Method for preparing Ritonavir as anti-AIDS drug

Abstract

The invention relates to a method for preparing Ritonavir applied to the technical field of pharmaceutical synthesis. According to the method, under the conditions of organic alkali and an organic solvent, HATU is used as a condensing agent, N-[2-Isopropylthiazol-4-ylmethyl(methyl)carbamoyl]-L-valine and (2S,3S,5S)-5-Amino-2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane are subjected to an acidamide reaction, and then a certain post-treatment is performed, so that the Ritonavir is obtained. According to the method disclosed by the invention, the synthesis yield of the Ritonavir is increased, the purity is high, and the cost of raw materials is effectively reduced. Besides, the reaction time is short, the feed is simple, nitrogen protection is not needed, and feeding temperature needs to be appropriately controlled, so that by-products of HATU can be easy to wash away, the preparation time is greatly shortened, the working efficiency is improved, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, in particular to a new method for preparing ritonavir. Background technique [0002] According to the estimates of WHO and UNAIDS, by the end of 2014, AIDS had caused more than 30 million deaths, about 35.8 million HIV-infected people, and an average of 6,000 new infections every day. In the same year, some 2.5 million people were newly infected with HIV and 1.7 million people died of AIDS, 230,000 of them children. More than two thirds of people living with HIV live in sub-Saharan Africa, Nigeria, South Africa and Uganda. The region accounts for almost 70% of all new HIV infections globally. According to statistics, currently only 51% of HIV carriers know their infection status. In addition, the hardest-hit areas are the Caribbean, Eastern Europe and Central Asia. According to the authoritative organization IMS knowledgeLink, the high-incidence areas of AIDS mainly include the United ...

AI Technical Summary

Problems solved by technology

At present, the synthetic route of ritonavir is similar, the synthetic route mainly includes US5567823 applied by the original research Abbott Company, in which N-methylmorpholine is used as the acid-binding agent, (2S,3S,5S)-5-amino- 2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane 2 forms corresponding ester intermediates with isobutyl chloroformate, and then With N-hydroxysuccinimide to form a lively imine intermediate, and finally with N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]- L-valine 1 forms ritonavir, and the yield of this method is about 70%. Although the operating conditions are acceptable, due to the need for expensive N-hydroxysuccinimide and isobutyl chloroformate , therefore, considering the cost of raw materials, it does not meet the requirements of real industrial production

In addition, the WO9414436 applied by the original Abbott Company uses expensive EDC as the condensing agent, and uses the relatively expensive weak base HOBt at the same time. unsuitable for industrialization

The patent CN1554647 applied by Xiamen University uses solid triphosgene to synthesize ritonavir. Solid triphosgene is a flammable and explosive substance, and the post-processing process is also cumbersome. From the perspective of safety, it is not suitable for large-scale industrial production.

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