JP3484510B2 - Method for producing optically active carboxylic acid - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION Optically active carboxylic acids are useful as intermediate raw materials for medicines, raw materials for liquid crystals, and other synthetic raw materials. The present invention recovers a resolving agent in high yield from unnecessary optical antipodal carboxylic acids and a resolving agent when producing an optically active carboxylic acid by using diastereomeric salt resolution, and also produces an unnecessary optical antipomic carboxylic acid. The present invention relates to a method for converting acids into useful racemic carboxylic acids for recycling.

[0002]

2. Description of the Related Art Conventionally, there have been known methods for producing optically active carboxylic acids such as diastereomeric salt resolution method, methods using enzymes such as lipase and esterase, and asymmetric synthesis methods. Since it does not require a special device, it is widely used industrially. For example, as a method for producing optically active tetrahydrofuran carboxylic acids, a method in which racemic tetrahydrofuran carboxylic acids are resolved by diastereomeric salts is known. Specifically, tetrahydrofuran-2-carboxylic acid is (1) optically resolved using optically active 1-phenylethylamine or the like as a resolving agent (JP-A-3-7272), (2) optically active 1- (4- After optically resolving with halogenophenyl) ethylamine as a resolving agent, the salt with optically active tetrahydrofuran-2-carboxylic acid / optically active 1- (4-halogenophenyl) ethylamine is desolvated with sodium hydroxide, and then optically active with ether. -(4-halogenophenyl)
After extracting ethylamine, acidifying with hydrochloric acid and then extracting optically active tetrahydrofuran-2-carboxylic acid with ether (Japanese Patent Laid-Open No. 1-216983) and the like, and tetrahydrofuran-3-carboxylic acid with (3) quinine. Method of optical resolution as a resolving agent (J. Org. Che
m. , 27, p921. (1962)) and the like are known.

After the optical resolution, each diastereomeric salt is desalted to be separated into an optically active carboxylic acid and a resolving agent. At this time, it is generally difficult to isolate the carboxylic acid by a simple operation from a diastereomeric salt of the carboxylic acid having a property of being easily dissolved in both water and an organic solvent. Tetrahydrofuran carboxylic acids are typical carboxylic acids that have the property of being easily soluble in both water and organic solvents.
Method (2) of extracting with ether, and method (4) of using a strongly acidic cation ion exchange resin (JP-A-4-9508).
No. 3 gazette) is proposed.

The racemization of optically active tetrahydrofuran carboxylic acids is carried out by heating at high temperature using a concentrated large excess aqueous sodium hydroxide solution.
(5) Method of heating optically active tetrahydrofuran-2-carboxylic acid to 100 ° C. or higher (JP-A-2-124881)
No. gazette) is only known.

In actual industrial production, the steps of optical resolution, salt removal, racemization, and recycling must be carried out in a linked manner. However, the following inconveniences cause the following inconveniences. Occurs.

For example, in order to isolate the unwanted optical antipodal carboxylic acid after optical resolution, if the optically active carboxylic acid has a property of being easily dissolved in both water and an organic solvent,
The salt-removing method of (2) is not practical because many methods are not practical because an organic amine salt is changed to an alkali metal salt and an ether that has a low boiling point and is easily inflammable is used. The concentration of active carboxylic acid is as low as 2.4% and the recovery rate is not so high. Further, in order to transfer the isolated optically active carboxylic acid to a high-concentration racemization step, the extraction solvent must be completely removed or a huge amount of water must be concentrated. Further, the racemization method (5) requires a strong excess of a strong base such as an aqueous sodium hydroxide solution, and a strict heating condition of 140 ° C. or higher is required to obtain a sufficient racemization rate. Therefore, in addition to restrictions such as the need for a reactor excellent in corrosion resistance and pressure resistance, the recovery rate is not always good. Then, in order to transfer the racemic carboxylic acids from the racemization step to the recycle separation step, it is necessary to isolate the racemic carboxylic acid from water again from the aqueous solution of sodium racemic carboxylate after the racemization. In particular, if the carboxylic acid is a carboxylic acid that is easily soluble in both water and an organic solvent, the isolation becomes very difficult, so a complicated operation is indispensable, and the number of steps may further increase.

[0007]

DISCLOSURE OF THE INVENTION Diastereomers for producing optically active carboxylic acids by using diastereomeric salts from racemic carboxylic acids by using an optical resolving agent and utilizing the solubility difference between the salts. In the salt resolution method, the desired yield of the optically active carboxylic acid is theoretically 5
It becomes 0%, which is insufficient as an industrial production method. Therefore, it is essential to racemize the unnecessary optical antipodes and recycle them as raw materials for optical resolution, but usually, before turning the unnecessary optical antipodes to the racemization step, the diastereomeric salt with the resolving agent. To separate the unwanted optical antipodes into the free state. At the same time, it is necessary to recover the resolving agent in good yield. Therefore, efficient coupling between the separation step of the optical antipode remaining in the mother liquor after the optical resolution and the optical resolution agent and the racemization step, that is, simplification of the operability and omission of the step can reduce the recovery rate of the carboxylic acid. And greatly contribute to the improvement of economic efficiency.

