion of the (2S)-2-hydroxy-3-phenylpropionic
acid/t-butyl methyl ether extract obtained in Example 2 (66.7 g,
containing 5.0 g of (.sup.2S)-2-hydroxy-3-phenylpropionic acid,
optical purity 95.2% ee) was concentrated under reduced pressure to
give 20.0 g of a concentrate. While stirring this concentrate, 60
ml of hexane was gradually added at 40.degree. C. to thereby cause
precipitation of crystals. Then, the resulting mixture was cooled
to 5.degree. C. and further stirred for 2 hours. The crystals
formed were filtered off under reduced pressure and then washed
with two 10-ml portions of hexane/t-butyl methyl ether (75/25 by
volume). The wet crystals obtained were dried under reduced
pressure (vacuum) (full vacuum, 40.degree. C., overnight) to give
4.5 g of (2S)-2-hydroxy-3-phenylpropionic acid (purity 98.7%,
optical purity not lower than 99.9% ee, crystallization yield
89%).
EXAMPLE 8
Crystallization of (2S)-2-hydroxy-3-phenylpropionic acid
[0142] A (2S)-2-hydroxy-3-phenylpropionic acid/t-butyl methyl ether
extract separately obtained (3,450 g, containing 253.3 g of
(2S)-2-hydroxy-3-phenylpropionic acid, optical purity 93.0% ee) was
concentrated under reduced pressure to give 734 g of a concentrate.
While stirring this concentrate, 2,230 ml of hexane was added over
3 hours at 40.degree. C. to thereby cause precipitation of
crystals. Then, the resulting mixture was cooled to 5.degree. C.
and further stirred for 2 hours. The crystals formed were filtered
off under reduced pressure and then washed with two 250-ml portions
of hexane/t-butyl methyl ether (75/25 by volume). The wet crystals
obtained were dried under reduced pressure (vacuum) (full vacuum,
40.degree. C., overnight) to give 232.2 g of
(2S)-2-hydroxy-3-phenylpropionic acid (purity 98.2%, optical purity
99.8% ee, crystallization yield 90%).
COMPARATIVE EXAMPLE 7
[0143] A (2S)-2-hydroxy-3-phenylpropionic acid/ethyl acetate
extract separately obtained (83.3 g, containing 5.0 g of
(2S)-2-hydroxy-3-phenylpropionic acid, optical purity 93.7% ee) was
concentrated under reduced pressure to give 20.0 g of a
concentrate. While stirring this concentrate, 50 ml of hexane was
gradually added at 40.degree. C. to thereby cause precipitation of
crystals. Then, the resulting mixture was cooled to 5.degree. C.
and further stirred for 2 hours. The crystals formed were filtered
off under reduced pressure and then washed with two 10-ml portions
of hexane/ethyl acetate (75/25 by volume). The wet crystals
obtained were dried under reduced pressure (vacuum) (full vacuum,
40.degree. C., overnight) to give 4.5 g of
(2S)-2-hydroxy-3-phenylpropionic acid (purity 98.8%, optical purity
98.0% ee, crystallization yield 88%).
EXAMPLE 9
Crystallization of (2S)-2-hydroxy-3-phenylpropionic acid
[0144] A (2S) -2-hydroxy-3-phenylpropionic acid/t-butyl methyl
ether extract separately obtained (66.4 g, containing 5.0 g of
(2S)-2-hydroxy-3-phenylpropionic acid, optical purity 95.3% ee) was
concentrated under reduced pressure to give 16.7 g of a
concentrate. While stirring this concentrate, 150 ml of toluene was
gradually added at 40.degree. C. to thereby cause precipitation of
crystals. Then, the resulting mixture was cooled to 5.degree. C.
and further stirred for 2 hours. The crystals formed were filtered
off under reduced pressure and then washed with two 10-ml portions
of toluene/t-butyl methyl ether (90/10 by volume). The wet crystals
obtained were dried under reduced pressure (vacuum) (full vacuum,
40.degree. C., overnight) to give 4.0 g of
(2S)-2-hydroxy-3-phenylpropionic acid (purity 99.2%, optical purity
not lower than 99.9% ee, crystallization yield 80%).
