Process for the preparation of L-menthol

Details Process for the preparation of L-menthol Process for the preparation of L-menthol

2002-01-07

2004-03-16

Saidha, Tekchand (Department: 1652)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Preparing oxygen-containing organic compound

C435S155000, C435S198000, C435S921000, C536S023200

Reexamination Certificate

active

06706500

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to a process for the preparation of L-menthol by enantioselective enzymatic cleavage of D,L-menthyl derivatives.
BACKGROUND OF THE INVENTION
Process for the synthetic preparation of menthol are generally known (Common Fragrance and Flavor Materials; Bauer, K., Garbe, D. and Surburg, H., Verlag V C H, Weinheim, 1990, 2
nd
edition, pp. 44-46). If the products obtained are racemic mixtures, they are markedly inferior in taste and odor to the naturally occurring L-menthol, for example from peppermint oil. Therefore, there is a great interest in separation processes for D,L-menthol.
The separation can be achieved, for example, using physical processes. Such processes include, for example, fractional crystallization of the salts of optically active amines with racemic methyl hydrogen phthalate or methyl hydrogen succinate. In addition, D- or L-menthol can be separated off from racemic menthol mixtures by esterifying the mixture with an optically active acid, for example menthoxyacetic acid, and separating the mixture of diastereomeric compounds by crystallization. The D- or L-menthol is obtained by saponification of the diastereomeric ester.
A further process used industrially (DE-A 2 109 456) for separating off optically pure D- and L-menthol from D,L-menthol mixtures proceeds via a carboxylic menthyl ester as intermediate. Preferably, the esters of benzoic acid or of hexahydrobenzoic acid, and in addition the esters of 4-methylbenzoic acid, of 3,5-dinitrobenzoic acid and of 4-ethoxybenzoic acid are used. The process is the selective crystallization of optical antipodes which are obtained in a purity so high that further processing can be carried out without further purification operations.
In addition, L-menthol can be isolated from D,L-menthol mixtures using enzymes or microorganisms.
It is also known that lipases hydrolyze esters in aqueous media and can have a high specificity and selectivity. In addition, in certain organic solvents, some lipases have the ability to catalyze the back-reaction, to synthesize esters from the corresponding acids and alcohols.
Various strategies have been employed to produce pure L-menthol from the racemic D,L-menthol mixture. Thus, for example, Tetrahedron Letters, 27, (1986) 29 discloses that the lipase of
Candida cylindrarea
preferentially releases L-menthol (ee: 70%) from a racemic menthyl laurate by hydrolysis in an aqueous medium. This enantioselective preference was also displayed in the esterification of racemic menthol with lauric acid, the L-menthyl laurate being formed with high enantiomeric purity (ee: 86%). In a non-aqueous medium, racemic menthol can be enantioselectively esterified with lauric acid using lipase, with, again, the L-menthyl laurate being formed preferentially (ee: 95%). This reaction is virtually complete after 10 hours. Transesterification of D,L-menthol with trilaurin or D,L-menthyl laurate with isobutanol proceeds with a similarly high enantioselectivity, but is extremely slow (reaction time: 15 days or more).
It is also known to carry out reactions under enzyme catalysis in nonaqueous media, if the substances are only poorly soluble in water. As an alternative to organic solvents, supercritical fluids, specifically supercritical carbon dioxide, may be used. Thus, this is also disclosed for racemate resolution of D,L-menthol by Chemie Ingenieur Technik, 69, (1986) 29, more precisely by the enantioselective transesterification of various acetates with racemic menthol. The best results are achieved with the enol ester isopropenyl acetate. Such esters have the benefit that after reaction is complete, the alcohol formed by the hydrolysis, in this case isopropenyl alcohol, immediately isomerizes to form the corresponding ketone and is therefore not available for any back-reaction. The enzymes studied are lipase AY from
