JPS62122596A - Production of (s)-3-halogeno-1,2-propanediol - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a synthetic raw material for pharmaceuticals and optically active physiologically active substance on an industrial scale at a low cost, by treating (R,S)-3-halogeno-1,2-propanediol with a specific microorganism. CONSTITUTION:A microbial strain belonging to Trichosporon genus, etc., such as Trichosporon fermentans is aerobically cultured in a medium containing carbon source, nitrogen source, etc., at 20-45 deg.C and 4.0-9.5pH for 10-96hr. The microbial cells, etc., separated from the culture liquid are added to a 0.1-10W/V% liquid of (R,S)-3-halogeno-1,2-propanediol and made to react at 15-50 deg.C and 4-10pH for 24-120hr under agitation until the residual substrate reaches about 50% of the added substrate, when the reaction is terminated. The obtained (S)-3-halogeno-1,2-propanediol is separated from the reaction liquid.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a method for producing (S)-8-halogeno-1,2-propanediol. (S)-8-halogeno-1,
2-Propanediol is a substance useful as a raw material for the synthesis of various pharmaceuticals and optically active physiologically active substances. Especially (S
) -8-Chloro-1,2-propanediol exhibits antibiotic activity against spermatozoa of various animals.
ty) is known as a substance with action [H, Jac
Kson et al., Chemical and Biol, In
(1977)
)'3Q (Conventional technology and points of interest) (S) Regarding the production method of -8-halogeno-1,2-propanediol, methyl-6
-Process for obtaining chloro-6-zooxy-α-DI' from lucopyranoside (West German Patent No. 2748858) Port
Method for obtaining 1,2,5.6-diacedone-D-mannitol by K. E. et al. (Chem.

-Biol, interactions 41,
95 (1982)) are known. However, these methods cannot be called industrial production methods because the raw materials are difficult to obtain and the steps are complicated. The manufacturing method was criticized.

(Means and effects for solving the problems) The present inventors have realized the industrial production of (S)-a-halogeno-1,2-propanediol, which was conventionally obtained by complicated reactions using expensive raw materials. As a result of intensive research aimed at
, 8) -8-halogeno-1,2-propanediol is treated with microorganisms to produce (R) -8-halogeno-
Selectively metabolize 1,2-propanediol, (S)
It was discovered that -8-halogeno-1,2-propanediol could remain, and the present invention was completed.

The vine microorganism used in the present invention is Trichosporon (
Trichosporon) Fs, Pichia (Pich
ia) genus, Corynebacterium
erium), Proteus 14, etc. For more details, please refer to Trichosporon fermentans
a) CR22264゜Pichia 7 allinosa (Pic
hia farinosa) IFO 10GB, Corynebacterium acetoacidophyllum (Coryneba
cterium acetoaci -dophilu
m) ATCO21476, Proteus morganii (
Proteus morganii) I F 081
68 etc.

The medium composition for supporting the above microorganisms is 1.
Generally, any medium in which these microorganisms can grow can be used. For example, as RAM, sugars such as glucose, sucrose, maltose, alcohols such as ethanol, glycerol, and 1,2-propanediol, 1 liter
Organic acids such as fF acid and lactic acid, or mixtures thereof; nitrogen sources such as ammonium IA acid, ammonium phosphate, urea, yeast extract, kiss extract, peptone, and other inorganic salts.

It is possible to use an appropriate mixture of ingredients used in normal culture, such as trace metals and vitamins.

The above-mentioned microorganisms may be cultured by conventional methods, such as culture medium [i
It is preferable to culture aerobically for 10 to 96 hours at a temperature of 4.0 to 9.5 and a culture width of 20 to 45°C.

(R,8)-23-halogeno-1,
2-Propanediol can be obtained by adding a substrate to the suspension of bacterial cells obtained from the culture medium or by centrifugation as described above, or by adding the substrate to the medium. There is a method in which culture and reaction are carried out simultaneously, and a method in which a substrate is added to a glazed surface of microorganisms that have been immobilized by a conventional method.The reaction temperature is 15 to 50°C, and the reaction temperature is 4. It is preferable to conduct the reaction at a range of 0.0 to 10.0 (2) m, and a buffer or the like may be used as appropriate to maintain the pIi.The substrate concentration in the reaction solution is 0.1 to 10.0 (W/V). )% is preferable, and the substrate may be added all at once at the beginning of the reaction or may be added in portions.The reaction is usually carried out with shaking or stirring, and the reaction period FJ8 varies depending on the substrate concentration, enzyme amount, and other reaction conditions. but,
Preferably, the conditions are selected to end between 24 and 120 W&. In terms of yield, it is preferable to stop the reaction by analyzing the remaining substrate by gas chromatography or the like, and stopping the reaction when the remaining substrate reaches approximately 50% of the added substrate.

