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Method for improving synthesis process of Acipimox

A cyclization, o-phenylenediamine technology, applied in the field of improvement of axiolimus synthesis process, can solve the problems of easy oxidation of intermediates by oxygen in the air, long process route, cumbersome operation, etc. The effect of improving the reaction yield and simplifying the process steps

Active Publication Date: 2012-05-30
LUNAN PHARMA GROUP CORPORATION
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

The inventor provides a simple and effective method for improving the synthesis process of acipimox through in-depth research on the synthesis process of acipimox. It is cumbersome, and the intermediate is easily oxidized by oxygen in the air during the processing process. At the same time, the H 2 o 2 Utilize appropriate catalyst to catalyze the oxidation in the oxidation process, make the reaction easy to carry out, be more conducive to industrialized production, and the total yield is 66%

Method used

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  • Method for improving synthesis process of Acipimox
  • Method for improving synthesis process of Acipimox
  • Method for improving synthesis process of Acipimox

Examples

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Embodiment 1

[0023] The preparation of embodiment 1 3-methylphenprozine

[0024] Put 6.5kg of sodium metabisulfite and 13kg of water into a 100L reactor, raise the temperature to 70-80°C and stir to dissolve, add 7kg of aceguvaldehyde, add dropwise a solution of 8.5kg of o-phenylenediamine dissolved in 17kg of water at 80°C while stirring, and keep stirring to react After 35 minutes, lower the temperature to 40°C, add dropwise sodium hydroxide solution to adjust the pH to 7.0-7.5, let stand to separate the water layer, wash the organic layer twice with 50L saturated saline and pure water, and heat the fine Distillation, 8.2Kg of distillate at 95-130°C was collected, which was 3-methylbenzopyrazine, yield 72%.

Embodiment 2

[0025] The preparation of embodiment 2 3-methylbenzopyrazine

[0026] Put 7kg of sodium metabisulfite and 15kg of water into a 100L reactor, heat up to 70-80°C and stir to dissolve, add 7kg of aceguvaldehyde, add dropwise a solution of 9kg of o-phenylenediamine dissolved in 19kg of water at 80°C while stirring, and keep stirring for 60 minutes , lower the temperature to 25°C, add sodium hydroxide solution dropwise to adjust the pH to 6.8-7.0, then let stand to separate the water layer, wash the organic layer twice with 55L saturated saline and pure water, and then heat and rectify under a vacuum of 0.092MPa. Collect 8.5Kg of fractions at 95-130°C, which is 3-methylbenzopyrazine, with a yield of 75%.

Embodiment 3

[0027] Example 3 Preparation of Acipimox

[0028] Put 6kg of 3-methylbenzopyrazine into a 200L reactor, add 3kg of pure water under stirring and raise the temperature to 80°C, add dropwise a solution prepared by 38kg of potassium permanganate and 110L of water, keep it warm at 100°C to 105°C for 45 minutes, and react Complete filtration and recovery of MnO 2 , distill the filtrate to remove moisture under reduced pressure, then add 10kg of concentrated sulfuric acid dropwise and use jacket cooling water to control the temperature at 80°C, then continue to quickly add 21kg of concentrated sulfuric acid in the reaction kettle, the temperature is controlled at 105~110°C, and keep warm after adding After reacting for 1 hour, cool to 45°C, add sodium tungstate aqueous solution (Na 2 WO 4 2H 2 O260g, H 2 (013.2L) and 3.2L of 30% hydrogen peroxide were reacted at 70°C for 3.5 hours, the reaction solution was cooled, filtered with suction, and dried to obtain 5.8kg of acipimox wit...

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Abstract

The invention provides a method for improving the synthesis process of Acipimox, which is characterized by carrying out one-pot method on the steps of oxidization, acidification, decarboxylation and oxidization after cyclizing methylglyoxal and o-phenylenediamine which are taken as the original raw materials to directly prepare Acipimox. The method dispenses with intermediate processing, thus greatly simplifying the process steps, and overcomes the defect that the intermediate is easy to oxidize slowly due to multi-step processing, simultaneously utilizes the catalyst for catalytic oxidation in the process of H2O2 oxidation so as to facilitate reaction, improves the reaction yield (66% of overall yield) and is more beneficial to industrial production.

Description

technical field [0001] The invention relates to the synthesis of a blood lipid-lowering drug, in particular to an improved method for the synthesis process of acipimox. Background technique [0002] Acipimox (Acipimox) alias: Oxymepyrazine, Lezhiping, is a 5-methylpyrazine-2-carboxylic acid-4-oxide, molecular structure is as follows: [0003] [0004] Acilimus is a niacin derivative with good lipid-lowering effect. It is widely used in the treatment of hypertriglyceridemia and hypercholesterolemia. Its lipolysis inhibitory activity is 20 times that of niacin. Decomposition reduces the generation of free fatty acids, can effectively reduce the risk of coronary heart disease, and can improve blood lipid levels in a short period of time after taking the medicine, so it is a blood lipid-lowering drug with great market prospects. [0005] Regarding the chemical synthesis method of acipimox, relevant materials at home and abroad have reported a variety of different synthetic r...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D241/24
Inventor 赵志全张贵民肖月华
Owner LUNAN PHARMA GROUP CORPORATION
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