JPH0971576A - Production of carboxylic acid or its ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To isolate carboxylic acid or its ester which is useful as an intermediate for medicines or as a starting material for liquid crystal in high purity and high yield by bringing a salt of carboxylic acid into contact with a hydrogen halide to effect salt dissolution in a substantially water-free (anhydrous) organic solvent. SOLUTION: Preferably, in an alcohol solvent or in at least one of organic solvent selected from ethers, halogenated hydrocarbons and hydrocarbons containing an alcohol, (A) a salt of carboxylic acid (a salt of tetrahydrofrancarboxylic acid or tetrahydropyranecarboxylic acid with an alkali metal ion, an alkaline earth metal ion or an organic amine) is brought into contact with (B) a hydrogen halide such as hydrogen chloride, hydrogen bromide or hydrogen iodide to dissolve the salt to give the objective carboxylic acid or its ester. The component A is preferably brought into contact with the component B at 0 deg.C-50 deg.C. The amount of the organic solvent is preferably 0.5-20 times, more preferably 1-10 times the component A in weight.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a carboxylic acid or an ester thereof by demineralizing a salt of a carboxylic acid. Carboxylic acids are useful as pharmaceutical intermediate materials, liquid crystal materials, and other synthetic materials. In the process of synthesis and purification, and in the case of an optically active carboxylic acid, carboxylic acids are in a salt state when optically resolved as a diastereomeric salt.

It is necessary that the salts of these carboxylic acids be demineralized to give free carboxylic acids. In the case of a diastereomeric salt of an optically active carboxylic acid, it is important not only to desolvate to obtain an optically active carboxylic acid, but also to recover a base used as a resolving agent.

[0003]

2. Description of the Related Art As a method for demineralizing salts of carboxylic acids,
A method of treating with an acid or an alkali in an aqueous solution, a method of using an ion-exchange resin, etc. are known. However, a carboxylic acid can be easily obtained from a salt of a carboxylic acid soluble in both water and an organic solvent with a simple operation. Is difficult to isolate.

For example, 1) a method in which an alkali metal salt of tetrahydrofuran-2-carboxylic acid is desalted using a strongly acidic cation exchange resin (Japanese Patent Laid-Open No. 4-95083), 2).
Method of demineralizing with hydrochloric acid aqueous solution (Japanese Patent Laid-Open No. 1248/1990)
81), and 3) optically active tetrahydrofuran-2.
A method is known in which a salt of a carboxylic acid and optically active 1- (4-chlorophenyl) ethylamine is demineralized using an aqueous sodium hydroxide solution (JP-A 1-216983).

[0005]

Usually, it is necessary to dissociate salts of carboxylic acids and then to isolate the free carboxylic acids with high purity and high yield. For that purpose, the released carboxylic acids must be isolated by extraction with water or an organic solvent.

However, when a salt of a carboxylic acid which is well soluble in both water and an organic solvent is desalted, it is very difficult to extract and isolate the carboxylic acid if the salt is dissolved in an aqueous solution.

[0007] For example, the salt that has been demineralized by the method 1) above is isolated as an aqueous solution, but the concentration of tetrahydrofuran-2-carboxylic acid in the aqueous solution is as low as 2.4%, and a huge amount of water is concentrated. I have to. In the method of 2), carboxylic acid is extracted with methyl isobutyl ketone, but tetrahydrofuran-2-carboxylic acid is easily soluble in water and its partition coefficient to methyl isobutyl ketone is low. The yield cannot be expected. Furthermore, in 3), the salted sodium carboxylate aqueous solution is acidified with hydrochloric acid and then extracted with ether.However, the organic amine salt is changed to an alkali metal salt, and ether is used because it has a low boiling point and is easily flammable. Many are not practical.