(S)-8-halogeno-1 thus obtained,
In order to collect 2-propanediol from the reaction solution, a general method for collecting (R,8)-1-halogeno-1,2-propanediol can be used. For example, after removing the substance from the reaction solution by centrifugation or the like, the supernatant is concentrated excessively and extracted with a solvent such as ethyl acetate. After dehydrating the extraction solution with anhydrous sulfuric acid or the like, and removing the 14-carrying agent under reduced pressure, a syrup of (S)-8-halogeno-1,2-7''lopanediol can be obtained.Further purification can be achieved by distillation. You may.

(Example) The present invention will be specifically explained below using Examples.

Examples 1 to 4 Glucose 4% m (NH4)2HPO4 1.8%.

KH2PO40.7%, M g 804.7) i20
800p p In * Z n 804 ・7
H2060p l' m+FeSO4-7H2090p
pm, 0uSO4・5M205ppm, Δ1nsO
4・4H2010p1)m.

Mail 300pp, yeast extract 0.3%
A medium consisting of pH 7.0), 2.
I! Dispense 500 Ill/su into a Sakalo flask and add 12
It was incubated at 0°C for 20 minutes.

Each of the bacterial strains shown in Table 1 was inoculated into the above medium, and cultured with shaking for 48 cycles at 30°C to obtain 1.5 J of a culture solution. This culture solution is centrifuged to collect the bacterial cells, and after washing with water, the bacterial cells are removed.
．． 8M IJ acid gauze solution (pH 7,0) 500mj7
(mL, 5)-8-chloro-1,2
- 2.9% of propanediol was added and reacted at 80°C for 72 hours with shaking.

500 ml of the reaction solution was sterilized by centrifugation, and the supernatant was concentrated to about 50 mJ and extracted eight times with 150 mJ of ethyl acetate (450 mJ in total). The extract was dehydrated over hydrous sodium sulfate and the solvent was removed under reduced pressure to obtain a syrup.

When the specific optical rotation of each was measured, the values shown in Table 1 were obtained.

In addition, after tosylating these syrups by a conventional method, an optical isomer separation column [Chiralcel O0C column (0,4
HPLC analysis was carried out using hexane-isopropyl alcohol (95:5) OS medium (manufactured by JASCO Corporation) under the conditions of a flow rate of 1.0 mJ/min and a wavelength of 285 nm (retention: 85 min for ins body, R Body 88.5
As a result, it was confirmed that each sample contained the corresponding fs1 body.

Table 1 However, the yield is based on the added (R,8)-8-chloro-1,2
- Determined from propanediol.

Examples 5 to 8 Using the same strain as in Table 1, changing the substrate to (R,8)-8-bromo-1,2-propanediol, and otherwise performing the same operations as in Examples 1 to 4, The results shown in Table 2 were obtained.

Procedural amendment October 31, 1986

Claims (4)

[Claims] (1) Trichosporon genus, Pichia genus, Corynebacterium (C
orynebacterium), Proteus (Pr
The method is characterized in that the remaining (S)-3-halogeno-1,2-propanediol is collected by allowing a microorganism belonging to the genus (R,S)-3-halogeno-1,2-propanediol to act on the (R,S)-3-halogeno-1,2-propanediol. A method for producing optically active (S)-3-halogeno-1,2-propanediol. (2) The microorganism is Trichosporon fermentans (T.
richosporon fermentans), Pichia farinosa (Pichia farinosa)
), Corynebacterium acetoacidophyllum
dophilum), the manufacturing method according to claim 1. (3) Claim 1 or 2, wherein the (R,S)-3-halogeno-1,2-propanediol is (R,S)-3-chloro-1,2-propanediol. manufacturing method. (4) Claim 1 or 2, wherein the (R,S)-3-halogeno-1,2-propanediol is (R,S)-3-bromo-1,2-propanediol. manufacturing method.