Patent ID: 6590127
Filing Date: 2003-07-08
Classification: C07C

Abstract:
A process for the preparation of pharmacologically active &agr;-asarone (trans isomer) of formula II from toxic &bgr;-asarone (cis isomer) or &bgr;-asarone rich Acorus calamus oil containing &agr; and &ggr;-isomer, the said process comprises steps of:(a) hydrogenating &bgr;-asarone or &bgr;-asarone rich calamus oil containing &agr; and &ggr;-asarone using 10% Pd/C catalyst, with or without ammonium formate under a pressure of 0-40 psi at room temperature, (b) purifying the product of step (a) over silica gel by performing column chromatography to obtain compound of formula (I), (c) dehydrogenating under inert atmosphere of compound of formula (I) of step (b) by treating with DDQ containing optionally silica or alumina in anhydrous organic solvent at room temperature for a period of 0.5 to 72 hours, (d) filtering the reaction mixture of step (c) to remove precipitated (DDQH2) washing the residue with an organic solvent and obtaining combined clear filtrate, (e) concentrating the combined filtrate of step (d) and pouring the concentrate into water, extracting with water immiscible organic solvent, (f) combining organic solvent extract of step (e), washing with brine, 10% aqueous bicarbonate, followed again by brine, drying over anhydrous sodium sulphate, filtering and evaporating to dryness to obtain a residue, (g) purifying the residue of step (f) over silica gel column, eluting with mixture hexane:ethylacetate to obtain &agr;-asarone as a viscous liquid and an yellow solid characterised as trans-2,4,5-trimethoxy cinnamaldehyde of formula (IIa), (h) crystallising the viscous liquid containing &agr;-asarone using hexane:methanol mixture to afford white solid of &agr;-asarone, (II) (i) obtaining &agr;-asarone also from compound of formula (I) of step (a) by treating with DDQ in an aqueous organic solvent at room temperature for a period of 16-20 hours, (j) filtering the reaction mixture of step (i) to remove precipitated solid (DDQH2), washing the residue with an organic solvent and obtaining a clear solution, (k) evaporating the clear solution of step (j) and pouring the residue into water, extracting with organic solvent washing the organic solvent extract with brine, drying over anhydrous sodium sulphate, filtering and evaporating to obtain a residue, (l) purifying the residue of step (k) over silica gel column, eluting with mixture of hexane:ethyl acetate to obtain a viscous liquid fraction containing isoacoramone which is crystallised from ethylacetate:hexane to afford white crystals of isoacoramone of formula (III), (m) treating compound of formula (III) of step (l) with sodium borohydride in an organic solvent in presence of aqueous alkali hydroxide solution at a temperature range of âˆ’5Â° C. to room temperature for a period of 16-20 hours, (n) diluting the reaction mixture of step (m) with saturated ammonium chloride solution, stirring for 20-30 minutes, (o) removing the organic solvent from solution of step (n) under reduced pressure and extracting the aqueous layer with ethyl acetate, (p) washing the ethyl acetate layer of step (o) with water, drying ethyl acetate layer over anhydrous sodium sulphate, filtering and evaporating the organic solvent to dryness to obtain a residue, (q) purifying residue of step (p) over neutral alumina column using an eluant hexane:ethylacetate to afford 1-(2,4,5-trimethoxy)-phenyl-1-propanol of formula (IIIa), (r) dehydrating the compound of formula (IIIa) by treating with p-toluene sulphonic acid in an aromatic hydrocarbon solvent at a reflux temperature using Dean-stack apparatus for continuous removal of water, (s) pouring the reaction mixture of step (r) into cold water, extracting with aromatic hydrocarbon solvent and separating organic layer, (t) washing the organic layer of step (s) with brine, saturated bicarbonate solution again followed by brine, drying over anhydrous sodium sulphate, filtering and evaporating organic solvent to obtain a residue, and (u) purifying the residue of step (t) over silica gel column, eluting with hexane:ethyl acetate mixture to obtain a white solid &agr;-asarone of formula (II).