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Procedure for the preparation of Donepezil hydrochloride forms I and III; and a compound Agent of same
专利权人:
CRISTÁLIA PRODUTOS QUÍMICOS FARMACÊUTICOS LTDA.
发明人:
ARIEL LZARO LLANES GARCA,OGARI DE CASTRO PACHECO
申请号:
ARP140104381
公开号:
AR098504A1
申请日:
2014.11.21
申请国别(地区):
AR
年份:
2016
代理人:
摘要:
The present application relates to an efficient and industrially feasible procedure for the preparation of East epoxy hydrochloride in the form of high purity and selective commercial crystals (first and third). The application also relates to a preparation procedure of an effective intermediate compound for the preparation of donepezilo hydrochloride. 1. Claim 1: procedure for preparation of donepezilo monohydrate, form I,The characteristics of the formula are as follows: (a) simultaneously reducing the reaction of a, b-external cyclic carbides and dechlorination of compound 1-benzene-4 (5,6-dimethoxi-1-indanon-2-ilideno) methyl) pyridine (2);in the presence of the 10% palladium metal catalyst on carbon and a hydrogen transfer agent, in an organic solvent, or mixture of an organic solvent with water, at a temperature of 53-63 ° C; followed by treatment of the reaction medium with concentrated hydrochloric acid to obtain the intermediate compound 5,6-dimethoxy-2 - [(piperidin-4-yl) methyl] indan-1-one hydrochloride, represented by the formula (3) ;b) benzylation reaction of the intermediate of formula (3) with a benzyl derivative represented by formula (4) in which X represents a leaving group selected from the group consisting of chloride, bromide, iodide, tosylate and mesylate; in the presence of a base and a phase transfer catalyst, in a heterogeneous mixture of solvents consisting of water and a dialkyl ether, in a ratio of 1: 1 to 1:10, at a temperature of 30 ° C to 80 ° C, obtaining donepezil in the form of a free base, which is dissolved in ethyl acetate or isopropyl,Secondly, the concentrated hydrochloric acid was used to treat the solution to produce the three forms of East cicerol hydrochloric acid represented by formula (5);c) conversion of anhydrous donepezil hydrochloride, Form III, to donepezil hydrochloride monohydrate, Form I, by dissolving donepezil hydrochloride in 3-6 parts of methanol containing 2% to 20% water, at a temperature between 40 ° C an
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