JPH0353886A - Production of optically active 3-chloro-1,2-propanediol and its ester - Google Patents

Abstract

PURPOSE:To easily produce 3-chloro-1,2-propanediol and its ester having high optical purity at a low cost by mixing an enantiomer mixture of 3-chloro-1,2- propanediol with a specific compound and reacting the obtained mixture with a hydrolase. CONSTITUTION:The objective 3-chloro-1,2-propanediol and its ester having excellent optical activity and suitable for pharmaceuticals, etc., can be produced by mixing a mixture of 3-chloro-1,2-propanediol enantiomers with a compound of formula I or II (R1 is 1-18C alkyl, etc.; R2 is 1-6C alkyl, etc.), reacting the mixture with a hydrolase (preferably a lipase produced by a microorganism of genus Aspergillus, etc.) and esterifying the hydroxyl group.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a method for producing optically active 3-chloro-1,2-propanediol and its ester. Optically active 3-chloro-1,2-propanediol is an important compound as an intermediate for various pharmaceuticals, physiologically active substances, and esters thereof.

(Prior art and problems to be solved by the present invention) Conventionally,
As a method for producing optically active 3-chloro-1,2-propanediol and its ester, ■Methyl-5
Method for synthesizing from -chloro-5-deoxy α-L-arabinofuranoside (Chemistry and ind
ustry, p. 533, 15 July, 1978
), (2) Synthesis method from 1,2,5,6-diacetonyl-D-mannitol [Chem. Biol. Inter
actions, 13, 193 (197B)), ■
Method for asymmetrically hydrolyzing 3-chloro-1,2-diacyloxypropane using microorganisms or enzymes
55954], ■3-chloro-2-acyloxy-
1p-}Method of asymmetrically hydrolyzing luenesulfonyloxypropane using microorganisms or enzymes [JP-A-61-1]
No. 73787, JP-A-61-212299, JP-A-6
1-227797], ■ A method for asymmetric hydrolysis of 3chloro-2-p-toluenesulfonyloxy-1-acyloxypropane using microorganisms or enzymes [JP-A-61-1
8'9258], ■ Method for asymmetric assimilation of racemic form of 3-chloro-1,2-propanediol using microorganisms [
JP 62-122596, JP 62122597
However, ■■ cannot be called an industrial manufacturing method because the raw materials are difficult to handle and the process is complicated.
Since there are problems with the optical purity and the amount of preparation for ■■, it is difficult to establish a method to obtain optically active 3-chloro-1,2-propanediol and its ester with high optical purity by an economically superior and simple means. desired.

Furthermore, esterification of alcohols using transesterification using lipase has been actively researched recently. For example, in Oil Chemistry, 36, 55 (1987), the transesterification reaction between aliphatic primary alcohols and tri-101-butyrin by lipase was studied, and the effect of trace water during the reaction, the effect of aliphatic We are investigating the reactivity of primary alcohols and the effects of reaction temperature. Furthermore, examples of utilizing the transesterification reaction by lipase for optical resolution of alcohols include JP-A-63112998 and JP-A-64-60398, which use (R,S) alcohol and triglyceride as substrates. However, the transesterification reaction by lipase of 3-chloro-1,2-propanediol is light, N,! , there are no known examples of its use for segmentation.

(Means for Solving the Problems) As a means for obtaining optically active 3-chloro-1,2-propanediol and its ester with high optical purity by an economically superior and simple method, the present inventors have Focusing on an enzyme-based production method using inexpensive racemic 3-chloro-1,2-propanediol as a raw material, and as a result of intensive research aimed at obtaining enzymes suitable for this purpose, Aspergillus spp., Pseudomonas spp. And, lipase produced by microorganisms belonging to the genus Penicillium is 3-chloro1,2-
It was discovered that this compound has an extremely high asymmetric transesterification ability for propanediol, and the present invention was completed.