Therefore, the object of the present invention is to obtain a high yield by smoothly connecting the separation step and the racemization step from the unnecessary optical antipodal carboxylic acid remaining in the mother liquor after the optical resolution and the salt of the resolving agent. An object of the present invention is to provide an industrial production method of an optically active carboxylic acid in which a resolving agent is recovered and unnecessary optical antipodal carboxylic acid is converted into a useful racemic carboxylic acid for recycling.

[0009]

Therefore, the present inventors have conducted a smooth separation step and a racemization step from the unnecessary optical antipodal carboxylic acid remaining in the mother liquor after the above optical resolution and the salt of the resolving agent. As a result of diligent examination of an industrial production method of optically active carboxylic acids which is converted into a useful racemic carboxylic acid by recycling, the purpose of this reaction is to perform solid-liquid separation of an organic solvent after optical resolution in an organic solvent. The optical antipodal carboxylic acid remaining in the mother liquor and the optical resolving agent are brought into contact with a chlorinating agent in the presence of an alcohol to simultaneously esterify the optical antipodal carboxylic acid, and the ester is racemized and hydrolyzed to racemate. This could be achieved by recycling the carboxylic acid to the splitting step. That is, (A) a step of mixing a racemic carboxylic acid and an optical resolving agent in an organic solvent and separating the optically active carboxylic acid and a diastereomeric salt of the optical resolving agent as crystals by solid-liquid separation, (B) solid-liquid separation The optical antipodal carboxylic acid and the optical resolving agent remaining in the mother liquor of the organic solvent are brought into contact with a chlorinating agent in the presence of an alcohol to form an optical antipodal carboxylic acid ester and an optical resolving agent hydrochloride, and then solidified. The resolving agent recovery step of separating the optical resolving agent hydrochloride as crystals by liquid separation, (C) the optical enantiomer carboxylic acid ester remaining in the mother liquor is racemized in the presence of a racemization catalyst, and then hydrolyzed and then racemic. Racemization step of recovering as carboxylic acid, (D) resolving agent releasing step of recovering optical resolving agent hydrochloride separated as crystals as free optical resolving agent, (E) recovered racemic cal A process for producing an optically active carboxylic acid, comprising the step of recycling the phosphate and an optical resolution agent to the optical resolution step (A). The outline of the manufacturing flow is shown in FIG.

According to the present invention, a diastereomeric salt of an optically active chiral carboxylic acid and a resolving agent is contacted with a chlorinating agent in an organic solvent containing an alcohol substantially free of water. , By simultaneously performing desolvation and esterification, the precipitated optical resolving agent hydrochloride can be recovered in high yield by solid-liquid separation, and the optical enantiomer carboxylic acid ester can be separated into a filtrate, so that continuous The separation step and the racemization step can be smoothly linked by migrating the optical antipodal carboxylic acid ester to the racemization step. Moreover, since the racemization of the present invention is a very mild condition, the recovery rate of racemic carboxylic acid ester is also high. After the racemization, it becomes possible to hydrolyze and recycle the racemic carboxylic acid to the resolution step, so that theoretically 100% of the optically active carboxylic acid can be obtained from the racemic carboxylic acid.

The structure of the present invention will be described in detail below.

The optical resolving agent used in the step (A) of the present invention is an optically active amine, which is a compound selected from optically active aromatic amines or optically active amino acid amide derivatives. The D body and the L body can be used properly according to the purpose.

Specifically, specific examples of the resolving agent used in the present invention include optically active 1-phenylethylamine and its derivatives, optically active 1- (1-naphthyl) ethylamine and its derivatives, optically active alanine amide derivatives, and optically active phenylalanine. Examples thereof include amide derivatives and optically active phenylglycine amide derivatives.

The resolving agent of the present invention can be applied to carboxylic acids which are soluble in both water and an organic solvent, and can be used particularly for producing optically active tetrahydrofuran carboxylic acids. Here, the tetrahydrofuran carboxylic acids are
It is preferable to use one in which one hydrogen bonded to carbon at the 2-position or 3-position of tetrahydrofuran is substituted with a carboxyl group.

As the carboxylic acid used as a raw material in the step (A) of the present invention, tetrahydrofuran carboxylic acids are used. For example, optically active tetrahydrofuran-
The tetrahydrofuran-2-carboxylic acid used for the purpose of obtaining the 2-carboxylic acid is industrially produced by hydrogenation of furan-2-carboxylic acid.

