JP2003231683A - Method for producing optically active tetrahydrofuran-2-carboxylic acid - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing optically active tetrahydrofuran-2- carboxylic acid of high optical purity by a simple crystallizing operation. <P>SOLUTION: The method for producing the optically active tetrahydrofuran-1- carboxylic acid comprises the following steps. A step of dissolving an optically active 1-aminoindan-2-ol and a racemic tetrahydrofuran-2-carboxylic acid in an organic solvent, a step of adding a salt of the optically active tetrahydrofuran-2-carboxylic acid with an optical resolving agent which is a seed crystal into the solution at ≥40°C, cooling the resultant solution to ≤20°C at ≤6°C/h cooling rate and depositing a crystal, and a step of collecting the deposited crystal by solid - liquid separation, then splitting the salt and affording the optically active tetrahydrofuran-2-carboxylic acid. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active tetrahydrofuran-2-carboxylic acid, and more specifically, to a method for producing an optically active tetrahydrofuran-2-carboxylic acid from a racemic raw material by using crystallization resolution of a diastereomeric salt. It relates to a method of manufacturing. Optically active tetrahydrofuran-2-carboxylic acid is useful as an intermediate drug raw material, a liquid crystal raw material, and other organic synthetic raw material, and is a very important compound as an intermediate for forming a pharmaceutical skeleton.

[0002]

2. Description of the Related Art Recently, the importance of optically active substances in the pharmaceutical field has been increasing. Currently, most of new drugs are optically active compounds, and conventional drugs are also being converted from racemic forms to optically active compounds. As the effects of side effects of trace amounts of impurities on the living body become clear, in order to avoid the effects of impurities, pharmaceutical products are required to have higher optical purity.

The conventional methods for producing optically active carboxylic acids are roughly classified into diastereomer salt resolution method, methods using enzymes such as lipase / esterase, and asymmetric synthesis methods. Among these techniques, as a method for producing an optically active tetrahydrofuran-2-carboxylic acid, a method of performing crystallization resolution by forming a diastereomeric salt of racemic tetrahydrofuran-2-carboxylic acid and an optically active resolving agent is used. It has been known.

For example, (1) a method of optically resolving an optically active 1-phenylethylamine or the like as a resolving agent (JP-A-3-7272), and (2) an optically active 1- (4-halogenophenyl) ethylamine as a resolving agent. (Japanese Patent Laid-Open No. 1-216983), (3) a method using an optically active quinine as a resolving agent (J. Org. Che
m. , 27, p921. (1962)), (4) A method of optically resolving a diastereomer by an esterification reaction using an optically active alcohol (JP-B-7-37455).
No.), (5) Optically active phenylalanine alanide.
A method of optically resolving phenylalanine amide as an optical resolving agent (JP-A-9-71576 and JP-A-9-14).
3101), and (6) a method of producing a diastereomeric salt using optically active 1-aminoindan-2-ol as an optical resolving agent (Japanese Patent Publication No. 11-511742). In each case, the diastereomeric salt obtained by crystallization is desolvated by a known method to recover optically active tetrahydrofuran-2-carboxylic acid.

[0005]

These conventional methods have made it possible to produce optically active tetrahydrofuran-2-carboxylic acid having an optical purity of about 85 to 99%. In order to obtain a high optical purity product, a complicated process of repeating recrystallization until the target purity is further reached is indispensable, which has been a major industrial problem.

[0006]

[Means for Solving the Problems] In producing the optically active tetrahydrofuran-2-carboxylic acid, the present inventors have achieved a very high optical purity which does not require repeated complicated recrystallization steps for improving the optical purity. As a result of diligent studies on a high diastereomeric salt resolution method, the present inventors have found that this object can be achieved by carrying out diastereomeric salt crystallization under a specific controlled condition, and arrived at the present invention.

That is, the present invention relates to a method for producing optically active tetrahydrofuran-2-carboxylic acid, which comprises the following steps. [I] Optically active 1-aminoindane which is an optical resolving agent
A step of dissolving 2-ol and racemic tetrahydrofuran-2-carboxylic acid in an organic solvent. [II] At a temperature of 40 ° C. or higher, a salt of an optically active tetrahydrofuran-2-carboxylic acid that is a seed crystal and the optical resolving agent is added to the solution, and the temperature is 20 ° C. or lower at a cooling rate of 6 ° C./hr or lower. The process of cooling to the temperature and precipitating crystals. [III] After separating the precipitated crystals by solid-liquid separation,
A step of desolving to obtain optically active tetrahydrofuran-2-carboxylic acid.

