Synthetic method of 2-((1-benzyl-4-piperidyl)-hydroxy-methyl)-5, 6-dimethoxy-1-indanone

A technology of dimethoxy, benzyl piperidine, applied in the field of organic synthesis, can solve the problems of insufficient reduction of pyridine ring, increased production cost of enterprises, low purity of target product, etc., achieves easy control, reduced production cost, and improved production The effect of high safety

Inactive Publication Date: 2012-06-27
JINAN CHENGHUI SHUANGDA CHEM
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  • Summary
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  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

According to the synthetic method disclosed by this product, 5,6-dimethoxy-1-indanone and methyl 4-pyridinecarboxylate are used as starting materials, and the target product is obtained by hydrogenation after benzylation. This synthetic method The disadvantage is that when hydrogenation is needed in the last step, the by-products of debenzylation and insufficient reduction of the pyridine ring will be generated, resulting in a low purity of the target product of synthesis, generally below 65%, and the yield is generally About 60%
The 2-((1-benzyl-4-piperidinyl)-hydroxy-methyl)-5,6-dimethoxy-1-indanone synthesized by this method needs to be further refined and purified in the middle and downstream enterprises , bring more inconvenience to the enterprise and increase the production cost of the enterprise

Method used

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preparation example Construction

[0016] A kind of synthetic method of 2-((1-benzyl-4-piperidinyl)-hydroxyl-methyl)-5,6-dimethoxy-1-indanone according to the present invention comprises the following steps :

[0017] ①Use methanol, thionyl chloride, and 4-piperidinecarboxylic acid to synthesize methyl 4-piperidinecarboxylic acid, use benzyl chloride as benzyl and triethylamine for benzylation to obtain N-benzyl-4-piperidinecarboxylic acid Methyl ester, the mass ratio of materials used is: methyl alcohol: thionyl chloride: 4-piperidinecarboxylic acid: benzyl chloride: the ratio of triethylamine is 6.67:3.08:1:1:1.52;

[0018] ② Use N-benzyl-4-piperidinecarboxylic acid methyl ester and 5,6-dimethoxy-1-indanone to obtain 2-(1-benzylpiperidine-4-carbonyl)-5 , 6-dimethoxy-1-indanone, the mass ratio of the materials used is: methyl N-benzyl-4-piperidinecarboxylate: the ratio of sodium methoxide (25% methanol solution) is 1.4:1.13;

[0019] ③Reduce 2-(1-benzylpiperidine-4-carbonyl)-5,6-dimethoxy-1-indanone with sod...

Embodiment 1

[0023] Specific steps are as follows:

[0024] ①Preparation of methyl N-benzyl-4-piperidinecarboxylate: put 100kg of methanol into the reaction kettle, add 46.24kg of thionyl chloride dropwise under temperature control at 15°C, add 15kg of 4-piperidinecarboxylic acid after the dropwise addition, Keep warm at 15°C for 30 minutes, then raise the temperature to 25°C for 20 hours, evaporate the solvent under reduced pressure after the reaction, wash the solid with 15kg of isopropyl ether, filter and dry in vacuum for 4 hours, add 100kg of di Chloromethane, after cooling to 10°C with ice water, add 14.96kg of benzyl chloride dropwise, the reaction temperature is controlled at 10°C, after the benzyl chloride has been added dropwise, add 22.86kg of triethylamine dropwise, and keep warm at 10°C for 30 minutes. Raise the temperature to 25°C and react for 20 hours. After the reaction, the solvent was evaporated under reduced pressure, and the oil was washed twice with 30 kg of water, an...

Embodiment 2

[0028] Specific steps are as follows:

[0029]①Preparation of methyl N-benzyl-4-piperidinecarboxylate: put 100kg of methanol into the reaction kettle, add 46.24kg of thionyl chloride dropwise under temperature control at 15°C, add 15kg of 4-piperidinecarboxylic acid after the dropwise addition, Keep warm at 15°C for 30 minutes, then raise the temperature to 25°C for 20 hours, evaporate the solvent under reduced pressure after the reaction, wash the solid with 15kg of isopropyl ether, filter and dry in vacuum for 4 hours, add 100kg of di Chloromethane, after cooling to 10°C with ice water, add 14.96kg of benzyl chloride dropwise, the reaction temperature is controlled at 10°C, after the benzyl chloride has been added dropwise, add 22.86kg of triethylamine dropwise, and keep warm at 10°C for 30 minutes. Raise the temperature to 25°C and react for 20 hours. After the reaction, the solvent was evaporated under reduced pressure, and the oil was washed twice with 30 kg of water, and...

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Abstract

The invention discloses a synthetic method of 2-((1-benzyl-4-piperidyl)-hydroxy-methyl)-5, 6-dimethoxy-1-indanone, which comprises the following steps of: 1) synthesizing 4-methyl piperidinecarboxylate with methanol, thionyl chloride and 4-nipecotic acid, carrying out benzylation on benzyl chloride taken as benzyl and triethylamine to obtain N-benzyl-4-methyl piperidinecarboxylate; 2) reacting the N-benzyl-4-methyl piperidinecarboxylate with 5, 6-dimethoxy-1-indanone under the catalysis of sodium methoxide to obtain 2-(1-benzylpiperidine-4-carbonyl)-5, 6-dimethoxy-1-indanone; 3) carrying out reducing reaction on the 2-(1-benzylpiperidine-4-carbonyl)-5, 6-dimethoxy-1-indanone with sodium borohydride in methanol to obtain the 2-((1-benzyl-4-piperidyl)-hydroxy-methyl)-5, 6-dimethoxy-1-indanone; and the reaction formula is shown in the specifications. The synthetic method has the beneficial effects that the defects of the prior art can be overcome, the product purity can be further improved, and the production cost can be reduced.

Description

technical field [0001] The invention relates to a synthesis method of organic matter, which is a synthesis method of 2-((1-benzyl-4-piperidinyl)-hydroxyl-methyl)-5,6-dimethoxy-1-indanone. Background technique [0002] 2-((1-benzyl-4-piperidinyl)-hydroxy-methyl)-5,6-dimethoxy-1-indanone is an intermediate of donepezil, used for localization of donepezil impurities, it The structural formula is: [0003] . [0004] The products currently in use are all imported products. According to the synthetic method disclosed by this product, 5,6-dimethoxy-1-indanone and methyl 4-pyridinecarboxylate are used as starting materials, and the target product is obtained by hydrogenation after benzylation. This synthetic method The disadvantage is that when hydrogenation is needed in the last step, the by-products of debenzylation and insufficient reduction of the pyridine ring will be generated, resulting in a low purity of the target product of synthesis, generally below 65%, and the yie...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/32
Inventor 于东海皇甫功凯杨彦军
Owner JINAN CHENGHUI SHUANGDA CHEM
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