JP3209041B2 - Optical resolving agent and process for producing optically active tetrahydrofurancarboxylic acids using the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an industrial process for producing optically active tetrahydrofuran carboxylic acids useful as intermediates for pharmaceuticals.

[0002]

2. Description of the Related Art Hitherto, as a method for producing optically active tetrahydrofurancarboxylic acids, a method of optically resolving racemic tetrahydrofurancarboxylic acids has been known. For example, tetrahydrofuran-2-carboxylic acid is (1)
Optical resolution using brucine dihydrate as a resolving agent (C
an. J. Chem. , 61, p1383. (198
3)), (2) optically active 1- (4-halogenophenyl)
An optical resolution method using ethylamine as a resolving agent (Japanese Patent Application Laid-Open No. 1-216983) is also known.
3-Carboxylic acid is (3) a method of optical resolution using quinine as a resolving agent (J. Org. Chem., 27, p921.
(1962)).

[0003]

SUMMARY OF THE INVENTION In a method for producing an optically active tetrahydrofurancarboxylic acid from a racemic tetrahydrofurancarboxylic acid by using an optical resolving agent, the method for preparing the resolving agent used in the above (1) and (3) is described. Brucine and quinine are naturally obtained compounds, but are extremely expensive and highly toxic. The optically active 1- (4-halogenophenyl) ethylamine of the resolving agent used in (2) is asymmetrically synthesized. Alternatively, it has to be obtained by optical resolution of a racemate, and it is difficult to say that it is an industrially advantageous production method, such as being expensive, and the obtained optical purity is not sufficient. Therefore, a method for industrially producing optically active tetrahydrofurancarboxylic acids with high purity and high yield has been desired.

[0004]

The inventors of the present invention have intensively studied a method for industrially producing high-purity optically active tetrahydrofuran carboxylic acids with high yield. It has been found that this can be achieved by optical resolution using a derivative obtained by chemically modifying an active amino acid as a resolving agent.

That is, the present invention provides an optically resolving agent for an optically active tetrahydrofurancarboxylic acid comprising an optically active amino acid amide derivative, and an optically resolving agent for converting tetrahydrofurancarboxylic acid to a compound selected from optically active amino acid amide derivatives. A process for producing optically active tetrahydrofurancarboxylic acids.

Hereinafter, the configuration of the present invention will be described in detail.

The resolving agent used in the present invention is a compound selected from optically active amino acid amide derivatives.
The body and L body can be used properly according to the purpose.

That is, specific examples of the resolving agent used in the present invention include an optically active alanine derivative, an optically active phenylalanine derivative, and an optically active phenylglycine derivative.

These optically active amino acid derivatives can be easily synthesized from inexpensive amino acids, and when the resolving agent is recovered, it is decomposed or racemized at room temperature to 50 ° C. under acidic or neutral conditions. Few things.

The resolving agent of the present invention can be used for producing optically active tetrahydrofurancarboxylic acids. Here, as the tetrahydrofuran carboxylic acids, those in which one hydrogen bonded to the 2-position or 3-position carbon of tetrahydrofuran is substituted with a carboxyl group are preferably used.

In the present invention, tetrahydrofuran carboxylic acids are used as a raw material. For example, tetrahydrofuran-2-carboxylic acid used for the purpose of obtaining an optically active tetrahydrofuran-2-carboxylic acid is furan-2-carboxylic acid. Manufactured industrially by hydrogenation.

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

The optical resolution of tetrahydrofurancarboxylic acids is preferably carried out according to the following procedure and conditions.

The resolving agent selected from the optically active amino acid amide derivatives is used in a solvent in an amount of 0.4 to 1.2 equivalents, preferably 0.5 equivalent to 1 equivalent of tetrahydrofurancarboxylic acid.
Contact with ~ 1.0 equivalents to form diastereomeric salts. At this time, sodium hydroxide, potassium hydroxide, alkali metal hydroxides such as lithium hydroxide, ammonia, methylamine, ethylamine, 1-propylamine, 2-propylamine, dimethylamine, diethylamine, trimethylamine, triethylamine and the like Amines and amino alcohols such as ethanolamine may coexist. The amount of the alkali metal hydroxides, amines, amino alcohols and the like to be used is preferably 0.5 to 1.2 equivalents, more preferably 0.6 equivalents, per 1 equivalent of tetrahydrofurancarboxylic acids together with the resolving agent.
~ 1.0 equivalents are preferred.