According to the present invention, the R-form salt of tetrahydrofuran-2-carboxylic acid and S are used as diastereomeric salts.
In a system containing both body salts and capable of precipitating both, for example, when the R form of tetrahydrofuran-2-carboxylic acid is required, the R form of tetrahydrofuran-2-carboxylic acid and the optical resolving agent 1-aminoindan- 2-all d
It is possible to precipitate only the diastereomer salt with the isomer with a high degree of purity by crystallization once, and when the S isomer of tetrahydrofuran-2-carboxylic acid is required, tetrahydrofuran-2-carboxylic acid S form and optical resolving agent 1-
Only the diastereomeric salt of aminoindan-2-ol with the 1-form can be precipitated with high purity in a single crystallization.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The method for producing the optically active tetrahydrofuran-2-carboxylic acid of the present invention will be described in detail below.

The starting material, tetrahydrofuran-2-carboxylic acid, used in the present invention is usually in a racemic form, but it can be highly purified by using an optically active substance having a low optical purity.

The optical resolving agent used in the present invention must be optically active 1-aminoindan-2-ol. In order to produce R-form tetrahydrofuran-2-carboxylic acid, dextrorotatory In order to produce d-form 1-aminoindan-2-ol, or S-form tetrahydrofuran-2-carboxylic acid, levorotatory l-form 1-aminoindan-
2-ol is used. These optical resolving agents can be synthesized by known methods and used, but it is convenient to use commercially available ones.

The organic solvent used in the present invention includes alcohols such as methanol, ethanol and isopropyl alcohol, ethers such as tetrahydrofuran, ketones such as methyl ethyl ketone and acetone, esters such as ethyl acetate, butyl acetate and pentyl acetate, Examples thereof include nitriles such as acetonitrile and propionitrile, chlorinated hydrocarbons such as chloroform, and aromatic hydrocarbons such as toluene and xylene. Acetonitrile is preferably used because of the high optical purity of the product and the ease of handling.

In the production method of the present invention, first, racemic tetrahydrofuran-2-carboxylic acid and optically active 1-aminoindan-2-ol as an optical resolving agent are added to an organic solvent and dissolved by heating. At this time, 1-of the optically active substance
The amount of aminoindan-2-ol used may be 0.1 times or more the molar ratio of racemic tetrahydrofuran-2-carboxylic acid, and there is no particular upper limit, but the molar ratio is not more than 2 times in practice. Is. A molar ratio of 0.3 to 1 times is more preferable, and it is most preferable to add an optical resolution agent of 0.5 to 0.7 times. In the case of obtaining the R-form of tetrahydrofuran-2-carboxylic acid, the d-form optical resolving agent is used,
When the purpose is to obtain the S-form of tetrahydrofuran-2-carboxylic acid, the l-form of the optical resolving agent is used.

Further, it is necessary that the dissolution concentration is such that the diastereomeric salt at a saturation concentration at 40 ° C. or higher is dissolved in the selected organic solvent. Therefore, the melting temperature is 40
It is performed at a temperature of not less than 0 ° C and usually not more than the boiling point of the organic solvent.
For example, in the case of acetonitrile solvent, the boiling point of the solvent is close to 8
It is preferable to sufficiently dissolve the racemic tetrahydrofuran-2-carboxylic acid and the optical resolving agent at about 0 ° C. Although it is possible to start cooling immediately after the dissolution in the organic solvent is confirmed and proceed to the crystallization operation, it is possible to ensure that the crystallization operation is continued for 30 minutes or longer (usually about 30 minutes to 3 hours) with stirring. It is desirable to eliminate dissolved compounds so that the remaining undissolved crystals do not form seed crystals.

In the production method of the present invention, the optically active tetrahydrofuran-2 which is a seed crystal is added to the diastereomer salt solution obtained as described above at a temperature of 40 ° C. or higher.
-Add a salt of a carboxylic acid and the optical resolving agent, and add 6 ° C /
The crystals are precipitated by cooling to a temperature of 20 ° C. or less at a cooling rate of hr or less.