Here, the tetrahydrofuran carboxylic acids used as a raw material are not only a racemic mixture containing equal amounts of (R) -tetrahydrofuran carboxylic acids and (S) -tetrahydrofuran carboxylic acids, but also one of the optical isomers. A mixture containing more than the amount can be used.

Optical resolution of tetrahydrofuran carboxylic acids is preferably carried out according to the following procedures and conditions.

The optical resolving agent is brought into contact with 0.4 to 1.2 equivalents, preferably 0.5 to 1.0 equivalents to 1 equivalent of tetrahydrofuran carboxylic acid in a solvent to form a diastereomeric salt.

Here, the solvent used may be one that selectively precipitates one of the diastereomeric salts. For example, water, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-
An alcohol such as butanol, an organic solvent such as acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, ethyl acetate, chloroform, toluene, chlorobenzene, or a mixed solvent thereof can be used. In the present invention, since the chlorinating agent is used in the salt-removing step after the resolution, it is better that the resolution solvent contains less water.
That is, the amount of water present during the division is preferably 10% by weight or less based on tetrahydrofuran carboxylic acids.

As a method of bringing the tetrahydrofuran carboxylic acid into contact with the resolving agent, the tetrahydrofuran carboxylic acid and the resolving agent may be added to the solvent at once, or they may be sequentially added. Further, a salt prepared in advance from tetrahydrofuran carboxylic acid and a resolving agent may be dissolved in the solvent. The order of adding them is not particularly limited.

When the solution containing the diastereomer salt thus obtained is cooled and / or concentrated, a hardly soluble diastereomer salt is precipitated from the solution.

The temperature for precipitating the slightly soluble diastereomer salt from the solution may be in the range from the freezing point to the boiling point of the solvent used and can be appropriately selected depending on the purpose, but is usually 0 ° C. to 100 ° C. Ranges are preferred.

Crystals of the sparingly soluble diastereomeric salt can be easily separated by a usual solid-liquid separation method such as filtration or centrifugation. The crystal of the sparingly soluble diastereomer salt can be recrystallized to obtain the desired highly pure diastereomer salt.

The (R) -tetrahydrofurancarboxylic acid or the (S) -tetrahydrofurancarboxylic acid and the resolving agent can be separated and collected by demineralizing the diastereomeric salt thus obtained by an appropriate method.

As a method for desolving the diastereomer salt, a conventionally known method, that is, a method of treating with an acid or an alkali in an aqueous solvent, a method of using an ion exchange resin, and the like can be applied. For example, when the diastereomeric salt is dissolved in water by adding an alkaline aqueous solution such as sodium hydroxide and then extracted with an organic solvent such as dichloromethane, the resolving agent is extracted into the organic layer. Then, after adding a mineral acid such as hydrochloric acid or sulfuric acid to the aqueous layer from which the resolving agent has been removed to adjust the pH to 1-2,
By extracting this with an organic solvent such as dichloromethane, the target optically active tetrahydrofuran carboxylic acids are extracted into the organic layer, so by concentrating and distilling the extract, or by diastereomer salt in an aqueous solvent, In a mixed solvent of water and organic solvent or in an organic solvent, sulfuric acid, hydrochloric acid, and other acids are added to demineralize the salt, and then the resolving agent is recovered by solid-liquid separation as a sulfate or hydrochloride salt, which is then used on the filtrate side. The optically active tetrahydrofuran carboxylic acids can also be easily obtained by obtaining the optically active tetrahydrofuran carboxylic acids of, followed by concentration and distillation.

Next, in the separation step of the present invention (B), the optical antipodal carboxylic acid and the optical resolving agent remaining in the organic solvent mother liquor after solid-liquid separation in the above-mentioned division step (A) are coexisted in the presence of alcohol. , A resolving agent recovery step in which the enantiomer carboxylate ester and the optical resolving agent hydrochloride are brought into contact with a chlorinating agent, and then the optical resolving agent hydrochloride is separated as crystals by solid-liquid separation.

Thionyl chloride or phosgene is used as the chlorinating agent, and the contact with the chlorinating agent is carried out in an organic solvent mother liquor. At this time, if the alcohol does not coexist in the mother liquor of the organic solvent, the alcohol may be added before the contact with the chlorinating agent. When brought into contact with a chlorinating agent in an organic solvent in the presence of alcohol, the produced carboxylic acid chloride reacts with alcohols to form a carboxylic acid ester. Since the resolving agent is precipitated as a resolving agent hydrochloride, the resolving agent can be recovered by solid-liquid separation.

