The synthetic method of oxiracetam intermediate 4-chloroacetoacetate ethyl

A technology of ethyl chloroacetoacetate and ethyl acetate, which is applied in the field of synthesis of oxiracetam intermediate 4-ethyl chloroacetoacetate, can solve the problems of low product yield, target product decomposition loss, separation and purification difficulties, etc. , to achieve high product purity, increase the probability of "collision" and low process cost

Active Publication Date: 2022-04-01
THE SECOND PEOPLES HOSPITAL OF SHENZHEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] This method product yield is on the low side, and reason is exactly that a certain amount of ethyl 2-chloroacetoacetate by-product can be generated in the reaction process, and this by-product is very close to 4-ethyl chloroacetoacetate physical property (as boiling point), causes separation Purification is difficult and often requires repeated rectification, resulting in the decomposition loss of the target product

Method used

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  • The synthetic method of oxiracetam intermediate 4-chloroacetoacetate ethyl
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  • The synthetic method of oxiracetam intermediate 4-chloroacetoacetate ethyl

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Embodiment 1

[0030] The synthetic method of ethyl 4-chloroacetoacetate, comprises the following steps:

[0031] 1) Mix the ethyl acetate, the catalyst and DMSO evenly, pass in argon, control the pressure to 4.8 atmospheres, control the temperature to 128°C, add the solution of ethyl chloroacetate and ethanol dropwise, and control the addition time to 21min; After finishing, raise the reaction temperature to 152° C., raise the pressure to 9 atmospheres, and then continue to react for 22 hours to complete the reaction;

[0032] The preparation method of the catalyst used is as follows: the molecular sieve of type 5A is soaked in 20% potassium carbonate aqueous solution for 50 hours, dried in the air, and then activated at 450 DEG C to obtain.

[0033] The consumption ratio of ethyl acetate and catalyzer is 1g:0.31g, the consumption ratio of ethyl acetate and DMSO is 1g:6.8ml, the consumption ratio of ethyl acetate and ethyl chloroacetate is 1mol:0.97mol, ethyl chloroacetate and The usage ra...

Embodiment 2

[0036] The synthetic method of ethyl 4-chloroacetoacetate, comprises the following steps:

[0037] 1) Mix ethyl acetate, catalyst and DMF, feed nitrogen, control the pressure to 3 atmospheres, control the temperature to 110°C, add the solution of methyl chloroacetate and methanol dropwise, and control the addition time to 15min; , raising the reaction temperature to 145°C, raising the pressure to 8 atmospheres, and then continuing to react for 15 hours to complete the reaction;

[0038] The preparation method of the catalyst is as follows: immerse the 4A type molecular sieve in 15% potassium carbonate or sodium carbonate aqueous solution for 2 days, then dry it, and then activate it at 350°C.

[0039] The consumption ratio of ethyl acetate and catalyzer is 1g:0.25g, and the consumption ratio of described ethyl acetate and DMF is 1g:5.6ml, and the consumption ratio of described ethyl acetate and methyl chloroacetate is 1mol:0.95mol, so The consumption ratio of methyl chloroace...

Embodiment 3

[0042] The synthetic method of ethyl 4-chloroacetoacetate, comprises the following steps:

[0043] 1) Mix the ethyl acetate, the catalyst and DMSO evenly, pass in argon, control the pressure to 5 atmospheres, control the temperature to 135°C, add the solution of ethyl chloroacetate and ethanol dropwise, and control the addition time to 25min; After finishing, raise the reaction temperature to 160° C., raise the pressure to 10 atmospheres, and then continue to react for 25 hours to complete the reaction;

[0044] The preparation method of the catalyst is as follows: immerse the 5A type molecular sieve in 25% potassium carbonate or sodium carbonate aqueous solution for 3 days, then dry it, and then activate it at 470 DEG C to obtain it.

[0045] The consumption ratio of ethyl acetate and catalyzer is 1g:0.33g, and the consumption ratio of described ethyl acetate and DMSO is 1g:7.5ml, and the consumption ratio of described ethyl acetate and ethyl chloroacetate is 1mol:1mol, and d...

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Abstract

The invention discloses a method for synthesizing oxiracetam intermediate 4-chloroacetoacetate ethyl, which belongs to the field of pharmacy, and is characterized in that chloroacetate and ethyl acetate are reacted under the action of a catalyst to obtain 4-chloroacetate Ethyl acetoacetate. The reaction process is as follows: 1) Mix ethyl acetate, catalyst and solvent A evenly, pass in protective gas, control the pressure to 3-5 atmospheres, control the temperature to 110-135°C, add chloroacetate and solvent dropwise B solution, and control the addition time to 15-25min; after adding, increase the reaction temperature to 145-160°C, increase the pressure to 8-10 atmospheres, and then continue to react for 15-25h to complete the reaction; 2) Cool the system After filtering to remove the solid, the filtrate was added to 3 to 5 times the volume of water, and then extracted with solvent C, the extract was dried with a desiccant, concentrated and evaporated to remove the solvent to obtain the product. The synthesis method of the invention has relatively short steps, low process cost and few side reactions.

Description

technical field [0001] The invention belongs to the field of pharmacy, in particular to a method for synthesizing oxiracetam intermediate 4-chloroacetoacetate ethyl. Background technique [0002] Oxiracetam (Oxiracetam) is pyrrolidone derivatives, chemical name is 4-hydroxyl-2-oxo-1-pyrrolidineacetamide, it can be used for the treatment of brain damage and the resulting neurological function loss, memory and intellectual impairment. Improve the memory and learning functions of patients with senile dementia and memory impairment; it can promote the synthesis of phosphorylcholine and phosphorylethanolamine, increase the ratio of ATP / ADP in the brain, and increase the synthesis of protein and nucleic acid in the brain. It is mainly used clinically. For the treatment of amnesia. [0003] Oxiracetam was first synthesized by the Italian ISF company in 1974. Over the years, although researchers have developed a variety of methods, it is still mainly synthesized using ethyl 4-chlo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C69/72C07C67/343B01J29/70
CPCC07C67/343B01J29/7003C07C69/72
Inventor 谭回李维平黄贤键刘文兰唐爱发李宗阳
Owner THE SECOND PEOPLES HOSPITAL OF SHENZHEN
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