JP2002114737A - METHOD FOR PRODUCING OPTICALLY ACTIVE o-CHLOROMANDELIC ACID - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a process for producing optically active o-chloromandelic acid having high optical purity by mixing and dissolving a racemic isomer of o-chloromandelic acid with optically active alanine, separating deposited inclusion complex as crystal and subsequently decomposing the inclusion complex. SOLUTION: This method for producing an optical isomer, (R)-(-)-o- chloromandelic acid or (S)-(+)-o-chloromandelic acid, having high optical purity of 98-100%ee is to mix and dissolve a racemic isomer of o-chloromandelic acid with easily available and highly safe amino acid, (S)-(+)-alanine, or a racemic isomer of o-chloromandelic acid with (R)-(-)-alanine, separate crude crystals of a deposited inclusion complex, (R)-(-)-o-chloromandelic acid.(S)-(+)- alanine or (S)-(+)-o-chloromandelic acid.(R)-(-)-alanine, purify the complex by repeating recrystallization once or twice, decompose the complex in a two layer mixture solution of water with a hydrophobic solvent, extract o- chloromandelic acid with an organic solvent and concentrate the extracted solution.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to the optical resolution of racemic o-chloromandelic acid.
The present invention relates to a method for producing an optically active o-chloromandelic acid useful as a pharmaceutical intermediate of a blood coagulation inhibitor described in Japanese Patent No. 20286 and a novel optical resolution agent.

[0002]

2. Description of the Related Art Conventional techniques 1 to 4 are known as methods for synthesizing optically active o-chloromandelic acid and optically active mandelic acid.

(Prior art 1) Japanese Patent Application Laid-Open No. 2-275877 An optical resolution method using (R)-(-)-o-chloromandelic acid as an optical resolving agent with ephedrine as shown by the following formula (3): Is described.

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(Prior Art 2) Japanese Patent Application Laid-Open No. Hei 6-237789 The use of bacterial cells and the production of an optically active form of (R)-(-)-o-chloromandelic acid from (±) -o-chloromandelonitrile The production method is described as shown in the following formula (4).

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(Prior Art 3) JP-A-55-147236
Japanese Patent Application Laid-Open Publication No. H11-163873 describes that (R)-(-)-mandelic acid is split by an optical resolution method using (R)-(+)-1-phenylethylamine as an optical resolving agent as shown in the following formula (5). Have been.

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(Prior Art 4) JP-A-58-1105 (R)-(-)-Mandelic acid is replaced by (S)-(+)-alanine as shown in the following formula (6): It is described that the light is split by an optical splitting method.

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[0007]

The prior art 1 uses ephedrine, an alkaloid compound, as an optical resolving agent.
A method of separating one optically active substance from a mixture of optical isomers of chloromandelic acid. Alkaloids are toxic plant bases, and ephedrine is legally restricted because of stimulant ingredients. In addition, there is a problem in supply amount due to natural products, and it is difficult to scale up to an industrial production method.

The prior art 2 is a method for synthesizing optically active o-chloromandelic acid from o-chloromandelonitrile using bacterial cells. Since the cells are used, a low-concentration and long-term reaction is required, and optically active o-chloromandelic acid cannot be obtained efficiently.In addition, only one optically active form of o-chloromandelic acid is used. It has the disadvantage of being limited to manufacturing.

The prior art 3 is an excellent optical resolution technique of mandelic acid using an optically active phenethylamine, which is an easily available optical resolution agent, as an optical resolution agent.
Mandelic acid of 8% ee or more is manufactured industrially.
However, the optical resolution of the racemic o-chloromandelic acid by optically active (R)-(+)-1-phenylethylamine by the diastereomer method was performed, and the optical purity of the obtained o-chloromandelic acid was 6 % Ee only
The optically active o-chloromandelic acid of high optical purity could not be isolated. The only structural difference between mandelic acid and o-chloromandelic acid is the presence of the chlorine atom at the o-position. However, due to the molecular recognition of optically active 1-phenylethylamine, it is possible to selectively incorporate only one optical isomer. could not. This is the result of the optically active resolving agent recognizing a slight difference in the structure of the molecule.

Prior art 4 is an optical resolution method of mandelic acid using optically active alanine as an optical resolution agent.
There is no description about o-chloromandelic acid.

[0011] Accordingly, an object of the present invention is to provide a novel optical resolution method, namely, a host-guest optical resolution method for synthesizing an inclusion complex, thereby obtaining an optical isomer having a high optical purity of one of o-chloromandelic acid. To provide the body on an industrial scale.

