JPH0678789A - Process for producing optically active exo-3-allyl-endo-2-norbornanol - Google Patents

Abstract

(57) [Summary] [Object] To provide a novel method for producing exo-3-allyl-endo-2-norbornanol useful as a pharmaceutical intermediate. [Structure] General formulas 1 and 2 (wherein R is 1 carbon atom)
The alkyl groups of 5 are shown. ) A method for producing exo-3-allyl-endo-2-norbornanol, which comprises asymmetrically hydrolyzing a mixture of ester compounds represented by the formula (1) preferentially with esterase.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a process for producing an optically active exo-3-allyl-endo-2-norbornanol useful as a pharmaceutical intermediate. More specifically, an optically active exo-3-allyl- useful as an intermediate of thromboxane A2 (TXA2) receptor antagonist.
The present invention relates to a method for producing endo-2-norbornanol.

[0002]

2. Description of the Related Art A method for producing a racemic form of exo-3-allyl-endo-2-norbornanol is described in, for example, Tetrah.
edron Lett., 1897 (1980). However, the production method of the optically active substance of the present compound has hitherto been
It was unknown and required the development of an industrial manufacturing method.

[0003]

The object of the present invention is to provide an optically active exo-3-allyl-e useful as a pharmaceutical intermediate.
It is in the development of a new production method of ndo-2-norbornanol.

[0004]

That is, the present invention is based on the general formula 1 (In formula, R shows a C1-C5 alkyl group.) And General formula 2 (Wherein R represents the same meaning as described above), asymmetric hydrolysis is performed using an esterase having the ability to preferentially hydrolyze either enantiomer of the mixture of ester compounds. The present invention provides a method for producing a featured optically active exo-3-allyl-endo-2-norbornanol.

A mixture of the ester compounds represented by the general formulas 1 and 2 of the raw material is prepared by reducing exo-3-allylnorcamphor with an alkali metal hydride such as sodium borohydride or lithium aluminum hydride, and further corresponding. It can be easily produced by esterification with an acid anhydride or an acid halide.

The esterase in the present invention means an esterase in a broad sense including lipase.

The esterase-producing microorganism used in this reaction is not particularly limited as long as it is a microorganism having the ability to asymmetrically hydrolyze a mixture of ester compounds represented by the general formulas 1 and 2. Specific examples of such microorganisms include, for example, Enterobacter, Arthrobacter, Prebibacterium, Pseudomonas, Alcaligenes, Micrococcus,
Chromobacterium, Corynebacterium, Bacillus, Lactobacillus, Trichoderma, Candida, Saccharomyces, Rhodotorula, Cryptococcus, Torlopsis, Pichia, Penicillium,
Examples include microorganisms belonging to the genus Aspergillus, Rhizopus, Mucor, Aureopasidium, Actinomucor, Nocardia, Streptomyces, Hansenula, Achromobacter, and the like.

Cultivation of the above microorganisms is usually carried out by liquid culture, but in some cases solid culture may be carried out.

Some of these esterases of microbial origin are commercially available, and they may be used.

In this reaction, esterase derived from animals or plants can be used, and specific examples thereof include steapsin, pancreatin, pig liver esterase (PLE), Wheat Germ esterase and the like.

Examples of the use form of esterase used in this reaction include a purified enzyme, a crude enzyme, an enzyme-containing substance, an immobilized enzyme, a microorganism culture solution, cells, a culture filtrate and the like. Good.

The asymmetric hydrolysis reaction of the present invention is carried out by mixing a mixture of the ester compounds represented by the general formulas 1 and 2 in a buffer solution in the presence of the above esterase.

As the buffer solution, a commonly used buffer solution of an inorganic acid salt such as sodium phosphate, potassium phosphate or sodium borate, or a buffer solution of an organic acid salt such as sodium acetate or sodium citrate is used. And its pH
Is preferably pH 8 to 11 for a culture solution of an alkalophilic bacterium or an alkaline esterase, and pH 5 to 8 for a culture solution of a non-alkalophilic microorganism or an esterase that is not alkali resistant. The salt concentration of the buffer solution is usually in the range of 0.01 to 2M, preferably 0.05 to 0.5M.

The reaction temperature is usually in the range of 10 to 60 ° C, preferably 15 to 45 ° C.

In addition, in the reaction, in addition to the buffer solution, an organic solvent inert to the reaction such as toluene, chloroform, methyl isobutyl ketone and dichloromethane may be used in combination. The amount of these used is not particularly limited.

By the asymmetric decomposition reaction, only one enantiomer of the mixture of the ester compounds represented by the general formulas 3 and 4 of the raw material is preferentially hydrolyzed to give an optically active exo-3. -Allyl-endo
2-norbornanol is formed, while the other enantiomer remains as the ester compound.

