JPH0481437B2 - - Google Patents

Description

Detailed Description of the Invention (Industrial Application Field) The present invention provides a highly purified optically active compound obtained by microbial treatment of racemic 2,3-dichloro-1-propanol or 2,3-dibumo-1-propanol. The present invention relates to a method for producing highly purified optically active glycidyl ether using epichlordrin or epibromohydrin as a raw material.

(Prior Art) Optically active glycidyl ether is an important compound as a key material in the synthesis of various useful physiologically active substances, agricultural chemicals, and even liquid crystal materials.

Conventionally, methods for producing such optically active glycidyl ether include D-mannitol, L-
A method of producing ascorbic acid, L-glutamic acid, and D-glutamic acid as starting materials is known (Takano, Ogasawara et al., "Organic Synthetic Chemistry" Vol. 40,
No. 11 (1982)). However, this method has the disadvantage that the reaction must be carried out in multiple steps, and the optical purity and yield are low, making it unsatisfactory for industrial production.

(Objective of the Invention) An object of the present invention is to provide a method for producing optically active glycidyl ether with high optical purity in a high yield through relatively simple operations.

(Structure of the Invention) The present invention is a method for producing high-purity optically active glycidyl ether, which is characterized in that it is obtained by the following steps (a) to (c).

(a) Bacteria belonging to the genus Pseudomonas or cultured cells thereof having the ability to assimilate R-(+)-2,3-dichloro-1-propanol or R-(+)-2,3-dibromo-1-propanol. S-(-)-2,3-dichloro-1-propanol or S-(-) by reacting with racemic 2,3-dichloro-1-propanol or 2,3-dibromo-1-propanol in a medium -2,3-zubromo-1-
Step of obtaining propanol (b) The above S-(-)-2,3-dichloro-1-propanol or S-(-)-2,3-dibromo-1
-R by reacting propanol with alkali-
Step (c) of obtaining (-)-epichlorhydrin or R-(-)-epibromohydrin (c) The above R-(-)-epichlorohydrin or R-
A process for obtaining optically active glycidyl ether by reacting (-)-epibromohydrin with an alcohol and an alkali in the presence of a quaternary basic salt. In the present invention, R-
(-)-Epichlorohydrin or R-(-)-epibromohydrin can be obtained by the method described in the specifications of Japanese Patent Application No. 59-254607 and Japanese Patent Application No. 60-179096 previously filed by the applicant. The obtained S-(-)-
2,3 dichloro-1-propanol or S-(-)
It is produced by treating -2,3-dibromo-1-propanol with an alkali. A series of methods for producing optically active epichlorohydrin including this alkali treatment are disclosed in the applicant's patent application No. 60-147065.
Optically active epibromohydrin can also be produced in the same manner as above.

The outline of the method for producing optically active epichlorohydrin or epibromohydrin using the above steps (a) to (c) will be explained below.

R-, a microorganism newly discovered by the applicant
Bacteria belonging to the genus Pseudomonas that have the ability to assimilate (+)-2,3-dichloro-1-propanol or R-(+)-2,3-dibromo-1-propanol (FERM P-7846 (FERM
BP-994) (hereinafter referred to as OS-K-29 strain) or its cultured cells were treated with racemic 2,3-dichloro-1-furopanol or racemic 2,3-dichloro-1-furopanol.
One enantiomer of the racemate, S-(-)-2,3-dichloro-1-, was obtained by contacting with stirring in a medium containing dibromo-1-propanol.
Propanol or S-(-)-2,3-dibromo-
1-propanol can be fractionated. The contact time of bacteria in the medium is usually 2 to 10 days, and the concentration of 2,3-dichloro-1-propanol or 2,3-dibromo-1-propanol in the ceramiform is approximately 0.2% by volume or less in the medium. good. It is advantageous to use the OS-K-29 strain of bacteria used in the present invention in an immobilized manner, and conventional methods for culturing and fixing bacteria can be used. Details of the mycological properties of the OS-K-29 strain, the above-mentioned culture method, immobilization method, culture operation conditions, etc. are described in the specifications of the above-mentioned Japanese Patent Applications No. 59-254607 and 1987-179096. There is.

The above fractionated S-(-)-2,3-dichloro-1
-Propanol or S-(-)-2,3-dibromo-1-propanol is prepared by a conventional method using an alkali such as caustic soda or caustic potash to form optically active epichlorohydrin or epiprohydrin, that is, R( -)-epichlorohydrin or R-(-)-epibromohydrin. The optically active epichlorohydrin or epibromohydrin thus obtained has a high optical purity, usually 90% or more, particularly 98% or more.