[0012]

DISCLOSURE OF THE INVENTION The present inventors have proposed, as a resolving agent, an optically active alanine which is a naturally occurring amino acid having the simplest stereospecific structure used in cosmetics and food additives. By performing optical resolution of (±) -o-chloromandelic acid using this method, a simple method for producing optically active o-chloromandelic acid was found. That is, o-
A mixed reaction of chloromandelic acid and optically active alanine,
The present inventors have found that an optically active o-chloromandelic acid can be produced by synthesizing and separating an clathrate complex, and decomposing the clathrate complex by extraction with an acid or a solvent.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION A racemic o-chloromandelic acid as a raw material used in the present invention can be synthesized by the method of the following formula (7). Reaction of o-chlorobenzaldehyde with hydrogen cyanide or alkali cyanide to form o-chloromandelonitrile, followed by hydrolysis in an aqueous medium to obtain a racemic o-chloromandelic acid as an objective substance Can be. [C. A. , 86, 1
89934x (1976)]

Embedded image That is, for example, o-chlorobenzaldehyde is added to an aqueous acetic acid solution under cooling, and then reacted with an aqueous sodium cyanide solution to synthesize a cyanohydrin intermediate,
By hydrolyzing with an acidic substance such as hydrochloric acid to remove by-product ammonium chloride and treating the separated mother liquor by a conventional method, a racemic o-chloromandelic acid can be isolated.

The present invention relates to a method for optical resolution of racemic o-chloromandelic acid, and more specifically, the following formula (8)

Embedded image A racemic o-chloromandelic acid represented by the following formula (9)

Embedded image (S)-(+)-alanine as a host molecule, and (S)-(+)-alanine (host molecule)
Has the following formula (10) in which (R)-(-)-o-chloromandelic acid (guest molecule), which is one of the racemates, is selectively incorporated by accurate molecular recognition.

Embedded image (R)-(-)-o-chloromandelic acid represented by
(S)-(+)-alane inclusion complex is separated as a crystal,
By decomposing the inclusion complex by acid or solvent extraction,
(R)-(-)-o-chloromandelic acid having high optical purity can be produced.

The optical resolution mechanism of (R)-(-)-o-chloromandelic acid in the present invention is not necessarily limited to this, but seems to proceed according to the following formula (11).

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The present invention also relates to a method for optical resolution of racemic o-chloromandelic acid.

Embedded image A racemic o-chloromandelic acid represented by the following formula (12)

Embedded image (R)-(-)-alanine as a host molecule, and the correct molecular recognition of (R)-(-)-alanine leads to one of the racemates (S)-(+) -O-chloromandelic acid (guest molecule)
The following equation (13) which selectively captures

Embedded image (S)-(+)-o-chloromandelic acid.
The (R)-(-)-alanine inclusion complex is separated as a crystal, and the inclusion complex is decomposed by extraction with an acid or a solvent to obtain (S)-(+)-o-chloromandel having high optical purity. Acids can be produced.

The optical resolution mechanism of (S)-(+)-o-chloromandelic acid in the present invention is not necessarily limited to this, but seems to proceed as shown in the following formula (14).

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Conventionally used optical resolving agents for alkaloid compounds are limited in industrial use due to their toxicity, cost and supply. However, the present invention provides an optically active o-chloromandelic acid by a simple process by allowing safe and inexpensive optically active alanine as an optically active substance to act on racemic o-chloromandelic acid as an optical resolving agent. Can be. Incidentally, optically active alanine is the optically active amino acid having the smallest molecular weight,
The partitioning efficiency by the host-guest method is also high.

In the optical resolution method by the host-guest method of the present invention, the optically active alanine as the optical resolution agent discriminates the difference in the steric structure of the optical isomer of o-chloromandelic acid, and is selected from one of the optical isomers To form an inclusion complex. The inclusion complex can be separated by utilizing the difference in solubility between the inclusion complex and the other optical isomer. An optically active o-chloromandelic acid can be produced by decomposing the clathrate complex by acid or solvent extraction.

