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Preparation method for nebracetam

A technology of neraracetam and benzyl, which is applied in the field of preparation of neraracetam, can solve the problems of cumbersome operation, cumbersome post-processing, high risk of azidation reaction, etc., and achieve simple preparation process, good therapeutic effect, strong pharmacological effect

Inactive Publication Date: 2015-03-11
重庆奥舍生物化工有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010]1) Using benzylamine and itaconic acid as raw materials, through condensation and esterification to obtain ethyl 1-benzyl-5-oxo-3-carboxylate, After reduction, chlorination, and Gabriel reaction, the product is obtained (Chinese Journal of Pharmaceutical Industry, 1999, 30(9): 387; CA, 1985, 102: 203872). The total yield of this method is low, and the post-treatment is cumbersome, which is not conducive to industrial production
[0011]2) Using benzylamine and itaconic acid as raw materials, amide intermediates are obtained through condensation and ammonia chloride, and then dehydrated to obtain cyano compounds. High-pressure catalytic hydrogenation to obtain products (China Journal of Pharmaceutical Industry, 2006, 37(6): 375-376). The synthesis route uses an autoclave, which is dangerous and unfavorable for large-scale preparation of the product
[0012]3) This method uses benzylamine and dimethyl itaconate as raw materials, and undergoes Michael addition and intramolecular cyclization to obtain l-benzyl-5-oxo Pyrrolidine-3-carboxylate methyl ester, then reduced by sodium borohydride to obtain 1-benzyl-4-hydroxymethylpyrrolidone-2-one, then chlorinated by thionyl chloride, and Gabriel reaction to obtain the product (Chinese medicine Chemical Journal, 2005, 15(5): 237-240), the last step of this method uses the Gabriel reaction, although this reaction is a common method for preparing relatively pure primary amines, but the separation of phthaloyl in the hydrazinolysis method Hydrazine is troublesome
[0013]4) Using benzylamine and dimethyl itaconate as raw materials, 1-benzyl-4-chloromethyl was obtained through addition, cyclization, reduction, and chlorination Pyrrolidin-2-one, the product is obtained by azidation and Pd / C catalytic hydrogenation at atmospheric pressure (China Pharmaceutical Industry Journal, 2008, 39(6): 404-405), and highly toxic Sodium azide, and the azide reaction is very dangerous and explosive
[0014]5) From the chiral compound N-Benzyl-(4S)-4-[(S)-2,2-dimethyl-1,3-dioxolan-4- yl]-pyrrolidin-2-one, after deprotection, mesylation to generate sulfonate, then azide, reduction to obtain R-type neraracetam (Tetrahedron: Asymmetry, 2008, 19: 1161-1165) , the disadvantage of this route is that there are too many steps, too cumbersome, not suitable for industrial production, and the azidation reaction is dangerous and difficult to operate
[0015] In summary, the above various methods generally have long reaction steps, cumbersome operations, large potential safety hazards, and shortcomings such as being unsuitable for industrial production. On the basis of referring to domestic and foreign literature, extensive and in-depth research has been carried out, and a simpler, economical and easy-to-operate synthetic route of neriracetam has been obtained

Method used

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  • Preparation method for nebracetam

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Experimental program
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Effect test

Embodiment 1

[0031] Methyl 1-benzyl-5-oxopyrrolidine-3-carboxylate 2 Synthesis

[0032]

[0033] Add 3.1g (50mmol) of dimethyl itaconic acid and 2.1g (50mmol) of benzylamine to a 50ml multi-necked bottle, under magnetic stirring, the oil bath is heated to 90°C, refluxed for about 21h, after the reaction is completed, a pale yellow liquid is obtained, After cooling to room temperature, it turned into a light yellow solid, 30 ml of dichloromethane and 30 ml of dilute hydrochloric acid were added to the reaction solution, the layers were shaken, and the organic phase was saturated with NaHCO. 3 The aqueous solution and the saturated NaCl aqueous solution were washed once each, and anhydrous NaSO 4 Dry, filter, evaporate dichloromethane, recrystallize from petroleum ether-ethyl acetate to obtain methyl 1-benzyl-5-oxopyrrolidine-3-carboxylate as a white solid 2 , the yield is 89%.

