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A kind of synthetic technique of vinpocetine related impurity a

A technology of vinpocetine and synthesis process is applied in the field of synthesis of polycyclic indole alkaloid raw material vinpocetine related impurity A, which can solve the problems of difficult separation of products, small production amount, etc. Simple equipment and mild reaction conditions

Active Publication Date: 2015-10-21
ZHANG JIA GANG VINSCE BIO PHARM
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, it appears as a by-product with a small amount, and it is difficult to separate and obtain a qualified and large amount of product

Method used

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  • A kind of synthetic technique of vinpocetine related impurity a

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Embodiment 1

[0015] The synthesis of embodiment 1 vincine

[0016] In a 500 mL three-necked flask, sequentially add 300 mL of solvent 70% ethanol-water solution, 20 g of reaction raw material vincamine, and 10 g of basic catalyst anhydrous potassium carbonate to make the pH of the system around 12, slowly raise the temperature to 50 °C, and react 9 h, Thin-layer chromatography monitors the complete reaction of the raw material vincamine, which is considered as the completion of the hydrolysis reaction. Then, stir and cool down to below 10°C, adjust the pH value to 6 with 1% dilute hydrochloric acid, and precipitate a white amorphous solid, which is the product vinblastine. After drying, 19.1 g of vinblastine product was obtained for use, with a weight yield of 95.5%.

Embodiment 2

[0017] Example 2 The preparation of Vinpocetine A complex 1

[0018] In a 500 mL three-neck flask, stir to lower the temperature below 5 °C, add 300 mL of absolute ethanol and 1.8 g of anhydrous p-toluenesulfonic acid in sequence, stir and dissolve, then add 18.0 g of dry vinblastine, and stir the system at 30 The reaction was carried out at ℃ for 6 h, and the complete reaction of the raw material vinblastine was monitored by thin-layer chromatography, and the ethyl esterification reaction was considered complete. Then the temperature was lowered to below 10°C, and the pH of the reaction solution was adjusted to about 7 with 5% alkali solution, which was regarded as the completion of the vinpocetine A hybrid synthesis step. Transfer the vinpocetine A mixed ethanol solution of the previous step into the concentration bottle, and concentrate under reduced pressure to recover ethanol. Then add dichloromethane and water, transfer to a separatory funnel for extraction twice, add 1...

Embodiment 3

[0019] Embodiment 3 Preparation of Vinpocetine A complex 2

[0020] In a 500 mL three-necked flask, stir to lower the temperature below 15 °C, add 300 mL of absolute ethanol, 5.0 g of N,N-dicyclohexyl imine and 3.5 g of 4-dimethylaminopyridine in sequence, stir to dissolve, then add dry 18.0 g of vinblastine, the system was stirred at 40 °C for 4 h, and the complete reaction of the raw material vincine was monitored by thin-layer chromatography, and the ethyl esterification reaction was considered complete. That is, the hybrid synthesis step of Vinpocetine A is completed. Transfer the vinpocetine A mixed ethanol solution of the previous step into the concentration bottle, and concentrate under reduced pressure to recover ethanol. Then add dichloromethane and water, transfer to a separatory funnel for extraction twice, add 150 mL of dichloromethane each time, combine the organic phases after extraction, and dry over anhydrous sodium sulfate. Then transfer to the concentration...

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Abstract

The invention establishes a preparation process of a related impurity A of vinpocetine serving as a polycyclic indole alkaloid raw material medicine, and specifically relates to a synthetic raw material namely vincamine. The related reactions comprise hydrolysis reaction and mild esterification reaction. Under a mild condition, hydrolysis reaction and esterification reaction are carried out, so that the yield is high and the byproducts are fewer. The product is then separated and purified to obtain the related impurity A of vinpocetine: vincamine ethyl ester. The best weight yield calculated according to the initial raw material vincamine can reach up to over 85%. The method has the advantages of high atomic economy, simple equipment and green and environment-friendly preparation process, and has a very huge economic benefit.

Description

technical field [0001] The present invention relates to the synthesis of a polycyclic indole alkaloid bulk drug vinpocetine-related impurity A, specifically relates to the synthesis of vincamine as a raw material, involving reactions including hydrolysis, mild esterification, separation and purification to obtain vinpocetine-related impurities Impurity A—vincine ethyl ester. Background technique [0002] Vinpocetine, English name Vinpocetine, is a natural indole alkaloid derivative. It was first successfully developed by a large Hungarian pharmaceutical company in the 1970s. More than 30 years of clinical application have shown that the drug has good activity and few side effects. Therefore, it is more and more widely used in Europe, America, Japan and China. As a cerebral vasodilator, vinpocetine can inhibit the activity of phosphodiesterase, increase the role of c-GMP, the messenger of vascular smooth muscle relaxation, selectively increase cerebral blood flow, and also i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D461/00
CPCC07D461/00
Inventor 彭学东张梅赵金召闫勇义
Owner ZHANG JIA GANG VINSCE BIO PHARM
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