Patent ID: 6417374
Filing Date: 2002-07-09
Classification: C07F

Abstract:
A process for the preparation of 6-hydroxymethyl-4-(tert-butyldimethylsilyloxy)-(4R,6S)-tetrahydro-2H-2-pyranone of formula 1 wherein the said process comprising:(a) reacting a compound of formula 2 with a lipase enzyme in a buffer having â€ƒpH ranging between 5 to 7, at a temperature ranging from 25 to 30Â° C. for a period ranging between 19 to 30 hrs. extracting the reaction mixture with an organic solvent, removing the solvent by evaporation to obtain cis,cis-3-hydroxy-5-methylcarbonyloxy-cyclohexylacetate having formula (3), (b) reacting a compound of formula 3 with tert-butyldimethylsilylchloride in an organic solvent in the presence of an organic base at a temperature ranging from âˆ’15 to 20Â° C. for a period ranging from 6 to 12 hrs, separating the organic solvent, drying and on evaporation to obtain cis,cis-3-(methylcarbonyloxy)-5-(tert.butyldimethylsilyloxy)cyclohexylacetate having formula 4, (c) reacting a compound 4 with a lipase enzyme in a buffer having pH in the range of 5 to 8, at a temperature ranging from 25 to 30Â° C. for a period ranging between 24 to 60 hrs., extracting the mixture with an organic solvent, removing the solvent by evaporation and on column chromatography to obtain 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylace-tate having formula 5, (d) reacting a compound of formula 5 with dihydropyran in an organic solvent in the presence of p-toluene sulphonic acid at a temperature ranging from 5 to âˆ’10Â° C. for a period ranging from 2 to 5 hrs, quenching the above reaction with an aqueous sodium bicarbonate, separating the organic layer, drying, on evaporating and column chromatography to obtain 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylacetate having formula 6, (e) reacting a compound of formula 6 with an anhydrous potassium carbonate in methanol at room temperature for a period ranging from 2 to 6 hrs, evaporating the solvent, extracting with an organic solvent, washing with brine solution, drying, evaporating and column chromatography to obtain 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexan-1-ol having formula 7, (f) reacting a compound of formula 7 with pyridinium chlorochromate in an organic solvent at room temperature for a period ranging from 6 to 8 hours, extracting the above mixture with an ether, washing with brine, drying, on evaporating and column chromatography to obtain 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexan-1-one having formula 8, (g) reacting a compound of formula 8 with magnesium bromide in an organic solvent at a temperature ranging from 5 to 30Â° C. for a period ranging from 1 to 12 hours, quenching the above reaction ammonium chloride, separating the organic layer, drying and on evaporating to obtain 3-hydroxy-5-(tert-butyldimethylsilyloxy)-(3S,5R)-cyclohexan-1-one having formula 9, (h) reacting a compound of formula 9 with m-chloroperbenzoic acid at room temperature for a period ranging from 16-24 hours, extracting the compound with an orgainc layer, washing with sodium metabisulphite, brine, drying and on evaporation to obtain 6-hydroxymethyl-4-(tert-butyldimethylsilyloxy)-(4R,6S)-tetrahydro-2H-2-pyranone having formula 1.