As described above, in the conventional methods, the salts of tetrahydrofuran carboxylic acids, which are carboxylic acids that are well soluble in water and organic solvents, are desalted and isolated in an aqueous solution, so that the operation is complicated and the yield is low. It was

[0009]

Therefore, the inventors of the present invention have an industrially feasible production method for demineralizing salts of carboxylic acids to isolate carboxylic acids or their esters in high yield and high purity. As a result of intensive studies, it was found that the above object can be achieved by carrying out a method of contacting hydrogen halide in an organic solvent substantially free of water, and completed the present invention. That is, the present invention is a method for producing a carboxylic acid or an ester thereof, which comprises contacting hydrogen halide in an organic solvent when a salt of the carboxylic acid is desolvated to produce a carboxylic acid or an ester thereof. Is the law.

According to the present invention, a salt of a carboxylic acid is hydrolyzed by bringing it into contact with hydrogen halide in an organic solvent, and a free carboxylic acid can be obtained in high yield and high purity. In particular, when the carboxylic acid is soluble in both water and an organic solvent, the present invention is effective because it is difficult to extract it with an organic solvent if the salt is dissolved in a system in which water is present.
In particular, when the optically active carboxylic acids are produced by the diastereomeric salt resolution method, the resolving agent can be quantitatively recovered as a neutralizing salt, and thus the resolving agent can be recycled.

[0011]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The configuration of the present invention will be described below in detail.

In the present invention, the salts of carboxylic acids used are salts of a compound having one or more carboxyl groups in one molecule with a base. Although any carboxylic acid may be used, the effect of the present invention is great when applied to those soluble in both water and organic solvents. Specifically, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, 3-chloropropionic acid, aliphatic carboxylic acids such as 2-chloropropionic acid, lactic acid, 3-hydroxybutyric acid, 4-hydroxybutyric acid,
Examples thereof include hydroxycarboxylic acids such as mandelic acid, and aliphatic heterocyclic carboxylic acids. The aliphatic heterocyclic carboxylic acids are compounds in which the aliphatic heterocyclic ring is substituted with a carboxylic acid, and may have a substituent other than the carboxylic acid. In particular, tetrahydrofuran-2-carboxylic acid, tetrahydrofuran-3-carboxylic acid and tetrahydropyran-
It is preferably applied to 2-carboxylic acid and the like. Further, each of the above-listed optically active carboxylic acids is naturally included. Bases that form salts with carboxylic acids are alkali metal ions such as sodium ions, potassium ions, and lithium ions, alkaline earth metal ions such as calcium ions, or aliphatic amines such as methylamine, ethylamine, triethylamine, and octylamine. Amines, or amines having an aromatic ring such as aniline, benzylamine, 1-phenylethylamine, 1-naphthylethylamine, and optically active compounds thereof, alanineanilide, alaninebenzylamide, phenylalanineamide, phenylalaninemethylamide, phenylalanineanilide , Phenylalanine benzylamide, phenylglycine methylamide, phenylglycine benzylamide and other amino acid amide derivatives, and optically active forms thereof.

In the present invention, a hydrogen halide is brought into contact with a salt of a carboxylic acid.

The contact with hydrogen halide is carried out in an organic solvent. By dissolving or suspending a salt of a carboxylic acid in an organic solvent such as hydrocarbons, halogenated hydrocarbons, ethers, etc. and contacting it with hydrogen halide, the base forming the salt is converted to hydrogen halide. Neutralizing salts can be made and precipitated and the carboxylic acid can be isolated in an organic solvent.
Moreover, if alcohols or organic solvents containing alcohols are used as the organic solvent, a part or all of the desolvated carboxylic acid can be isolated as an ester of the carboxylic acid. At this time, free carboxylic acids, bases and the like may be present in addition to the carboxylic acid salt.

The amount of ester produced depends on the amount of alcohol used, and the alcohol can be selected according to the desired ester. The produced ester can be isolated as a carboxylic acid ester as it is, or can be isolated as a carboxylic acid by hydrolyzing the ester.