Candida rugosa
, lipase PS from
Burkholderia cepacia
(formerly
Pseudomonas cepacia
), Novozyme 435 from
Candida antarctica
B, lipozyme IM 60 from
Rhizomucor miehei
and esterase EP 10 from
Pseudomonas marginata.
Esterase EP 10 can be obtained from recombinant
E. coli
strains which contain the gene for EP 10 esterase. Esterase EP 10 shows by far the highest enantioselectivities in the system. Novozyme 435, under the conditions selected, shows virtually no conversion in the transesterification using the various acetates.
The enantioselectivity of the lipase from
Candida rugosa
(lipase AY) towards racemic menthol may be significantly increased, according to the reports in Biotechnol. Prog. 11, (1995) 270 by targeted treatment of the lipase with nonionic surfactants. These studies clearly show that the effectivity of esterification of L-menthol with lauric acid in organic medium depends greatly on the enzyme. The lipase from
Candida rugosa
is significantly more effective in this reaction than the lipase from Rhizopus sp.,
Burkholderia cepacia
, Pseudomonas sp.,
Mucor javanicus, Aspergillus niger
and from pig pancreas. In addition, it is found that as a result of the treatment with nonionic surfactants, the effectivity of the lipase from
Candida rugosa
increases to about five fold.
Tetrahedron Letters 39, (1998) 4333 discloses that using microwave irradiation, in the case of pig pancreas lipase, leads to no change in reaction velocity or enantioselectivity in the esterification of racemic menthol with palmitic acid.
Lipases are also able to accept carboxylic anhydrides as acyl donor. Carboxylic anhydrides, as has already been mentioned in the case of the enol esters, have the advantage that acyl transfer is quasi-irreversible. According to Enzyme and Microbial Technology 18, (1996) 536, the lipase AY-30 from
Candida rugosa
is able to exercise a certain enantioselectivity in the reaction of racemic menthol with acetic anhydride, propionic anhydride and butyric anhydride. The best results with this enzyme are achieved with butyric anhydride after 48 hours in n-hexane as solvent (ee: 86% of the L-menthyl butyrate formed).
The enantioselectivity of the reaction is greatly dependent both on the lipase used and on the anhydride used. Thus, Microbiol. Biotechnol 43, (1995) 639, discloses that the lipase OF 360 from
Candida rugosa
and propionic anhydride gives a very high optical purity of the L-menthyl propionate formed (ee: 95%).
A further possible method of preparing L-menthol from D,L-menthol mixtures is to cleave racemic ester mixtures enantioselectively enzymatically. Thus, Dechema Biotechnol. Conf. (1989) 141 discloses reacting D,L-menthyl acetate with the lipase from
Candida rugosa
in a hydrolysis, the L-menthol released indicating a rather low enantioselectivity of the enzyme.
SUMMARY OF THE INVENTION
It is an object of the present invention to resolve a D,L-menthol suitable for industrial use, or derivatives thereof, with high absolute enantioselectivity, in order to obtain pure L-menthol or D-menthol or a pure L-menthyl ester or D-menthyl ester.
A process has been found for the preparation of D- or L-menthol and derivatives, characterized in that D,L-menthyl derivatives are enantioselectively enzymatically cleaved by lipases.
DETAILED DESCRIPTION OF THE INVENTION
According to the inventive process, the enantiomers are surprisingly obtained at an enantiomeric excess (ee value) of greater than 99%, and a selectivity (E value) of >100.
D,L-Menthyl derivatives for the inventive process are, for example, compounds of the formula
where
R denotes hydrogen, unbranched or branched C
1
-C
20
-alkyl, C
3
-C
8
-cycloalkyl, C
6
-C
14
-aryl, C
7
-C
15
-arylalkyl, C
1
-C
20
-alkoxy, C
1
-C
20
-alkylamino, where the above-mentioned hydrocarbon radicals can optionally be monosubstituted or polysubstituted with hydroxyl, formyl, oxy, C
1
-C
6
-alkoxy, carboxyl, mercapto, sulfo, amino, C
1
-C
6
-alkylamino or nitro or halogen, preferably chlorine.
Preferred D,L-menthyl derivatives are esters of D,L-menthol with aliphatic or aromatic carboxylic acids. For example, the following esters may be mentioned:
D,L-menthyl acetate, D,L-menthyl benzoate, D,L-m

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