The seed crystal used at this time is a diastereomeric salt of the R-form tetrahydrofuran-2-carboxylic acid and the d-form optical resolving agent when the purpose is to obtain the R-form tetrahydrofuran-2-carboxylic acid. , The diastereomeric salt of the S-form of tetrahydrofuran-2-carboxylic acid and the l-form of the optical resolving agent is selected for the purpose of obtaining the S-form of tetrahydrofuran-2-carboxylic acid.

The seed crystal is added at 40 ° C. or higher, the boiling point of the organic solvent (for example, about 80 ° C. when acetonitrile is used as the solvent).
The following temperature is used, but a higher seed crystal addition temperature is advantageous for improving optical purity, and it is most preferable for actual production to add a seed crystal at 60 ° C. or higher to precipitate crystals. .

It is particularly important to maintain the cooling rate of the crystallization solution at 6 ° C./hr or less. There is no particular lower limit of the cooling rate, but it is industrially and economically about 0.5 ° C./hr or more. Preferred cooling rate is 5 ° C / hr or less, 1 ° C / h
r or more. In addition, a certain time (for example, 3
If the temperature is kept constant for about 0 minutes and stirring is stopped if necessary to give a state more suitable for crystal growth, a crystal with higher optical purity is obtained, which is a hard crystal that cannot be seen by the conventional method, and a solid-liquid separation step. The liquid will be drained well. The cooling operation is continued until the temperature falls below 20 ° C. The preferred temperature at the end of cooling is 0 to 20 ° C. In addition, if the temperature is maintained for a certain period of time (for example, 1 hour or more) after cooling and an operation of increasing the yield is added, a high-purity crystal can be obtained in the solid-liquid separation step without a rinse solution washing step.

Further, during cooling crystallization, it is possible to continue stirring with stirring during the melting operation, but more preferably, 30 r. p.
m. It is more desirable to obtain a high optical purity product by agitating so that only the liquid causes convection under the interface with low rotation in the front and rear and without waviness.

Crystals are separated from the crystallization liquid obtained as described above by a conventional solid-liquid separation means (for example, filtration, centrifugation, etc.) to obtain a diastereomer of high purity of 99.9% ee or more. It became possible to obtain salt.

After solid-liquid separation of crystals of the diastereomeric salt, the salt is desolvated by a known method to isolate the optically active tetrahydrofuran-2-carboxylic acid.

[0022]

EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited to these examples. The optical purity analysis method for the product was as follows. The optically active tetrahydrofuran-2-carboxylic acid, which was desalted by a known method, was analyzed by liquid chromatography. Column is SUMICHIRAL OA60
0 (Sumitomo Chemical Analysis Center), the eluent was a 2 mM aqueous solution of copper sulfate, and the analytical sample was diluted with a 0.2 wt% aqueous solution. The elution amount was 6 ml for R isomer and 7.5 ml for S isomer.

Example 1 1.74 g of racemic tetrahydrofuran-2-carboxylic acid and d-form of 1-aminoindan-2-ol (manufactured by Tama Chemical Industry Co., Ltd.) 1.1
Add 3 g to 29.25 g of acetonitrile, heat, 8
Heat to 0 ° C. to dissolve everything. With the temperature kept constant,
After standing for 1.5 hours, cooling is started. At this time, the cooling rate was maintained at 5 ° C./hr, and the stirring rate was about 30 rpm. p. m
And 0.01 g of diastereomeric salt crystals of R-form tetrahydrofuran-2-carboxylic acid and d-form 1-aminoindan-2-ol are added as seed crystals at 60 ° C.
After cooling to 20 ° C., the mixture was allowed to stand for 1 hour for aging, and then solid-liquid separated to obtain crystals. This crystal had grown into a columnar crystal. 0.02 g of the obtained crystal was dissolved in 1 g of water,
After 0.2 g of concentrated sulfuric acid was added dropwise and stirred, 1.5 g of methyl isobutyl ketone was added, stirred, extracted and left for 1 hour, then the methyl isobutyl ketone phase was separated and the solvent was distilled off. As a result of analyzing the residual liquid by the above-mentioned optical purity analysis method, the R-form of tetrahydrofuran-2-carboxylic acid was 99.9% ee or more. In addition, the yield is
It was 50% of the R form present in the 2-carboxylic acid.

