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Method for synthesizing N-benzyl-4-piperidinecarboxylate

A technology of piperidinic acid and a synthesis method, applied in the field of medicine and chemical industry, can solve the problems of increasing production cost, easy oxidation, and reducing overall yield, and achieves the effects of reducing raw material cost, reducing environmental protection pressure, and reducing time cost.

Active Publication Date: 2018-04-06
山东诚汇双达药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are several problems in this method: benzaldehyde is easily oxidized in the reaction, and nitrogen should be needed for protection in the reaction; there is also NaBH(OAc) 3 Reagents are expensive, which pushes up production costs, and the reaction time is too long, etc.
Although the problem of oxidation and long reaction time in the reaction is avoided, the price of benzyl bromide is more expensive
In addition, the solvent acetonitrile after the reaction is difficult to recover and apply mechanically because of miscibility with water; although methylene chloride can be applied mechanically, the solvent recovery rate is low because of its low boiling point
[0005] In addition, GB2351733 reported that benzyl bromide was used as raw material, and N,N-diisopropylethylamine was used as an acid-binding agent to react to obtain N-benzyl-4-piperidinecarboxylic acid methyl ester with a yield of 85%, and then hydrolyzed to obtain N- Benzyl-4-piperidinecarboxylic acid; overall yield will be lower

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Add 1500g of dichloromethane into a 3000ml reaction flask, add 129.16g of 4-piperidinecarboxylic acid and 121.43g of triethylamine under stirring, and add 139.24g of benzyl chloride under temperature control below 20°C. After dropping, the temperature was slowly raised to reflux for 24 hours, the reaction solution was lowered to room temperature, and 600 g of water was added to stir evenly, and the liquid was separated; the organic layer was washed by adding 300 g of saturated saline, and the organic layer was separated and dried; the obtained filtrate was filtered and concentrated to obtain the oil N-benzyl -4-piperidinecarboxylic acid 197.79g; molar yield 90.2%, liquid phase purity 96.53%.

Embodiment 2

[0034] Add 775g of 1,2-dichloroethane into a 2000ml reaction flask, add 129.16g of 4-piperidinecarboxylic acid and 155.1g of diisopropylethylamine under stirring, and add 139.24g of benzyl chloride under temperature control below 20°C. After dropping, slowly raise the temperature to 83.5°C for reflux reaction for 8.5h, then drop the reaction solution to room temperature, add 300g of water, stir evenly, and separate the liquids; add 150g of saturated saline to the organic layer, wash the organic layer, separate and dry the organic layer; - Benzyl-4-piperidinecarboxylic acid 201.52g; molar yield 91.9%, liquid phase purity 96.81%.

Embodiment 3

[0036] Add 775g of 1,2-dichloroethane into a 2000ml reaction flask, add 129.16g of 4-piperidinecarboxylic acid and 131.55g of triethylamine under stirring, and add 189.87g of benzyl chloride under temperature control below 20°C. After dropping, the temperature was slowly raised to 83.5°C for reflux reaction for 10 hours, the reaction liquid was lowered to room temperature, and 300 g of water was added to stir evenly, and the liquid was separated; the organic layer was washed by adding 150 g of saturated saline, and the organic layer was separated and dried; the obtained filtrate was filtered and concentrated to obtain an oily substance N- Benzyl-4-piperidinecarboxylic acid 201.96g; molar yield 92.1%, liquid phase purity 97.21%.

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PUM

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Abstract

The invention belongs to the technical field of pharmaceutical chemicals and in particular discloses a method for synthesizing N-benzyl-4-piperidinecarboxylate. The process comprises the following steps: by taking isonipecotic acid and benzyl chloride as raw materials and taking 1,2-dichloroethane as a solvent, heating and reacting, adding water to wash after cooling, drying the organic layer, filtering and concentrating, thereby obtaining the N-benzyl-4-piperidinecarboxylate. According to the synthetic method, the used solvent 1,2-dichloroethane is concentrated and collected and can be recycled, the method is environmentally friendly, and the cost of the raw materials is greatly reduced.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to a synthesis method of N-benzyl-4-piperidinecarboxylic acid. Background technique [0002] N-benzyl-4-piperidinecarboxylic acid is an important pharmaceutical and chemical intermediate, and has received extensive attention in the pharmaceutical and chemical industries. In the field of medicine, N-benzyl-4-piperidinecarboxylic acid is an important intermediate of donepezil hydrochloride, a long-acting Alzheimer's disease symptomatic drug. Donepezil hydrochloride is a second-generation cholinesterase inhibitor. Its therapeutic effect is to reversibly inhibit the hydrolysis of acetylcholine caused by acetylcholinesterase and increase the content of acetylcholine at the receptor site. Donepezil has other mechanisms, including direct effects on peptide disposition, neurotransmitter receptors, or calcium ion channels; therefore, it is suitable for mil...

Claims

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Application Information

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IPC IPC(8): C07D211/62
CPCC07D211/62
Inventor 李跃东王庭见刘学文孙宝亮薛智龙
Owner 山东诚汇双达药业有限公司