Here, the solvent used is one which does not chemically change both the tetrahydrofurancarboxylic acid and the resolving agent in the solution and selectively precipitates one diastereomer salt. I just need. For example, water, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, alcohols such as tert-butanol, ketones such as acetone and methyl ethyl ketone, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,3
-Organic solvents such as dioxolane, ethyl acetate, chloroform, toluene, chlorobenzene and the like or a mixed solvent thereof can be used.

As a method of bringing the resolving agent into contact with the tetrahydrofurancarboxylic acids, the tetrahydrofurancarboxylic acids and the resolving agent may be added to the solvent at once, or they may be added sequentially. Further, a salt previously prepared from tetrahydrofuran carboxylic acids and a resolving agent,
It may be dissolved in the solvent. In the case where alkali metal hydroxides, amines, amino alcohols, and the like coexist, they may be added at once, or they may be added sequentially. The order in which they are added is not particularly limited.

When the solution containing the diastereomer salt thus obtained is cooled and / or concentrated, a sparingly soluble diastereomer salt precipitates out of the solution.

The temperature at which the sparingly soluble diastereomer salt is precipitated from the solution may be in the range of the freezing point to the boiling point of the solvent used, and can be appropriately selected according to the purpose. A range is preferred.

Crystals of the sparingly soluble diastereomer salt can be easily separated by ordinary solid-liquid separation methods such as filtration and centrifugation. By subjecting the crystals of the sparingly soluble diastereomer salt to a recrystallization operation, the intended high-purity diastereomer salt can be obtained.

By subjecting the diastereomer salt thus obtained to salting by an appropriate method, (R) -tetrahydrofurancarboxylic acids or (S) -tetrahydrofurancarboxylic acids and a resolving agent can be separated and collected.

As a method for desolving the diastereomer salt, a generally 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 a diastereomer salt is salted by adding an aqueous alkali solution such as sodium hydroxide in water 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 desired optically active tetrahydrofurancarboxylic acids are extracted into the organic layer, and the extract is concentrated and distilled, or the diastereomer salt is converted into an aqueous solvent, After adding an acid such as sulfuric acid or hydrochloric acid in a mixed solvent of water and an organic solvent or in an organic solvent to demineralize, the resolving agent is recovered by solid-liquid separation as sulfates and hydrochlorides, and the filtrate is recovered. The optically active tetrahydrofuran carboxylic acids can also be easily obtained by obtaining the optically active tetrahydrofuran carboxylic acids, followed by concentration and distillation.

The resolving agent used in the present invention can be recovered in a high yield in any of ordinary salting methods, and almost no racemization occurs in the recovery process. That is, since these resolving agents retain their optical activity, they can be reused for optical resolution.

[0023]

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 the tetrahydrofurancarboxylic acids contained in the diastereomeric salts obtained in the examples was determined by the following method. The crystals of the diastereomer salt were salted with 25% sulfuric acid in an amount equivalent to tetrahydrofurancarboxylic acid, then dichloromethane was added, and the mixture was stirred for 10 minutes, and then the insoluble matter was filtered. Next, the dichloromethane layer was dried over anhydrous magnesium sulfate, and then dichloromethane was distilled off to obtain crude optically active tetrahydrofurancarboxylic acids. An excess of diazomethane in diethyl ether was added to 70 to 80 mg of the optically active tetrahydrofurancarboxylic acid, and the mixture was allowed to stand for about 15 minutes to synthesize tetrahydrofurancarboxylic acid methyl ester.
The reaction solution was concentrated, and the residue was dissolved by adding 0.8 ml of n-hexane / 2-propanol = 995/5 (v / v).
The PLC was injected with 1-2 μl and analyzed. The column used for the analysis was CHIRALCEL OD (manufactured by Daicel),
The mobile phase was n-hexane / 2-propanol = 995/5
(V / v) was used. Column temperature 25 ° C, flow rate 1.5m
At 1 / min, detection was performed with UV (220 nm). S of tetrahydrofuran-2-carboxylic acid methyl ester
The body was detected at 9.5 minutes, and the R body was detected at 17.4 minutes. Tetrahydrofuran-3-carboxylic acid methyl ester was used at a flow rate of 0.5 ml / min.
Detected at 6.4 minutes.

