JPH0481436B2 - - Google Patents

Description

Detailed Description of the Invention (Industrial Application Field) The present invention provides a highly purified optically active product obtained by microbial treatment of racemic 2,3-dichloro-1-propanol or 2,3-dibromo-1-propanol. The present invention relates to a method for producing highly pure optically active glycidyl ether using epichlorohydrin 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 using relatively simple operations and in high yield.

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

(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-dibumoro-1-
Step of obtaining propanol (b) Obtained S-(-)-2,3-dichloro-1-
Propanol or S-(-)-2,3-dibromo-1-propanol is treated with an alkali and
-(-)-Epichlorohydrin or R-(-)-epibromohydrin step (c) The above R-(-)-epichlorohydrin or R-
(-)-Process of reacting epibromohydrin with alcohol under an acidic catalyst to obtain R-chlorohydrin ether or R-bromohydrin ether (d) The above R-chlorohydrin ether or R-bromohydrin Step of obtaining optically active glycidyl ether by reacting an alkali with ether 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 filed in 1983.
It is described in detail in the specification of No. 147065, and 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 through the above steps (a) to (b) 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-propanol or racemic 2,3-dichloro-1-propanol.
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 racemic 2,3-dichloro-1-propanol or 2,3-dibromo-1-propanol in the medium is approximately 0.2% by volume or less. 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 immobilizing 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 Application No. 59-254607 and Japanese Patent Application No. 60-179096. ing.

The above preparative S-(-)-2,3-dichloro-1-propanol or S-(-)-2,3-dibromo-1
- Propanol is converted into optically active epichlorohydrin or epibromhydrin by reacting with an alkali such as caustic soda or caustic potash in a conventional manner, that is, R-(-)-epichlorohydrin or R-(-)-epibromhydrin. shall be.
The optically active epichlorohydrin or epibromvitrin thus obtained has high optical purity;
Usually 90% or more, especially 98% or more can be obtained.

The present invention uses such highly purified optically active epichlorohydrin or epibromohydrin, and the above (c) in which alcohol and further alkali are reacted on the optically active epichlorohydrin or epibromohydrin.
Through the steps (d) and (d), particularly highly purified optically active glycidyl ether can be obtained.

Examples of the alcohol used in the step (c) include saturated alcohols such as methyl alcohol and ethyl alcohol, unsaturated alcohols such as allyl alcohol, and aralkyl alcohols such as benzyl alcohol. The appropriate amount of alcohol to be used is 2 to 10 moles per mole of optically active epichlorohydrin or epibromohydrin. When the amount of alcohol is less than 2 moles, the optically active chlorohydrin ether or bromohydrin ether produced reacts with the optically active epichlorohydrin or epibromhydrin to give by-products, reducing the yield of the target product. Furthermore, if the alcohol amount exceeds 10 moles, the reaction efficiency decreases and economic efficiency deteriorates.

An acidic catalyst is used during the reaction. Examples of the acidic catalyst include commonly known Bronsted acids such as H ₂ SO ₄ and HF, Lewis acids, or complexes thereof, and Lewis acids or complexes thereof are particularly preferably used in the present invention.

Specific examples of Lewis acids and their complexes include boron trifluoride, ether complexes of boron trifluoride, phenol complexes of boron trifluoride, complexes of boron trifluoride and water, and boron trichloride. Aluminum, aluminum tribromide, zinc dichloride,
Examples include metal halides such as tin tetrachloride and iron trichloride. The amount of contact used is per mole of optically active epichlorohydrin or epibromohydrin.
A range of 0.0001 to 0.1 mol, preferably 0.001 to 0.05 mol is suitable. If the contact amount is less than 0.0001 mol, the catalytic effect will be poor, and if it exceeds 0.1 mol, side reactions will easily occur, which is not preferred. Further, if the catalyst amount is outside the above range, racemization of the product tends to occur, causing a decrease in the optical purity of the target product.

The reaction in step (c) is usually carried out at a reaction temperature of 0 to 80°C, preferably 20 to 60°C. If it is too low, the reaction is too slow, and if it is too high, side reactions are likely to occur, causing a decrease in yield.

The optically active chlorohydrin ether or bromohydrin ether obtained by the above reaction is epoxidized by reacting with an alkali in the next step (d). As the alkali, caustic alkali is used as in the above step (b). The appropriate amount to be used is 1 to 8 mol, preferably 1 to 2 mol, per mol of optically active epichlorohydrone or epibromohydrin. The reaction is carried out in aqueous solution,
Add an organic solvent as necessary to adjust the reaction temperature to 0 to 80°C.
The temperature is preferably 10 to 40°C.

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. A method for extracting optically active glycidyl ether from a reaction product is commonly used. Technical means can be employed.

(Effects of the Invention) The present invention utilizes D-mannitol and L-mannitol, which are conventionally known methods for obtaining optically active glycyl ether.
- Compared to the method using ascorbic acid as a starting material, the operation is relatively simple, and the target product with very high optical purity 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
was placed in a 30-capacity shear fermentor, and after heat sterilization in the usual manner, the OS-K29 strain was inoculated 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 the cultivation was completed, the microbial cells and the culture filtrate were separated using a centrifuge to obtain 540 g of viable bacterial 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 racemic 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 ), its optical purity was 99% or more.

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 1.5N aqueous sodium hydroxide solution.
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, epichlorohydrin contained in the ether layer is distilled as a fraction at 115 to 117°C.
Obtained 16.74g. (Yield 72.9%). 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 distillation residue is unreacted 2,3-dichloro-
It was 1-propanol (4.3 pr), was not racemized at all, and could be used again.

Next, this (R)-(-)-epichlorohydrin
5.00g (54.0mmol) and benzyl alcohol 14.61
g (135.1 mmol) into another reactor, and to this was added 0.20 ml (1.62 mmol) of boron trifluoride ether complex salt.
mol) at room temperature and reacted at 50°C for 18 hours with stirring to obtain a reaction mixture containing R-(-)-benzylchlorohydrin ether (1-benzyloxy-3-chloro-2-propanol). . As a result of analysis, the obtained R-(-)-benzyl chlorohydrin ether was [α] ²⁵ _D = -4.6° (C = 0.96,
CH ₃ OH).

Add 80 ml of ether, 40 ml of water and
After adding 3.24 g (81.0 mmol) of NaOH and reacting with stirring at 20° C. for 30 minutes, the organic layer was separated. The water bath was extracted with 80 ml of ether, and this and the previous organic layer were combined, washed with saturated brine (30 ml x 2), and dried over magnesium sulfate. This was converted into ether-n by silica gel chromatography (SiO ₂ 500g).
Purification using -hexane (1:1.5 volume) as a carrier gave 5.82 g (yield 65.7%) of (R)-(-)-benzyl glycidyl ether as a colorless oil. This product had [α] ²⁰ _D = -2.12° (C = 4.61, CHCl ₃ ).

In addition, benzyl glycidyl ether produced from D-mannitol as 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 (d). (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) Obtained S-(-)-2,3-dichloro-1-
Propanol or S-(-)-2,3-dibromo-1-propanol is reacted with an alkali
A step of obtaining -(-)-epichlorohydrin or R-(-)-epibromohydrin. (c) The above -(-)-epichlorohydrin or R-
A step of reacting (-)-epibromohydrin with alcohol under an acidic catalyst to obtain R-chlorohydrin ether or R-bromohydrin ether. (d) A step of reacting the R-chlorohydrin ether or R-bromohydrin ether with an alkali to obtain an optically active glycidyl ether.