As the hydrogen halide, one selected from hydrogen chloride, hydrogen bromide and hydrogen iodide can be used. It is effective that the amount is 1.0 equivalent mol or more with respect to the base present in the organic solvent. When the amount is 1.0 equivalent mol or less, salt dissolution is insufficient and the isolation yield of carboxylic acids becomes low. Considering economic efficiency, it is 1.0 to 3.0, preferably 1.0 to 1.8 equivalent mole.

Here, as the organic solvent used, hydrocarbons, halogenated hydrocarbons, ethers and alcohols are preferably used. Specifically, benzene, toluene, xylene, hexane, cyclohexane, chlorobenzene, chloroform, tetrahydrofuran, isopropyl ether, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2- Pentanol, 3-pentanol, octanol, benzyl alcohol, etc., or any mixed solvent thereof can be used.

The amount of the organic solvent used is preferably 0.5 to 20 times by weight, more preferably 1 to 10 times by weight, based on the carboxylic acid salt in consideration of operability and economy.

Also, a small amount of water may be present in the organic solvent. If a large amount of coexisting water is present, the neutralizing salt is likely to be dissolved, and the recovery rate of the neutralizing salt is reduced, and at the same time, the residual amount of the neutralizing salt in the organic solvent is increased and the purity of the carboxylic acid is reduced.
Although the amount of coexisting water varies depending on the solubility of the neutralized salt in water as described above, the coexisting amount of water is 100% by weight or less, preferably 70% by weight or less with respect to the carboxylic acid. However, when solid-liquid separation is performed on the neutralized salt that has precipitated after the salt is removed, it is preferable to remove water that is present in a small amount by topping in advance.

The temperature for contacting with hydrogen halide in an organic solvent is not particularly limited, but it is usually preferably in the range of 0 ° C to 50 ° C. When the temperature is high, the amount of hydrogen halide dissolved in the organic solvent is low, and the efficiency is low.

The order of addition is arbitrary. The salt of a carboxylic acid may be dissolved or suspended in an organic solvent and hydrogen halide may be added directly, or an organic solvent containing hydrogen halide may be added dropwise. Alternatively, a salt of a carboxylic acid may be added to an organic solvent containing hydrogen halide in advance.

In this way, the neutralized salt, which is the hydrogen halide salt of the base precipitated by contacting the salt of the carboxylic acid with the hydrogen halide, removes coexisting water by concentration, topping, etc., if necessary. After that, solid-liquid separation can be performed to recover in high yield. Further, when the base is an optically active resolving agent, it can be recovered without racemization, so the hydrogen halide salt of the resolving resolving agent is liberated with a base such as sodium hydroxide or sodium methoxide. After that, it is also possible to recycle to the diastereomer salt resolution step. By concentrating / distilling or concentrating / recrystallizing water isolated in an organic solvent and carboxylic acids soluble in an organic solvent, a highly pure carboxylic acid can be easily obtained in a high yield. Further, even an optically active carboxylic acid can be isolated in high yield while maintaining high optical purity.

[0023]

EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

Example 1 (R) -Tetrahydrofuran-2-carboxylic acid (hereinafter referred to as
(R) -Tetrahydrofuran-2-carboxylic acid was converted to "R-
Abbreviated as "THC".) L-phenylalanine amide salt 50.0 g (0.178 mol, optical purity 99.2%)
ee), 299.6 g of tetrahydrofuran and 11.6 of water
g was charged into a 4-neck 1 L flask equipped with a thermometer, a condenser, a stirrer, and a gas blowing port, and 6.5 g (0.179 mol) of hydrogen chloride was blown into this slurry liquid at 25 ° C. or lower, and then, as it was, for 2 hours. It was stirred. The precipitated L-phenylalanine amide hydrochloride was centrifuged and dried under reduced pressure at 50 ° C. to obtain 35.4 g of cake. The recovery rate of L-phenylalanine amide was 99%. The filtrate was concentrated with an evaporator and then distilled under reduced pressure to obtain 18.2 g of R-THFC (boiling point 107 ° C./800 Pa). Preparation R
-88% yield from THFC, 99.7% chemical purity,
The optical purity was 99.2% ee.

