JPH05317089A - Production of optically active 1-phenyl-1,3-propanediol and its derivative - Google Patents

Abstract

PURPOSE:To easily obtain the subject compound having high optical purity and useful as a synthetic intermediate for pharmaceuticals, etc., at a low cost by reacting an enantiomer mixture of phenylpropanediol and an acylation agent with a hydroxylase. CONSTITUTION:The objective compound can be produced by reacting an enantiomer mixture of 1-phenyl-1,3-propanediol and an acylation agent (e.g. acetic anhydride) with a hydroxylase (preferably lipase originated from Pseudomonas fluorescens, etc.), thereby stereoselectively converting the hydroxyl group into ester group. The substrate concentration in the reaction liquid is preferably 1-30% and the reaction temperature is preferably 20-50 deg.C.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing optically active 1-phenyl-1,3-propanediol and its derivatives. Optically active 1-phenyl-1,3
-Propanediol and its derivatives are important compounds as intermediates for the synthesis of pharmaceuticals and physiologically active substances such as floxetine and tomoxetine, or as starting materials for functional materials such as liquid crystal compounds.

[0002]

2. Description of the Related Art Hitherto, optically active 1-phenyl-
As a method for producing 1,3-propanediol and its derivatives, ethyl benzoylacetate is hydrogenated to give ethyl 3-phenyl-3-hydroxypropionate, which is used as Pseudomonas fluorescens (Pseudomonas fluorescens).
monas fluorescens) -derived lipase, which is stereoselectively hydrolyzed and then further reduced to obtain S-(-)-1-phenyl-1,3-propanediol (US Pat. No. 4,921,798). ).
However, the conventional methods have drawbacks in that the reaction steps are long and complicated, and that expensive reaction reagents must be used, and therefore they are not necessarily industrially superior methods.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a method for obtaining 1-phenyl-1,3-propanediol and its derivatives having high optical purity by a simple and economical means. ..

[0004]

SUMMARY OF THE INVENTION The present inventors have found that 1-phenyl- having a high optical purity is a simple and economical means.
As a result of intensive research to develop a method for producing 1,3-propanediol and its derivatives, as a result, a hydrolase was allowed to act on an enantiomeric mixture of 1-phenyl-1,3-propanediol and an acylating agent, It was found that 1-phenyl-1,3-propanediol and its derivatives with high optical purity can be obtained in high yield by converting a hydroxyl group into an ester group stereoselectively, and the present invention is based on this finding. It came to completion.

That is, the present invention relates to 1-phenyl-1,
An optically active 1-phenyl-1,3-propanediol characterized in that a hydroxyl group is stereoselectively converted into an ester group by causing a hydrolase to act on an enantiomeric mixture of 3-propanediol and an acylating agent. And a method for producing the derivative thereof.

The 1-phenyl-1,3-propanediol derivative used as the reaction substrate in the present invention may be a racemic mixture produced by a chemical synthesis method, but the enantiomeric mixing ratio is not particularly limited. Absent. As the acylating agent, carboxylic acids such as (anhydrous) acetic acid, (anhydrous) butyric acid, (anhydrous) succinic acid or carboxylic acid esters such as ethyl acetate, ethyl propionate, vinyl acetate, vinyl propionate are used.

Examples of hydrolases that can be used in the present invention include Pseudomonas spp., Candida spp. And Aspergill spp.
us), Penicillium genus, Geotrichum genus, Rhizopus genus or Bacillus genus, etc., and any lipase derived from a microorganism can be used as long as the object of the present invention can be achieved. However, a preferred example is Pseudomonas fluorescen.
s), Pseudomonas flagi,
Pseudomonas sp., Candida cylindracea,
Candida rugosa, Aspergillus niger, Penicillium camembertii, Rhizopus delemar, Rhizopus niveus and B. acillus sp. Derived lipase. These lipases are obtained by culturing microorganisms that produce them, and the enzymes shown in Table 1 are commercially available, and it is preferable to use these. Further, these lipases may be used alone or in combination as the case requires. In addition, these lipases can also be used after being immobilized by a conventional method.

[0008]

[Table 1]

The substrate concentration in the reaction solution is usually 0.1 to 5
It is 0% by weight, preferably 1 to 30%, and the enzyme concentration in the reaction solution can be determined according to the enzyme activity of the enzyme preparation to be used, but is, for example, 0.1 to 25% by weight. can do.

The reaction is an ester synthesis reaction when a carboxylic acid is used as an acylating agent, and an ester exchange reaction when a carboxylic acid ester is used. In any reaction, the acylating agent itself is used as a solvent. The reaction can be carried out as, but if necessary, the reaction may be carried out in an organic solvent. Examples of the organic solvent include toluene, hexane, benzene, dichloromethane, diethyl ether, acetone and the like, and these can be used alone or in combination.

The reaction temperature is not necessarily constant depending on the enzyme used, but is usually in the range of 10 to 60 ° C., preferably
Select between 20 and 50 ° C. The reaction may be carried out by stirring or standing.

The reaction substrate 1-phenyl-1,
Two hydroxyl groups are present in one molecule of 3-propanediol, but the number of hydroxyl groups converted into ester groups may be either one or two. The reaction stereoselectively proceeds to 1-phenyl-1,3-propanediol of R-form or S-form, and thus 1-phenyl-1,3-propanediol and its derivatives with high optical purity can be obtained by this reaction. You can

After the reaction is carried out for about 1 to 12 days, a suitable organic solvent such as ethyl acetate, n-hexane, 2-propanol, or toluene is added to the reaction solution, if necessary, to obtain the substrate and the product. By performing extraction and applying a conventional method such as distillation or column chromatography, the produced optically active 1-phenyl-1,3-propanediol and its derivative can be separated and collected. When the optically active 1-phenyl-1,3-propanediol derivative is obtained, it can be easily converted into the optically active 1-phenyl-1,3-propanediol by a conventional method such as alkali hydrolysis.