In the optical resolution by the diastereomer method, it is necessary to cause an equimolar optical resolution agent to act on racemic o-chloromandelic acid. The optical resolving agent can be used in half the amount of the diastereomer method in order to work with one optical isomer. Furthermore, since an inclusion complex is formed by two molecules of o-chloromandelic acid and one molecule of alanine, it is theoretically possible to perform optical resolution with a quarter of the diastereomer method, and achieve high efficiency, resource saving, and It is an optical splitting process that places less burden on the environment. The charged molar ratio (B / A) at the time of synthesis of the inclusion complex of the optically active alanine (B) per racemic o-chloromandelic acid (A) is determined in consideration of the optical purity and the yield, and the charged molar ratio (B /A)=0.25-1.00
It is preferable to use an optically active alanine so that

The reaction for forming the clathrate complex can be carried out under solvent-free conditions, but it is usually preferable to use a solvent. As a solvent, racemic o-chloromandelic acid and an optically resolving agent optically active alanine are dissolved, and an inclusion complex composed of o-chloromandelic acid and optically active alanine is precipitated to form an inclusion complex. A solvent that does not dissolve the other optical isomer is convenient for operation. For example, water,
Alcohols such as methanol, ethanol and isopropanol; ketones such as acetone and methyl ethyl ketone;
Ethers such as diethyl ether, methyl-t-butyl ether and diisopropyl ether; esters such as ethyl acetate; aliphatic hydrocarbons such as n-hexane and cyclohexane; aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as chloroform and dichloromethane, aprotic polar solvents such as dimethylformamide and acetonitrile, and the like can be used alone or in combination of two or more, but water is particularly preferable.

The amount of the solvent used is such that o-chloromandelic acid and optically active alanine are dissolved and an inclusion complex consisting of o-chloromandelic acid and optically active alanine is precipitated, and the other one does not form an inclusion complex. The range in which the optical isomer is dissolved is desirable. Usually, 1 to 5 relative to o-chloromandelic acid
The range is 0 times by weight.

The reaction temperature during the synthesis of the inclusion complex of o-chloromandelic acid and optically active alanine is in the range from the melting point to the boiling point of the solvent used. For example, when water is used as a solvent, racemic o-chloromandelic acid and optically active alanine are dissolved by heating to 60 to 90 ° C., and 10 to 30 ° C.
By cooling to room temperature and filtering out the precipitated crystals, the target inclusion complex crystal of optically active o-chloromandelic acid and optically active alanine can be obtained. In the case of supercooling or the like, the other optical isomer is precipitated, which is not preferable because it causes a decrease in the optical purity of the obtained inclusion complex.

The other optically active o-chloromandelic acid is mixed with the inclusion complex of optically active o-chloromandelic acid and optically active alanine, thereby lowering the optical purity of the target optically active o-chloromandelic acid. In this case, purification can be performed by repeating recrystallization of the inclusion complex. By performing the recrystallization purification twice, the specific rotation of the inclusion complex reaches a steady state, whereby the optically pure o-
An inclusion complex crystal containing chloromandelic acid can be obtained, and by decomposing it, an optically active o-chloromandelic acid having high optical purity can be obtained.

The method for decomposing the inclusion complex crystal of optically active o-chloromandelic acid and optically active alanine is as follows. The inclusion complex crystal is added to a mixed solution of water and a hydrophobic solvent, and stirred at room temperature. By decomposing into mandelic acid and optically active alanine and separating the liquid, optically active o-chloromandelic acid can be obtained. The inclusion complex is dispersed in water,
A clathrate complex can be decomposed by adding a mineral acid such as hydrochloric acid, sulfuric acid or nitric acid, or an organic acid such as formic acid or acetic acid to adjust the pH to an acidic aqueous solution having a pH of 1 to 3, and stirring the mixture at around room temperature. After decomposing the inclusion complex, the optical activity o in the reaction solution
The optically active o-chloromandelic acid can be obtained by extracting -chloromandelic acid with a hydrophobic solvent and concentrating the extract under reduced pressure.

Specific examples of the hydrophobic solvent used in the present invention include ethers such as diethyl ether, t-butyl methyl ether and diisopropyl ether, esters such as ethyl acetate, and fats such as n-hexane and cyclohexane. Group hydrocarbons, and halogenated hydrocarbons such as chloroform and dichloromethane. The amount of the hydrophobic solvent used for the extraction is not particularly limited as long as the inclusion complex crystal is dissolved. The amount of the solvent used varies depending on the type and the like, but is usually in the range of 1 to 200 times by weight based on the complex crystal.

The amount of water used for dissolving the clathrate complex crystal is not limited as long as the clathrate complex can be dissolved, but is usually in the range of 1 to 200 times the weight of the clathrate complex crystal. is there. The temperature at the time of extraction is usually selected from the range of the melting point to boiling point of water and the solvent used, but is preferably 0 to 6
0 ° C.