That is, the present invention provides a mixture of enantiomers of 3-chloro-1,2-propanediol having the general formula (1) R'
-COOR2 (wherein Rl and R2 are the above-mentioned meanings), or a compound represented by the general formula (II) 5CH20COR'CH-OCOR'1CH20COR'' (wherein R1 is the above-mentioned meaning) A method for producing optically active 3-chloro-1,2-propanediol and its ester, which comprises stereoselectively esterifying a hydroxyl group by reacting it with a hydrolase together with a compound represented by It provides:

In the present invention, specific examples of the acyl group represented by -COR' include acetyl, propionyl, isobutyryl, valeryl, palmitoyl, oleyl, stearoyl, and the like. Further, specific examples of the alkyl group or alkenyl group represented by R2 include a methyl group, an ethyl group, a probyl group, an isoprobyl group,
Examples include isobropenyl group, butyl group, isobutyl group, hexyl group, trichloroethyl group, and vinyl group.

The racemic form of 3-chloro6lo-1,2-propanediol used as a substrate in the present invention is preferable in terms of its price, but the mixing ratio of its enantiomers is not particularly limited; It can be applied to any mixing ratio.

The lipase that can be used in the present invention may be any lipase produced by microorganisms belonging to the genus Aspergillus, Pseudomonas, and Penicillium as long as it can achieve the purpose of the present invention, but preferred examples include: As, Aspergillus niger (Aspergillus niger)
illus niger), Pseudomonas fluorescens (Pseudomonas fluorescens)
scens), Penicillium cyclopium-
Examples include lipase derived from These lipases are
They can be obtained by culturing the microorganisms that produce them, but they can be used in the form of bacterial cell culture as is, crude enzymes,
It is not limited to purified enzymes, etc. Also, Aspergillus niger
iger) is derived from Palatase 750.
L (manufactured by Novo), Pseudomonas fluorescens
ns) is derived from Penicillium cyclopium (Lipase Pr Amano) (manufactured by Amano Pharmaceutical).
icillium cyclopium) is commercially available as Lipase G (manufactured by Amano Pharmaceutical Co., Ltd.).
You can use these.

These lipases can be used alone or in combination as necessary.

Moreover, these can also be used after being immobilized by a conventional method.

In the present invention, the ratio of 3-chloro-1,2-propanediol and the compound represented by general formula (1) or general formula (n) in the reaction solution is 1:0.6 to 1:5 ( molar ratio), preferably 1:0.9 to 1:3.

The reaction temperature varies depending on the enzyme used, but is usually 0°C to
A temperature of 60°C, preferably 4°C to 50°C is suitable.

The enzyme concentration in the reaction wave can be determined depending on the enzyme activity of each enzyme preparation when a commercially available product is used, and may be, for example, 0.1 to ]0% by weight.

The reaction can be carried out either under stirring or standing still, but is preferably carried out under stirring.

3-chloro-1,2-propanediol and general formula (1)
Alternatively, when reacting with the compound represented by general formula (II), it is not necessary to add any particular solvent, but a suitable organic solvent such as n-hexane, chloroform, etc. may be added. A small amount of water of about 2% may be added.

After the reaction is completed, the enzyme can be removed by centrifugation or filtration, and can be reused.

The optically active 3-chloro-1,2-
It can be separated into propanediol and its ester. In addition, after adding water to the reaction solution from which the enzyme has been removed, an appropriate organic solvent such as
After extraction with chloroform, etc., and using a conventional method such as distillation or column chromatography, optically active 3-chloro-1,2-propanediol is extracted from the remaining aqueous layer, and optically active 3-chloro-1 is extracted from the extracted organic solvent. , 2-propanediol ester can be purified and obtained.

The optically active 3-chloro-1,2-propanediol ester obtained in the above reaction can also be converted into optically active 3-chloro-1,2-propanediol by hydrolysis by a conventional method.

Hereinafter, the present invention will be explained with reference to examples, but the present invention is not limited by these examples.