EXAMPLE 10
Crystallization of (2R)-2-hydroxy-3-(p-fluorophenyl)propionic
acid
[0145] A mixture of 4.96 g of crude crystals of
(2R)-2-hydroxy-3-(p-fluorophenyl)propionic acid (apparent purity
80%, optical purity 97.2% ee) and 10 ml of t-butyl methyl ether was
slowly added to 40 ml of hexane containing 20 mg of seed crystals
added, with stirring at 30.degree. C. to thereby cause
precipitation of crystals, and the mixture was then cooled to
5.degree. C. and further stirred for 2 hours. The crystals formed
were filtered off under reduced pressure and then washed with two
10-ml portions of hexane/t-butyl methyl ether (80/20 by volume) The
wet crystals obtained were dried under reduced pressure (vacuum)
(full vacuum, 40.degree. C., overnight) to give 3.80 g of
(R)-2-hydroxy-3-(p-fluorophenyl)propionic acid (apparent purity
99%, optical purity 99.9% ee, crystallization yield 95%).
EXAMPLE 11
(2R)-2-Chloro-3-phenylpropionic acid chloride
[0146] ##STR12##
[0147] Toluene (50 ml) was added to 5.0 g (30.1 mmol) of
(2S)-2-hydroxy-3-phenylpropionic acid, 10.7 g (90.3 mmol) of
thionyl chloride was added dropwise, and the mixture was stirred at
40.degree. C. for 2 hours. To the mixture was added 0.44 g
(6.0-mmol) of dimethylformamide, and the resulting mixture was
stirred at 40.degree. C. for 24 hours. The reaction mixture was
concentrated under reduced pressure, 90 ml of toluene was further
added to the concentrate, and the dilution was again concentrated
under reduced pressure. The thus-obtained concentrate was distilled
under reduced pressure (boiling point: about 1 mm Hg,
102-103.degree. C.) to give 3.1 g (14.1 mmol, yield 47%) of
(2R)-2-chloro-3-phenylpropionic acid chloride.
[0148] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 7.36-7.23
(5H, m), 4.71 (1H, t, J=7.3 Hz), 3.47 (1H, dd, J=14.2 Hz, 6.4 Hz),
3.02 (1H, dd, J=14.2 Hz, 7.8 Hz). .sup.13C NMR (100 MHz.
CDCl.sub.3) .delta. (ppm): 170.25, 134.30, 129.36, 128.83, 127.84,
65.44, 40.68. IR (neat) (cm.sup.-1): 3034, 1783, 1605, 1499, 1456,
1435, 1246, 1175, 1080, 1003, 925, 887, 835, 737, 698, 648, 548,
484.
EXAMPLE 12
(2R)-2-Chloro-3-phenylpropionic acid
[0149] ##STR13##
[0150] Thionyl chloride (0.66 ml, 9.0 mmol) was added dropwise to a
solution of (2S) -2-hydroxy-3-phenylpropionic acid (500 mg, 3.0
mmol, optical purity 100% ee (S)) in 5 ml of tetrahydrofuran at
room temperature, and the mixture was stirred for 15 hours. To the
reaction mixture was added 170 mg (0.60 mmol) of
tetra-n-butylammonium chloride, and the mixture was heated at
40.degree. C. for 4 hours. Water (5 ml) was added to the reaction
mixture and, after 30 minutes of stirring, the mixture was
extracted with 90 ml of ethyl acetate. The organic phase was washed
with 10 ml of a saturated aqueous solution of sodium chloride and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure to give 499 mg (yield 90%) of the
desired (2R)-chloro-3-phenylpropionic acid.
[0151] .sup.1H NMR (400 MHz. CDCl.sub.3) .delta. (ppm): 7.36-7.23
(5H, m), 4.49 (1H, t, J=7.3 Hz), 3.39 (1H, dd, J=14.1 Hz, 6.9 Hz),
3.02 (1H, dd, J=14.2 Hz, 7.8 Hz).
[0152] The optical purity of the product was determined by
derivatization into the corresponding methyl ester by the following
method. The product (25 mg, 0.14 mmol) was dissolved in a mixed
solvent composed of 1 ml of methanol and 3.5 ml of toluene, 200 mg
(0.18 mmol) of a 10% solution of trimethylsilyldiazomethane in
hexane was added dropwise at room temperature and, after allowing
the reaction to proceed at room temperature for 30 minutes, the
solvents were distilled off under reduced pressure. The concentrate
was purified on a silica gel column (hexane/ethyl acetate=4:1) to
give methyl 2-chloro-3-phenylpropionate. This methyl ester was
analyzed by HPLC [column: Chiralcel OD-H (product of Daicel
Chemical Industries), eluent: hexane/isopropanol=100:1, flow rate:
1.0 ml/min, temperature: 40.degree. C., detection wavelength: 210
nm, retention time: R form 26 min, S form 28 min] and found to have
an optical purity of 98.9% ee (R) (rate of configurational
inversion 98.9%).
