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Preparation method of vinpocetine analogue

A technology for vinpocetine and its analogues, applied in the field of preparing vinpocetine analogues, achieving the effects of high yield, simple operation and high purity

Inactive Publication Date: 2014-03-26
HUNAN KEYUAN BIO PRODS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] EP20080165083 and EP2168963A1 reported methods for synthesizing vinpocetine analogues, using a mixture of maleic anhydride and hydrogen peroxide as an oxidant, but the yield was still only about 70%, and nearly 30% became impurities

Method used

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Examples

Experimental program
Comparison scheme
Effect test

reference example 1

[0041] The oxidizing agent UHP that each embodiment uses can buy from the market, also can prepare according to the following method:

[0042] Weigh 0.8g of salicylic acid and place it in a 500ml three-neck bottle, add 75ml of 30% hydrogen peroxide solution, slowly cool down, keep the temperature at 1-5°C, add 40g of urea slowly in batches under stirring, the reaction is exothermic during the addition process , keep the reaction at 1-5°C during the addition, after the addition is complete, place it at 5°C for 8 hours, precipitate crystals, filter, place the obtained filtrate at 5°C for another 24 hours, filter, crystallize again, and then put the obtained crystals in Keep ventilation in a fume cupboard and air-dry for 24 hours to obtain a total of 57.6 g of white solid, which is qualitatively analyzed by nitric acid-potassium dichromate method, and its purity is 99.0% by sodium thiosulfate indirect iodometric method. The yield is over 89%, and the melting point is 77-81°C.

Embodiment 1

[0044] Preparation of Vinpocetine Analogs by Selective Oxidation of Tabonin Analogs:

[0045] Add 500g of bonin (if using bonin sulfate or hydrochloride, remove the molecular weight of the corresponding salt), add 5 liters of methanol, add it to a 30 liter reaction kettle, start stirring to dissolve the raw materials, and cool down to -25 ℃, slowly add 140g of oxidizing agent UHP dropwise, the dropwise addition is completed in 3 hours, and then continue to react for 5 hours. In the process, when using potassium iodide starch test paper to detect no oxides, slowly raise the temperature to 38°C, keep the temperature ≥ 5 hours, add 800 ml of 25wt% ammonia water dropwise, after the dropwise addition, the pH=8.5, cool and filter, and obtain the yellow solid vinpocetine analogue 435 gram, about 87% yield, HPLC: 98.2%, solvent recycling.

reference example 2

[0047] Raw material it bonine reducer analogue preparation:

[0048] In a 5L sealable glass reaction bottle, add 50g of bonin, 500g of methanol, and 20g of active nickel, seal it, replace it with hydrogen for 3 times, pressurize to a pressure of 5 kg, start stirring, react at 50°C for 1 night, and take a sample for TLC. Raw materials (developer: EA:PE=1:5, iodine color development), stop the reaction when all vinformin is formed, filter to obtain about 700g of taponin reduced analogue solution for use.

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PUM

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Abstract

A preparation method of a vinpocetine analogue comprises the following steps: using UHP (urea hydrogen peroxide) for selective oxidation of a tabersonine analogue, then performing reduction, rearrangement, crystallization, and the like; or using the UHP for selective oxidation of a tabersonine reduction analogue (vinca-fuming analogue), then performing rearrangement, crystallization, and the like to obtain the vinpocetine analogue. Compared with the prior art, the preparation method has the advantages of high yield, direct quantification, simple operation, mild reaction conditions, suitability for industrial production, the yield reaching over 87%, more than 99% of HPLC (high performance liquid chromatography), a white product, good quality and low preparation cost.

Description

technical field [0001] The invention relates to a method for preparing vinpocetine analogues, belonging to the technical field of organic synthesis. Background technique [0002] Vinpocetine analogs are an alkaloid that was first isolated from Vinca vinca by Zabolatnaya et al. in 1950. Its structural formula is as follows: [0003] [0004] In terms of structural formula, vinpocetine analogues belong to eburnamine-vincamine alkaloids and are commonly found in plants of the family Apocynaceae in nature. Most compounds in this class of alkaloids have pharmacological activities on cell proliferation, cardiovascular, cerebrovascular and nervous system functions, which have aroused widespread interest of medicinal chemists. [0005] In recent decades, many vincamine derivatives with higher biological activity and less toxic side effects than their parent natural products have been synthesized; the most famous one is apovincine ethyl ester, also known as Vinpocetine. The co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/20
CPCC07D461/00C07D471/20
Inventor 杨昌勇刘志强
Owner HUNAN KEYUAN BIO PRODS
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