[0014]

EXAMPLES Next, the present invention will be described in more detail by way of examples.

Example 1 1 g of racemic 1-phenyl-1,3-propanediol, 1.2 ml of vinyl acetate, 0.4 g of lipase shown in Table 2 and 6 ml of n-hexane were placed in a screw cap test tube, and 3
A shaking reaction was carried out at 0 ° C. for 1 to 5 days. After completion of the reaction, high performance liquid chromatography (column: YMC YMC-Pack
SIL06, solvent: n-hexane / 2-propanol = 9 /
1, detection: UV 210 nm) 1-phenyl-1,
The amount of 3-propanediol diester produced was measured. The solvent was distilled off from the reaction solution, which was then dissolved in an eluent (n-hexane: ethyl acetate = 10: 1), which was then subjected to column chromatography packed with silica gel (Kieselgel 60 manufactured by Merck) and subjected to 1-phenyl. The -1,3-propanediol diester fraction was separated. Then, after hydrolyzing the ester group with 4N sodium hydroxide to convert it into a diol, high performance liquid chromatography using an optical resolution column (column: Daicel Chemical Industries Chiralcel O
B, solvent: n-hexane / 2-propanol = 9/1,
Detection: UV 210 nm), R-form, S-form of 1-phenyl-1,3-propanediol diester in each reaction solution
The body production ratio was determined, and the optical purity and the reaction yield were calculated. The results are shown in Table 2.

[0016]

[Table 2]

Example 2 1 g of racemic 1-phenyl-1,3-propanediol, 1.2 ml of vinyl acetate, 0.4 g of lipase shown in Table 3 and 6 ml of n-hexane were placed in a screw cap test tube, and 3
A shaking reaction was performed at 0 ° C. for 5 days. After the reaction was completed, the amount of 1-phenyl-1,3-propanediol monoester produced was measured and the same fraction was separated by the same method as in Example 1 to determine the production ratio of the R-form and S-form. , Optical purity and reaction yield were calculated. The results are shown in Table 3.

[0018]

[Table 3]

Example 3 1 g of 1-phenyl-1,3-propanediol racemate, 1.2 ml of vinyl acetate, 0.4 g of lipase shown in Table 4 and 6 ml of n-hexane were placed in a screw cap test tube, and 3
A shaking reaction was performed at 0 ° C. for 5 days. After completion of the reaction, the amount of 1-phenyl-1,3-propanediol produced was measured by the same method as in Example 1, the same fractions were separated, and the production ratio of the R isomer and S isomer was determined. Purity and reaction yield were calculated. The results are shown in Table 4.

[0020]

[Table 4]

Example 4 1 g of racemic 1-phenyl-1,3-propanediol, 5 ml of ethyl acetate, 0.5 g of lipase shown in Table 5 and 5 ml of n-hexane were placed in a screw cap test tube and the mixture was kept at 40 ° C. for 3 days. The reaction was shaken for one day. After the reaction was completed, the amount of 1-phenyl-1,3-propanediol diester produced was measured by the method described in Example 1, and the same fraction was separated.
The production ratio of the R isomer and the S isomer was determined, and the optical purity and the reaction yield were calculated. The results are shown in Table 5.

[0022]

[Table 5]

Example 5 1 g of racemic mixture of 1-phenyl-1,3-propanediol in a screw cap test tube, 10 m of acylating agent shown in Table 6
1 and 0.5 g of lipase were added, and the mixture was shaken at 40 ° C. for 3 to 12 days. After completion of the reaction, the amount of 1-phenyl-1,3-propanediol diester produced was measured by the same method as in Example 1, and the same fraction was separated.
The production ratio of the isomer and the S-isomer was determined, and the optical purity and the reaction yield were calculated. The results are shown in Table 6.

[0024]

[Table 6]

[0025]

INDUSTRIAL APPLICABILITY The production method of the present invention makes it possible to produce optically active 1-phenyl-1,3-propanediol and its derivatives by a simple and economical means. This is an extremely advantageous method.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location (C12P 41/00 C12R 1:66) (C12P 41/00 C12R 1:80) (C12P 41/00 (C12R 1: 845) (C12P 41/00 C12R 1:07) (72) Inventor Wataru Nakamatsu 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa Ajinomoto Co., Inc. Central Research Laboratory

Claims (3)

[Claims] 1. An optical system characterized in that a hydroxyl group is stereoselectively converted into an ester group by allowing a hydrolase to act on an enantiomeric mixture of 1-phenyl-1,3-propanediol and an acylating agent. Process for producing active 1-phenyl-1,3-propanediol and its derivatives. 2. The optically active 1-phenyl-1,3 according to claim 1, wherein the hydrolase is a lipase derived from a microorganism belonging to the genus Pseudomonas, Candida, Aspergillus, Penicillium, Rhizopus or Bacillus.
-Method for producing propanediol and its derivatives. 3. The method for producing optically active 1-phenyl-1,3-propanediol and its derivatives according to claim 1, wherein the acylating agent is a carboxylic acid or a carboxylic acid ester.