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Novel process for production of highly pure polymorph (I) donepezil hydrochloride

A kind of technology of donepezil hydrochloride and donepezil base, applied in the field of 1-benzyl-4-[-2-yl]methylpiperidine hydrochloride, can solve the problem of expensive method, can not avoid the risk of insufficient hydrogenation and overhydrogenated products , can not completely control the hydrogenation and other problems

Inactive Publication Date: 2009-01-07
RICHTER GEDEON NYRT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The use of this catalyst not only makes the process too expensive, but also involves the risk of not being able to fully control the hydrogenation and not avoiding the generation of underhydrogenated and overhydrogenated products

Method used

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  • Novel process for production of highly pure polymorph (I) donepezil hydrochloride
  • Novel process for production of highly pure polymorph (I) donepezil hydrochloride
  • Novel process for production of highly pure polymorph (I) donepezil hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Example 1: Preparation of 2-(4-piperidinylmethyl)-5,6-dimethoxy-1-indanone-p-toluenesulfonic acid according to Example 2 in PCT publication No.WO 2005 / 044805A1 Salt reproduction experiment:

[0057] 4.02 g of 2-(4-pyridyl (piridyl) methylene)-5,6-dimethoxy-1-indanone p-toluenesulfonate were dissolved in 300 ml of absolute methanol, followed by addition of 330 mg PtO 2 catalyst, and the mixture was hydrogenated for 10.5 hours at atmospheric pressure with stirring at room temperature. The solid was filtered off and washed with 50 mL of anhydrous methanol. The liquid phase was evaporated to dryness, the residue was dissolved in 150 ml of dry isopropanol while heating, and the solution was cooled to crystallize to obtain 2.02 g of the title compound. The mother liquor was evaporated to a volume of 15ml to give a further 0.46g of material. The two fractions were combined to obtain 2.86 g of the title compound.

[0058] The results of the HPLC analysis on the product con...

Embodiment 2

[0060] Embodiment 2: Preparation of 2-(4-piperidinylmethyl)-5,6-dimethoxy-1-indanone hydrochloride according to Example 2 in PCT publication No.WO 2005 / 044805A1 Reproduce experiment:

[0061] 3.17 g of 2-(4-pyridylmethylene)-5,6-dimethoxy-1-indanone hydrochloride was dissolved in 300 mL of anhydrous methanol, followed by the addition of 330 mg of PtO 2 catalyst, and the mixture was hydrogenated for 10.5 hours at atmospheric pressure with stirring at room temperature. The solid was filtered off and washed with 50 mL of anhydrous methanol. The liquid phase was evaporated to dryness, the residue was dissolved in 150 ml of anhydrous isopropanol while heating, and the solution was cooled to 0°C for crystallization to obtain 2.02 g of the title compound. The mother liquor was evaporated to a volume of 15ml to give a further 1.11g of material. The two fractions were combined to obtain 3.13 g of the title compound.

[0062] The results of the HPLC analysis on product content are s...

Embodiment 3

[0064] Example 3: 200 liters of acetic acid, 2.2 kg of charcoal containing 10% palladium suspended in 22 liters of acetic acid and 22.24 kg of 4-[(5,6-dimethoxy-1-indanone)-2- Subunit]-methyl-pyridine hydrochloride (IV) was measured into a 500 liter inert hydrogenation autoclave, and the mixture was hydrogenated at 68-72° C. under a 5-atm overpressure while vigorously stirring until the pressure dropped to until the end. The autoclave was cooled to 20-25°C and the catalyst was filtered off. The filtrate was concentrated in vacuo to a volume of 66 liters, to which 72 liters of methyl-isobutyl-ketone were then added dropwise with stirring. The crystalline material was filtered off and washed with methyl-isobutyl-ketone. The wet material was dissolved in 210 liters of boiling methanol, which was then cooled to 0-5°C. The crystalline material was filtered off, washed and dried to obtain 15.12 kg of 4-[(5,6-dimethoxy-1-indanon)-2-yl]-methyl-piperidine (V).

[0065] The results ...

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Abstract

The present invention provides a novel, industrially realisable and economically preferable process for production of highly pure l-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-yl]methyl piperidine hydrochloride, i.e., donepezil hydrochloride shown in the following reaction scheme, in Polymorph (I) morphological crystal form. (I) In one of the key steps of the process, during the hydrogenation 5,6-dimethoxy-2-(pyridine-4-yhnethylene)indan-l-one hydrochloride is saturated using Pd carbon to get 4-[(5,6-dimethoxy-l-indanon)-2-yl]-methyl piperidine at more than 97 % HPLC purity. In the crystallization step donepezil-hydrochloride is crystallized from an aqueous alcoholic solvent to get Polymorph (I) in at least 99.95 % HPLC purity.

Description

technical field [0001] The present invention relates to donepezil hydrochloride (donepezil) for the preparation of high-purity polymorph (I) morphological crystal form, that is, 1-benzyl-4-[(5,6-dimethoxy-1- Indanone)-2-yl]methylpiperidine hydrochloride. Background technique [0002] Donepezil hydrochloride of formula I is known for its excellent anti-acetylcholinesterase activity, and it is an effective active ingredient in pharmaceutical preparations for the treatment and prevention of diseases such as Alzheimer's disease and senile dementia. [0003] [0004] Several methods are known for the preparation of donepezil hydrochloride. Most of them involve the catalytic hydrogenation of ethylene double bonds ("ylide" bonds) in the side chains and / or of the pyridine ring. Some of these methods employ hydrogenation after benzylation. According to Example 4 of European Patent No. 296,560, as shown in the next scheme, by reducing 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yli...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/02C07D211/32
CPCC07D211/02C07D211/32A61P25/28
Inventor J·诺伊I·格赖纳J·乔鲍伊S·高劳德瑙伊
Owner RICHTER GEDEON NYRT
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