Reference Example 1 10.0 g (0.04 L-phenylalanine ethyl ester hydrochloride) was added to 20.3 g of a 40% aqueous solution of methylamine.
35 mol) and stirred with a stirrer at room temperature for 5 hours. After the reaction, extraction was performed three times with 30 ml of chloroform. After the extract was dried over magnesium sulfate, chloroform was distilled off using an evaporator. To 7.6 g of the residue, 7 ml of chloroform was added to redissolve, and then 35 ml of cyclohexane was added and stirred, and the precipitated crystals were filtered. Drying under reduced pressure gave 5.8 g of L-phenylalanine methylamide. Melting point 68-69 ° C, chemical purity 99.5%
And the yield was 75%.

Example 1 (RS) -tetrahydrofuran-2-carboxylic acid (hereinafter, (RS) -tetrahydrofuran-2-carboxylic acid is abbreviated as "RS-THFC") 92.9 g (0.
80 mol) and 83.7 g of D-alanine anilide (0.5
1 mol) and 400 ml of 1-butanol were charged into a four-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, 4
Cooled to 15 ° C. over time. After stirring at 15 ° C. for 2 hours, the precipitate was filtered and diastereomeric salt 8 of white crystals was obtained.
0.2 g was obtained. The optical purity of R-THFC in the crystal is 9
It was 1.5% ee, and the yield based on the charged R-THFC was 71.5%.

Example 2 33.1 g of THFC with R: S = 95.9: 4.1 (0.
29 mol), 46.9 g of D-alanine anilide (0.2
9 mol) and 1-butanol (800 ml) were charged into a four-necked 1 L flask equipped with a thermometer, a condenser, and a stirrer, and dissolved by heating at 82 ° C. Cooled to 15 ° C. over 4 hours. After stirring at 15 ° C. for 2 hours, the precipitate was filtered to obtain 68.9 g of white crystals. The optical purity of R-THFC in the crystal was 99.0% ee, and the yield based on the charged R-THFC was 89.1%.

Example 3 S-THFC1.3 was placed in a 50 ml flask equipped with a condenser.
2 g (0.011 mol), L-alanine anilide 1.7
2 g (0.010 mol) and 4 ml of ethanol were added, and the mixture was heated and dissolved at about 70 ° C. and then slowly cooled. 25
After stirring at 2 ° C. for 2 hours, the precipitated crystals were separated by filtration to obtain 1.38 g of white crystals. The optical purity of S-THFC in the crystal was 75.8% ee, and the yield based on the charged S-THFC was 86.3%.

Example 4 In a 50 ml flask equipped with a condenser, RS-THFC1.
29 g (0.011 mol), 1.80 g (0.010 mol) of L-alanine benzylamide and ethanol 20
The mixture was heated and dissolved at about 70 ° C., and then slowly cooled. After stirring at 25 ° C. for 2 hours, the precipitated crystals were separated by filtration to obtain 0.97 g of white crystals. S-THFC in crystal
Has an optical purity of 94.6% ee and is charged with S-THFC
Was 59.4%.