EXAMPLE 13
(2R)-2-Chloro-3-phenylpropionic acid
[0153] Thionyl chloride (43.8 g, 368.4 mmol) was added dropwise to
a solution of 20.4 g (122.8 mmol) of
(2S)-2-hydroxy-3-phenylpropionic acid (optical purity 100% ee (S))
in 200 ml of tetrahydrofuran, and the mixture was stirred at 35 to
40.degree. C. for 2 hours. To that solution was added 1.8 g (24.6
mmol) of dimethylformamide, and the mixture was stirred at 42 to
44.degree. C. for 6 hours. This reaction mixture was cooled and,
while maintaining the temperature at 20.degree. C., 70 ml of water
was added dropwise and, after about an hour of stirring, the
mixture was extracted with 200 ml of toluene. Water (70 ml) was
added to the organic phase and, after pH adjustment to 9.0 with a
30% aqueous solution of sodium hydroxide, the organic phase was
removed by phase separation. To the aqueous phase obtained was
added 200 ml of toluene, the pH was adjusted to 1.0 with 35%
aqueous hydrochloric acid, and the aqueous phase was removed by
phase separation. The toluene was distilled off under reduced
pressure from the thus-obtained toluene phase to give 21.1 g (114.3
mmol, yield 93%) of (2R)-2-chloro-3-phenylpropionic acid. The
optical purity of the product as determined by the same method as
in Example 12 was 99.8% ee (R) (rate of configurational inversion
99.8%).
EXAMPLE 14
(2R)-2-Chloro-3-phenylpropionic acid
[0154] 1,4-Dioxane (200 ml) was added to 20.4 g (122.8 mmol) of
(2S)-2-hydroxy-3-phenylpropionic acid (optical purity 100% ee (S)),
43.8 g (368.4 mmol) of thionyl chloride was added dropwise, and the
mixture was stirred at 40.degree. C. for 2 hours. To that solution
was added 1.8 g (24.6 mmol) of dimethylformamide, and the mixture
was stirred at 40.degree. C. for 6 hours. This reaction mixture was
cooled and, while maintaining the temperature at 20.degree. C., 70
ml of water was added dropwise and, after about an hour of
stirring, the mixture was extracted with 200 ml of toluene. Water
(70 ml) was added to the organic phase and, after pH adjustment to
9.0 with a 30% aqueous solution of sodium hydroxide, the organic
phase was removed by phase separation. To the aqueous phase
obtained was added 200 ml of toluene, the pH was adjusted to 1.0
with 35% aqueous hydrochloric acid, and the aqueous phase was
removed by phase separation. The toluene was distilled off under
reduced pressure from the thus-obtained toluene phase to give 19.1
g (103.3 mmol, yield 84%) of (2R)-2-chloro-3-phenylpropionic acid.
The optical purity of the product as determined by the same method
as in Example 12 was 99.7% ee (R) (rate of configurational
inversion 99.7%).
EXAMPLE 15
(2R)-2-Chloro-3-phenylpropionic acid
[0155] Thionyl chloride (43.8 g, 368.4 mmol) was added dropwise to
a solution of 20.4 g (122.8 mmol) of
(2S)-2-hydroxy-3-phenylpropionic acid (optical purity 100% ee (S))
in 200 ml of toluene, and the mixture was stirred at 40.degree. C.
for 2 hours. To that solution was added 1.8 g (24.6 mmol) of
dimethylformamide, and the mixture was stirred at 40.degree. C. for
24 hours. This reaction mixture was cooled and, while maintaining
the temperature at 20.degree. C., 70 ml of water was added dropwise
and, after about an hour of stirring, extracted with 200 ml of
toluene. Water (70 ml) was added to the organic phase and, after pH
adjustment to 9.0 with a 30% aqueous solution of sodium hydroxide,
the organic phase was removed by phase separation. To the aqueous
phase obtained was added 200 ml of toluene, the pH was adjusted to
1.0 with 35% aqueous hydrochloric acid, and the aqueous phase was
removed by phase separation. The toluene was distilled off under
reduced pressure from the thus-obtained toluene phase to give 21.6
g (116.8 mmol, yield 95%) of (2R)-2-chloro-3-phenylpropionic acid.
The optical purity of the product as determined by the same method
as in Example 12 was 99.5% ee (R) (rate of configurational
inversion 99.5%).