Optically active o-chloromandelic acid obtained by solvent extraction or acid decomposition has an optical purity of 97 to 100% ee.
It is about. However, when the other optical isomer remains in a small amount and the optical purity is reduced to 90 to 97% ee, it can be purified to 99% ee or more by repeating recrystallization.

The yield of the inclusion complex crystal of optically active o-chloromandelic acid and optically active alanine is affected by the molar ratio of the charge, the solvent used and the separation temperature of the precipitate inclusion complex crystal. It is about 25 to 50% based on the body o-chloromandelic acid. The yield of optically active o-chloromandelic acid after decomposition of the inclusion complex is 10 to 30 based on the racemic o-chloromandelic acid used.
%.

Racemic o-chloromandelic acid and (S)-
(R)-precipitated by allowing (+)-alanine to act mixedly.
The separated mother liquor from which (-)-o-chloromandelic acid / (S)-(+)-alanine inclusion complex was separated was extracted with a hydrophobic solvent and concentrated to obtain (S)-(+)-o- A mixture of (S)-(+)-o-chloromandelic acid and (R)-(-)-o-chloromandelic acid, in which chloromandelic acid is the main component, can be recovered. The recovery of the charged o-chloromandelic acid was determined by the (R)-in the inclusion complex.
(−)-O-chloromandelic acid and recovery from separated mother liquor o
-Quantitative when combined with chloromandelic acid. Also,
When an inclusion complex is synthesized using racemic o-chloromandelic acid and (R)-(-)-alanine as starting materials, (R)-(-)-is obtained from the separated mother liquor in the same manner as described above.
(R)-(-)-containing o-chloromandelic acid as a main component
A mixture of o-chloromandelic acid and (S)-(+)-o-chloromandelic acid can be recovered.

[0031]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the present invention. The optical purity was determined by optical rotation and high performance liquid chromatography.

Reference Example 1 Synthesis of (±) -o-chloromandelic acid 635.8 g (4.52 mol) of o-chlorobenzaldehyde and water 353. were placed in a 5 L glass four-necked flask.
2 g, 327.8 g (5.46 mol) of acetic acid were charged,
Cooled to 7 ° C. 985.1 g (5.20 mol) of a 26.4% aqueous sodium cyanide solution was added to this mixture at 15 ° C.
It was dropped so as not to exceed. After completion of the dropwise addition, the mixture was aged for 30 minutes, and the resulting cyanohydrin was extracted with toluene. Cyanohydrin formation rate was 90.4% by silver nitrate titration.
Met. This extract was added dropwise to 681.4 g of 36% hydrochloric acid in 3 hours. Thereafter, a dehydration tube was attached, water and an excessive amount of hydrochloric acid were dehydrated and distilled off, and ammonium chloride by-produced from the distilled toluene solution was separated and removed. Next, the separated mother liquor was gradually cooled to separate the precipitated crystals, which were then dried under reduced pressure to give 518.6 g (2.78 mol) of (±) -o-chloromandelic acid in a yield of 61.5%. Obtained. Content 99.48% (caustic titration), mp 82-83 ° C.
It was identified from the melting point of o-chloromandelic acid described in the literature.
[Edward L .; Compare, Jr. , J. et al.
O. C. , 1968, 33, 2565. ]

