JPH0413659A - Production of optically active 1-benzyl-3-hydroxypyrrolidine - Google Patents

Abstract

PURPOSE:To obtain the subject optically active compound, simultaneously recover a resolving agent in an ultrahigh yield and reuse the aforementioned agent by carrying out optical resolution using (RS)-1-benzyl-3-hydroxypyrrolidine with a specific optically active carboxylic acid as the resolving agent. CONSTITUTION:(RS)-1-Benzyl-3-hydroxypyrrolidine is optically resolved with an optically active carboxylic acid (e.g. p-toluenesulfonyl-D-phenylglycine) expressed by the formula (R is benzenesulfonyl, toluenesulfonyl, benzoyl or toluoyl) as a resolving agent to afford optically active 1-benzyl-3- hydroxypyrrolidine. The optically active carboxylic acid, used as the resolving agent and expressed by the formula is sparingly soluble and can be recovered from a diastereomer salt solution in an ultrahigh yield. Since the optical purity is held by the above-mentioned resolving agent, optical resolution can be carried out by reuse thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a method for producing optically active 1-benzyl-3-hydroxypyrrolidine.

Optically active 1-benzyl-3-hydroxypyrrolidine is useful as a pharmaceutical intermediate.

<Prior art> Conventionally, as a method for producing optically active 1-benzyl-3-hydroxypyrrolidine, (RS)-1-benzyl-3-hydroxypyrrolidine was prepared in acetone using optically active mandelic acid as a resolving agent. A method of optically splitting is known (Japanese Unexamined Patent Publication No. 61-267577).

<Problem to be solved by the invention> However, although the conventionally known methods are excellent as methods for producing highly pure optically active 1-benzyl-3-hydroxypyrrolidine, the resolving agent mandelic acid cannot be recovered.・Due to some racemization during recycling, there is a problem when continuously used industrially.

Means for Solving the Problems> Therefore, the present inventors conducted extensive studies with the aim of producing optically active 1-penzyl-3-hydroxypyrrolidine by an industrially practical method.

As a result, this purpose can be achieved by using the general formula
n means 0 or 1. It has been found that this can be achieved by optical resolution using a photoactive carboxylic acid shown in ) as a resolving agent.

That is, the present invention uses <R5)-1-benzyl-3-hydroxypyrrolidine with an optically active carboxylic acid represented by the general formula 2 (wherein R and n are the same as above) as a resolving agent. This is a method for producing optically active 1-benzyl-3-droxypyrrolidine, which is characterized in that optical resolution is carried out using the following method.

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

The resolving agent used in the present invention is an optically active carboxylic acid represented by the above formula (hereinafter simply referred to as "optically active carboxylic acid"), and both its D-form and L-form can be used.

In the present invention, (R8)-1- used as a raw material
Benzyl-3-hydroxypyrrolidine is not only a racemic mixture containing (R)-1-benzyl-3-hydroxypyrrolidine and (S)-1-benzyl-3-hydroxypyrrolidine, but also an optical isomer of either one. It also includes mixtures containing equal or more amounts of the same amount.

Optical resolution of (RS)-1-benzyl-3-droxypyrrolidine is carried out under the following procedure and conditions.

First, (R8)-1-benzyl-3-hydroxypyrrolidine is contacted with 0.1 to 2.1 mol, preferably 0.3 to 1.1 mol of an optically active carboxylic acid in a solvent to form a diastereoisomer. Make mar salt. At this time, hydrochloric acid, vA acid,
Mineral acids such as phosphoric acid or organic acids such as acetic acid from 0.1 to
1.0 mol, preferably 0.3 to 0.7 mol, may be present.

The solvent used here is one that dissolves 1-benzyl-3-hydroxypyrrolidine and the optically active carboxylic acid, does not chemically alter these compounds in solution, and precipitates diastereomeric salts. For example, water, methanol, ethanol,
Alcohols such as propatool, ketones such as acetone, methyl ethyl getone, methyl isobutyl getone,
Esters such as methyl acetate and ethyl acetate can be used. Further, these solvents can be used alone or as a mixed solvent.

As a method for bringing an optically active carboxylic acid into contact with (RS)-1-benzyl-3-hydroxypyrrolidine, (RS)-1-benzyl-3-hydroxypyrrolidine may be added all at once to the solvent, or sequentially. Furthermore, a salt made from (RS>-1-benzyl-3-droxypyrrolidine and a resolving agent) may be formed in advance and then dissolved in the solvent. Similarly, when acetic acid and acetic acid are present together, they may be added all at once or sequentially.

Next, the solution containing the diastereomeric salt thus obtained is cooled and/or concentrated.

Then, the B-soluble diastereomer salt crystallizes out of the solution.

The temperature at which a sparingly soluble diastereomeric salt is precipitated from a solution may range from the freezing point to the boiling point of the solvent used, and is determined as appropriate depending on the purpose, but is usually between 0°C and 1°C.
A range of 00°C is sufficient.

