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Semi-synthesis of vinpocetine through one kettle way and preparation of water-soluble vinpocetine salt

A semi-synthetic technology of vinpocetine, which is applied in the field of semi-synthesis of indole alkaloids, can solve the problems of lengthy process, low water solubility, unfavorable bioavailability, etc., and achieve simple and controllable process, high atom economy sexual effect

Inactive Publication Date: 2012-06-06
江苏斯威森生物医药工程研究中心有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are many disadvantages in the above semi-synthetic method, such as low yield, high industrialization cost; lengthy process, complicated equipment; high energy consumption of the process, use of toxic reagents, not environmental protection, etc.
[0013] In addition, although vinpocetine has high activity and more and more clinical applications, its extremely low water solubility greatly affects the diversity of its preparations and is not conducive to improving its bioavailability

Method used

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  • Semi-synthesis of vinpocetine through one kettle way and preparation of water-soluble vinpocetine salt
  • Semi-synthesis of vinpocetine through one kettle way and preparation of water-soluble vinpocetine salt
  • Semi-synthesis of vinpocetine through one kettle way and preparation of water-soluble vinpocetine salt

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Experimental program
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Effect test

Embodiment 1

[0025] The synthetic technique 1 of embodiment 1 Vinpocetine

[0026] Weigh 5kg of vincamine with a purity greater than 99.0% in a 100L enamel reaction kettle, add 25L of absolute ethanol, start stirring, add 4L of concentrated phosphoric acid and 1kg of anhydrous potassium hydrogensulfate dropwise, and heat to 90°C for 1 hour. Then add 15L of glacial acetic acid (or formic acid or propionic acid), and rapidly raise the temperature to 100-105° C., and react for another 5 hours. The reaction was tracked by thin-layer chromatography until the reaction of vincamine was complete, the heating was stopped, and the temperature was lowered to room temperature. While stirring, 1% NaOH solution was added dropwise to adjust the pH value to 8, and then extracted twice with 15 L of dichloroethane, the organic phases were combined, and 1 kg of anhydrous sodium sulfate was added to dry overnight. Dichloromethane was concentrated and recovered, and the solid was crystallized from ethyl aceta...

Embodiment 2

[0027] The synthetic technique 2 of embodiment 2 Vinpocetine

[0028] Weigh 5kg of vincamine with a purity greater than 99.0% into a 100L enamel reaction kettle, add 30L of absolute ethanol, start stirring, add 4kg of p-toluenesulfonic acid and 1kg of anhydrous sodium bisulfate in batches, and heat to 90°C for 1 hour. Then 10L of trifluoroacetic acid was added, and the temperature was rapidly raised to 100-105°C, and then reacted for another 3 hours. The reaction was tracked by thin-layer chromatography until the reaction of vincamine was complete, the heating was stopped, and the temperature was lowered to room temperature. While stirring, 1% NaOH solution was added dropwise to adjust the pH value to 8, and then extracted twice with 15 L of dichloroethane, the organic phases were combined, and 1 kg of anhydrous sodium sulfate was added to dry overnight. Dichloromethane was concentrated and recovered, and the solid was crystallized from ethyl acetate to obtain coarse crystals...

Embodiment 3

[0029] Embodiment 3 Vinpocetine sulfate preparation

[0030] Weigh 10 g of Vinpocetine with a purity greater than 99.5%, disperse and dissolve it in 100 mL of absolute ethanol, stir and heat to 50°C, add 10% sulfuric acid ethanol solution dropwise, Vinpocetine gradually dissolves, add sulfuric acid ethanol solution dropwise to pH 4.5 . Concentrate under reduced pressure to remove about 60 mL of ethanol, and then cool to below 10°C to precipitate coarse crystals of vinpocetine sulfate, filter and wash with cooled absolute ethanol. Obtain 8.5kg of pure vinpocetine sulfate, the yield is 85.0%, and the purity is greater than 99.5%.

[0031] Embodiment 3 Vinpocetine maleate preparation

[0032] Take by weighing 10 g of Vinpocetine with a purity greater than 99.5%, disperse and dissolve it in 100 mL of absolute ethanol, stir and heat to 80° C., add dropwise 10% maleic acid dilute ethanol solution, Vinpocetine gradually dissolves, add dropwise sulfuric acid ethanol solution to Sol...

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Abstract

The invention relates to a semi-synthesis of vinpocetine and a preparation of a vinpocetine salt, wherein vincamine is used as a raw material. The one kettle way for the synthesis of vinpocetine allows the production efficiency to be improved and the total yield to be above 85%; and a method of the preparation of the vinpocetine salt is simple, and the yield is above 85%. Compared with original production methods, the method of the invention, which has the advantages of high atom economy, and concise and controllable process flow, is in favor of the production of GMP (good manufacturing practice) grade bulk medicines and food additives.

Description

technical field [0001] The invention relates to the semi-synthesis of an indole alkaloid compound with extensive cardiovascular and cerebrovascular activities and the preparation of its water-soluble salt. The synthesis process adopts a new one-pot reaction, applies a special catalyst and a new solvent system, and semi-synthesizes vinpocetine from vincamine. The vinpocetine is salted with an acid in a special solvent to obtain a vinpocetine salt with good water solubility, high bioavailability and low toxic and side effects. Background technique [0002] Vinpocetine, namely apovincine acid ethyl ester, is semi-synthesized from the monoindole alkaloid vincamine. It is used to improve the sequelae of cerebral infarction, sequelae of cerebral hemorrhage, cerebral arteriosclerosis and other symptoms. In recent years, other physiological activities have been further discovered to improve senile memory impairment and mental activity of healthy people. In addition, it has certai...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D461/00
Inventor 彭学东王正濂龚福春张梅
Owner 江苏斯威森生物医药工程研究中心有限公司
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