Example 1 46.6 g of (±) -o-chloromandelic acid (0.25 m
ol) and 22.4 g of (S)-(+)-alanine (0.2
5 mol), 65.0 g of water was added, and the temperature was raised to 70 ° C.
Heated and dissolved. By slowly cooling to 45 ° C. over 1 hour under stirring, (R)-(−)-o-chloromandelic acid · (S)-(+)-alanine inclusion complex crystal was precipitated.
The mixture was further cooled to 27 ° C. over 2 hours, and the precipitated crystals were separated by filtration and dried under reduced pressure to obtain (R)-(−)-.
28.1 g of o-chloromandelic acid / (S)-(+)-alanine crude inclusion complex crystal was obtained (based on the amount of o-chloromandelic acid in caustic titration based on racemic o-chloromandelic acid). 44.8%). The formation of the inclusion complex was confirmed from the change in absorption of the stretching vibration of the hydroxyl group in IR. Incidentally, by caustic titration, 0.13 mol of o-chloromandelic acid and 0.17 mol of (S)-(+)-alanine remained in 93.8 g of the separated mother liquor. Analytical value of crude inclusion complex crystal: specific rotation [α] _D = -58.7 ° (C = 2.38, H
The ₂ O)該包contact complex crystals 27.5g dissolved in water 60.0g was recrystallized, with reference to the o- chloro mandelic acid to obtain purified inclusion complex crystals 20.6 g (racemic, caustic titration O-
Yield 34.8% determined from the amount of chloromandelic acid). From the elemental analysis and the caustic titration, the composition ratio of the inclusion complex (R)-
(-)-O-chloromandelic acid / (S)-(+)-alanine = 2/1 was determined. Analytical value of purified inclusion complex: specific rotation [α] _D = -88.0 ° (C = 2.31, H
₂ O) mp 146 to 148 ° C. moles determined from caustic titration (R) - (-) - o- chloro mandelic acid 0.087m
ol (S) - (+) - alanine 0.044mol elemental analysis C ₁₉ H ₂₁ Cl ₂ NO ₈ theory C49.37%, N3.03% Found C49.47%, N3.01% IR 3450~3300cm ^{- 1} (νO-H) 1703 cm ⁻¹ (νC = O)

Example 2 80.2 g of water was added to 20.1 g of the purified clathrate complex crystal of Example 1.
And hydrochloric acid 40.0 g, methyl-t-butyl ether 8
0.0 g was added, and the mixture was stirred and dissolved at room temperature to decompose the inclusion complex. The organic layer containing (R)-(-)-o-chloromandelic acid is separated, concentrated under reduced pressure, and dried under reduced pressure to obtain 1
4.4 g of (R)-(-)-o-chloromandelic acid were obtained (30.8% yield based on racemic o-chloromandelic acid). Analytical value of (R)-(-)-o-chloromandelic acid: specific rotation [α] _D = -142.4． (C = 1.0, acetone) Optical purity 91% ee Melting point 100-104 ° C. And 13.8 g of (R)-(-)-o-chloromandelic acid having an optical purity of 91% ee was dissolved in 60.1 g of toluene and recrystallized to obtain 13.2 g of (R)-(-)-o-chloro. Mandelic acid was obtained (28.3% yield based on racemic o-chloromandelic acid). Analytical value of purified (R)-(−)-o-chloromandelic acid: Specific rotation [α] _D = −148.9 ° (C = 1.0, acetone) Optical purity 95% ee Melting point 106-108 ° C.

Example 3 Hydrochloric acid (18.0 g) was added to the separated mother liquor (88.9 g) at the time of forming the crude clathrate complex of Example 1, and methyl-t-butyl ether (5) was added.
After extracting with 0.0 g and separating the organic layer containing o-chloromandelic acid, the mixture was concentrated under reduced pressure and dried under reduced pressure to obtain 21.
4 g of (S)-(+)-o-chloromandelic acid was recovered (46.0% recovery based on racemic o-chloromandelic acid). Analytical value of (S)-(+)-o-chloromandelic acid: Specific rotation [α] _D = + 89.9 ° (C = 1.0, acetone) Optical purity 54% ee Melting point 94 to 101 ° C.

Example 4 186.6 g of (±) -o-chloromandelic acid (1.00
mol) and 44.6 g of (S)-(+)-alanine (0.
(50 mol) was added with 260.1 g of water, heated to 62 ° C., and dissolved by heating. By slowly cooling to 42 ° C. over 1 hour under stirring, (R)-(−)-o-chloromandelic acid · (S)-(+)-alanine inclusion complex crystal was precipitated. After further cooling to 25 ° C. over 3 hours, the precipitated crystals were separated by filtration and dried under reduced pressure to obtain (R)-.
91.8 g of (-)-o-chloromandelic acid / (S)-(+)-alanine crude inclusion complex crystal was obtained (racemic o-
Yield determined from the amount of o-chloromandelic acid by caustic titration based on chloromandelic acid) (38.9%). By the caustic titration, 0.59 mol of o-chloromandelic acid and 0.29 mol of (S)-(+)-alanine remained in 370.3 g of the separated mother liquor. Analytical value of crude inclusion complex crystal: specific rotation [α] _D = -75.6 ° (c = 2.40, H
₂ O) mp 138.2 ° C. The crude inclusion complexes 91.3g recrystallized dissolved in water 220.2G, reference o- chloro mandelic acid to obtain an inclusion complex crystals 68.4 g (racemic And the yield determined from the amount of o-chloromandelic acid in the caustic titration was 29.2%). Note that, by caustic titration, 0.09 mol of o-chloromandelic acid and 0.05 mol of (S)-(+)-alanine remained in 214.9 g of the separated mother liquor. Analytical value of purified inclusion complex crystal (one recrystallization): Specific rotation [α] _D = -93.2 ゜ (c = 2.34, H
₂ O) mp 146.1 ° C. Further該包contact complexes (recrystallized once) to 67.9g water 18
The crystals were recrystallized from 0.2 g to obtain 55.4 g of a purified inclusion complex crystal (based on racemic o-chloromandelic acid, a yield of 22 determined from the amount of o-chloromandelic acid by caustic titration). .8%). In 171.2 g of the separated mother liquor, 0.05 mol of o-chloromandelic acid was determined by caustic titration.
0.03 mol of (S)-(+)-alanine remained. Analytical value of purified inclusion complex crystal (twice recrystallization): Specific rotation [α] _D = −95.4. (C = 2.36, H
₂ O) Melting point 147.4 ° C