The coexisting alcohol is preferably a lower alcohol, specifically methanol, ethanol, 1-propanol, 2-propanol, 1-butanol or 2-butanol. The amount is required to be 1 equivalent or more with respect to the optical antipodal carboxylic acid present in the mother liquor of the organic solvent. If the amount of the alcohol is 1 equivalent or less, the optical antipode carboxylic acid cannot be completely converted to the ester.

The amount of the chlorinating agent to be used is 1.0 equivalent or more, with respect to the optical antipodal carboxylic acid present in the mother liquor of the organic solvent or the resolving agent, whichever has the larger mole number.
When the amount is 1.0 equivalent or less, esterification of the optical antipode carboxylic acid,
Alternatively, hydrochloric acid salification of the resolving agent is insufficient, and the recovery rate of the optical antipodal carboxylic acid ester or the resolving agent hydrochloride is low. Considering economy, it is 1.0 to 3.0, preferably 1.0 to 2.0 equivalents.

Further, it is preferable that water in the organic solvent is substantially absent, but water and the like mixed in during operation such as water in the air are acceptable. When water is present, thionyl chloride or phosgene is decomposed by water, so that the amount of use increases, and the amount of generated hydrochloric acid, sulfurous acid gas, and carbon dioxide increases. Therefore,
The amount of water present is 20% by weight or less, preferably 10% by weight, based on the optical antipodal carboxylic acid present in the organic solvent mother liquor.
The following is good. When a large amount of water is contained in the resolving solvent, it may be removed by an operation such as concentration before contact with the chlorinating agent.

The temperature at which the chlorinating agent is brought into contact with the chlorinating agent in the organic solvent is not particularly limited, but is usually 0 ° C. or higher and 5
It is preferable to carry out in the range of 0 ° C or lower. When the temperature is high, hydrochloric acid, sulfurous acid gas, and carbon dioxide are rapidly generated, and side reactions may occur simultaneously.

The method of addition is arbitrary. The chlorinating agent may be added directly to the organic solvent mother liquor, or the organic solvent containing the chlorinating agent may be added dropwise.

In this way, the hydrochloride of the resolving agent precipitated by contacting the optical antipodal carboxylic acid and the resolving agent remaining in the mother liquor of the organic solvent with the chlorinating agent in the presence of alcohol is solid-liquid. By separating, it can be recovered in high yield without racemization. On the other hand, the optical antipodal carboxylic acid ester can be isolated and recovered in high yield in the filtrate. Since there is almost no resolving agent hydrochloride in this filtrate,
The optical antipodal carboxylic acid ester in the filtrate can be sent to the next racemization step as it is, or after being concentrated or distilled.

The present invention (C) is a step of racemizing the optical antipodal carboxylic acid ester in the filtrate. The racemization of the present invention can be carried out under remarkably mild conditions, and the racemate recovery rate is also high. The type of ester depends on the coexisting alcohol when the chlorinating agent is added.

Here, the optically active carboxylic acid ester and the optically active carboxylic acid in the present invention mean a carboxylic acid ester and a carboxylic acid in which one optical isomer is contained more than the other optical isomer. , Substantially means a carboxylic acid ester having an optical purity of 20% ee or more, and a carboxylic acid. The racemic carboxylic acid ester and the racemic carboxylic acid mean a carboxylic acid ester and an carboxylic acid having an optical purity of less than 20% ee.

The racemization of the present invention can be carried out in an inert solvent or without a solvent. Since it is economically industrially advantageous to have a high concentration of the optical antipodal carboxylic acid ester, a concentrated solution obtained by normally concentrating the filtrate of the optical antipodal carboxylic acid ester obtained in the salt-removing step (B), Alternatively, an optical antipodal carboxylic acid ester obtained by concentration and distillation purification is used as a raw material.

The racemization catalyst used in this step is preferably a base selected from the group consisting of alkali metal alkoxides, alkali metal hydrides and alkali metal amides. Specific examples of the base used include alkali alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium-s-butoxide, potassium-t-butoxide; sodium hydride, Examples thereof include alkali metal hydrides such as potassium hydride; alkali metal amides such as lithium amide, sodium amide, and potassium amide. The amount of the racemization catalyst used is influenced by the temperature or time of the racemization or the amount of unreacted optical antipodal carboxylic acid coexisting, but is preferably 0.01 mol% or more based on the optical antipodal carboxylic acid ester. . Further, even if it is used in a large amount, it does not have any influence on the racemization reaction, but it is not necessarily advantageous in terms of chemical costs and isolation operation. In the presence of the optical antipodal carboxylic acid, it is necessary to add more than the equivalent amount of the carboxylic acid. However, the addition of the chlorinating agent in the separation step of (B) causes esterification via the acid chloride, so that it is substantially optical. The remaining amount of the enantiomer carboxylic acid is 5% or less. Therefore, the amount of the racemization catalyst used is preferably 0.01 to 40 mol% based on the optical antipodal carboxylic acid ester in consideration of reactivity and economy.
More preferably, it is 0.01 to 20 mol%. In addition,
If water is present in the reaction system, the racemization catalyst may be deactivated, so it is preferable to take sufficient care not to mix water.