The present invention uses such highly purified optically active epichlorlinidone or epibromohydrin, and the above (c) in which alcohol and alkali are applied to it.
Through these steps, optically active glycidyl ether of particularly high purity can be obtained.

Examples of the alcohol used in the above step (c) include saturated alcohols such as methyl alcohol and ethyl alcohol, unsaturated alcohols such as allyl alcohol, benzyl alcohol, and aralkyl alcohols. The amount of alcohol used is 0.9 to 2.0 mol, preferably 0.9 to 2.0 mol, per 1 mol of optically active epichlorohydrin or epibromohydrin.
A range of 1.0 to 1.5 moles is suitable. If the alcohol amount is less than 0.9 mol, expensive optically active epichlorridrin or epibromohydrin remains as an unreacted product, which is not economical. Furthermore, if the amount of alcohol exceeds 2.0 mol, side reactions between the desired product and the alcohol will increase, causing a decrease in yield.

During the reaction, a quaternary basic salt is used as a catalyst. The quaternary basic salt has the general formula [R ₄ Y]
X (wherein R is an alkyl group, an aryl group, Y
(N, P, X represent monovalent anions), specifically tetramethylammonium chloride, benzyltriethylammonium chloride, tetrabutylammonium chloride, trioctylmethylammonium chloride, trioctylallylammonium chloride , phenyltriethylammonium chloride, tetraethylammonium bromide, triethylcyclohexyl ammonium bromide, quaternary ammonium salts such as tetrabutylammonium hydrogen sulfate, tetraethylphosphonium chloride, triphenylmethylphosphonium iodide, dimethyldicyclohexylphosphonium bromide, tetrabutylphosphonium chloride Quaternary phosphonium salts such as The amount of catalyst used is optically active epichlorohydrin or epibromohydrin 1
1 to 0.001 mole, preferably 0.1 to 0.001 mole
A range of 0.005 mol is suitable. If it is more than 1 mole, separation from the product may be hindered, and if it is less than 0.001 mole, the reaction requires high temperature and a long time, causing racemization.

The alkali used in this step is
Caustic alkalis such as caustic soda and caustic potash are suitable. The amount used is 1 to 20 mol per 1 mol of optically active epichlorohydrin or epibromohydrin.
A suitable range is preferably 1 to 10 moles. If the amount of alkali used exceeds 20 moles, side reactions will increase and cause a decrease in yield. The reaction is carried out in aqueous solution,
Add an organic solvent if necessary and adjust the reaction temperature to 0 to 50℃.
It is carried out within the range of If the reaction temperature exceeds 50°C, side reactions will increase and cause a decrease in yield.

The optically active glycidyl ether obtained by the above reaction becomes a compound with absolute configuration (R) or (S) depending on the type of alcohol used. As a method for extracting optically active glycidyl ether from the reaction product, commonly used technical means can be employed.

(Effects of the Invention) The present invention is relatively simple in operation compared to the conventionally known method of obtaining optically active glycidyl ether using D-mannitol or L-ascorbic acid as a starting material, and has a high optical purity. The desired product can be obtained in high yield. Since the product of the present invention has high optical purity, it is expected to be a key material for synthesizing other useful physiologically active substances, liquid crystal materials, agricultural chemicals, etc.

Example: Meat extract 1.0%, glucose 2.5%, polypeptone 1.0% (all of the above are volume %), pH 7.0 medium 20
The mixture was placed in a 30-capacity jar fermentor, sterilized by heat in a conventional manner, and then inoculated with OS-K-29 strain and cultured for 48 hours under the following conditions.

Temperature: 30°C PH: Initial pH: 7.0 Aeration rate: 20/min Stirring speed: 300 rpm After culturing, microbial cells and culture filtrate were separated using a centrifuge to obtain 540 g of viable cells. continue,
Suspend the viable bacterial cells in the synthetic medium shown below10.
After making up the volume, it was fixed with acrylamide in a conventional manner. The immobilized product was crushed into pieces of 0.5 to 1 mm square using a mixer and thoroughly washed with a synthetic medium.

