Preparation method of donepezil hydrochloride

A technology for forming donepezil hydrochloride and salt formation is applied in the field of preparation of donepezil hydrochloride, which can solve the problems of many steps, low yield and the like, and achieves the effects of mild reaction conditions, high yield and reduced production cost

Active Publication Date: 2016-03-23
SHANDONG LUOXIN PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] With diethyl malonate as the starting material, donepezil hydrochloride is prepared through five-step reactions including condensation, reduction, substitution, and final ring-closing decarboxylation. There are many steps and the yield is low.

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Using 1-ethyl-3-methylimidazole-aluminum chloride as the ionic liquid catalytic system, the specific steps are as follows:

[0029] [Emim]Cl-AlCl 3 Preparation of (Emim=1-ethyl-3-methylimidazole)

[0030] A stirrer was installed on the reaction kettle, and 26.67g (0.2mol) of anhydrous aluminum trichloride was added under nitrogen protection, and 29.3g (0.2mol) of 1-ethyl 3-methylimidazole chloride was added in batches, and kept Stir at around 50°C for 3 hours to ensure complete reaction and produce transparent light yellow [Emim]Cl-AlCl 3 ionic liquid.

[0031] Preparation of 1-benzyl-4-(5,6-dimethoxy-1-indanone-2-methylene)-piperidine (Ⅳ)

[0032] Under nitrogen protection, 22.9 g (0.1 mol) of 3-chloro-1-(3,4-dimethoxyphenyl) propan-1-one (II), N-benzyl-4 -Piperidinyl formaldehyde (Ⅲ) 20.3g (0.1mol), [Emim]Cl-AlCl 3 (0.2mol), control the temperature at 40-45°C and maintain the time for 4.5 hours, raise the temperature to 145-155°C and maintain the reaction for 5.5...

Embodiment 2

[0035] Preparation of ionic liquids

[0036] Install a stirrer on the reactor, add 27.3g (0.2mol) of anhydrous ZnCl under nitrogen protection 2 , 34.9 g (0.2 mol) of 1-butyl-3-methylimidazole chloride ([Bmim]Cl) was added in portions. After adding the imidazolium salt, keep stirring at about 40°C for 3 hours to ensure that the reaction is complete, and a colorless and transparent [Bmim]Cl-ZnCl is obtained 2 ionic liquid.

[0037] Preparation of 1-benzyl-4-(5,6-dimethoxy-1-indanone-2-methylene)-piperidine (Ⅳ)

[0038] Under nitrogen protection, 22.9 g (0.1 mol) of 3-chloro-1-(3,4-dimethoxyphenyl) propan-1-one (II), N-benzyl-4 -Piperidinyl formaldehyde (Ⅲ) 20.3g (0.1mol), [Bmim]Cl-ZnCl 2 (0.2mol), control the temperature at 45-50°C and maintain it for 4 hours, raise the temperature to 155-165°C and maintain the reaction for 5 hours, monitor the end point of the reaction by TLC, after the reaction, cool down to room temperature, the product and the ionic liquid are automatica...

Embodiment 3

[0040] Preparation of ionic liquids

[0041] Install a stirrer on the reaction kettle, add 40.0g (0.3mol) of anhydrous AlCl under nitrogen protection 3 , add 27.5g (0.2mol) triethylamine hydrochloride ([Et 3 NH]Cl). After adding triethylamine hydrochloride, keep stirring at about 60°C for 3 hours to ensure complete reaction and obtain transparent [Et 3 NH]Cl-AlCl 3 ionic liquid.

[0042] Preparation of 1-benzyl-4-(5,6-dimethoxy-1-indanone-2-methylene)-piperidine (Ⅳ)

[0043] Under nitrogen protection, 22.9 g (0.10 mol) of 3-chloro-1-(3,4-dimethoxyphenyl) propan-1-one (II), N-benzyl-4 -Piperidinyl formaldehyde (Ⅲ) 22.4g (0.11mol), [Et 3 NH]Cl-AlCl 3 (2:3, by AlCl 3 Calculated as 0.3mol), control the temperature at 55-60°C and maintain it for 5 hours, raise the temperature to 165-175°C and maintain the reaction for 6 hours, TLC monitors the end point of the reaction, after the reaction, cool down to room temperature, the product and the ionic liquid are automatically sep...

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PUM

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Abstract

The invention discloses a preparation method of donepezil hydrochloride. The preparation method comprises the steps that 3-chlorine-1-(3, 4-dimethoxy phenyl) propane-1-ketone (II) is made to react with N-benzyl-4-formyl-piperidine (III) under the condition of a lewis acid ionic liquid catalyst, and 1-benzyl-4-(5, 6dimethoxy-1-indanone-2-methylene)-piperidine (IV) is obtained through a one-pot method, and then the donepezil hydrochloride (I) is obtained through reduction and salt formation. The preparation method of the donepezil hydrochloride has the advantages of being simple in process, low in production cost, environmentally friendly and suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, in particular to a preparation method of donepezil hydrochloride. Background technique [0002] Donepezil hydrochloride is an acetylcholinesterase inhibitor developed by Japan's Eisai Company for the treatment of Alzheimer's dementia (AD). It has the advantages of high selectivity, small dose, long half-life, small adverse reactions, and no liver toxicity. The chemical name is: 1-benzyl-4-[(5,6-dimethoxyindanon-2-yl)methyl]piperidine hydrochloride. The structural formula of donepezil hydrochloride (I) is as follows: [0003] [0004] Its existing process route is synthesized as follows: [0005] 1) The synthetic route reported by CN201010600277.X, using N-benzyl-4-piperidinecarboxylic acid as raw material to prepare compound 4, compound 4 and compound 5 undergo aldehyde and ketone condensation reaction under strong alkali conditions, and then undergo reduction and salt formation ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/32
CPCC07D211/32
Inventor 孙松刘桂军李文婷
Owner SHANDONG LUOXIN PHARMA GRP CO LTD
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