The racemization reaction proceeds at 0 ° C. or higher, but it is preferably in the range of 0 ° C. to 100 ° C. in consideration of the reaction time. A particularly preferred temperature is 0 ° C or higher and lower than 65 ° C. The time required for the racemization depends on the temperature or the kind and amount of the racemization catalyst, but it is usually completed in 0.1 to 30 hours.

After the racemization reaction, the racemic carboxylic acid ester can be recovered by a known method. For example, it can be distilled directly or after the racemization catalyst is neutralized with a hydrogen halide gas such as hydrogen chloride, and then distilled. Alternatively, if the amount of the catalyst is small, the base of the racemization catalyst may be decomposed with water, extracted with an organic solvent immiscible with water, and then distilled. When a racemic carboxylic acid is obtained, the racemic carboxylic acid ester may be hydrolyzed by a known method after the racemization reaction. For example, water is added to the racemization reaction liquid to heat it, or it is hydrolyzed by treatment with an acidic aqueous acid solution of a mineral acid such as hydrochloric acid or sulfuric acid, or an alkaline aqueous solution such as sodium hydroxide. Then, it is made into an acidic solution and then directly extracted with an organic solvent immiscible with water. If necessary, concentrate and then extract. In addition, the racemic carboxylic acid can be easily recovered by directly or directly distilling the concentrated solution obtained by filtering out the inorganic salt formed by neutralization, if necessary.

The racemic carboxylic acid thus obtained can be recycled as a starting material for optical resolution in the recycling step (E) of the present invention.

The hydrochloride salt of the optical resolving agent recovered in a high yield in the step (B) is liberated in the step (D) to be a free optical resolving agent. The hydrochloride of the optical resolving agent becomes a free optical resolving agent upon contact with a base in an organic solvent, and is recycled from the step (E) to the optical resolving step (A).

The base used in this step includes alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide, and sodium methoxide. ,
Sodium ethoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium-s
Alkali metal alkoxides such as -butoxide and potassium t-butoxide, and organic amines such as ammonia and methylamine can be used. These bases are gases,
It can be used in the form of a solid such as powder or a liquid dissolved in a solvent.

Any organic solvent may be used as long as it dissolves a free optical resolving agent and precipitates a neutralized chloride formed by the addition of a base. Specifically, methanol, ethanol, 1 -Alcohols such as propanol, 2-propanol, 1-butanol, 2-butanol, acetonitrile, tetrahydrofuran, 1,4
-Dioxane, 1,3-dioxolane, ethyl acetate, chloroform, toluene, chlorobenzene, or a mixed solvent thereof can be used. There is no problem even if a small amount of water is present, but if it is too large, the neutralized chloride tends to dissolve, which is not preferable. Therefore, the water ratio in the solvent after addition of the base is preferably 25% or less. Alternatively, a free optical resolving agent may be dissolved in an organic solvent immiscible with water, and the neutralized chloride may be extracted with water. This method can be applied to water-insoluble resolving agents.

The liberation of the recovered optical resolving agent hydrochloride is carried out as follows. That is, the hydrochloride of the optical resolving agent may be suspended or dissolved in an organic solvent, and the base may be added at a rate corresponding to the neutralization rate of the hydrochloride. If the addition rate is too fast, the partial resolving agent is likely to be hydrolyzed. Chloride will precipitate when the base is added, and this is removed by solid-liquid separation. Alternatively, the mixture is extracted with water, the layers are separated, and the aqueous layer is removed. Then, a free optical resolving agent is obtained in the organic solvent layer. The organic solvent layer is recycled to the step (E) of the present invention together with the racemic carboxylic acid.

Thus, in the recycling step (E), the optical resolution is carried out by adjusting the concentration, the solvent composition, the molar ratio of the optical resolving agent and the racemic carboxylic acid so as to meet the conditions of the optical resolving step (A).

The adjusting method is arbitrary. After the racemic carboxylic acid is added to the organic solvent layer containing the free optical resolving agent, it is concentrated to a predetermined concentration or the solvent is added to perform optical resolution. Moreover, after concentrating the organic solvent layer containing the free optical resolving agent to a predetermined concentration, racemic carboxylic acid may be added, or solid-liquid separation is performed by changing to a solvent composition in which the free optical resolving agent precipitates. It may be adjusted by adding a racemic carboxylic acid and a solvent after separating as a cake.