Example 5 101.0 g (0.87 mol) of RS-THFC, 100.0 g (0.61 mol) of L-phenylalaninamide,
40.0 g of water and 161.0 g of 2-propanol were charged into a 4-neck 1-L flask equipped with a thermometer, a condenser, and a stirrer, and were heated and dissolved at 60 ° C. 20 over 6 hours
After cooling to 20 ° C. and stirring at 20 ° C. for 2 hours, the precipitate was filtered to obtain 78.7 g of a diastereomer salt as white crystals. The optical purity of R-THFC in the crystal is 92.2% ee
And the yield based on the charged R-THFC was 64.5%.

Example 6 155.0 g of THFC with R: S = 96.1: 3.9
(1.34 mol), L-phenylalaninamide 21
9.2 g (1.33 mol) and 1123.2 g of a 10% water / 2-propanol mixed solution were charged into a four-neck 2 L flask equipped with a thermometer, a condenser, and a stirrer, and 78
It melted by heating at ° C. Cooled to 20 ° C. over 5 hours. 2
After stirring at 0 ° C. for 2 hours, the precipitate was filtered to obtain 325.4 g of a diastereomer salt as white crystals. R- in the crystal
The optical purity of THFC was 99.0% ee or more. The yield based on the charged R-THFC was 90.5%.

Example 7 104.5 g (0.90 mol) of RS-THFC, 98.5 g (0.60 mol) of L-phenylalaninamide and 400 ml of 1-butanol were added to a thermometer, a condenser,
Charge into a 4-neck 1L flask equipped with a stirrer,
Heat at 0 ° C. for 30 minutes. Next, the mixture was cooled to 15 ° C. over 6 hours, and further stirred at 15 ° C. for 2 hours, and then the precipitate was filtered to obtain 96.5 g of a diastereomer salt as white crystals.
The optical purity of R-THFC in the crystal was 90.5% ee, and the yield based on the charged R-THFC was 76.5%.

Example 8 38.6 g (0.33 mol) of RS-THFC, 38.2 g (0.23 mol) of L-phenylalaninamide and 107.4 g of a 7% water / ethanol mixed solution were charged with a thermometer, a condenser and a stirrer. The mixture was charged into a provided four-necked 500 ml flask and heated and dissolved at 70 ° C. Then, the mixture was cooled to 15 ° C. over 6 hours, and further stirred at 15 ° C. for 2 hours. Then, the precipitate was filtered, and 27.5 g of a diastereomer salt of white crystals was obtained.
I got The optical purity of R-THFC in the crystal is 92.4%
ee, and the yield based on the charged R-THFC was 59.0.
%Met.

Example 9 100.0 g (0.61 mol) of L-phenylalaninamide, 15.3 g (0.26 mol) of 29% aqueous ammonia
And 24.9 g of water and 160.8 g of 2-propanol were equipped with a thermometer, a dropping funnel, a condenser and a stirrer.
Charged into a 500 ml-necked flask and RS-TH at 20 ° C
101.0 g (0.87 mol) of FC was added dropwise. After stirring at the same temperature for 15 hours, the precipitate was filtered to obtain 91.2 g of a diastereomer salt as white crystals. R-THF in the crystal
C The optical purity is 90.7% ee, and the charged R-THFC
Was 74.8%.

Example 10 In a 50 ml flask equipped with a condenser, RS-THFC1.
37 g (0.012 mol), 2.68 g (0.011 mol) of D-phenylglycine benzylamide and 9 ml of 2-propanol were added, and the mixture was heated and dissolved at about 70 ° C. and then slowly cooled. After stirring at 25 ° C. for 3 hours, the precipitated crystals were separated by filtration to obtain 1.85 g of white crystals. The optical purity of S-THFC in the white crystals was 60.9% ee, and the yield based on the charged S-THFC was 88.0%.

Example 11 In a 50 ml flask equipped with a condenser, RS-THFC1.
33 g (0.011 mol), D-phenylglycine (4
(Methoxy) anilide (2.53 g, 0.010 mol), 2-propanol (20 ml) and water (2 ml) were added.
After heating and dissolving at 0 ° C., the mixture was slowly cooled. After stirring at 25 ° C. for 3 hours, the precipitated crystals were separated by filtration and white crystals 2.5
4 g were obtained. The optical purity of S-THFC in the crystal was 58.
It was 1% ee, and the yield based on the charged RS-THFC was 59.5%.

