Process for synthesizing glimepiride raw material medicine

Abstract

The invention discloses a process for synthesizing a glimepiride raw material medicine. A compound A, namely 3-ethyl-4-methyl-3-pyrroline-2-ketone and a compound B, namely 2-phenethyl isocyanate are taken as start raw materials. The process is characterized in that when an intermediate 1 is synthesized, filtrate is applied mechanically, so that the loss of the intermediate 1 can be reduced, the yield can be increased, and the production efficiency can be improved; when an intermediate 2 is synthesized, hydrochloric ether is adopted as a solvent, so that isomer impurities can be greatly reduced, the content of the isomer impurities can be reduced to 0.5% or less from 8%, and later purification procedures can be simple to operate; when a glimepiride metallic salt is synthesized, acetonitrileis adopted as a solvent, sufficient reactions can be achieved, the reaction time can be greatly shortened, the residue of an intermediate 3 is reduced to 0.2% or less from 5-10%, in addition, a highsolvent recycling rate can be achieved. The process disclosed by the invention is simple and safe, low in production cost, high in yield, stable in intermediate and finished product quality and applicable to industrial large-scale production and hypoglycemic drug, namely glimepiride, synthesis processes with relatively great social, economic and environmental-friendly benefits.

Description

technical field [0001] The invention relates to a new synthesis process of glimepiride bulk drug, which belongs to the technical field of drug synthesis. Background technique [0002] Glimepiride (glimepiride), a new sulfonylurea hypoglycemic drug, was first developed by the German company Hoechst, initially listed in Germany, and later listed in Switzerland, Sweden, Denmark and other countries. It was approved by the United States in 1995. Approved by the FDA, in 2000, it was developed, produced and launched by many manufacturers in China. Compared with other sulfonamide drugs, it has the advantages of strong hypoglycemic effect, small dose, long action time, small side effects, safety and reliability. [0003] There are many patent literature reports on the synthesis process of glimepiride, such as: Shandong Chemical Industry 2009, 38 (6): 14-16, the first step verification yield is only about 70%, the reason is that intermediate 1 has Certain solubility; WO2006103690 co...

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Problems solved by technology

[0005] In the third step of ammoniation, the long reaction time and high reaction temperature reported in the above documents cause the hydrolysis of intermediate 2; in addition, the amount of ammonia water is also very large, which increases the cost of wastewater treatment

Intermediate 3 crude product recrystallization method, but there is no report in the existing literature, WO2006103690 uses a mixed solvent, and the method of steaming most of it after reflux is cumbersome; Shandong Chemical Industry 2009, 38 (6): 14-16 reports that 95% Ethanol is recrystallized twice to achieve 99% purity

[0006] In the fourth step addition 2, the literature reports that acetone or acetone-toluene mixed solvent is used. This method takes a long time and the reaction is incomplete, resulting in the formation of viscous precipitate, which makes filtration difficult.

In addition, acetone is a flammable, explosive and volatile solvent, which is not conducive to recovery and safe operation

[0007] In the fifth step of removing insoluble matter, Shandong Chemical Industry 2009, 38 (6): 14-16, CN101671290, and WO2006103690 all acidify Glimepiride metal hydrochloride, dry it, and then use methanol as a solvent. The weak acidity of urea forms a salt with ammonia or methanol amine to dissolve, filter out the insoluble matter, and then acidify with acetic acid or hydrochloric acid. This operation is complicated and may easily cause more inorganic salts in the product, which need to be washed many times with water to remove

According to CN101486674 operation, a large amount of carbon dioxide gas will be produced during acidification, which is prone to material spraying accidents and causes great potential safety hazards

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