As described above, (A) the dividing step, (B) the separating step, (C) the racemizing step, (D).
By theoretically performing the step of liberating the optical resolving agent and the step of adjusting the recycled salt (E), theoretically all the racemic carboxylic acid can be converted into the optically active carboxylic acid. Moreover, since the optical resolving agent can be recovered in high yield without racemization, it can be recycled many times.

[0048]

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 of tetrahydrofuran-2-carboxylic acid contained in the diastereomeric salts obtained in the examples was determined by the following method. To 300 mg of diastereomeric salt crystals, 5 m of 10% hydrochloric acid methanol solution
After adding 1 and stirring for 30 minutes, excess hydrochloric acid, methanol and water were removed by an evaporator. Cyclohexane (1.5 ml) was added and the insoluble material was filtered. Then
After the cyclohexane layer was dried over anhydrous magnesium sulfate, 5 μl was injected into HPLC for analysis using the supernatant as a sample solution.

Further, the tetrahydrofuran-2-of the example
The optical purity of the carboxylic acid ester is 70-80.
mg to n-hexane / isopropanol = 995/5
(V / v) 0.8 ml was dissolved to form a sample solution, and in the case of racemization, a part of the racemization reaction liquid was sampled, water was added to deactivate the base, and then the ester was extracted with dichloromethane. The dichloromethane layer was dried over magnesium sulfate, and then 1-2 μl was injected into HPLC for analysis. The column used for analysis is CHIRALC
EL OD (manufactured by Daicel), mobile phase is n-hexane / 2
-Propanol = 995/5 (v / v) was used. UV detection at a column temperature of 25 ° C and a flow rate of 1.5 ml / min
(220 nm). Tetrahydrofuran-2-carboxylic acid methyl ester has S-form of 9.5 minutes and R-form of 1
7.4 minutes, the S-form of tetrahydrofuran-2-carboxylic acid butyl ester was detected at 8.0 minutes, and the R-form was detected at 13.4 minutes.

Example 1 (A) Optical Resolution Step <First Crystallization> (RS) -Tetrahydrofuran-2-carboxylic acid ((RS) -tetrahydrofuran-2-carboxylic acid is abbreviated as "RS-THFC" hereinafter. .) 92.9
g (0.80 mol) and D-alanine anilide 83.7 g
(0.51 mol) and 1-butanol (400 ml) were placed in a 4-neck 1 L flask equipped with a thermometer, a condenser and a stirrer, and heated to 65 ° C. After stirring at 65 ° C for 1 hour, the mixture was cooled to 15 ° C over 4 hours. After stirring at 15 ° C. for 2 hours, the precipitate was filtered and dried under reduced pressure at 50 ° C. to obtain 80.2 g of white crystalline diastereomeric salt. The optical purity of R-THFC in the crystal is 91.5% ee,
The yield based on R-THFC was 71.5%.

<Second Crystallization> 1-Butanol 80 was added to this salt.
It melt | dissolved by heating at 82 degreeC using 0 ml. 1 over 4 hours
Cooled to 5 ° C. After stirring at 15 ° C. for 2 hours, the precipitate was filtered to obtain 73.3 g of white wet crystals (dry crystals 6).
8.9 g) was obtained. The optical purity of R-THFC in the crystals was 99.1% ee.

<Isolation / Purification> The above R-THFC.D-
68.0 g (0.243 mol, optical purity 99.1% ee) of alanine anilide salt, 217.6 g of toluene and 54.4 g of tetrahydrofuran were added to a thermometer, a condenser,
A four-neck 500 ml flask equipped with a stirrer and a gas blowing port was charged, and 9.7 g of hydrogen chloride was added to this slurry liquid.
(0.267 mol) was blown in at 25 to 35 ° C or lower, and the mixture was stirred at room temperature for 2 hours. After the excess hydrogen chloride was removed under a slight reduced pressure, the precipitated D-alanine anilide hydrochloride was centrifuged to obtain 95.6 g of wet cake. The recovery rate of D-alanine anilide was 98%. The filtrate was concentrated and then distilled under reduced pressure to obtain R-THFC (boiling point 107 ° C./0.8
kPa) 24.9 g was obtained. The chemical purity was 99.5% and the optical purity was 99.1% ee.

(B) Desalting Step The mother liquor of the first crystallization was charged into a 4-neck 500 ml flask equipped with a thermometer, a condenser, a stirrer and a dropping funnel.
The mixture was concentrated to 2.4 g under reduced pressure, and 220 g of toluene was added. From the upper part of the condenser, while removing hydrochloric acid gas and sulfurous acid gas generated by slight decompression, thionyl chloride 67.2
g was added dropwise at 20 to 30 ° C. over 2 hours. As it is 2
After stirring for an hour, the mixture was concentrated under reduced pressure to obtain 300 g of a slurry liquid. After further stirring at 20 ° C. for 1 hour, the precipitated D-alanine anilide hydrochloride (dry 43.5 g) was subjected to solid-liquid separation. The recovery rate of D-alanine anilide was 95%.