Example 5 203.2 g of water and 201.5 g of methyl-t-butyl ether were added to 54.5 g of the purified clathrate complex of Example 4 (twice recrystallization).
g was added and stirred and dissolved at room temperature to decompose the inclusion complex.
The organic layer containing (R)-(−)-o-chloromandelic acid was separated, concentrated under reduced pressure, and dried under reduced pressure to obtain 41.4.
g (0.22 mol) of (R)-(-)-o-chloromandelic acid was obtained (yield 22.2% based on racemic o-chloromandelic acid). Incidentally, 217.0 g of the aqueous layer contained 0.01 m of o-chloromandelic acid by caustic titration.
ol remained. Analytical value of (R)-(−)-o-chloromandelic acid: Specific rotation [α] _D = −154.6 ° (C = 1.0, acetone) Optical purity 100% ee Melting point 119.3 ° C.

Example 6 A total of 370.3 g of the separated mother liquor at the time of forming the inclusion complex, 214.9 g of the separated mother liquor at the time of purification (one recrystallization), and 171.2 g of the separated mother liquor at the time of purification (two recrystallizations) 765.4 g was extracted with 200.3 g of methyl-t-butyl ether, and o-
The organic layer containing chloromandelic acid was separated, concentrated under reduced pressure, and dried under reduced pressure to obtain 116.3 g (0.62 mol).
1) (S)-(+)-o-chloromandelic acid was recovered (recovery rate 62.3% based on racemic o-chloromandelic acid). Incidentally, 0.13 mol of o-chloromandelic acid remained in 579.2 g of the aqueous layer by caustic titration. From Example 5 and Example 6, the total recovery of o-chloromandelic acid was 98%. Analytical value of (S)-(+)-o-chloromandelic acid: Specific rotation [α] _D = + 54.1 ° (C = 1.0, acetone) Optical purity 29% ee Melting point 99.2 ° C.

Example 7 46.5 g of (±) -o-chloromandelic acid (0.25 m
ol) and 5.6 g (0.06) of (S)-(+)-alanine.
mol), and the mixture was heated to 72 ° C. and dissolved by heating. By slowly cooling to 31 ° C. over 1 hour under stirring, (R)-(−)-o-chloromandelic acid
(S)-(+)-alanine inclusion complex crystals precipitated. The mixture was further cooled to 25 ° C. over 1 hour, and the precipitated crystals were separated by filtration and dried under reduced pressure to obtain (R)-(−)-.
15.7 g of o-chloromandelic acid / (S)-(+)-alanine crude inclusion complex crystal was obtained (based on the amount of o-chloromandelic acid in caustic titration based on racemic o-chloromandelic acid). Yield 28.5%). In addition, the separated mother liquor 89.
O-chloromandelic acid was added to 2 g by caustic titration.
17 mol, 0.03 mol of (S)-(+)-alanine
l remained. Analytical value of crude inclusion complex crystal: Specific rotation [α] _D = −62.5 ° (c = 2.35, H
₂ O) mp 120-127 ° C. The crude inclusion complex crystal 15.2g recrystallized dissolved in water 50.0 g, to obtain a purified inclusion complex crystals 9.0 g (racemic o- chloro mandelic acid The caustic titration o-
Yield 16.0% determined from the amount of chloromandelic acid). Analytical value of purified inclusion complex crystal: Specific rotation [α] _D = −88.6 ° (C = 2.36, H
₂ O) Melting point 136-139 ° C

