Industrialized semisynthesis of medicine-vincamine for treating cerebral ischemia

A technology of vincamine and nitrogen oxides, applied in the direction of organic chemistry, can solve the problems of low chemical atom economy, high production equipment requirements, high cost, etc., and achieve the goal of green production process, simple equipment, large economic and social benefits Effect

Inactive Publication Date: 2011-06-29
GUANGZHOU SWELLXIN SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In summary, there are some following problems in the method of producing vincamine at home and abroad at present: chemical atom economy is low, and total yield is less than 10%, and produced chemical waste will certainly cause very big burden to environment; high, will inevitably lead to higher costs, and the production enterprise will bear high operational risks; all synthetic routes are more than 10 steps, and all have high requirements for production equipment, which will increase the fixed cost of production enterprises

Method used

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  • Industrialized semisynthesis of medicine-vincamine for treating cerebral ischemia

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Experimental program
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Effect test

Embodiment 1

[0019] Embodiment 1 Synthesis of Changchun Fermin (3)

[0020] Weigh 5.0 kg of tarponin hydrochloride (2) into a 100 L stainless steel reaction kettle, add 50 L of 75% ethanol, and stir to dissolve at room temperature. Then 250g of Raney nickel was added, hydrogen was introduced immediately, stirred after 0.5h, and the hydrogen pressure was controlled to 1.1atm, and the reaction was carried out for 8h. After the reaction was completed, nitrogen gas was introduced for 10 minutes, the catalyst was removed by filtration, and the crude product of vincaurmin was obtained by concentration. Crystallization with ethyl acetate-ethanol gave 4.8 kg of vincaurmin hydrochloride with a purity greater than 99.0%, with a yield of 96%.

Embodiment 2

[0021] Example 2 Synthesis of 1,2-dehydro-16-methoxycarbonyl-16-hydroxyl-vinfofermin nitrogen oxide (4)

[0022] Take 5.0 kg of vinchun phermin hydrochloride and place it in a 100 L stainless steel reaction kettle, add 50 L of 1,3-dioxane, stir and dissolve at room temperature. Filled with nitrogen protection, protected from light and reacted at room temperature for about 16 hours. TLC detects the progress of the reaction until the intermediate (3) disappears substantially, and the intermediate (4) is generated. Add 5% NaHCO to the reaction solution 3 The solution was free of bubbles, and the excess peroxyacid and the generated acid were removed. Separate the organic phase, then extract twice with 20L dichloroethane, combine the organic phases, dry over 500 g of anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 1,2-dehydro-16-methoxycarbonyl-16-hydroxyl - The crude product of vinchun fermin nitrogen oxide (structural formula 4), which is an oily sub...

Embodiment 3

[0023] The synthesis of embodiment 3 vincamine (1)

[0024] Take 5.0kg of 1,2-dehydro-16-methoxycarbonyl-16-hydroxy-vinfofermin nitrogen oxide and place it in a 100L stainless steel reaction kettle, add 60L of trichloroacetic acid, control the temperature at about 0°C and stir to dissolve, then add Triphenylphosphine 3.0kg, reflux reaction for about 3h. TLC detects the progress of the reaction until the intermediate (4) disappears substantially. Cool the reaction solution, add an equal amount of ice water, and wash away triphenylphosphine oxide with dichloroethane. The aqueous phase was then adjusted to pH 8-9 with 1% NaOH, extracted twice with dichloromethane, the combined organic phases were concentrated to 20 L volume, and decolorized by adding activated carbon for 30 min. The organic phase was obtained by filtration, dried overnight with 500 g of anhydrous sodium sulfate, and a certain amount of methanol was added to the mother liquor to crystallize to obtain the crude p...

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Abstract

The invention relates to a semisynthesis process route which takes tabersonine salt as raw material for producing vincamine. Catalytic hydrogenation, peroxidation, rearrangement, crystallization and recrystallization are sequentially performed on the tabersonine salt for getting the high-purity vincamine, and the content is greater than 99.0%. Calculated according to the tabersonine salt, the overall yield of the vincamine is 55.3%. The method has the characteristics of low cost, high yield, short time, and simplicity and safety in operation, and is completely applicable to industrialized large-scale production.

Description

technical field [0001] The invention relates to the synthesis of vincamine (vincamine), a drug for treating cardiovascular and cerebrovascular diseases, in particular to the purification of the semi-synthetic raw material vincaine, the synthesis of the intermediate vincadifamine, the synthesis of the intermediate vincadifamine nitrogen oxide, and the synthesis of vincadifamine. Amine synthesis and industrial scale purification process. Background technique [0002] Vincamine is a monoindole alkaloid with strong physiological activity. Early foreign studies focused on its hypotensive activity. Because it can penetrate the blood-brain barrier, it was later found that it has a good effect on dilating blood vessels and increasing cerebral blood flow, but has no effect on the heart, blood vessels, and blood pressure. It is currently the first-line drug for the treatment of cerebral ischemia, and its clinical indications include cerebrovascular disorders, cerebral embolism, cereb...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/20C07D461/00
Inventor 彭学东王小波赵金召王正濂
Owner GUANGZHOU SWELLXIN SCI & TECH
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