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Method for preparing vinpocetine intermediate gamma-hydroxypropyl-ethylmalonic acid

A technology of ethylmalonate and diethyl ethylmalonate, which is applied in the field of preparing and synthesizing vinpocetine intermediate γ-hydroxypropyl-ethylmalonate, can solve complex operation, large amount of ethanol, Increase the process cost and other problems, to achieve the effect of simple experimental operation, simplified operation and cost saving

Active Publication Date: 2014-03-12
NORTHEAST PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method requires a large amount of reaction solvent ethanol, and all ethanol needs to be evaporated after the reaction, which increases the cost of the process and makes the operation more complicated.

Method used

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  • Method for preparing vinpocetine intermediate gamma-hydroxypropyl-ethylmalonic acid
  • Method for preparing vinpocetine intermediate gamma-hydroxypropyl-ethylmalonic acid
  • Method for preparing vinpocetine intermediate gamma-hydroxypropyl-ethylmalonic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Add 500mL of anhydrous tetrahydrofuran into a 2L dry four-necked bottle, mechanically stir and add 68g (1.98mol) of 70% sodium hydride at the same time, the reaction solution is gray and turbid. At 10°C, 282 g (1.5 mol) of diethyl 2-ethylmalonate was slowly added dropwise, and the dropwise addition was completed in 2 hours, followed by mechanical stirring for 1 hour. Then, 234 g (1.5 mol) of 1-bromo-3-chloropropane was slowly added dropwise, and the dropwise addition was completed within 2 hours, followed by stirring for 8 hours. 300 mL of water was added to the solution and stirred for 1 hour. Extracted with ethyl acetate and concentrated under reduced pressure to obtain 394 g of light yellow oily product γ-chloropropyl-ethylmalonate diethyl ester, the yield was 99%, and the content was 95.8%.

[0018] Add 394g of diethyl ethylmalonate to a 2L four-neck flask, add 200mL of ethanol, and then add 600mL of a prepared 25% sodium hydroxide aqueous solution. Raise the temp...

Embodiment 2

[0020] Add 400mL of N,N-dimethylformamide (DMF) into a 2L dry four-necked bottle, mechanically stir and add 56g (1.63mol) of 70% sodium hydride at the same time, the reaction solution is gray and turbid. At 40°C, 282 g (1.5 mol) of diethyl 2-ethylmalonate was slowly added dropwise, and the dropwise addition was completed in 2 hours, followed by mechanical stirring for 1 hour. Then, 281 g (1.8 mol) of 1-bromo-3-chloropropane was slowly added dropwise, and the dropwise addition was completed within 2 hours, followed by stirring for 15 hours. Add 300 mL of water to the solution and stir for 1 h. Extracted with ethyl acetate and concentrated under reduced pressure to obtain 389 g of light yellow oil γ-chloropropyl-ethylmalonate diethyl ester, the yield was 98%, and the content was 95.2% (GC).

[0021] Add 389g of diethyl ethylmalonate to a 2L four-neck flask, add 200mL of ethanol, and then add 600mL of a prepared 25% sodium hydroxide aqueous solution. Raise the temperature and r...

Embodiment 3

[0023] Add 500mL of anhydrous tetrahydrofuran into a 2L dry four-necked bottle, mechanically stir and add 60g (1.75mol) of 70% sodium hydride at the same time, the reaction solution is gray and turbid. At 20°C, 282 g (1.5 mol) of diethyl 2-ethylmalonate was slowly added dropwise, and the dropwise addition was completed in 2 hours, followed by mechanical stirring for 1 hour. Then, 240 g (1.54 mol) of 1-bromo-3-chloropropane was slowly added dropwise, and the dropwise addition was completed within 2 hours, followed by stirring for 12 hours. 300 mL of water was added to the solution and stirred for 1 hour. Extracted with ethyl acetate, concentrated under reduced pressure to obtain 395 g of light yellow oily product γ-chloropropyl-ethylmalonate diethyl ester, the yield was 99%, and the content was 96.5% (GC).

[0024] Add 395g of diethyl ethylmalonate to a 2L four-neck flask, add 200mL of ethanol, and then add 600mL of a prepared 25% sodium hydroxide aqueous solution. Raise the ...

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Abstract

The invention discloses a method for preparing vinpocetine intermediate gamma-hydroxypropyl-ethylmalonic acid, and belongs to the chemical industry synthesis field. The preparation method comprises the following steps: 1, adding sodium hydride into an organic solvent, adding 2-ethyl diethylmalonate and 1-bromo-3-chloropropane, extracting by using ethyl acetate, and carrying out reduced pressure concentration of a solvent to obtain gamma-chloropropyl-ethyl diethylmalonate; and 2, adding gamma-chloropropyl-ethyl diethylmalonate to an ethanol-water solvent of sodium hydroxide, refluxing, adding a proper amount of water, adjusting the pH value to 1 by using concentrated hydrochloric acid, crystallizing, and carrying out pumping filtration to obtain a white solid gamma-hydroxypropyl-ethylmalonic acid, wherein a molar ratio of 2-ethyl diethylmalonate to 1-bromo-3-chloropropane to sodium hydride in step 1 is 1:1-1.2:1-1.3; and a reaction temperature in the step 1 is 10-40DEG C, and a reaction time of 1-bromo-3-chloropropane, 2-ethyl diethylmalonate and 1-bromo-3-chloropropane is 8-15h. The intermediate is gamma-hydroxypropyl-ethylmalonic acid, and the preparation method has the advantages of cheap and easily available raw materials, low cost, short reaction steps, simple operation, good product quality, and benefit for protecting the green resource.

Description

[0001] The invention relates to a method for preparing and synthesizing vinpocetine intermediate γ-hydroxypropyl-ethylmalonic acid in the field of chemical synthesis. Background technique [0002] Vinpocetine, also known as apovincine ethyl ester, is a derivative of the alkaloid vincamine. Vincamine is a natural medicine extracted from the wild plant Vinca vinca, belonging to indole alkaloids. Vinpocetine exhibits neuronal metabolic activity by aiding aerobic glycolysis and promoting redistribution of blood flow to ischemic areas, and vinpocetine can also increase cerebral circulation and oxygen utilization. Due to its unique pharmacological activity, vinpocetine plays an important role in the field of cerebrovascular treatment clinically. Vinpocetine is often used for cerebral arteriosclerosis, cerebral ischemic and hemorrhagic sequelae, transient ischemic attack and other cerebral circulation disorders, and is also used to treat symptoms induced by cerebral circulation diso...

Claims

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Application Information

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IPC IPC(8): C07C59/245C07C51/367
CPCC07C51/367C07C67/343C07C59/245C07C69/63
Inventor 祝春艳白洁吴静刘杰刘九知陈铮
Owner NORTHEAST PHARMA GRP
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