Example 12 In a 50 ml flask equipped with a condenser, RS-THFC1.
33 g (0.011 mol), 1.64 g (0.010 mol) of D-phenylglycine methylamide and 20 ml of 2-propanol were added, and the mixture was heated and dissolved at about 70 ° C. and then slowly cooled. After stirring at 25 ° C. for 3 hours, the precipitated crystals were separated by filtration to obtain 1.67 g of white crystals. S in the crystal
-The optical purity of THFC is 60.5% ee.
-The yield based on THFC was 104.5%.

Example 13 Diastereomer salt obtained in Example 6 (including R-
The optical purity of THFC is 99.0% ee or more.
g (1.08 mol) was suspended in 180.0 g of water and 400 ml of dichloromethane, and an aqueous solution obtained by dissolving 48.0 g of sodium hydroxide in 53.3 g of water was stirred while stirring.
It was added dropwise at 1 ° C. After stirring for 20 minutes, liquid separation was performed, and 300 ml of dichloromethane was added to the raffinate aqueous layer to extract L-phenylalaninamide three times. The dichloromethane layer was concentrated to dryness to give L-phenylalanine amide 16
7.4 g were recovered.

300 ml of dichloromethane was added to the raffinate water layer, and the pH was adjusted to 1 with 169.4 g of 50% sulfuric acid while stirring. After stirring for 20 minutes, the layers were separated, and the raffinate aqueous layer was further extracted five times with 300 ml of dichloromethane. The obtained dichloromethane layers were combined, concentrated and distilled under reduced pressure to obtain an R-THFC (boiling point: 109 ° C./800 Pa).
7.1 g were obtained. The optical purity was 99.0% ee or more, and the chemical purity was 99.5%.

Example 14 68.9 g of the diastereomer salt obtained in Example 2 was treated in the same manner as in Example 13 to extract D-alanine anilide with dichloromethane. Then, the aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid, extracted with dichloromethane, concentrated and distilled to obtain 24.3 g of R-THFC having an optical purity of 99.0% ee.

Example 15 61.0 g (0.525 mol) of RS-THFC, 49.4 g (0.301 mol) of L-phenylalaninamide,
318.8 g of tetrahydrofuran and 15.0 g of water were charged into a four-neck 1 L flask equipped with a thermometer, a condenser, and a stirrer, heated under reflux for 30 minutes, and then cooled to room temperature over 3 hours. After stirring at room temperature for 1 hour, the precipitated crystals were separated by filtration to obtain 58.4 g of white crystals. R-TH in crystals
The optical purity of FC is 87.8% ee, and the charged R-TH
The yield based on FC was 79.4%. 25.0 g of this white crystal was mixed with 274.6 g of tetrahydrofuran and 1 part of water.
Recrystallization with 9.6 g of the mixed solvent gave 18.4 g. The optical purity of R-THFC in the crystal was 99.5% ee or more.

Example 16 50.4 g (0.434 mol) of RS-THFC, 49.4 g (0.301 mol) of L-phenylalaninamide and 190.9 g of methyl ethyl ketone were added to a 500 ml four-neck port equipped with a thermometer, a condenser and a stirrer. The flask was charged and heated under reflux for 30 minutes, and then cooled to room temperature over 4 hours. The mixture was stirred at room temperature for 1 hour, and the precipitated crystals were separated by filtration to obtain 42.4 g of white crystals. The optical purity of R-THFC in the crystal was 89.8% ee, and the yield based on the charged R-THFC was 69.7%. 40.0 g of this salt was recrystallized with a mixed solvent of 227.2 g of methyl ethyl ketone and 20.8 g of water to obtain 26.4 g. R-THF in the crystal
The optical purity of C was 99.5% ee.

