ZA200303201B

ZA200303201B - Process for preparing (-)-menthol and similar compounds.

Info

Publication number: ZA200303201B
Application number: ZA200303201A
Authority: ZA
Inventors: Jennifer Ann Chaplin; Neil Stockenstroem Gardiner; Robin Kumar Mitra; Parkinson Christopher John; Madrie Portwig; Butana Andrew Mboniswa; Melanie Daryl Evans-Dickson; Dean Brady; Stephanus Francois Marais; Shavani Reddy
Original assignee: Csir
Priority date: 2000-11-02
Filing date: 2003-04-24
Publication date: 2004-04-26

Description

? PROCESS FOR PREPARING (-)- MENTHOL AND SIMILAR COMPOUNDS

BACKGROUND TO THE INVENTION

THIS invention relates to a process for producing (-)-menthol and similar compounds.

Menthol has been the subject of much research in the flavour industry. The molecule of menthol has three asymmetric carbon atoms, and hence, a total of eight optically active isomers are possible. The eight isomers are (-)-menthol, (+)-menthol, (-)}-isomenthol, (+)-isomenthol, (-)-neomenthol, (+)-neomenthol, (-)-neoisomenthol and (+)- neoisomenthol. Of all of these isomers only (-)- menthol has a strong refreshing character and is widely used in perfumes and medicines. Thus, the isolation of (-)-menthol from the other isomers is industrially important.

As previously discussed, racemic menthol contains four stereoisomeric pairs of : menthols. The isolation of (-)-mentho!l from this isomeric mixture can be performed chemically via crystallisation, freeze-drying or distillation.

CONFIRMATION COPY

IN

) The hydrogenation of thymol results in the formation of eight menthol isomers which can then be esterified and the (-)-menthy! ester selectively hydrolysed by ' microbial enzymes to yield (-)-menthol. The use of enzymes, either as free enzymes or part of a whole cell system, has been widely studied for the resolution of (-}-menthol from racemic mixtures.

A large variety of bacteria, fungi and yeasts have been identified with the ability to perform the hydrolysis of menthyl esters. It was reported in Biotechnol. Gen.

Engineer. Rev. 6:271-320 by Y Mikami (1988) that, of the microorganisms capable of hydrolysing menthyl acetates, bacteria and fungi also hydrolyse isomenthyl acetate. in a patent issued to Takasago Perfumery Co Ltd. (US Patent 3,607,651; 21

September 1971) the following organisms were claimed to possess a carboxylic hydrolase: Penicillium, Gliocladium, Trichoderma, Geotrichum,

Aspergillus, Pullularia, Fusarium, Absida, Cunninghamella, Rhizopus,

Actinomucor, Chlamydomucor, Mucor, Gibberella, Streptomyces, and Bacillus.

They were all shown to hydrolyse (-}- menthyl esters as well as (-)- isomenthyl esters. The two isomers of menthol formed can then be separated using rectification, recrystallisation and chromatography.

Some of the yields obtained in the examples are: 47.5% conversion of (%)- menthyl acetate with Absidia hyalospora in 24 hours; 28.8% (-)-menthol and 17.4% (-)-isomenthol was also obtained from a mixture of menthyl acetates (5.8% (+)-neomenthol; 30.4% (+) isomenthol; 63.8% (x)-menthol and others) in 24 hours with Trichoderma viride; 50.3% from (+)menthyl acetate with

Bacillus subtilus var niger after 48 hours.

A novel process for the stereoselective hydrolysis of the monochloroacetate of . (£)-menthol has been developed using Pseudomonas sp. NOF-5, which appears to have been reclassified as Alginomonas nonfermentans NOF-5.

) The organism was shown to hydrolyse (x)-isomenthyl acetate to (-)-isomenthol and also to hydrolyse (+)-neoisomenthyl acetate nonstereospecifically. (See again US Patent No 3,607,651).

The most widely studied lipase is that of Candida cylindracea (which has been reclassified as Candida rugosa). It was studied for the separation of (-)- menthol from the esters formed by the esterification of a menthol mixture obtained from the Haarmann-Reimer process, which consisted of 55% (%)- menthol, 29% (#)-neomenthol, 14% (£)-isomenthol and 2% (%)-neocisomenthol.

The order of selectivity for the menthol isomers by the C. rugosa lipase used (lipase MY, Meito Sangyo Ltd) was (-)-menthol (100%), (-)-isomenthol (48%), (-)-necisomenthol (35%), (-)-neomenthol (3.3%), (+)-menthol (2%), (+)- neoisomenthol (0.6%) and (+)-neomenthol (<0.1%). The (-)-menthol and (-)- isomenthol esters were converted first; this occurred at a conversion ratio of 35%, after which the (-)-neomenthol, (+)-menthol and (+)-isomenthol esters were consumed. It was therefore not possible to isolate (-)-menthol from its other isomers; a two-step reaction was then attempted using lipase catalysed ester synthesis to obtain a mixture enriched in (-}-menthol ester, followed by lipase catalysed ester solvolysis, resulting in (-)-menthol. The process was not successful in completely eliminating the (-)-isomenthol and the purity was not considered adequate for industrial scale. (See Bioflavour '87, C

Triantaphylides et al, (1988) Walter dr Gruter & Co. Berlin 531-542).

None of the microorganisms and enzymes described above have the ability to react with (-)-menthol with a high degree of selectivity when the (-)-menthol is included in a mixture with (+)-menthol and the other stereoisomers, isomenthol, neomenthol and neocisomenthol.