After completion of the reaction, the reaction solution is extracted with an organic solvent such as toluene, ethyl acetate or methyl isobutyl ketone, the obtained organic layer is concentrated, and the residue is treated by a method such as column chromatography. Optically active e
Xo-3-allyl-endo-2-norbornanol can be obtained.

Further, the ester compound remaining after hydrolysis can be obtained at the same time by the above-mentioned operation. However, if this ester compound is hydrolyzed under ordinary conditions, the optically active exo-former previously obtained by the asymmetric hydrolysis reaction is obtained. Optically active exo-3-, which has an antipodal relationship with 3-allyl-endo-2-norbornanol
Allyl-endo-2-norbornanol can be obtained.

[0019]

Industrial Applicability According to the present invention, an optically active exo-3-allyl-endo-2-norbornanol useful as a pharmaceutical intermediate can be industrially advantageously produced.
This compound is, for example, J. Med. Chem., 31, 1847 (198
It can be suitably used as an intermediate of the TXA2 receptor antagonist described in 8).

[0020]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Production Example 1 15.0 g of (±) -exo-3-allylnorcamphor and 100 ml of ethanol were charged into a four-necked flask equipped with a stirrer, a thermometer and a condenser, and cooled to 0 ° C. 4.2 g of sodium borohydride was added to this, and it stirred at 0-5 degreeC for 2 hours.

After completion of the reaction, the reaction mixture was poured into 300 ml of water and extracted twice with 100 ml of ether. The organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain colorless liquid (±) -ex.
o-3-allyl-endo-2-norbornanol 1
4.7 g was obtained.

This product was placed in a four-necked flask equipped with a stirrer, a thermometer, a condenser and a dropping funnel, dissolved in 100 ml of dichloromethane, then 15.3 g of pyridine was added, and the mixture was cooled to 0 ° C. 0 for this mixture
11.4 g of acetyl chloride was added dropwise at -5 ° C, and the mixture was stirred at the same temperature for 5 hours.

After completion of the reaction, the reaction mixture was poured into ice water and extracted with 50 ml of toluene. After liquid separation, add 1 organic layer
The extract was washed with 0% aqueous hydrochloric acid, 5% aqueous sodium hydrogen carbonate and saturated brine in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain (±) -endo.
-2-acetoxy-exo-3-allyl norbornane 1
4.4 g was obtained as a colorless liquid.

Example 1 (±) -endo-2-acetoxy-exo was placed in a four-necked flask equipped with a stirrer, a thermometer and a condenser.
Charge 8.3 g of 3-allyl norbornane, 200 ml of 0.5M phosphate buffer (pH 7.0) and 1.6 g of lipase (genus Arthrobacter) at 48 at 35-40 ° C.
Stir vigorously for hours.

After completion of the reaction, ethyl acetate 10 was added to the reaction mixture.
0 ml was added, the insoluble material was filtered off, and the filtrate was separated. The obtained organic layer was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: hexane-ethyl acetate), and exo-3-allyl-2S-norbornanol 3.
3g (optical purity 92% ee) and end of 2R body rich
4.6 g of o-2-acetoxy-exo-3-allylnorbornane was obtained.

Example 2 Reaction was carried out in the same manner as in Example 1 except that lipase (Pseudomonas sp.) Was used instead of the lipase (genus Arthrobacter) used in Example 1 and the reaction time was 100 hours. And post-treatment are carried out, and 2.4 g (optical purity 98.5% ee) of exo-3-allyl-2S-norbornanol and endo-2-acetoxy-exo-of 2R form rich.
5.5 g of 3-allyl norbornane was obtained.

Example 3 In the same manner as in Example 1 except that lipase (genus Candida) was used in place of the lipase (genus Arthrobacter) used in Example 1 and the reaction time was 24 hours, After reaction and post-treatment, 3.9 g of exo-3-allyl-2S-norbornanol (optical purity 76% ee) and 2R-form r were obtained.
3.7 g of ich's endo-2-acetoxy-exo-3-allylnorbornane was obtained.

Example 4 In place of (±) -endo-2-acetoxy-exo-3-allylnorbornane used as a raw material in Example 1,
(±) -endo-2-butanoyloxy-exo-3
-Reaction and post-treatment were carried out in the same manner as in Example 1 except that 9.7 g of allyl norbornane was used, and exo-3
-Allyl-2S-norbornanol 3.0 g (optical purity 96% ee) and 2R rich endo-2-butanoyloxy-exo-3-allyl norbornane 5.7 g
Got

Claims (2)

[Claims] 1. A general formula 1 (In formula, R shows a C1-C5 alkyl group.) And General formula 2 (Wherein R represents the same meaning as described above), asymmetric hydrolysis is performed using an esterase having the ability to preferentially hydrolyze either enantiomer of the mixture of ester compounds. A process for producing an optically active exo-3-allyl-endo-2-norbornanol. 2. The method according to claim 1, wherein the esterase is lipase.