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Novel donepezil synthesis process

A technique for the synthesis of donepezil hydrochloride, which is applied in the direction of organic chemistry, can solve problems such as difficulty in industrialized large-scale production, and achieve the effects of low price, easy control, and good reaction selectivity

Inactive Publication Date: 2008-11-26
PKUCARE PHARMA R&D CENT +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Therefore, it is not easy to industrialize large-scale production

Method used

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Examples

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Effect test

Embodiment 1

[0032] The preparation of compound 4'-(1'-Boc-piperidinyl) methylene malonate diethyl ester (II):

[0033] Dissolve 3.4g (0.014mol) of 1-Boc piperidine formaldehyde in 50mL of toluene, add 2.3g (0.014mol) of diethyl malonate, 0.17g (0.002mol) of piperidine and 0.12g (0.002mol) of glacial acetic acid , 140 ° C water reaction 8h. 50 mL of water and 50 mL of ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed twice with 60 mL of saturated NaCl, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 4.3 g of light yellow oil (II). Yield 75%.

Embodiment 2

[0035] The preparation of compound 4'-(1'-Boc-piperidinyl) methylene malonate diethyl ester (II):

[0036] Dissolve 3.4g (0.014mol) of 1-Boc piperidine formaldehyde in 50mL of benzene, add 2.3g (0.014mol) of diethyl malonate, 0.17g (0.002mol) of piperidine and 0.12g (0.002mol) of glacial acetic acid , 90 ° C water reaction for 12h. 50 mL of water and 50 mL of ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed twice with 60 mL of saturated NaCl, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 3.7 g of light yellow oil (II). Yield 66%.

Embodiment 3

[0038] The preparation of compound 4'-(1'-Boc-piperidinyl) diethyl methylmalonate (III):

[0039] Dissolve 3.8g (0.011mol) of the above oil (II) in 25mL of methanol, add NaBH in batches under ice-cooling 4 0.45g (0.012mol), stirred and reacted for 3h, after the reaction was completed, 1mL of concentrated hydrochloric acid and 25mL of water were added, extracted with 50mL of ethyl acetate, the ethyl acetate layer was separated, dried over anhydrous sodium sulfate, concentrated to give a light yellow oil (III )3.6g, yield 94.2%.

[0040] 1 HNMR (300MHz, CDCl 3 )δ: 4.19 (q, J=7.1Hz, 4H, CH 2 ), 4.09-4.05 (m, 2H, NCH 2 ), 3.45-3.40 (t, J=7.5Hz, 1H, CH), 2.68-2.59 (m, 2H, NCH 2 ), 1.84(t, J=7.3Hz, 2H, CH 2 ), 1.67-1.65 (m, 3H, piperidine ring), 1.44 (s, 9H, CH 3 ), 1.28-1.24 (t, J=7.5Hz, 6H, CH 3 ), 1.16-1.07 (m, 2H, piperidine ring).

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Abstract

The invention discloses a novel process for synthesizing Donepezil by using diethyl malonate as the starting raw material, which comprises condensation, reduction, substitution, cycling reaction and decarboxylation.

Description

technical field [0001] The invention relates to a synthesis process of donepezil hydrochloride. Background technique [0002] Donepezil hydrochloride (Donepezil) is a second-generation reversible acetylcholinesterase inhibitor developed by Japan's Eisai Pharmaceutical Company in the late 1980s. It was approved by the US FDA in 1996 and is currently on the market in more than 40 countries and regions around the world. . Donepezil hydrochloride is a highly selective, long-acting and reversible acetylcholinesterase inhibitor, which mainly increases the concentration of important neurotransmitter - acetylcholine by specifically inhibiting the activity of acetylcholinesterase in the brain, thereby delaying the development of Alzheimer's disease. Alzheimer's disease (AD) patients have memory loss, improve their cognitive function, and improve the self-care ability of patients. Compared with the first-generation reversible acetylcholinesterase inhibitor tacrine (tacrine), donepez...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/32
Inventor 梁国祥贺清凯
Owner PKUCARE PHARMA R&D CENT
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