Process for production of donepezil derivative

Details Process for production of donepezil derivative Process for production of donepezil derivative

2000-06-27

2001-06-26

Morris, Patricia L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S340000, C546S343000, C546S347000

Reexamination Certificate

active

06252081

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel industrial process for production of medicaments disclosed in JP-A 64-79151(1989) (EP-296,560-A1, U.S. Pat. No. 4,895,841), specifically, Donepezil derivative having an excellent pharmacological action as prophylactic or medicament for senile dementia, especially for Alzheimer disease, and synthetic intermediates thereof. More specifically, it relates to a process for production of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine (free base) as a synthetic precursor of Donepezil Hydrochloride (chemical name; 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine hydrochloride) disclosed in Example 4 of the aforementioned specification.
PRIOR ARTS
As it was disclosed in Example 3 and 4 of JP-A 64-79151(1989), indanone derivative was produced by reacting 5,6-dimethoxy-1-indanone with 1-benzyl-4-formylpiperidine in the presence of strong base such as lithium diisopropylamide (Example 3), followed by reduction (Example 4) for example. According to this method, yield for Donepezil through Example 3 and 4 was 50.8% (62%×82%).
Additionally, it is disclosed in Example 2, 4 and 6 of JP-A 8-225527 (1996) (EP-711,756-A1, U.S. Pat. No. 5,606,064) that reaction of 5,6-dimethoxy-1-indanone with pyridin-4-aldehyde afforded 5,6-dimethoxy-2-(pyridin-4-yl)methyleneindan-1-one (Example 2), followed by reaction with benzyl bromide afforded 1-benzyl-4-(5,6-dimethoxyindan-1-on-2-ylidene)methylpiridinium bromide (Example 4), then reduction in the presence of platinum oxide afforded Donepezil (Example 6). According to this method, yield for Donepezil through Example 2, 4 and 6 was 58.5% (87%×83%×81%).
Moreover, it is disclosed in Preparation Example 1 to 3 and Example 1 to 6 of WO97/22584 that reaction of (pyridin-4-yl) carboxyaldehyde with malonic acid afforded 3-(pyridin-4-yl) -2-propenoic acid (Preparation 1), followed by reduction afforded 3- (piperidin-4-yl) -2-propionic acid (Preparation 2), followed by reaction with methyl chlorocarbonate afforded 3-[N- (methoxycarbonyl) piperidin-4-yl] propionic acid (Preparation 3), followed by reaction with oxalyl chloride afforded methyl 4-(2-chlorocarbonylethyl)piperidin-1-carboxylate (Example 1), followed by reaction with 1,2-dimethoxybenzene in the presence of aluminum chloride afforded methyl 4-[3-(3,4-dimethoxyphenyl)-3-oxopropyl]piperidin-1-carboxylate (Example 2), followed by reaction with tetramethyldiaminomethane afforded methyl 4-[2-(3,4-dimethoxybenzoyl)allyl]piperidin-1-carboxylate (Example 3), followed by treatment with sulfuric acid afforded methyl 4-(5,6-dimethoxy-1-oxoindan-2-ylmethyl) piperidin-1-carboxylate (Example 4), followed by treatment with base afforded 5,6-dimethoxy-2-(piperidin-4-ylmethyl)indan-1-one (Example 5), then reaction with benzyl bromide afforded Donepezil (Example 6).
Yield of Example 1 was not disclosed in this specification though, even it is supposed as 100%, total yield through all the steps was 19.3% (70%×84%×100%×68%×79%×61%).
However, maximum total yield for Donepezil from the generally used starting material was 58.5% in JP-A 8-225527 (1996), next was 50.8% in JP-A 64-79151 (1989), and the lowest was 19.3% in WO97/22584. Therefore, it was not sufficient in either case as an industrial process.
Additionally, the maximum yield among all was the method of JP-A 8-225527(1996), however, yield of reduction in the last step was not reproducible, it, therefore, is assumed that the yield is inferior to JP-A 64-79151(1989) actually. (See Reference example described below.) Even the yield disclosed in this specification was correct, the total yield was not superior to Prior Arts (50.8%, a yeild throughout all the steps in JP-A64-79151(1989)), therefore, it did not show any superior effects.
