Method for synthesizing Teprenone

Abstract

The invention discloses an improved process for synthesizing Teprenone with Carroll reaction and a separation and purification method. In the method, aiming at the condition that alcohol byproducts which are difficult to separate are always produced in reaction, a treated organic aluminum catalyst is adopted, a ketone solvent is added for diluting; and low vacuum is adopted in the reaction process for rapidly transferring the low-level alcohol and the carbon dioxide generated in the reaction, and therefore, the reaction temperature is reduced, the side reaction is well controlled, the generation of the alcohol byproducts is decreased and the reaction conversion rate is higher than 95%. According to the invention, the emulsification problem in the purification process is solved so that the yield of the product before the rectification is increased to be higher than 87%, the short-distance distillation is well realized, the separated Teprenone completely meets the standards on the marketed drugs, the purity is not less than 99.0% and the yield of the high-purity product is above 66%. The improved process and the post-treatment and separation technology are simple for operation, easy for control, good in stability, achieve high reaction conversion rate and stable quality and are easy for industrialized production.

Description

technical field [0001] The invention relates to a method for synthesizing teprenone, in particular to a technique for synthesizing teprenone by Carroll reaction and a separation and purification technology. Background technique [0002] Teprenone, geranylgeranylacetone, is a kind of terpene, also known as pentacentrone, chemical name is 6, 10, 14, 18-tetramethyl-5, 9, 13, 17-nineteen Carbon tetraenyl 2-ketone, the structural formula is as follows: [0003] [0004] Launched in Japan in 1984, approved by FDA in 1994, imported capsules from Japan in 2000, imported raw materials in 2006, Eisai (China) Pharmaceutical Co., Ltd. approved capsules in 2009, exclusive production. Teprenone is a broad-spectrum anti-ulcer drug, which has strong anti-ulcer effect and improvement effect on various experimental ulcers and gastric mucosal lesions. This drug can promote the synthesis and secretion of main regenerative defense factors, high molecular glycoproteins and phospholipids in g...

AI Technical Summary

Problems solved by technology

[0008] However, in the existing reported Carroll reaction, due to the presence of organoaluminum catalysts, alcohol by-products are inevitably produced, and the generated alcohol by-products are difficult to separate, and in the post-treatment process, emulsification after solvent extraction, separation and washing Seriously, high-purity products cannot be obtained, and the conversion rate of the reaction is low, which leads to a low yield of the final product

And the Carroll reaction uses nitrogen or atmospheric distillation to eliminate the lower alcohols (methanol, ethanol, etc.) and carbon dioxide produced during the reaction. The reaction temperature exceeds 170°C, and high-temperature distillation will also lead to an increase in impurities.

Japanese Eisai Patent WO0203981A1 discloses that n-hexane is used as the extraction and separation solvent, and methanol, ethanol or isopropanol is continuously added. The solvent system has a low boiling point and is easy to distill, but has a large water solubility and the demulsification effect is not ideal, so it cannot be well realized. industrialization

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