Components of synthetic medium Ammonium sulfate 0.05% by weight Ammonium nitrate 0.05 〃 Potassium hydrogen phosphate 0.1 〃 Sodium phosphate 0.2 〃 Dibasic sodium phosphate 0.1 〃 Magnesium sulfate 0.05 〃 Iron sulfate, copper sulfate, manganese sulfate Trace amount PH Initial PH 6. 8 Next, the immobilized material prepared in this way was
Place it in a jar fermenter with a capacity of 80 ml with synthetic medium. Furthermore, 160 ml of racemate and 2,3-dichloro-1-propanol,
150 g of calcium carbonate was added and stirred under the following conditions.

Temperature: 30℃ Aeration rate: 40/min Rotation speed: 300r.pm 72 hours after the start of the reaction, the supernatant liquid and the immobilized substance are separated by filtration, and the remaining optically active 2,3-dichloro-1-propanol is extracted from this liquid by activated carbon. The residue was fractionated by column, ether extraction, and distillation under reduced pressure to obtain 88 g. The substance was identified by gas chromatography, IR, and specific optical rotation by adjusting dichloropropyl-N-phenyl carbamate using the method described in Japanese Patent Application No. 59-254607.
Comparison was made with 3-dichloro-1-propanol. As a result, this substance is S-(-)-2,3-dichloro-1
-propanol, [α] ²⁵ _D = -10.4° (C =
1.36, CH ₂ Cl ₂ ), and its optical purity was over 99%.

Next, put 40 g of this S-(-)-2,3-dichloro-1-propanol into a 300 ml Erlenmeyer flask, stir vigorously using a magnetic stirrer, and add 258 ml of 1.5 W aqueous sodium hydroxide solution to 50 ml.
It was added dropwise over a period of minutes. After the dripping is complete, stir
Continued for another 20 minutes. After this, the reaction solution is 150ml.
The mixture was thoroughly mixed with ether in a separatory funnel, and the ether layer was separated and dried over magnesium sulfate. Next, the epichlorohydrin contained in the ether layer is distilled as a fraction of 115 to 117°C.
16.74g was obtained (yield 72.9%). The obtained R-(-)-
Epichlorohydrin was found to have a purity of 98.5% or more and an optical purity of 99% or more ([α] ²⁵ _D = -34.0°; C = 1.2, methanol) by gas chromatography analysis. In addition, the residual vapor residue is unreacted 2,3-dichloro-
It was 1-propanol (4.3gr) and was not racemized at all and could be used again.

Next, this (R)-(-)-epichlorohydrin
2.00g (21.6mmol) and benzyl alcohol 2.35
ml (22.7 mmol) into another reactor, and add 290 mg of tetrabutylammonium hydrogen sulfate to this.
(0.86 mmol) and 45 wt% caustic soda 15 g (169 mmol)
mol) were mixed under cooling and stirred at the same temperature for 30 minutes, followed by further stirring at room temperature for 3 hours.

The above reaction mixture was extracted with ether (200ml x 2 times), and the ether layer was extracted with saturated saline (100ml x 4 times).
and dried over magnesium sulfate. The solvent used was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (90 g of SiO ₂ ) using ether-hexane (1:1.5 volume) as a carrier to obtain (R)-(-)-benzyl as a colorless oil. 1.48 g (yield 41.8%) of glycidyl ether was obtained. This product had [α] ²⁵ _D = -1.94° (C = 5.34, CHCl ₃ ).

In addition, benzyl glycidyl ether produced from D-mannitol described in Heterocycles, 16 , 381 (1981) is [α] _D = +1.79° (C =
5.02, _CHCl3 ).

Claims (1)

[Scope of Claims] 1. A method for producing high-purity optically active glycidyl ether, which is obtained by the following steps (a) to (c). (a) Bacteria belonging to the genus Pseudomonas or cultured cells thereof having the ability to assimilate R-(+)-2,3-dichloro-1-propanol or R-(+)-2,3-dibromo-1-propanol. S-(-)-2,3-dichloro-1-propanol or S-(-) by reacting with racemic 2,3-dichloro-1-propanol or 2,3-dibromo-1-propanol in a medium -2,3-dibromo-1-
Process of obtaining propanol. (b) The above S-(-)-2,3-dichloro-1-propanol or S-(-)-2,3-dibromo-1
-R by reacting propanol with alkali-
A step of obtaining (-)-epichlorohydrin or R-(-)-epibromohydrin. (c) The above R-(-)-epichlorohydrin or R-
A step of reacting (-)-epibromohydrin with an alcohol and an alkali in the presence of a quaternary basic salt to obtain an optically active glycidyl ether.