In PCT/IB 01/01008 there is disclosed a process of separating a single desired ‘ stereoisomer from a racemic mixture of eight stereoisomers of a compound of the formula Hl by contacting the racemic mixture in a suitable organic solvent

' with an esterifying agent and a stereospecific enzyme which stereoselectively esterifies the —OH group of the desired stereoisomer, for a time sufficient to convert a desired percentage of the desired stereoisomer to a compound of the formula IV, to give a first reaction product including the compound of the formula IV, the organic solvent, the unconverted stereoisomers of the compound of the formula lll, excess esterifying agent and by-products of the reaction; and then separating the compound of the formula IV from the first reaction product.

This invention is an improvement in or modification of the process described above.

SUMMARY OF THE INVENTION

According to the invention there is provided a process of separating a desired (-) stereoisomer which is selected from (-)-menthol or an equivalent (-) compound where the isopropyl group is replaced with an isopropanol or an isopropylene group, from a starting material comprising: (a) 40to 100 m/m% of a mixture of (-)-menthol and (+)-menthol; (b) up to 30 m/m % of a mixture of (-)—isomenthol and (+)-isomenthol; (¢) upto 20 m/m % of a mixture of (-)}-neomenthol and (+)-neomenthol; and (d) up to 10 mm % of a mixture of (-}-neoisomenthol and (+)- neoisomenthol, or an equivalent (+) mixture where the isopropyl group is replaced with an isopropanol or an isopropylene group (i.e a (+) stereoisomer and a (-) stereoisomer which are respectively equivalent to (+)-menthol and (-)- : menthol, and (+)-isomenthol and (-)—isomenthol, and (+)-neomenthol and (-)-neomenthol, and (+)-neoisomenthol and (-)-neoisomenthol ) except for replacement of the isopropyl group), including the steps of:

Claims

CLAIMS 1 A process of separating a desired (-) stereoisomer which is selected from (-) menthol or an equivalent (-) compound where the isopropyl group is replaced with an isopropanol or an isopropylene group, from a starting material comprising: (a) 40 to 100 m/m% of a mixture of (-)-menthol and (+)-menthol; (b) up to 30 m/m % of a mixture of (-)-isomenthol and (+)-isomenthol; (c) upto 20 m/m % of a mixture of (-)-neomenthol and (+)-neomenthol; and (d) up to 10 m/m % of a mixture of (-)-necisomenthol and (+)- neoisomenthol, or an equivalent (+) mixture where the isopropyl! group is replaced with an isopropanol or an isopropylene group, including the steps of:

(1) contacting the starting material with an esterifying agent and a stereospecific enzyme which is a Pseudomonas lipase enzyme which stereoselectively esterifies the -OH group of the desired (-) steroisomer, for a time sufficient to convert a desired percentage of the desired (-) stereoisomer to a desired (-) esterified compound where the -OH group is converted to a group —O-C(0O)-R4, wherein R, is an alkyl or an aryl group or hydrogen, to give a first reaction product including the desired (-) esterified compound, the organic solvent, the unconverted stereoisomers, excess esterifying agent and by-products of the reaction; and

(2) separating the desired (-) esterified compound from the first reaction product.

: 2 A process according to claim 1 wherein step (2) comprises the sub-steps of: (2)(a) separating the first reaction product from the enzyme;

(2)(b) removing the organic solvent, the excess esterifying agent, and the by-products of the reaction to give a second reaction product; and (2)(c) separating the desired (-) esterified compound from the second reaction product to give a third reaction product containing the unconverted stereoisomers. 3 A process according to claim 1 or claim 2 including the following step prior to step (1) of: (I) subjecting a racemic mixture of the eight stereoisomers of a compound of the formula Il.

OH Ri IIx wherein R; represents an isopropanol group, an isopropyl group or an isopropylene group, to a distillation step to separate at least a portion of one or more of the (+) mixtures of isomenthol, neomenthol and necisomenthol or their equivalents where the isopropyl group is replaced with an isopropanol or an isopropylene group, from the (+) mixture of menthol or its equivalent where the isopropyl group is replaced with an isopropanol or an isopropylene group, to give the starting material for step (1). 4 A process according to claim 3 including the step, after step (2) of:

(3) racemizing any unconverted desired (-) stereoisomer, and the other unconverted stereoisomers in the third reaction product, and the six other stereoisomers of the compound of the formula lil obtained in the step (1), to give a fourth reaction product containing a mixture approaching the thermodynamic equilibrium of the eight stereoisomers and recycling the fourth reaction product to step (1).

A process according to claim 4 including the step, after step (3) of:

(4) hydrolysing the desired (-) esterified compound to give the desired (-) stereoisomer.

6 A process according to claim 5 wherein when the desired (-) stereoisomer or the desired (-) esterified compound has an isopropanol group or an isopropyl group, before or after step (4), the desired (-) esterified compound or the desired (-) stereocisomer is subjected to a reduction step to convert the isopropanol or the isopropylene group to an isopropy! group.

7 A process according to any one of claims 1 to 6 wherein in step (1) the starting material comprises:

(a) about 80 m/m% of a mixture of (--menthol and (+)-menthol,

(b) about 10 m/m% of a mixture of (-)}-isomenthol and (+)-isomenthol;

(c) about 6 m/m% of a mixture of (-)-neomenthol and (+)-neomenthol; and

(d) about 4 m/m% of a mixture of (-)-necisomenthol and (+)- neoisomenthol;

or an equivalent (+) mixture where the isopropyl group is replaced with an isopropanol or an isopropylene group.

’ 8 A process according to any one of claims 1 to 7 wherein in step (1) the enzyme is Amano AK lipase enzyme.