Example 2 R-THFC-L-phenylalanine amide salt 150.
0 g (0.535 mol, optical purity 99.2% ee), 600.0 g of toluene, thermometer, condenser, stirrer,
Charge into a 4-neck 1L flask equipped with a gas injection port,
20.6 g (0.565 mol) of hydrogen chloride was blown into this slurry liquid at 25 to 35 ° C or lower, and the mixture was stirred at room temperature for 2 hours. The precipitated L-phenylalanine amide hydrochloride was rinsed with 600 g of toluene and centrifuged, wet cake 1
72.3 g was obtained. The recovery rate of L-phenylalanine amide was 98%. R-THFC is 56.5 in the filtrate.
g were isolated. Then, concentrate and distill under reduced pressure to perform R-TH
54.2 g of FC (boiling point 97 ° C./600 Pa) was obtained. The isolated yield from the salt was 87%, and the optical purity was 99.2% ee.

Example 3 R-THFC.L-phenylalanine amide salt 50.0
g (0.178 mol, optical purity 99.2% ee), toluene 166.0 g and tetrahydrofuran 34.0 g were charged into a four-neck 500 ml flask equipped with a thermometer, a condenser, a stirrer, and a gas inlet, and this slurry liquid Hydrogen chloride (6.8 g, 0.187 mol) was blown into the flask at 25 to 35 ° C., and the mixture was stirred at room temperature for 2 hours. The precipitated L-phenylalanine amide hydrochloride was rinsed with 50 g of toluene / tetrahydrofuran (1/1) and centrifuged to obtain 66.0 g of wet cake. The recovery rate of L-phenylalanine amide was 99%. R-THFC is 2 in the filtrate
0.5 g was isolated. The isolated yield from the salt was 99%, and the optical purity was 99.2% ee.

Example 4 R-THFC.L-phenylalanine amide salt 130.
2 g (0.465 mol, optical purity 99.2% ee) and 520.2 g of tetrahydrofuran were charged into a 4-necked 1 L flask equipped with a thermometer, a condenser, a stirrer and a gas blowing port, and hydrogen chloride was added to this slurry 17. 8 g
(0.487 mol) was blown in at 15 to 25 ° C., and the mixture was stirred at room temperature for 1 hr. Excess hydrogen chloride gas was removed under reduced pressure at 30 ° C., and the precipitated L-phenylalanine amide hydrochloride was rinsed with 83 g of tetrahydrofuran and centrifuged,
196.3 g of wet cake was obtained. The recovery rate of L-phenylalanine amide was 99%. The isolated yield of R-THFC was 94%.

Example 5 8.82 g (0.063 mol, optical purity 99.4% ee) of R-THFC.sodium salt, 100.0 g of toluene
Was charged into a 4-neck 200 ml flask equipped with a thermometer, a condenser, a stirrer, and a gas blowing port, and 2.45 g (0.066 mol) of hydrogen chloride was added to the slurry liquid in an amount of 15 to 2
It was blown in at 5 ° C. and stirred at room temperature for 2 hours. When the supernatant of the solution was analyzed, it was confirmed that 98% of R-THFC was desalted.

Example 6 R-THFC / sodium salt 50.0 g (0.362 mol, optical purity 99.4% ee), toluene 160.0 g
And 40.0 g of methanol with a thermometer, a condenser,
A four-neck 500 ml flask equipped with a stirrer and a gas blowing port was charged, and 13.8 g of hydrogen chloride was added to this slurry liquid.
(0.378 mol) was blown in at 15 to 25 ° C., and the mixture was stirred at room temperature for 2 hours. When the supernatant of the solution was analyzed, 96% of R-THFC was esterified. Further, the reaction solution was concentrated to remove water, and the precipitated sodium chloride was filtered off. Then, the filtered solution was concentrated and distilled to obtain R-
THFC methyl ester 42.4 g (83 ° C./4.0 k
Pa) was obtained with an isolated yield of 90% and an optical purity of 99.3% ee.