Example 17 84.8 g (0.516 mol) of L-phenylalaninamide, 20.9 g (0.354 mol) of 1-propylamine, 79.9 g of 2-propanol and 33.2 g of water were added to a thermometer and a condenser. , 500ml with 4 ports equipped with stirrer
The flask was charged and 99.4 g of RS-THFC (0.8
56 mol) was added dropwise at 40-50 ° C. After stirring at 45 ° C for 1 hour, the mixture was cooled to 15 ° C over 4 hours. The mixture was stirred at the same temperature for 2 hours, and the precipitated crystals were separated by filtration to obtain white crystals.
6 g were obtained. The optical purity of R-THFC in the crystal is 85.
3% ee, and the yield based on the charged R-THFC was 6%.
7.2%.

Example 18 99.7 g (0.859 mol) of RS-THFC, 10.2 g (0.172 mol) of 2-propylamine, 84.0 g of 2-propanol and 21.0 g of water were added to a thermometer, a condenser and a stirrer. Was charged into a four-necked 500 ml flask equipped with D-phenylalaninamide (84.8 g, 0.51 g).
6 mol) at 45-55 ° C in 5 portions. 45 ° C
, And cooled to 15 ° C. over 4 hours. After stirring at the same temperature for 2 hours, the precipitated crystals were separated by filtration to obtain 87.3 g of white crystals. The optical purity of S-THFC in the crystal was 83.5% ee, and the yield based on the charged S-THFC was 72.5%. 85.0 g of the obtained diastereomer salt was recrystallized with a mixed solvent of 90.1 g of 2-propanol and 22.5 g of water to obtain 68.9 g.
The optical purity of S-THFC in the crystal was 99.0% ee.

Example 19 29.0 g (0.25 mol) of RS-THFC and 44.6 g (0.25 mol) of L-phenylalanine methylamide
Then, 175.0 g of tetrahydrofuran was added thereto, and the mixture was heated and dissolved at 50 ° C., and then seed crystals were added at 30 ° C. and the mixture was slowly cooled. After stirring at 15 ° C. for 2 hours, the precipitated crystals were separated by filtration to obtain 17.8 g of white crystals. The optical purity of R-THFC in the crystal was 67.9% ee. 11. this white crystal
3 g was recrystallized with 50.3 g of chlorobenzene to obtain 9.2 g.
I got The optical purity of R-THFC in the crystal is 97.7%
ee, and the yield based on the charged R-THFC was 36.2.
%Met.

Example 20 11.6 g (0.10 mol) of RS-THFC, 24.0 g (0.10 mol) of L-phenylalanine anilide, and 35.6 g of water were equipped with a thermometer, a condenser and a stirrer.
The first crystallization was carried out in a 200 ml-necked flask. The mixture was heated and melted at 50 ° C, and cooled to 20 ° C over 5 hours. After further stirring at 20 ° C. for 1 hour, the precipitate was filtered,
White crystals were obtained. The crystals were crystallized twice with 50.0 g of water to obtain 9.7 g of a diastereomer salt. RT in the crystal
The optical purity of HFC is 96.8% ee,
The yield based on HFC was 54.7%.

Example 21 53.5 g of the first crystallization mother liquor of Example 20 was evaporated.
The mixture was concentrated on a tar, and further concentrated by adding 40 ml of tetrahydrofuran. This was repeated twice to remove water by azeotropic dehydration, and then 80.0 g of tetrahydrofuran was added.
When a seed crystal was added at 30 ° C., crystals precipitated. Gradually 10
After cooling to ℃ and stirring for 1 hour at the same temperature, the precipitate was filtered to obtain 6.8 g of white crystals. S- in the crystal
The optical purity of THFC is 93.8% ee,
The yield based on THFC was 38.4%.

Example 22 9.3 g (0.08 mol) of RS-THFC, 10.2 g (0.04 mol) of L-phenylalanine benzylamide, and 14.9 g of water were added to a four-port equipped with a thermometer, a condenser, and a stirrer. It was charged in a 100 ml flask and dissolved by heating at 50 ° C. After seeding at 44 ° C., the mixture was cooled to 23 ° C. over 6 hours. The precipitate was filtered, and 7.5 g of white crystals were obtained.
I got The optical purity of R-THFC in the crystal is 89.7%
The crystal was recrystallized from 6.9 g of water with 30.6 g of water to obtain 5.5 g of a diastereomer salt. R- in the crystal
The optical purity of THFC is 98.9% ee,
The yield based on THFC was 40.3%.