Crystals of poorly soluble diastereomeric salts can be easily separated by conventional solid-liquid separation methods such as 3-filtration and centrifugation.

On the other hand, it is also possible to cool and/or concentrate the remaining mother liquor from which the poorly soluble diastereomeric salts have been separated to precipitate the easily soluble diastereomeric salts, and then separate them.

Furthermore, when mineral acids and acetic acids are present, if the mother liquor is cooled and/or concentrated, mineral acid salts and acetate salts will precipitate, and these can also be separated.

By decomposing each diastereomer salt thus obtained by an appropriate method, (R)-1-benzyl-3-hydroxypyrrolidine or (S)-1-benzyl-3-
Hydroxypyrrolidine and resolving agent can be separated and collected.

Any method can be used to decompose the diastereomeric salt, and for example, a method of treating with acid or alkali in an aqueous solvent can be applied. For example, when a mineral acid such as sulfuric acid or hydrochloric acid is added to a diastereomer salt dissolved or dispersed in water, an optically active carboxylic acid that is sparingly soluble in water precipitates, and (R)-1
-benzyl-3-hydroxypyrrolidine or (S) -
The 1-benzy-3-droxypyrrolidine acid salt dissolves in water. After solid-liquid separation of the resolving agent by normal means, what about the mother liquor? IAfta crystallization yields (R)-1-benzyl-3-hydroxypyrrolidine or (S)-1-benzyl-3-hydroxypyrrolidine mineral acid salt. Furthermore, if the obtained mineral salt is added to an alkaline aqueous solution such as sodium hydroxide, extracted with an organic solvent such as toluene or chloroform, and then concentrated and distilled (R>-1-benzyl-3-hydroxypyrrolidine or ( S)-1-benzyl-3hydroxypyrrolidine is obtained.

The optically active carboxylic acid used as a resolving agent in the present invention is sparingly soluble and can be recovered from a diastereomer salt solution in an extremely high yield.

Since this resolving agent retains its optical purity, it can be reused to perform optical resolution.

<Example> Hereinafter, the present invention will be specifically explained with reference to Examples.

In the examples, the optical purity (%ec) of 1-benzyl-3-hydroxypyrrolidine was analyzed by high performance liquid chromatography (HPLC) under the following conditions after derivatizing it with 3,5-dinitrophenyl isocyanate.

Column: CHIRALCEL OD (
Transfer N: n-hexane/in-10panol/isopropylamine mixture (90:10:0.1) i Amount 2 1,0 cnl/ Low it birth detector: UV 254 ■ Retention time = R form -19,8m1nS body -23,
2m1n Example 1 (RS)-1-benzyl-3-hydroxypyrrolidine 1
7.7g (0.1 mol), p-toluenesulfonyl-D
- 30.6 t (0.1 mol) of phenylglycine and 200 ml of methyl isobutyl ketone were charged into a flask,
It was heated at about 70° C. for 30 minutes to dissolve it. This was slowly cooled to room temperature, stirred at room temperature for 60 minutes, and the precipitated crystals were separated. After drying the P crystal, it was recrystallized with methyl isobutyl ketone to obtain 14.5 g of white crystals of p-toluenesulfonyl-D-7enylglycine salt of R)-1-benzyl-3-hydroxypyrrolidine.

The crystals were suspended in 60 ml of IN aqueous sodium hydroxide solution, and (R)-1-benzyl-3-droxypyrrolidine was extracted with methyl isobutyl ketone 200 (Ql). After washing this methyl isobutyl ketone solution with water, it was concentrated and distilled. As a result, 5.2 g of pale yellow oily (R)-1-benzyl-3-hydroxypyrrolidine was obtained.
The yield was 58.8% based on the amount of benzyl-3-hydroxypyrrolidine, and the optical purity was 9 as a result of HPLC analysis.
It was 8%ee.

On the other hand, concentrated sulfuric acid was added to the extracted mother liquor to make it strongly acidic and stirred for about 1 hour.The precipitated white crystals were filtered, washed with water and dried.
．． 9 g of P-)luenesulfonyl-D-phenylglycine was not recovered (recovery rate 97%).

8.9 g of the recovered P-)luenesulfonyl-D phenylglycine, 5.2 g of (RS)-1-benzyl-3-droxypyrrolidine, and 60 g of methyl isobutyl getone.
o1 was placed in a flask and heated at about 70°C for 30 minutes to dissolve it. This was slowly cooled to room temperature, stirred at room temperature for 1 hour, and the precipitated crystals were separated. After drying these crystals, they were recrystallized from methyl isobutyl getone to produce white crystals of p-toluenesulfonyl-D-phenylglycine salt of (R)-1-benzyl-3-hydroxypyrrolidine.4. I got the OK. As a result of HPLC analysis, the optical purity of (R)-1-benzyl-3-hydroxypyrrolidine in this salt was 99%.
It was ee.