Example 1 0.2 g of Lipase G (manufactured by Amano Pharmaceutical) was placed in a screw cap test tube with a diameter of 21 mm, and 2.0 g of the racemic form of 3-chloro-1,2-propanediol, 5.9 g of l-lyacetin, and water were added. 5
0 mg was added and shaken at 30°C for 94 hours. After the reaction was completed, gas chromatography] 0 - (column conditions: Shimadzu Thermon-3000
5%, 2 m, 140 °C), the remaining 3-chloro-1,
2-propanediol was quantitatively determined to determine the yield. Reaction solution 1
．． Take 0 ml, remove the enzyme by centrifugation, add 3 ml of water, and add 3-chloro-1,2-propanediol monoacetate, 3-chloro-1,2-propanediol diacetate-1 and 1. Liacetin and the like were extracted and removed with chloroform.

Water was distilled off from the aqueous layer, and the remaining 3-chloro-1,2-propanediol was converted to 3-chloro-1,2-propanediol dibenzoate by a conventional method, followed by high performance liquid chromatography using an optical resolution column. - (Column: Chiralce/lzOJ manufactured by Daicel Chemical Industries, Ltd. + solvent: n-hexane/2-propanol = 19:1) to determine the absolute configuration and optical purity. As a result, the yield was 68%, and the absolute configuration and optical purity of the remaining 3-chloro-1,2-propanediol were R-form 32%QQ.

Example 2 With public stopper 1. Lipase P in 0 ml Erlenmeyer flask
11 1.0 g of "Amano" (manufactured by Amano Pharmaceutical Co., Ltd.) was taken, 10 g of a racemic form of 3-chloro-1,2-propanediol, 18.4 g of isopropenyl acetate, and 250 ml of water were added, followed by shaking at 30°C for 18 hours. After the reaction was completed, the same operation as in Example 1 was carried out to determine the reaction yield and remaining 3-chloro-1,2-
As a result of determining the absolute configuration and optical purity of propanediol, the yield was 82%, and the S-form was 28% ee.

Example 3 Lipase Pr Amano in a screw cap test tube with a diameter of 21 mm+
(Manufactured by Amano Pharmaceutical) Take 0.2g of 3-chloro1,2-
1.0 g of racemic propanediol, 1.0 g of vinyl acetate.
8 g and 8 ml of chloroform were added thereto, and the mixture was shaken at 30°C for 48 hours. After the reaction was completed, the same operation as in Example 1 was performed to determine the reaction yield and the absolute configuration and optical purity of the remaining 3-chloro-1,2-propanediol. As a result, the yield was 4.
It was 9%, and the R form was 44%ee.

Example 4 Palatase1 in a screw cap test tube with a diameter of 21+nn+
Take 0.2 g of 2 750 L (manufactured by Novo) and add 3-chloro-
2.0 g of racemic 1,2-propanediol and 4.6 g of 1-vinyl acetate were added, and the mixture was shaken at 30°C for 71 hours. After the reaction was completed, the same operation as in Example 1 was carried out to determine the reaction yield and the absolute configuration and optical purity of the remaining 3-chloro 1,2-propanediol. As a result, the yield was 35%, and R
The body weight was 86%ee.

(Effects of the Invention) The method for producing optically active 3-chloro-1,2-propanediol and its ester of the present invention can be easily performed using optically active 3-chloro-1,2-propanediol and its ester.
Chloro-1,2-propanediol and optically active 3-
It makes it possible to produce esters of chloro-1,2-propanediol and is of great industrial use.

Claims (2)

[Claims] (1) A mixture of enantiomers of 3-chloro-1,2-propanediol is expressed by the general formula (I) R^1-COOR^2 (where R^1 is
Indicates a linear or branched C_1 to C_1_8 alkyl group or alkenyl group. R_2 represents a C1 to C6 alkyl group or alkenyl group, and this alkyl group or alkenyl group may be substituted with halogen)
A compound represented by general formula (II) ▲ mathematical formula,
There are chemical formulas, tables, etc. ▼ Optical activity 3 characterized by stereoselectively esterifying a hydroxyl group by reacting with a hydrolase together with a compound represented by (in the formula, R^1 has the above meaning) -Production method of chloro-1,2-propanediol and its ester (2) The hydrolase is produced by Aspergillus (Aspergillus).
llus), Pseudomonas
s) and the genus Penicilliu
m) The manufacturing method according to claim (1), which is a lipase produced by a microorganism belonging to the genus