EXAMPLE 16
(2R)-2-Chloro-3-phenylpropionic acid
[0156] Thionyl chloride (0.18 ml, 2.4 mmol) was added dropwise to a
solution of 200 mg (1.2 mmol) of (2S)-2-hydroxy-3-phenylpropionic
acid (optical purity 100% ee (S)) in 2 ml of dimethoxyethane at
room temperature, and the mixture was stirred for 15 hours. To that
reaction mixture was added 0.01 ml (0.12 mmol) of pyridine, and the
mixture was stirred at 60.degree. C. for 4 hours. Water (10 ml) was
added to the reaction mixture and, after 30 minutes of stirring,
the mixture was extracted with 50 ml of ethyl acetate. The organic
phase was washed with 10 ml of a saturated aqueous solution of
sodium chloride and dried over sodium sulfate. The solvent was
distilled off under reduced pressure to give 135 mg (yield 61%) of
the desired (2R)-2-chloro-3-phenylpropionic acid. The optical
purity of the product as determined by the same method as in
Example 12 was 97.6% ee (R) (rate of configurational inversion
97.6%).
EXAMPLE 17
(2R)-2-Chloro-3-phenylpropionic acid
[0157] The reaction was carried out in the same manner as in
Example 16 using 2 moles of thionyl chloride per mole of the
starting material except that the solvents specified below in Table
1 were respectively used as the reaction solvent. The results
obtained are shown below in Table 1. TABLE-US-00001 TABLE 1 Optical
purity Configuration Solvent Yield (%) (% ee) inversion rate (%)
THF 35 99.4 99.4 1,4-Dioxane 17 99.9 99.9 Toluene 23 72.6 72.6 No
solvent 20 87 87
EXAMPLE 18
(2S)-2-Acetylthio-3-phenylpropionic acid
[0158] ##STR14##
[0159] Potassium thioacetate (68 mg, 0.64 mmol) was added to a
solution of 100 mg (0.54 mmol) of the
(2R)-2-chloro-3-phenylpropionic acid obtained in Example 14 in 2 ml
of dimethylformamide at room temperature, and the mixture was
stirred for 24 hours. A 6% aqueous solution of sodium thiosulfate
(0.5 ml) was added to the reaction mixture, and the whole mixture
was extracted with 30 ml of ethyl acetate. The organic phase was
washed with 3 ml of 6% sodium thiosulfate aqueous solution, 3 ml of
water and 3 ml of a saturated aqueous solution of sodium chloride,
and dried over sodium sulfate. The solvent was removed under
reduced pressure to give 101 mg (yield 83%) of the desired
(2S)-2-acetylthio-3-phenylpropionic acid.
[0160] .sup.1H NMR (400 MHz. CDCl.sub.3) .delta. (ppm): 7.34-7.22
(5H, m), 4.43 (1H, t, J=7.6 Hz), 3.30 (1H, dd, J=13.9 Hz, 7.9 Hz),
3.02 (1H, dd, J=13.9 Hz, 7.6 Hz), 2.33 (3H, s).
[0161] The optical purity of the product was determined by
derivatization into the corresponding methyl ester by the following
method. The product (25 mg, 0.12 mmol) was dissolved in a mixed
solvent composed of 1 ml of methanol and 3.5 ml of toluene, 166 mg
(0.15 mmol) of a 10% trimethylsilyldiazomethane solution in hexane
was added dropwise. The reaction was allowed to proceed at room
temperature for 30 minutes, the solvent was then distilled off
under reduced pressure, and the concentrate was purified on a
silica gel column (hexane/ethyl acetate=4:1) to give methyl
2-acetylthio-3-phenylpropionate. This methyl ester was analyzed by
HPLC [column: Chiralcel OD-H (product of Daicel Chemical
Industries), eluent: hexane/isopropanol=100:1, flow rate: 1.0
ml/min, temperature; 40.degree. C., detection wavelength: 210 nm,
retention time: R form 37 min, S form 38 min] and found to have an
optical purity of 97.9% ee (S) (configurational inversion rate
98.2%).
EXAMPLE 19
(2S)-2-Acetylthio-3-phenylpropionic acid
[0162] Potassium thioacetate (93 mg, 0.81 mmol) was added to a
solution of 100 mg (0.54 mmol) of (2R)-2-chloro-3-phenylpropionic
acid in 2 ml of N-methyl-2-pyrrolidone at room temperature, and the
mixture was stirred for 24 hours. The work-up procedure in the same
manner as in Example 18 of the reaction mixture was followed to
give 114 mg (0.51 mmol, yield 94%) of the desired
(2S)-2-acetylthio-3-phenylpropionic acid.