Accordingly, there was no industrially or economically preferable process for Donepezil derivative having an excellent pharmacological action as prophylactic or medicament for senile dementia, especially for Alzheimer disease increasing the numbers of patients dramatically and having much social interest.
SUMMARY OF THE INVENTION
Regarding the foregoing problems, the present inventors have proceeded with extensive research. As a result, it has been found surprisingly that a reaction using a novel quaternary ammonium salt (I) affords 82.5% of total yield from a generally used material to Donepezil derivative, establishing the present invention.
Namely, the present invention provides an industrially preferable process for production of Donepezil and synthetic intermediates thereof.
The invention provides a process for producing a hydrogen halogenide salt of a Donepezil derivative (II) represented by the following formula;
(wherein R
1
, represents, the same as or different from each other, a hydrogen atom or a lower alkoxy group; n represents an integer of 1 to 4; and X represents a halogen atom.), comprising the step of reducing a quaternary ammonium salt (I) represented by the following formula;
(Wherein R
1
, n and X have the same meaning as defined above).
The invention provides a process for producing a Donepezil derivative from the salt (II) according to a conventional neutralization and then a process for producing a pharmacologically acceptable salt of the Donepezil derivative according to a conventional reaction to form such a salt.
The invention provides a quaternary ammonium salt (I) represented by the following formula;
(Wherein R
1
, n and X have the same meaning as defined in claim
1
.).
Details for the present invention is one of the following processes for Donepezil.
(1) reduction of quaternary ammonium salt (I),
(2) reaction of 2-(4-pyridyl)methyl-1-indanone derivative (III) with halogenated benzyl to obtain quaternary ammonium salt (I), then reduction of (I),
(3) reaction of 2-alkoxycarbonyl-1-indanone derivative (IV) with halogenated (4-pyridyl)methyl (V) or a salt thereof and decarboxylation successively to obtain 2-(4-pyridyl)methyl-1-indanone derivative (III), then reaction of (III) with halogenated benzyl to obtain quaternary ammonium salt (I), then reduction of (I) or
(4) reaction of 1-indanone derivative (VI) with carbonate ester (VII) to obtain 2-alkoxycarbonyl-1-indanone derivative (IV), followed by reaction of (IV) with halogenated (4-pyridyl)methyl (V) or a salt thereof and decarboxylation successively to obtain 2-(4-pyridyl)methyl-1-indanone derivative (III), then reaction of (III) with halogenated benzyl to obtain quaternary ammonium salt (I), then reduction of (I).
These processes are illustrated in the following chemical reaction scheme.
(Wherein R
1
, R
2
, n and X have the same meaning as defined above.)
Quaternary ammonium salt (I) in the present invention is represented by the following formula.
Wherein R
1
represents, same as or different from each other, a hydrogen atom or a lower alkoxy group, n represents an integer of 1 to 4 and X represents a halogen atom.
Lower alkoxy group herein means a straight or branched lower alkyl group having 1 to 6 carbon atoms bonded with oxygen atom, for example, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, pentyloxy or hexyloxy group. Among these, methoxy group, in particular 5, 6-dimethoxy, is preferable on the basis of pharmacological effect or safety for Donepezil derivative as a final compound.
Halogen atom herein represents bromine atom, chlorine atom, iodine atom or fluorine atom, and among them, bromine atom, chlorine atom or iodine atom affords preferable results.
Concrete examples for the quaternary ammonium salt (I) are in the following, however the invention is not limited to these examples only.
(1) 1-benzyl-4-(1-indanon-2-yl)methylpiridinium chloride,
(2) 1-benzyl-4-[(4-methoxy-1-indanon)-2-yl]methylpiridinium chloride,
(3) 1-benzyl-4-[(5-methoxy-1-indanon)-2-yl]methylpiridinium chloride,
(4) 1-benzyl-4-[(6-methoxy-1-indanon)-2-yl]methylpiridinium chloride,
(5) 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]met

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