Asymmetric synthesis of (−)-venlafaxine using organocatalyst

摘要

The patent discloses an asymmetric synthesis of (−)-venlafaxine using an organocatalyst via a unified strategy employing organcatalytic Michael addition, regio-selective dehydration and selective epoxide ring opening.

主权项

1. A process for asymmetric synthesis of enantiomerically pure venlafaxine with ee≧99% comprising the steps of:
a. reacting anisaldehyde with nitromethane in mole ratio 1:11.8 in presence of ammonium acetate in acetic acid under sonication condition at room temperature ranging between 25-35° C. for a period ranging between 2-4 hrs to obtain nitro styrene; b. michael addition of nitrostyrene as obtained in step (a) with cyclohexanone in mole ratio 1:5 in presence of proline based organocatalyst under stirring at room temperature ranging between 25-35° C. for a period ranging between 23-25 hrs in the presence of p-toluene sulphonic acid to obtain nitro ketone; c. reducing nitro ketone of step (b) using NaBH4 in THF:H2O (9:1) to obtain crude alcohol (2S)-2-((R)-1-(4-methoxyphenyl)-2-nitroethyl)cyclohexan-1-ol which on subjecting to nitro reduction by NiCl2.6H2O and sodium borohydride in MeOH as a solvent, afforded the resultant amine (2S)-2-((R)-2-amino-1-(4-methoxyphenyl)ethyl)cyclohexan-1-ol which on in situ protection by benzylchloroformate in presence of Et3N as a base furnished Cbz protected amino alcohol benzyl ((2R)-2-((1S)-2-hydroxycyclohexyl)-2-(4-methoxyphenyl)ethyl)carbamate; d. treating amino alcohol of step (c) with mesyl chloride in presence of Et3N as a base in DCM solvent under reflux condition at temperature ranging between 40-4° C. for a period ranging 14-25 hrs to give the crude mesylated reaction mixture which further on treatment with DBU in acetonitrile solvent furnished selectively more substituted double bond product benzyl (R)-(2-(cyclohex-1-en-1-yl)-2-(4-methoxyphenyl)ethyl)carbamate; e. subjecting compound (R)-2-(cyclohex-1-en-1-yl)-2-(4-methoxyphenyl)ethyl)carbamate of step (d) with NaH and MeI in dry THF to obtain benzyl (R)-(2-(cyclohex-1-en-1-yl)-2-(4-methoxyphenyl)ethyl)(methyl)carbamate; f. epoxidation of benzyl (R)-(2-(cyclohex-1-en-1-yl)-2-(4-methoxyphenyl)ethyl)(methyl)carbamate of step (e) by treating with m-CPBA in presence of NaHCO3 in DCM under stirring at temperature ranging between 25-35° C. for a period ranging between 1-3 hrs to afford crude epoxide benzyl ((2R)-2-(7-oxabicyclo[4.1.0]heptan-1-yl)-2-(4-methoxyphenyl)ethyl)(methyl)carbamate; g. subjecting the crude epoxide of step (f) to selective epoxide opening as well as carbamate reduction in one pot using lithium aluminum hydride at reflux condition at temperature ranging between 65-70° C. for a period ranging 4-5 hrs in THF to afford (−)-venlafaxine.