The above R-THFC methyl ester 30.0
30.0 g of water was added to g to heat the mixture at 95 ° C. for 20 hours while distilling methanol. The reaction solution was concentrated and distilled to obtain 21.4 g of R-THFC (96 ° C./600 Pa). The yield was 80% and the optical purity was 99.3% ee.

Example 7 R-THFC.sodium salt 20.0 g (0.145 mol, optical purity 99.4% ee), chlorobenzene 50.
0 g was charged into a four-necked 300 ml flask equipped with a thermometer, a condenser, a stirrer and a dropping funnel, and 50.5 g of isopropanol containing 6.3 g (0.173 mol) of hydrogen chloride was added dropwise to this slurry at 20 to 25 ° C. Then, the mixture was stirred at room temperature for 2 hours. When the supernatant of the solution was analyzed, 92% of R-THFC was esterified.

[0032]

【The invention's effect】

(1) According to the present invention, a carboxylic acid and its ester can be isolated from a salt of a carboxylic acid with high purity and high yield, and therefore, it is industrially feasible.

(2) According to the present invention, optically active water- and organic solvent-soluble carboxylic acids and their esters are isolated from diastereomeric salts in high purity and high yield, and at the same time, they are optically active. The resolving agent can be reused because it can be recovered in high yield and does not substantially racemize.

Claims (11)

[Claims] 1. A method for producing a carboxylic acid or an ester thereof, which comprises contacting a hydrogen halide in an organic solvent when a salt of a carboxylic acid is desalted to produce a carboxylic acid or an ester thereof. . 2. The method for producing a carboxylic acid according to claim 1, wherein the contact with hydrogen halide is carried out in at least one organic solvent selected from ethers, halogenated hydrocarbons and hydrocarbons. . 3. The method according to claim 1, wherein the contact with hydrogen halide is performed in an alcohol solvent or in at least one organic solvent selected from ethers containing alcohols, halogenated hydrocarbons, and hydrocarbons. A method for producing a carboxylic acid ester, comprising: 4. A method for producing carboxylic acids, which comprises hydrolyzing the carboxylic acid esters obtained in claim 3. 5. The method for producing a carboxylic acid or an ester thereof according to claim 1, which is brought into contact with hydrogen halide in an organic solvent at 0 ° C. or higher and 50 ° C. or lower. 6. The method for producing a carboxylic acid or its ester according to any one of claims 1 to 5, wherein the carboxylic acid is soluble in water and an organic solvent. 7. The solubility of carboxylic acids in water is 25 ° C.
And 10 g / 100 g or more, and the solubility in an organic solvent in which carboxylic acids are contacted with hydrogen halide therein is 25 ° C., 5 g / 100 g or more. A method for producing an acid or an ester thereof. 8. The method for producing a carboxylic acid or an ester thereof according to any one of claims 1 to 7, wherein the carboxylic acid salt is a diastereomeric salt of an optically active substance. 9. The method for producing a carboxylic acid or an ester thereof according to any one of claims 1 to 8, wherein the carboxylic acid is tetrahydrofuran carboxylic acid, tetrahydropyrancarboxylic acid or a derivative thereof. 10. The carboxylic acid salt is a salt of a carboxylic acid and an alkali metal ion, an alkaline earth metal ion or an organic amine.
A method for producing the carboxylic acid or its ester according to any one of 1. 11. The method for producing a carboxylic acid or an ester thereof according to claim 10, wherein the organic amine is an amine having at least one aromatic ring.