Example 8 48.4 g of water, 20.0 g of hydrochloric acid and 40.1 g of methyl-t-butyl ether were added to 8.4 g of the purified clathrate complex of Example 7.
g was added and stirred and dissolved at room temperature to decompose the inclusion complex.
The organic layer containing (R)-(-)-o-chloromandelic acid was separated, concentrated under reduced pressure, and dried under reduced pressure to give 6.2 g.
(R)-(-)-o-chloromandelic acid (yield 13.3 based on racemic o-chloromandelic acid).
%). Analytical value of (R)-(-)-o-chloromandelic acid: Specific rotation [α] _D = -139.4 ゜ (C = 1.0, acetone) Optical purity 86% ee Melting point 106-109 ° C.

Example 9 20.0 g of hydrochloric acid was added to 84.9 g of the separated mother liquor at the time of forming the crude inclusion complex of Example 7, and methyl-t-butyl ether 5
The mixture was extracted with 0.2 g, and the organic layer containing o-chloromandelic acid was concentrated under reduced pressure and dried under reduced pressure to recover 28.7 g of (S)-(+)-o-chloromandelic acid (racemic o -Recovery based on chloromandelic acid
6%). Analytical value of (S)-(+)-o-chloromandelic acid: Specific rotation [α] _D = + 37.0 ° (C = 1.0, acetone) Optical purity 22% ee Melting point 82-90 ° C.

Example 10 46.5 g of (±) -o-chloromandelic acid (0.25 m
ol) and 12.2 g of (R)-(-)-alanine (0.1
45.2 mol), 65.2 g of water was added, and the temperature was raised to 69 ° C.
Heated and dissolved. By slowly cooling to 42 ° C. over 1 hour under stirring, (S)-(+)-o-chloromandelic acid · (R)-(−)-alanine inclusion complex crystal was precipitated.
After further cooling to 6 ° C. over 3 hours, the precipitated crystals were separated by filtration and dried under reduced pressure to obtain (S) − (+) − o.
26.3 g of a crude inclusion complex crystal of -chloromandelic acid. (R)-(-)-alanine was obtained (based on the amount of o-chloromandelic acid in caustic titration based on racemic o-chloromandelic acid). Yield 45.7%). The separated mother liquor 83.0
g was 0.1 g of o-chloromandelic acid by caustic titration.
3 mol, 0.07 mol of (S)-(+)-alanine
It remained. Analytical value of crude inclusion complex crystal: Specific rotation [α] _D = + 60.9 ° (c = 2.36, H
The ₂ O) mp 122 to 124 ° C. The crude inclusion complex 25.8g recrystallized dissolved in water 60.2 g, to obtain a purified inclusion complex crystals 18.1g of (racemic o- chloro mandelic acid The yield was 31.6% determined from the amount of o-chloromandelic acid by caustic titration as a reference.) Analytical value of purified inclusion complex crystal (one recrystallization): Specific rotation [α] _D = + 86.8 ° (C = 2.38, H
₂ O) mp 128-132 ° C. Further該包contact complexes (recrystallized once) to 17.6g of water 50.
The crystals were recrystallized from 1 g to obtain 13.5 g of a purified inclusion complex crystal (based on racemic o-chloromandelic acid, yield 23.4 determined from the amount of o-chloromandelic acid by caustic titration). %). Analytical value of purified inclusion complex crystal (twice recrystallization): Specific rotation [α] _D = + 93.9 ° (c = 2.35, H
₂ O) Melting point 140-143 ° C

Example 11 60.0 g of water, 30.0 g of hydrochloric acid and 60.1 g of methyl tert-butyl ether were added to 13.0 g of the purified clathrate complex of Example 10 (twice recrystallization), and dissolved by stirring at room temperature. The inclusion complex was decomposed. The organic layer containing (S)-(+)-o-chloromandelic acid was separated, concentrated under reduced pressure, and dried under reduced pressure to obtain 9.5 g of (S)-(+)-o-chloromandelic acid. (Yield 20.5% based on racemic o-chloromandelic acid). Analytical value of (S)-(+)-o-chloromandelic acid Specific rotation [α] _D = + 151.3 ° (C = 1.0, acetone) Optical purity 97% ee Melting point 107-110 ° C.