Example 2 (RS)-1-benzyl-3-hydroxypyrrolidine 1
7.7 g (0.1 mol), 31.9 g (0.1 mol) of p-toluenesulfonyl-phenylalanine and 200 ml of ethanol were placed in a flask, and the mixture was heated at about 80°C for 30 minutes.
It was dissolved by heating for 0 minutes. This was gradually cooled to room temperature and stirred at room temperature for 60 minutes, and then the precipitated crystals were separated. After drying the separate P crystal, it was recrystallized with ethanol to obtain 17.3 g of white crystals of p-toluenesulfonyl-phenylalanine salt of 5)-1-benzyl-3-hydroxypyrrolidine.

When this crystal was suspended in a mixture of 100 ml of water and 10 ml of concentrated sulfuric acid and stirred strongly at room temperature, the crystal form changed and white crystals of P-1 lyenesulfonyl-phenylalanine were precipitated. After stirring for about 1 hour, it was filtered, and the crystals were washed with water and dried to obtain 10.9 g of p-toluenesulfonyl-phenylalanine (recovery rate: 98%).Next, sodium hydroxide was added to the mother liquor and the mixture was strengthened. The mixture was made basic, and the liberated oil was extracted with chloroform, washed with water, concentrated, and distilled to obtain 6.1 g of (S)-1-benzyl-3-droxypyrrolidine as a pale yellow oil.

The yield was 68.9% based on the amount of (S)-1-benzyl-3-hydroxypyrrolidine used, and the optical purity was 98%.

Example 3 (RS)-1-benzyl-3-hydroxypyrrolidine 1
．． 8 g (10 mmol), benzoyl-D-phenylglycine 2.6+r (10 mmol) and ethanol 1
5 ml of the solution was placed in an Erlenmeyer flask and heated to about 40°C to dissolve. This was slowly cooled to room temperature, stirred for 30 minutes, and the precipitated crystals were separated from P and (S)-1-benzyl-
1.8 g of benzoyl-D-phenylglycine salt of 3-hydroxypyrrolidine was obtained. Analysis results by HPLC,
Optical purity was 55%te.

Example 4 (RS)-1-benzyl-3-hydroxypyrrolidine 1
．． The same procedure as in Example 3 was carried out using 8sr (10 mmol), p-tolutoyl-D-phenylglycine 2.7 g (10 mmol), and 20 ml of acetone.
P- of S)-1-benzyl-3-droxypyrrolidine
) 2.8 tons of luo-D-phenylglycine salt were obtained.

As a result of HPLC analysis, the optical purity of 1-benzyl-3-hydroxypyrrolidine was 52%ee.

Example 5 (RS)-1-benzyl-3-hydroxypyrrolidine 1
．． The same procedure as in Example 3 was carried out using 8 g (10 mmol) of benzenesulfonyl-phenylalanine (3.1 g <10 mmol) and 20 ml of ethyl acetate. Sulfonyl-phenylalanine salt 1.92
I got it. As a result of HPLC analysis, the optical purity of (S)-1-benzyl-3-hydroxypyrrolidine was 51%ee.
Met.

Example 6 (RS)-1-benzyl-3-droxypyrrolidine 3
．． 6 g < 20 mmol), p-toluenesulfonyl-7-enylalanine 1.6 g (5 mmol), R SO
+0.25 g (2.5 mmol) and ethanol 3
When the same operation as in Example 3 was performed using 0ml, (
P- of S)-1-benzyl-3-droxypyrrolidine
Toluenesulfonyl-phenylalanine salt 1゜6K
(yield 64%), analysis results by HPLC, (S
)-1-Benzyl-3-hydroxypyrrolidine had an optical purity of 60%ee.

Example 7 (R8)-1-benzyl-3-hydroxypyrrolidine 1
．． The same procedure as in Example 3 was carried out using 8 g (10 mmol) of p-toluenesulfonyl-7-enylalanine, 6.4 g (20 mmol) of p-toluenesulfonyl-7-enylalanine, and 30 ml of ethanol. Hydroxypyrrolidine was purified by p-1 luenes-ruphonyl to obtain 2.1 g of monophenylalanine salt (yield: 42%). As a result of HPLC analysis, the optical purity of (S)-1-benzyl-3-hydroxypyrrolidine was 67%ee.

<Effects of the Invention> According to the present invention, the resolving agent can be recovered from the diastereomer solution in an extremely high yield without racemization. A practical method for producing optically active 1-benzyl-3-hydroxypyridine can be provided. Furthermore, the method of the present invention is superior to the conventional method in terms of yield and optical purity, with no negative differences.

Claims (1)

[Claims] (RS)-1-benzyl-3-hydroxypyrrolidine is expressed by the general formula (I) ▲There are numerical formulas, chemical formulas, tables, etc.▼……(I) (In the formula, R is a benzenesulfonyl group, Representing a toluenesulfonyl group, benzoyl group or toluoyl group, and
n means 0 or 1. 1. A method for producing optically active 1-benzyl-3-hydroxypyrrolidine, which comprises optically resolving the optically active carboxylic acid shown in ) as a resolving agent.