Eisai R&d Management Co., Ltd.

Akio Imai

Akihiko Shimotani

Hiroshi Nishimura

Processes for preparing 1-benzyl-4-[(5,6-dimethoxy-lindanon)-2-yl]methylpiperidine (donepezil), which is useful as an intermediate for medicines, and for producing 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine hydrochloride (donepezil hydrochloride), which is useful as a medicine. The process for donepezil hydrochloride production comprises catalytically hydrogenating the compound represented by the structural formula (III) [1-benzyl-4-[(5,6-dimethoxy-lindanon)-2-ylidene]methylpiperidine] with a Raney nickel catalyst under mild conditions and subsequently treating it with hydrochloric acid. Thus, impurities are further diminished. The operations are simple and the process is suitable for industrial production.

Processes for producing 1-benzyl-4-[(5,6-dimethoxy-1indanon)-2-yl]methylpiperidine and hydrochloride

The present invention provides a simple method of producing polymorphic crystal (III), which has high safety to environment and the bodies of operators; is gentle to environment; and can produce at low costs; and has a high refining effect. It is a method of producing polymorphic crystal (III) of donepezil hydrochloride (chemical name: 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine&#x2022;monohydrochloride) represented by the following structural formula (formula (I)), which comprises dissolving donepezil (chemical name: 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine) in ethanol; and adding hydrochloric acid or hydrogen chloride thereto, followed by stirring.

Method of producing polymorphic crystals of donepezil hydrochloride

1-Benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine or hydrochloride thereof, which is useful as a drug, can be produced in high purity by safer and easier operations suitable for industrial production by subjecting 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methyl-piperidine or a solvate thereof to catalytic hydrogenation in the presence of a palladium-alumina catalyst and if necessary, converting the thus obtained compound to its hydrochloride.

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Hasaki, Japan

Akio Imai