Example 23 (RS) -tetrahydrofuran-3-carboxylic acid
1 g (0.096 mol), 15.8 g (0.096 mol) of L-phenylalaninamide, 1,4-dioxane 1
53.0 g was equipped with a thermometer, a condenser and a stirrer.
The mixture was charged in a 200 ml-necked flask and heated and dissolved at 50 ° C. It was cooled to room temperature over 6 hours and left at room temperature for 2 days. The precipitate was filtered to obtain 5.8 g of white crystals. 5.0 g of these crystals were recrystallized with 33.5 g of 1,4-dioxane to obtain 3.1 g of a diastereomer salt. (R) in the crystal
-The optical purity of tetrahydrofuran-3-carboxylic acid is 7
It was 9.4% ee.

Example 24 58.1 g (0.500 mol) of RS-THFC, 82.2 g (0.500 mol) of L-phenylalaninamide and 75.5 g of methanol were prepared using a thermometer, a condenser and a stirrer. Charge into a 500 ml-necked flask, 60-6
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 separated by filtration to obtain 55.8 g of white crystals. R-THFC in crystal
Has an optical purity of 89.1% ee and is charged with R-THFC
Was 79.6%.

Example 25 58.1 g (0.500 mol) of RS-THFC, 82.2 g (0.500 mol) of L-phenylalaninamide,
43.4 g of toluene and 96.7 g of methanol were measured with a thermometer.
The mixture was charged into a four-necked 500 ml flask equipped with a condenser and a stirrer, stirred at 60 to 64 ° C for 1 hour, and then cooled to 10 ° C over 4 hours. After stirring at the same temperature for 2 hours, the precipitated crystals were separated by filtration to obtain 52.5 g of white crystals. The optical purity of R-THFC in the crystal is 93.8% ee
And the yield based on the charged R-THFC was 74.9%.

Example 26 R-THFC.L-phenylalanine amide salt 60.0
g (0.214 mol, optical purity: 99.2%) and 407.8 g of acetone were charged into a four-neck 1 L flask equipped with a thermometer, a condenser, and a stirrer.
After 10.8 g (0.105 mol) of sulfuric acid was added dropwise at 25 to 26 ° C, the mixture was stirred at 50 ° C for 1.5 hours. 19.2 g of water
Was added and the mixture was cooled to room temperature and stirred for 1.5 hours. The precipitated L-phenylalanine amide sulfate monohydrate was centrifuged, dried at 50 ° C. under reduced pressure, and dried.
g was obtained. The recovery of L-phenylalaninamide is 99
%Met. The filtrate is concentrated on an evaporator and then
Vacuum distillation to R-THFC (boiling point 107 ° C / 800P
a) 21.2 g were obtained. 85% yield from charged R-THFC, 99.7% chemical purity, 99.2% optical purity
e.

[0053]

(1) The resolving agent used in the present invention can be industrially used because it is inexpensive and can be obtained in high yield from raw materials having high optical purity.

(2) The resolving agent used in the present invention can be recovered from the diastereomer salt solution in high yield, and does not substantially racemize, so that the resolving agent can be reused.

(3) The optically active tetrahydrofurancarboxylic acids obtained by the method of the present invention are also excellent in yield and optical purity.

(4) Therefore, according to the present invention, there can be provided a process for producing optically active tetrahydrofurancarboxylic acids which can be industrially practically used.