Example 12 20.1 g of hydrochloric acid was added to 82.4 g of the separated mother liquor at the time of formation of the inclusion complex in Example 10, and methyl-t-butyl ether 5
The mixture was extracted with 0.1 g, and the organic layer containing o-chloromandelic acid was concentrated under reduced pressure and dried under reduced pressure to recover 21.2 g of (R)-(−)-o-chloromandelic acid (racemic o -Recovery based on chloromandelic acid
6%). Analytical value of (R)-(−)-o-chloromandelic acid: Specific rotation [α] _D = -85.7 ° (C = 1.0, acetone) Optical purity 42% ee Melting point 93 to 101 ° C.

Comparative Example 1 (JP-A-55-147236) 57.0 g of (±) -o-chloromandelic acid (0.31 m
ol), (R)-(+)-1-phenylethylamine 1
5.2 g (0.13 mol) and sodium hydroxide 7.0
g (0.18 mol), add 100.0 g of water,
Until heated. Crystals were precipitated by slowly cooling to 39 ° C. over 1 hour with stirring. One more hour, 21
After slowly cooling to ° C., the precipitated crystals were separated by filtration and dried under reduced pressure to obtain o-chloromandelic acid (R)-(+)-1.
-Phenylethylamine crude diastereomer salt crystal 4
5.3 g were obtained (48.2% yield determined from the amount of o-chloromandelic acid by caustic titration based on racemic o-chloromandelic acid). Analytical value of crude diastereomer salt crystal: specific rotation [α] _D = + 5.6 ° (c = 1.02, Et
OH) 43.0 g of the diastereomer salt was recrystallized once from 120.1 g of water to give 24.7 g of purified crystals (based on racemic o-chloromandelic acid, o -Yield 26.2% determined from the amount of chloromandelic acid). Analytical value of purified diastereomeric salt crystal: Specific rotation [α] _D = + 7.9 ° (c = 0.99, Et
OH) Melting point: 128-133 ° C. 50 g of water and 7.6 g of sodium hydroxide were added to 23.9 g of the purified diastereomer salt to decompose the diastereomer salt. Toluene was added to extract and remove (R)-(+)-1-phenylethylamine, and 72.4 g of the aqueous layer was acidified by adding 19.0 g of hydrochloric acid, extracted with methyl-t-butyl ether, and extracted with o-chloromandelic acid. Is separated, and then concentrated under reduced pressure and dried under reduced pressure to obtain 19.6 g.
Of (S)-(+)-o-chloromandelic acid (crude yield based on racemic o-chloromandelic acid).
3%). Analytical value of (S)-(+)-o-chloromandelic acid: Specific rotation [α] _D = + 8.9 ° (C = 1.00, acetone) Optical purity 6% ee

[0046]

According to the present invention, a racemic form of an amino acid (S)-(+)-alanine or (R)-(-)-alanine, which is easily available and highly safe, is used as an optical resolving agent. An inclusion complex, which acts on o-chloromandelic acid, mixes and dissolves both, and precipitates, (R)-(-)-o-chloromandelic acid. (S)-(+)-alanine, or (S)-
The (+)-o-chloromandelic acid / (R)-(−)-alanine crude crystal is separated and purified by repeating recrystallization once or twice, and the inclusion complex is purified by adding water and a hydrophobic solvent It is decomposed by a simple operation of stirring and dissolving in the layer mixture, and by extracting and concentrating optically active o-chloromandelic acid, 9
(R)-(-) having high optical purity of 8 to 100% ee
An optically active form of -o-chloromandelic acid or (S)-(+)-o-chloromandelic acid can be easily and efficiently produced. That is, the present invention relates to (R)-(-)-o-
An object of the present invention is to provide an industrial production method of chloromandelic acid or (S)-(+)-o-chloromandelic acid optically active substance.

Claims (2)

[Claims] 1. A racemic o-chloromandelic acid and an optically active form (S)-(+)-alanine are mixed and dissolved to precipitate (R)-(−)-o-chloromandelic acid. (S). −
(+)-Alanine inclusion complex is separated, and the inclusion complex is decomposed by extraction with an acid or a solvent. A method for producing (R)-(-)-o-chloromandelic acid represented by the formula: 2. A racemic o-chloromandelic acid and an optically active form (R)-(-)-alanine are mixed and dissolved, and (S)-(+)-o-chloromandelic acid. (R) is precipitated. −
(-)-Alanine inclusion complex is separated, and the inclusion complex is decomposed by extraction with an acid or a solvent. The method for producing (S)-(+)-o-chloromandelic acid represented by