Patent ID: 8729260
Filing Date: 2014-05-20
Classification: A61P,C07D,C07F

Abstract:
1. A process for the preparation of a compound of formula II: or a pharmaceutically acceptable salt thereof, wherein R is hydrogen and M and M′ are hydrogen, sodium ion, or potassium ion comprising: i) providing a compound of formula I: ii) converting the compound of formula I into the compound of formula II, wherein Ar is 2,4-dichlorophenyl or phenyl, P is phosphorous, and P′ is selected from the group consisting of alkyl, 2,2,2,-trichloroethyl, 2-bromoethyl, benzhydryl, trityl, aryl, trimethylsilyl, triethylsilyl, 4-methoxybenzyl, t-butyl, p-nitrobenzyl and hydrogen; and wherein the converting comprises the step of condensing the compound of formula I with a compound of formula V: to form a compound of formula VI: wherein P″ is selected from the group consisting of alkyl, 2,2,2,-trichloroethyl, dibromoethyl, benzhydryl, trityl, aryl, trimethylsilyl, triethylsilyl, 4-methoxybenzyl, t-butyl, p-nitrobenzyl and hydrogen; wherein the compound of formula VI is converted into the compound of formula II by hydrogenolysis in presence of a metal catalyst, a base, water and a first organic solvent to produce a first solution of the compound of formula II, and the compound of formula II is obtained from the first solution of the compound of formula II by (a) adjusting a pH value to 5.0 to 5.4 of the first solution of the compound of formula II and then filtering out the metal catalyst; (b) separating an aqueous layer from the first solution of the compound of formula II and removing the first organic solvent from the aqueous layer by distillation or extraction; (c) extracting a first aqueous concentrated extract from the aqueous layer with dichloromethane under the pH value of the aqueous layer adjusted to 6.3-6.7, and then extracting a second aqueous concentrated extract with n-butanol or isoamyl alcohol (IAA); (d) filtering the second aqueous concentrated extract to obtain an aqueous concentrated solution and adding isopropanol (IPA) or a mixture of methanol and tetrahydrofuran in the aqueous concentrated solution then chilled to a temperature of −8˜0° C.; (e) adding a mixture of methanol and tetrahydrofuran or a mixture of methanol and methyl acetate in the aqueous concentrated solution and adjusting the pH value to 5.7 thereof; (f) adding a mixture solvent of isopropanol, methanol and tetrahydrofuran or a mixture solvent of methanol and tetrahydrofuran, or a mixture of IPA, methanol and methyl acetate in the aqueous concentrated solution and adding a seed material to the aqueous concentrated solution to age thereof; (g) adding a crystallization solvent into the aqueous concentrated solution to crystallization then the aqueous concentrated solution is chilled to a temperature of −5˜−15° C. and filtering to obtain a crystalline compound of formula II and residual liquid; and (h) washing the crystalline compound of formula II with a mixture of methanol and tetrahydrofuran or a mixture of 1-propanol, methanol and tetrahydrofuran, or a mixture of methanol and methyl acetate, and pressing with nitrogen to remove the crystallization solvent to yield the compound of formula II, the first organic solvent is selected from the group consisting of tetrahydrofuran, acetonitrile, ethylacetate, propionitrile, n-butanol, methanol, ethanol, dichloromethane, NN-dimethylformamide, N-ethylpyrrolidinone, and mixtures thereof; and the crystallization solvent is a mixture selected from the group consisting of: (i) IPA, methanol and tetrahydrofuran; (ii) methanol and tetrahydrofuran; (iii) IPA, methanol and methyl acetate; and (iv) 1-propanol, methanol and tetrahydrofuran.