Preparation method of donepezil

A technology of donepezil and production method, which is applied in the field of donepezil production technology, can solve the problems of product purity decrease, high price, poor reduction stability, etc., and achieve the effects of product purity improvement, small equipment investment and short reaction time

Inactive Publication Date: 2010-06-09
浙江东亚药业股份有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The inventor has found through tests that the reduction stability of the last step of the process of the method is very poor, and there are mainly the following problems: (1) because the benzyl group is easy to take off during the reduction process to generate more impurities, it needs repeated refining to remove , leading to low and unstable hydrogenation yields
(2) Use platinum dioxide as a catalyst, which is expensive and difficult to rec

Method used

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  • Preparation method of donepezil
  • Preparation method of donepezil
  • Preparation method of donepezil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Hydrate (4) 28.9g (0.1mol), sodium bicarbonate 12.6g (0.15mol), tetrabutylammonium bromide 1.6g (5.0mmol), benzyl methanesulfonate 19.5g (0.105mol) and 300ml formazan mixed with isobutyl ketone, heated to 50°C, reacted for 4 hours, cooled to room temperature, successively washed with 1% (wt) sodium hydroxide aqueous solution and water, dried over anhydrous sodium sulfate, filtered off the desiccant and evaporated to dryness 35 g of white solid was obtained, yield 92.3%, melting point: 91-93° C., HPLC>97.5%.

[0028] MS(TOF): 380(M + +H + );402(M + +K + )

[0029] 1 HNMR (400Hz, CDCl 3 )δ: 7.23-7.32 (5H, m), 7.16 (1H, s), 6.85 (1H, s), 3.90-3.95 (6H, s), 3.50 (2H, s), 3.19-3.26 (1H, m) , 2.87-2.92(2H, m), 2.66-2.72(2H, m), 1.88-2.01(3H, m), 1.64-1.75(2H, m), 1.46-1.51(1H, m), 1.37-1.42( 3H, m).

Embodiment 2

[0031] The hydride (4) 28.9g (0.1mol), sodium bicarbonate 12.6g (0.15mol), tetramethylammonium bromide 0.77g (5.0mmol), benzyl methanesulfonate 19.5g (0.105mol) and 300ml formazan mixed with isobutyl ketone, reacted at 0°C for 5 hours, then washed with 1% (wt) aqueous sodium hydroxide solution, washed with water, dried over anhydrous sodium sulfate, filtered off the desiccant and evaporated to dryness to obtain 34.4 g of a white solid. The yield was 90.8%, and HPLC>97.5%.

Embodiment 3

[0033] Hydride (4) 28.9g (0.1mol), potassium bicarbonate 15.0g (0.15mol), tetramethylammonium chloride 0.77g (5.0mmol), benzyl methanesulfonate 19.5g (0.105mol) and 300ml formazan Base isobutyl ketone mixed, reflux reaction for 2 hours, then after washing with 1% (wt) aqueous sodium hydroxide solution, water, anhydrous sodium sulfate, filter off the desiccant and evaporate the solvent to dryness to obtain white solid 34.5g, yield 91.0 %, HPLC>97.5%.

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Abstract

The invention provides a preparation method of donepezil. The method comprises the following steps: using hydride (4) and substituted benzyl ester of substituted sulfuric acid to perform the condensation reaction, and then collecting donepezil (1) from the reaction product. The method of the invention can not generate impurities, the purity of the obtained product is greatly increased, the yield is up to 85%, the reaction time is as short as 2-5 hours, the operation is simple, the stability is good, the equipment investment is small and the method is applicable to industrial production. The reaction formula is shown below.

Description

technical field [0001] The invention relates to a production process of donepezil. technical background [0002] Donepezil hydrochloride (1) is an acetylcholinesterase inhibitor (AchEI) developed by Japan's Eisai Pharmaceutical Company, which was first launched in the United States in 1997. This product is highly selective for neuronal acetylcholinesterase, has no liver toxicity, and is clinically used for the treatment of Alzheimer's disease. Donepezil is the raw material of donepezil hydrochloride, and donepezil hydrochloride can be obtained by making donepezil hydrochloride. Bibliographical information synthetic donepezil method mainly contains two big classes: [0003] Method 1: EP0711756A1 reacts 5,6-dimethoxy-2-(4-pyridyl)methylene]-1-indanone (2) with benzyl bromide to generate quaternary ammonium salt (3), and then use Platinum oxide catalytic hydrogenation obtains donepezil (1), and the general reaction formula is as follows: [0004] [0005] Method 2, US200...

Claims

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Application Information

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IPC IPC(8): C07D211/32A61P25/28
Inventor 赵建宏刘强池正明
Owner 浙江东亚药业股份有限公司
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