EXAMPLE 20
(2S)-2-Acetylthio-3-phenylpropionic acid
[0163] The (2R)-2-chloro-3-phenylpropionic acid obtained in Example
13, 20.0 g (108.0 ml), to a mixture of 16.1 g (141.0 mmol) of
potassium thioacetate and 40 ml of dimethylformamide was added
dropwise at 0.degree. C. and the mixture was stirred at room
temperature for 24 hours. To the reaction mixture were added 60 ml
of 6% sodium thiosulfate aqueous solution and 200 ml of toluene.
The mixture was then adjusted to pH 1.7 with 35% aqueous
hydrochloric acid and, after phase separation, the organic phase
was recovered. This organic phase was washed with 60 ml of a 6%
aqueous solution of sodium thiosulfate, 60 ml of a saturated
aqueous solution of sodium chloride and 60 ml of water. The solvent
was distilled off under reduced pressure to give 20.7 g (91.8 mmol,
yield 85%) of the desired (2S)-2-acetylthio-3-phenylpropionic acid.
The optical purity of the product as determined by the same method
as in Example 18 was 98.9% ee (S) (configurational inversion-rate
99.1%).
EXAMPLE 21
(2S)-2-Acetylthio-3-phenylpropionic acid
[0164] The reaction was carried out in the same manner as in
Example 18 except that the solvents specified below in Table 2 were
respectively used as the reaction solvent. Based on the integrated
area values obtained by HPLC analysis for
(2S)-2-acetylthio-3-phenylpropionic acid (A) and
(2R)-2-chloro-3-phenylpropionic acid (B) after the lapse of each
time indicated in Table 2, the percentage of
(2S)-2-acetylthio-3-phenylpropionic acid (A) as defined by the
following formula 3 was calculated: Percentage of A (%)=[(HPLC
integrated area value for (A))(HPLC integrated area value for
(B)+HPLC integrated area value for (A))].times.100
[0165] The results are shown below in Table 2. For evaluating the
integrated values for the above compounds, the following system for
HPLC analysis was used.
[0166] (HPLC)
[0167] [Column: Develosil ODS-HG-3 (product of Nomura Chemical),
150 mm.times.4.6 mm I.D., mobile phase: 0.1% (wt/v) phosphoric acid
water/acetonitrile=75/25, flow rate: 1.0 ml/min, detection: UV 210
nm, column temperature: 40.degree. C., retention time:
(2R)-2-chloro-3-phenylpropionic acid (B) 19.9 min,
(2S)-2-acetylthio-3-phenylpropionic acid (A) 22.6 min]
TABLE-US-00002 TABLE 2 Solvent After 3 hours After 20 hours Water
1% -- Methanol 2% -- Toluene 0% -- Ethyl acetate 36% 92% t-butyl
methyl ether Reaction failed to proceed due to solidification
Tetrahydrofuran 32% 93% 1,4-Dioxane 29% 90% Dimethoxyethane 67% 98%
Acetonitrile 52% 96% Acetone 79% 97% Dimethylformamide 100% --
N-Methyl-2- 100% -- pyrrolidone
EXAMPLE 22
(2S)-2-Acetylthio-3-phenylpropionic acid
[0168] The reaction was carried out in the same manner as in
Example 18 except that the solvents specified below in Table 3 were
respectively used as the reaction solvent. After the lapse of the
time indicated in Table 3, the percentage of
(2S)-2-acetylthio-3-phenylpropionic acid as defined by the above
formula 3 was calculated in the same manner as in Example 21.
TABLE-US-00003 TABLE 3 Solvent After 3 hours
Dimethylformamide:t-butyl methyl ether = 2:5 97% (by volume)
Dimethylformamide:ethyl acetate = 2:5 93% (by volume)
INDUSTRIAL APPLICABILITY
[0169] The invention, which has the constitution mentioned above,
makes it possible to produce optically active 2-hydroxycarboxylic
acids, optically active 2-chlorocarboxylic acids and optically
active 2-acetylthiocarboxylic acids, which are important in the
production of pharmaceuticals and the like, from readily available
starting materials with high optical purity and high efficiency. It
also makes it possible to isolate or purify optically active
2-hydroxycarboxylic acids expediently and efficiently.
* * * * *