(C) Racemization step (B) The filtrate obtained in the desalting step is concentrated under reduced pressure and distilled to obtain S.
-THFC Butyl ester 74-75 ° C / 0.3kPa
A distillate of 82.7 g was obtained. The optical purity was 51% ee. 76.0 g of this ester and 1.0 g of sodium methoxide were charged into a 4-neck 500 ml flask equipped with a thermometer, a condenser, a stirrer and a dropping funnel, and stirred at 35 ° C. for 4 hours under a nitrogen stream to complete racemization. . 2-
While adding 80 g of propanol and 20 g of water and stirring,
37.6 g of 48% aqueous sodium hydroxide solution was slowly added dropwise so as not to exceed 60 ° C. After stirring at 50 to 60 ° C for 1 hour, 23.5 g of 98% sulfuric acid was added dropwise at 40 ° C or lower. After dropping, the mixture was stirred for 1 hour, and the precipitated sodium sulfate was separated into solid and liquid. The filtrate was concentrated under reduced pressure to 65 g, 90 g of toluene was added, and the mixture was further concentrated under reduced pressure to give 58.2 g of RS-THFC solution in toluene (RS-
THFC concentration 87%) was obtained.

(D) Optical resolving agent liberating step (A) Optical resolving step (isolation / purification) and D-alanine anilide hydrochloride (dry91.
4 g, 0.451 mol), and 1-butanol 600
4L 1g equipped with a thermometer, condenser and stirrer
A flask was charged, and 24.4 g of sodium methoxide was added at 20 to 30 ° C. in 4 portions. After the addition, the mixture was stirred for 4 hours, and 25.7 g of precipitated sodium chloride was solid-liquid separated. The D-alanine anilide concentration of the filtrate was 10.7%.

(E) Recycle salt preparation step (D) Toluene solution 58.2 of RS-THFC obtained in the resolving step and (C) racemization step
g (RS-THFC concentration 87%) was charged into a 4-neck 1 L flask equipped with a thermometer, a condenser, and a stirrer, and 1-butanol was distilled off under reduced pressure to obtain 415 g of a concentrated liquid.
While stirring, add 31.5 g of new RS-THFC to 50 g.
The mixture was added dropwise at ˜65 ° C., stirred at 65 ° C. for 1 hour, and then cooled to 15 ° C. over 4 hours. After stirring at 15 ° C. for 2 hours, the precipitate was filtered and dried under reduced pressure at 50 ° C. to obtain 69.5 g of diastereomer salt as white crystals. R-TH in crystals
The optical purity of FC is 90.1% ee, R-THFC
The yield was 70.0%.

Example 2 (A) Optical Resolution Step RS-THFC 58.1 g (0.500 mol), L-phenylalanine amide 82.2 g (0.500 mol) and methanol 75.5 g were thermometered, and a condenser, Charge to a 4-neck 500 ml flask equipped with a stirrer, 60 to 6
After stirring at 4 ° C for 1 hour, the mixture was cooled to 10 ° C over 4 hours. After stirring at the same temperature for 2 hours, the precipitated crystals were filtered off to obtain 55.8 g of white crystals. R-THFC in crystals
Has an optical purity of 89.1% ee and is charged with R-THFC
The yield was 79.6%.

(B) Desalting step The mother liquor optically resolved in the step (A) was charged into a 4-neck 500 ml flask equipped with a thermometer, a condenser, a stirrer and a dropping funnel, and concentrated under reduced pressure to distill 37 g of methanol. . Toluene (200 g) was added and thionyl chloride (37.9 g) was added dropwise from the upper part of the condenser at 25 to 35 ° C. over 1 hour while removing hydrochloric acid gas and sulfurous acid gas generated by slight depressurization. After stirring for 2 hours as it was, it was concentrated under reduced pressure to obtain 216 g of a slurry liquid. 200 more toluene
After adding g and stirring at 20 ° C. for 2 hours, the precipitated L-phenylalanine amide hydrochloride (dry 58.0 g) was subjected to solid-liquid separation. The recovery rate of L-phenylalanine amide is 94.
%Met.