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-5-213921 (JP, A) JP-A-4-89462 (JP, A) JP-A-57-188563 (JP, A) (58) Investigation Field (Int.Cl. ⁷ , DB name) C07B 57/00 346 C07D 307/24 C07M 7:00 G01N 30/48 G01N 30/88

Claims (6)

(57) [Claims] 1. A compound represented by the following general formula (I) or general formula (II) : (Wherein R1 is i) an alkyl group having 1 to 10 carbon atoms, i
i) unsubstituted or an alkyl group having 1 to 10 carbon atoms,
Substituted with an alkoxyl group or hydroxyl group having 1 to 10 carbon atoms
Aryl group, iii) the aromatic ring is unsubstituted, or
An alkyl group having 1 to 10 carbon atoms, an alkyl group having 1 to 10 carbon atoms
An aralkyl group substituted with a lucoxyl group or a hydroxyl group
And R2 and R3 are i) hydrogen atom, ii) carbon number 1
10 alkyl groups, iii) unsubstituted or 1 carbon atom
To 10 alkyl groups, C1 to C10 alkoxy
Aryl or halogen-substituted aryl, v
i) an aromatic ring is unsubstituted or has 1 to 10 carbon atoms;
Kill group, alkoxyl group having 1 to 10 carbon atoms or halo
An aralkyl group substituted with a phenyl group;
3 may be the same or different, and R4 is
Shown are 3 to 10 cyclic alkylamine residues. )
An optical resolution agent for tetrahydrofuran carboxylic acids comprising an optically active amino acid amide derivative. 2. A tetrahydrofuran carboxylic acids, generally
Formula (I) or Formula (II) (Wherein R1 is i) an alkyl group having 1 to 10 carbon atoms, i
i) unsubstituted or an alkyl group having 1 to 10 carbon atoms,
Substituted with an alkoxyl group or hydroxyl group having 1 to 10 carbon atoms
Aryl group, iii) the aromatic ring is unsubstituted, or
An alkyl group having 1 to 10 carbon atoms, an alkyl group having 1 to 10 carbon atoms
An aralkyl group substituted with a lucoxyl group or a hydroxyl group
And R2 and R3 are i) hydrogen atom, ii) carbon number 1
10 alkyl groups, iii) unsubstituted or 1 carbon atom
To 10 alkyl groups, C1 to C10 alkoxy
Aryl or halogen-substituted aryl, v
i) the aromatic ring is unsubstituted or has 1 to 10 carbon atoms;
Kill group, alkoxyl group having 1 to 10 carbon atoms or halo
An aralkyl group substituted with a phenyl group;
3 may be the same or different, and R4 is
Shown are 3 to 10 cyclic alkylamine residues. )
A method for producing optically active tetrahydrofurancarboxylic acids, comprising optically resolving a compound selected from optically active amino acid amide derivatives to be used as a resolving agent. 3. The method according to claim 1, wherein R1 is an alkyl group having 1 to 5 carbon atoms, a phenyl group, a phenyl group substituted with an alkyl group having 1 to 4 carbon atoms or an alkoxyl group, or a benzyl group. Item 4. The method for producing an optically active tetrahydrofurancarboxylic acid according to Item 2 . (4) R2 and R3 are hydrogen, an alkyl group having 1 to 5 carbon atoms, a phenyl group, or a phenyl group substituted with an alkyl group or an alkoxyl group having 1 to 4 carbon atoms;
Claim 2 also, characterized in that or a benzyl group
Is a process for producing optically active tetrahydrofurancarboxylic acids according to 3. 5. A compound selected from optically active amino acid amide derivatives, wherein the compound is optically active alanine benzylamide, optically active alanine anilide, optically active phenylalanine amide,
Optically active phenylglycine benzylamide, optically active phenylglycine methylamide, optically active phenylglycine (4-methoxy) anilide, optically active phenylalanine methylamide, optically active phenylalanineanilide,
3. The method for producing optically active tetrahydrofurancarboxylic acids according to claim 2 , wherein the method is optically active phenylalanine benzylamide. 6. A process for producing an optically active tetrahydrofuran carboxylic acids according to claim 2, 3, 4 or 5, wherein the tetrahydrofuran carboxylic acid is tetrahydrofuran-2-carboxylic acid.