Donepezil polycrystals and process for producing the same

Details Donepezil polycrystals and process for producing the same Donepezil polycrystals and process for producing the same

2000-06-05

2001-06-12

Reamer, James H. (Department: 1614)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06245911

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel polymorphic crystals (A) to (C) of donepezil (1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]methylpiperidine, free compound) as a precursor for production of donepezil hydrochloride (chemical name: 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]methylpiperidine hydrochloride) having an excellent action as a medicament disclosed in Example 4 of JP-A 64-79151 (EP-A 296560, U.S. Pat. No. 4,895,841), specifically as a prophylactic and therapeutic agent for senile dementia, and in particular as a prophylactic and therapeutic agent for Alzheimer's disease, and an industrial process for producing the same.
Hereinafter, polymorphic crystals (A) to (C) are referred to as types (A) to (C), respectively.
PRIOR ART
Donepezil hydrochloride is a therapeutic agent having an inhibitory action on acetylcholinesterase for treating a variety of senile dementia, is particularly useful as a prophylactic, therapeutic and ameliorating agent for Alzheimer-type senile dementia and is on the market or under development in all the countries of the world.
Donepezil hydrochloride is produced by first producing donepezil which is a free compound and then converting it into a hydrochloride. On the one hand, donepezil is, in itself, an excellent medicament but is also used as a precursor for production of donepezil hydrochloride.
Accordingly, donepezil preferably has such physical properties as to allow it to occur in the form of crystals not being sticky but being dry in order to achieve excellent filtering properties after crystallization and to facilitate recovery of its filter cake by scraping. However, crystals of donepezil excellent in handling properties is not known so far. Further, the presence of polymorphic crystals of donepezil is not known.
In a method described in Example 4 of JP-A 64-79151, a crude donepezil product was purified by column chromatography, and residues obtained by concentrating desired fractions were immediately converted into a hydrochloride. Accordingly, donepezil has not been obtained as crystals.
However, it goes without saying that donepezil in the form crystals not being sticky but being dry is preferable because of excellent filtering properties, easy scraping and handling.
Further, in the prior art, the desired compound is purified by column chromatography (methylene chloride system), but purification by column chromatography requires a large amount of solvent and the column is discarded after use, and is thus very disadvantageous in production cost. In addition, the used solvent is evaporated in a large amount into the atmosphere, and therefore, the column chromatography is preferably not used if possible from the viewpoint of working environment or environmental protection.
Further, because donepezil according to the present invention is a raw material of a medicament, the solvent remaining therein should be as low as possible and simultaneously be an uninfluential solvent in order to prevent its unpleasant effect on the human body.
DISCLOSURE OF THE INVENTION
The present inventors extensively studied to improve the problems described above. As a result, they found that the novel polymorphic crystals (A) to (C) of donepezil described below are very dry, can be purified without using column chromatography and have a very low content of residual solvent, and therefore these crystals are a very preferable raw material as a medicament, thus completing the present invention.
That is, the present invention provides three kinds of novel polymorphic crystals (A) to (C) of donepezil which are capable of purification without using column chromatography, are dry and thus excellent in handling properties, and have an extremely low content of residual solvent, and an industrial process for producing the same.
The present invention specifically relates to the novel polymorphic crystals (A) to (C) of donepezil represented by the following formula:
which are characterized by a powder X-ray diffraction pattern and/or IR absorption peaks in potassium bromide.


REFERENCES:
patent: 5985864 (1999-11-01), Imai et al.
patent: 179151 (1989-03-01), None
patent: 1053576 (1998-02-01), None
patent: A1-9746527 (1997-12-01), None
Kryger et al, J. Physiol. Paris, vol. 92, # 3-4, pp. 191-194, Jun. 1998.*
Kawakami et al, Bioorg. Med. Chem., vol. 4, # 9, pp. 1429-1446, Sep. 1996.

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