Embodiment 2

[0035] 1-Benzyl-4-hydroxymethyl-pyrrolidin-2-one 3 Synthesis

[0036]

[0037] Weigh 0.10 g (0.43 mmol) of methyl 1-benzyl-5-oxopyrrolidine-3-carboxylate 2 Put it in a 25ml multi-necked bottle, add 5ml methanol to dissolve, when the reaction solution is cooled to below 0°C, slowly add NaBH under stirring 4 (0.05g, 3eq) solid, after adding, continue the reaction at 0-5°C, the solution is colorless and has a small amount of white insoluble matter, TLC monitors the reaction process, and stops the reaction after the spot plate confirms that the reaction raw material disappears. , after the reaction is complete, slowly add 1M HCl dropwise to the reaction solution to pH=5-6, evaporate methanol under reduced pressure, add water to the residue, then extract three times with dichloromethane, wash once with water, combine the organic phases, no Dry over sodium sulfate, filter, spin-dry the filtrate to obtain a viscous liquid, and cool to obtain a yellow solid 1-benzyl-4-hydroxymeth...

Embodiment 3

[0039] In a 50ml three-necked flask equipped with a thermometer, add 0.95g (4.08mmol) of methyl 1-benzyl-5-oxopyrrolidine-3-carboxylate 2 Dissolve in 12ml methanol to get a colorless clear liquid, add NaBH slowly at 10-15℃ 4 Solid (0.46g, 3eq), after the addition, the reaction was incubated at 10-15°C, and the reaction was monitored by TLC. After the reaction was completed, 1M HCl was slowly added dropwise to the reaction solution to pH=5-6, and evaporated under reduced pressure. Methanol, water was added to the residue, extracted three times with dichloromethane, washed once with water, combined the organic phases, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a viscous liquid, which was cooled to obtain a yellow solid 1-benzyl-4-hydroxyl Methyl-pyrrolidin-2-one 3 0.81g, yield 96.9%, purity 97%.

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Abstract

The invention discloses a preparation method for nebracetam, and belongs to the technical field of medical chemistry. The key points of the technical scheme of the invention are as follows: the preparation method for the nebracetam comprises the following steps: performing Michael addition reaction and intramolecular cyclization on dimethyl itaconate and benzylamine serving as raw materials to obtain 1-benzyl-5-oxopyrrolidin-3-carboxylic methyl ester; reducing the 1-benzyl-5-oxopyrrolidin-3-carboxylic methyl ester by sodium borohydride to obtain 1-benzyl-4-hydroxymethyl-pyrrolidine-2-keton; performing methyl sulfonylation on the 1-benzyl-4-hydroxymethyl-pyrrolidine-2-keton to obtain 1-benzyl-5-oxopyrrolidin-3-carboxylic methanesulfonate; finally, performing ammonification and reduction on the 1-benzyl-5-oxopyrrolidin-3-carboxylic methanesulfonate by using ammonia water to obtain the nebracetam. The preparation method is simple in preparation process, easy to control and high in target product yield, and meets the requirement for green chemistry.

Description

Technical field [0001] The present invention is a pharmaceutical chemical technology field, which involves a method of preparation of Nalacan. Background technique [0002] Alzheim ’s Disease (AD), also known as Alzheimer’ s Disease (AD), is a brain degeneration disease mainly based on dementia. The clinical manifestation is performed mental retardation and abnormal behavior, and even vague consciousness.Its main pathological changes are: Elderly spots, neurons entangled in the cerebral cortex and subcutaneous structure, which are related to the starch -like protein that is extracellular in the nerve cells and the excessive phosphoric acidization of TAU protein in the cell, which is also related to the decrease in the activity of choline energy.Acetylcholine synthesis is reduced, choline acelase activity is closely related, and it forms a vicious circle to exacerbate the deterioration of AD.The results of domestic epidemiological surveys show that with the aging development of so...

Claims

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Application Information

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IPC IPC(8): C07D207/267
CPCC07D207/26
Inventor 姜玉钦李幸娟张玮玮过治军郭利兵
Owner 重庆奥舍生物化工有限公司
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