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AssigneeCsir
InventorsJennifer Ann Chaplin, Neil Stockenstrom Gardiner, Robin Kumar Mitra, Christopher John Parkinson, Madrie Portwig, Butana Andrew Mboniswa, Melanie Daryl Evans-Dickson, Dean Brady, Stephanus Francois Marais, Shavani Reddy
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A process of separating a single desired stereoisomer from a racemic mixture of eight stereoisomers of a compound of formula (III), wherein R1 represents an isopropanol group, an isopropyl group or an isopropylene group, includes the steps of: 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 formula (IV), wherein R1 is as defined above and R4 is an alkyl or an aryl group, to give a first reaction product including the compound of formula (IV), the organic solvent, the unconverted stereoisomers of the compound of formula (III), excess esterifying agent and by-products of the reaction; and separating the compound of formula (IV) from the first reaction product. The process is of particular application for the production of (−)-menthol.
1 A process of separating a single desired stereoisomer from a racemic mixture of eight stereoisomers of a compound of the formula III
2 A process according to claim 1 wherein step (2) comprises the sub-steps of:
3 A process according to claim 1 or claim 2 including the step, after step (2) of:
4 A process according to claim 3 including the step, after step (3) of:
5 A process according to claim 4 wherein when R1 is an isopropanol group or an isopropylene group, before or after step (4), the compound of the formula IV or the desired stereoisomer of the compound of the formula III is subjected to a reduction step to convert R1 to an isopropyl group.
6 A process according to any one of claims 1 to 5 including the following steps, prior to step (1) of:
7 A process according to any one of claims 1 to 6 wherein in step (1) the solvent is selected from the group consisting of isooctane;
8 A process according to claim 7 wherein in step (1) the solvent is n-heptane.
9 A process according to any one of claims 1 to 8 wherein in step (1) the esterifying agent is selected from the group consisting of vinyl acetate, butyl acetate, octanoic acid, isopropenyl acetate, vinyl butyrate, ethyl lactate and ethyl acetate.
10 A process according to claim 9 wherein in step (1) the esterifying agent is vinyl acetate.
11 A process according to any one of claims 1 to 10 wherein in step (1) the esterifying agent is used in a molar ratio to the desired stereoisomer of the compound of the formula III of 0.5:1 to 30:1 inclusive.
12 A process according to any one of claims 1 to 11 wherein in step (1) the stereospecific enzyme is selected from the group consisting of Candida cylindracea lipase, lipase Hog pancreas, lipase Pseudomonas fluorescens, lipase Aspergillus oryzae, lipase Rhizopus niveus, lipase Rhizomucor miehei, lipase Candida antarctica, lipase Mucor javanicus, lipase Rhizopus arrhizus, lipase Penicillium roqueforti, lipase Candida lipolytica, lipoprotein lipase Pseudomonas sp., type B, lipoprotein lipase Pseudomonas cepacia, lipoprotein lipase Chromobacterium viscosum, esterase Bacillus thermoglucosidasius, esterase Bacillus stearothermophilus, esterase Mucor miehei, esterase hog liver, Candida rugosa lipase, lipase Mucor miehei, Candida antarcitica B lipase, Candida antarctica A lipase, Chiro-CLEC-CR, Chiro-CLEC-CR (slurry), porcine liver esterase, Penicillin acylase, Subtilisin Carlsberg, Chiro-CLEC-BL (slurry), Chiro-CLEC-PC (slurry), Chiro-CLEC-EC (slurry), Aspergillus oryzae protease, PeptiCLEC-TR (slurry), ESL-001-01, ESL-001-01 with stabiliser, ESL-001-02, ESL-001-03, ESL-001-05, Chirazyme L4 (Pseudomonas sp.), Chirazyme L5 (Candida antarctica fraction A), Chirazyme L1 (Burkholderia), Chirazyme L6 (Porcine pancreas), Chirazyme L7, Chirazyme L8, Naproxen esterase, Lipomax, Genzyme, Lipoprotein lipase, Novozyme 868, Novozyme 435, immobilised Candida antarctica lipase, Nagase enzyme, Lipase A-10FG (Rhizopus javanicus), Amano AYS, Amano PS, Amano PSD, Amano AKD11, and Amano AKD111.
13 A process according to any one of claims 1 to 12 wherein in step (1) the enzyme is Amano AK lipase enzyme.
14 A process according to any one of claims 1 to 13 wherein in step (1) the stereospecific enzyme is used in an amount of from 1 g/l to 60 g/l inclusive of the mixture of the racemic mixture of the eight stereoisomers of the compound of the formula III, the suitable organic solvent and the esterifying agent.
15 A process according to any one of claims 1 to 14 wherein step (1) is carried out at a temperature of from 20° C. to 100 ° C. inclusive and at atmospheric or higher pressure.
16 A process according to any one of claims 2 to 15 wherein after step (2)(a) the stereospecific enzyme is recycled to step (1).
17 A process according to any one of claims 2 to 15 wherein in step (1) the stereospecific enzyme is used in a continuous system wherein the stereo specific enzyme is retained within a reactor and wherein in step (2)(a) the first reaction product exits the reactor leaving behind the enzyme.
18 A process according to any one of claims 4 to 17 wherein in step (4) the hydrolysis is carried out in the presence of a base, in a suitable solvent, and at a temperature below the boiling point of the solvent or the reflux temperature of the mixture of reactants at the pressure at which the reaction is carried out.
19 A process according to any one of claims 1 to 18 wherein in the compound the formula III, R1 represents an isopropyl group.