(C) Racemization step (B) The filtrate obtained in the salt-removing step is concentrated under reduced pressure and distilled to obtain S.
-THFC methyl ester 61-63 ° C / 1.3kPa
A fraction of 34.0 g was obtained. The optical purity was 58% ee. 34.0 g of this ester and 0.5 g of sodium methoxide were placed in a four-neck 500 ml flask equipped with a thermometer, a condenser, a stirrer and a dropping funnel, and stirred at 30 ° C. for 4 hours under a nitrogen stream to complete racemization. . 2-
While adding 48 g of propanol and 12 g of water and stirring,
22.8 g of 48% aqueous sodium hydroxide solution was slowly added dropwise so that the temperature did not exceed 60 ° C. After stirring at 50 to 60 ° C. for 1 hour, 14.1 g of 98% sulfuric acid was added dropwise at 40 ° C. or lower. After dropping, the mixture was stirred for 1 hour, and the precipitated sodium sulfate was separated into solid and liquid. The filtrate was concentrated under reduced pressure to 40 g, 60 g of toluene was added, and the mixture was further concentrated under reduced pressure to give 34.0 g of RS-THFC solution in toluene (RS-
THFC concentration 89%) was obtained.

[0061]

【The invention's effect】

(1) In a method of diastereomer-salt resolution from a racemic carboxylic acid using an optical resolving agent, according to the present invention, the optical antipodal carboxylic acid and the optical resolving agent remaining in the mother liquor after the optical resolution are desolvated. And esterification can be carried out at the same time to isolate the enantiomer carboxylic acid ester and the optical resolving agent hydrochloride in high yield and high purity.

(2) According to the present invention, since the optical antipodal carboxylic acid ester can be racemized and hydrolyzed in a high yield under a very mild condition, a racemic carboxylic acid can be recovered in a high yield. The following optical resolution is possible by recycling the.

(3) According to the present invention, since the optical resolving agent hydrochloride recovered in high yield and high purity can be liberated quantitatively and easily, it can be recycled to the next optical resolution. It is possible.

[Brief description of drawings]

FIG. 1 is a schematic view showing a production method of the present invention.

─────────────────────────────────────────────────── ─── Continuation of the front page (58) Fields surveyed (Int.Cl. ⁷ , DB name) C07B 57/00 346 C07B 55/00 C07D 307/24 C07D 309/08

Claims (9)

(57) [Claims] 1. When producing an optically active carboxylic acid from a racemic carboxylic acid, (A) a racemic carboxylic acid and an optical resolving agent are mixed in an organic solvent and solid-liquid separation is carried out to obtain a diastere of the optically active carboxylic acid and the optical resolving agent. The step of separating the stereomeric salt as crystals, (B) the optical enantiomer carboxylic acid and the optical resolving agent remaining in the solid-liquid separated organic solvent mother liquor are brought into contact with a chlorinating agent in the presence of alcohol to give an optical compound. After making antipodal carboxylic acid ester and optical resolving agent hydrochloride,
The resolving agent recovery step of separating the optical resolving agent hydrochloride as crystals by solid-liquid separation, (C) after racemizing the optical antipodal carboxylic acid ester remaining in the mother liquor in the presence of a racemizing catalyst,
A racemization step of recovering as a racemic carboxylic acid after hydrolysis, (D) a resolving agent releasing step of recovering the optical resolving agent hydrochloride separated as crystals as a free optical resolving agent,
(E) a step of recycling the recovered racemic carboxylic acid and the optical resolving agent to the optical resolving step (A), which is a method for producing an optically active carboxylic acid. 2. The method for producing an optically active carboxylic acid according to claim 1, wherein the optically active carboxylic acid is soluble in both water and an organic solvent. 3. The process for producing an optically active carboxylic acid according to claim 1, wherein the optically active carboxylic acid is an optically active tetrahydrofuran carboxylic acid, an optically active tetrahydropyrancarboxylic acid, or a derivative thereof. 4. The method for producing an optically active carboxylic acid according to claim 1, 2 or 3, wherein the optical resolving agent is an optically active amine. 5. The method for producing an optically active carboxylic acid according to claim 4, wherein the optical resolving agent is an optically active aromatic amine or an amino acid amide derivative. 6. The method for producing an optically active carboxylic acid according to claim 1, wherein the alcohol coexisted in the resolving agent recovery step is a lower alcohol. 7. The chlorinating agent used in the step of recovering the resolving agent comprises:
It is thionyl chloride or phosgene, The manufacturing method of the optically active carboxylic acid of any one of Claims 1-6 characterized by the above-mentioned. 8. The racemization catalyst used in the racemization step comprises:
The method for producing an optically active carboxylic acid according to any one of claims 1 to 7, wherein the method is at least one selected from the group consisting of alkali metal alkoxides, alkali metal hydrides and alkali metal amides. 9. A racemization catalyst used in the racemization step,
0.01 mol% to the optical antipode carboxylic acid ester
The method for producing an optically active carboxylic acid according to any one of claims 1 to 8, wherein 40 mol% coexists and racemization is performed at a temperature of 0 ° C or higher and lower than 100 ° C.