(Example 2) 1.74 g of racemic tetrahydrofuran-2-carboxylic acid and 1-amino 1-aminoindan-2-ol (manufactured by Tama Chemical Industry Co., Ltd.) 1.1
Add 3 g to 29.25 g of acetonitrile, heat, 8
Heat to 0 ° C. to dissolve everything. With the temperature kept constant,
After standing for 1.5 hours, cooling is started. At this time, the cooling rate was maintained at 5 ° C./hr, and the stirring rate was about 30 rpm. p. m
And At 50 ° C., 0.01 g of crystals of diastereomeric salt of S-form tetrahydrofuran-2-carboxylic acid and 1-form 1-aminoindan-2-ol are added as seed crystals at 50 ° C.
After cooling to 20 ° C., the mixture was allowed to stand for 1 hour for aging, and then solid-liquid separated to obtain crystals. This crystal had grown into a needle crystal. 0.02 g of the obtained crystal was dissolved in 1 g of water,
After 0.2 g of concentrated sulfuric acid was added dropwise and stirred, 1.5 g of methyl isobutyl ketone was added, stirred, extracted and left for 1 hour, then the methyl isobutyl ketone phase was separated and the solvent was distilled off. As a result of analyzing the residual liquid by the aforementioned optical purity analysis method, the S-form of tetrahydrofuran-2-carboxylic acid was 99.9% ee or more. In addition, the yield is
It was 50% of the S-form present in the 2-carboxylic acid.

Comparative Example 1 An experiment was repeated in the same manner as in Example 1 except that the cooling rate was controlled at 10 ° C./hr and the seed crystal addition temperature was 40 ° C. As a result, the R isomer of tetrahydrofuran-2-carboxylic acid was 15% ee. Moreover, the yield is the tetrahydrofuran-2 added.
-65.1% of the R form present in the carboxylic acid.
The crystal shape was a mixture of needles and columns.

Comparative Example 2 The experiment was repeated in the same manner as in Example 1, except that the cooling rate was controlled at 5 ° C./hr and the seed crystal addition temperature was 20 ° C. As a result, the S form of tetrahydrofuran-2-carboxylic acid was 12.6% ee. In addition, the yield is
It was 34.7% of the S-form present in the 2-carboxylic acid. The crystal shape was a mixture of needles and columns.

[0027]

According to the production method of the present invention, an optically active tetrahydrofuran-2- having an optical purity of 99.9% ee or higher in one crystallization operation, which is unprecedented in the prior art, is used.
A carboxylic acid can be obtained. Therefore, as compared with the conventional division method, a simple and short manufacturing process is required, the optical division cost is reduced, and the production capacity is increased, which is extremely economically advantageous.

Claims (4)

[Claims] 1. A method for producing an optically active tetrahydrofuran-2-carboxylic acid, which comprises the following steps. [I] Optically active 1-aminoindane which is an optical resolving agent
A step of dissolving 2-ol and racemic tetrahydrofuran-2-carboxylic acid in an organic solvent. [II] At a temperature of 40 ° C. or higher, a salt of an optically active tetrahydrofuran-2-carboxylic acid that is a seed crystal and the optical resolving agent is added to the solution, and the temperature is 20 ° C. or lower at a cooling rate of 6 ° C./hr or lower. The process of cooling to the temperature and precipitating crystals. [III] After separating the precipitated crystals by solid-liquid separation,
A step of desolving to obtain optically active tetrahydrofuran-2-carboxylic acid. 2. The optically active tetrahydrofuran-2-carboxylic acid according to claim 1, wherein the optical resolving agent 1-aminoindan-2-ol is a d-isomer, and the resulting optically active tetrahydrofuran-2-carboxylic acid is an R-isomer. Manufacturing method. 3. The optically active tetrahydrofuran-2-carboxylic acid according to claim 1, wherein the optical resolving agent 1-aminoindan-2-ol is an l-isomer, and the resulting optically active tetrahydrofuran-2-carboxylic acid is an S-isomer. Manufacturing method. 4. The method for producing an optically active tetrahydrofuran-2-carboxylic acid according to claim 1, wherein the organic solvent is acetonitrile.