Method for preparing anti-HIV (human immunodeficiency virus) medicine ritonavir

Abstract

The invention discloses a method for preparing anti-HIV medicine ritonavir and belongs to the technical field of medicines. In conditions of proper temperature, taking weak base as acid-binding agent and certain organic solvent, N-[N(-methyl-N-[(2-isopropyl-4-thiazolyl) methyl] amino-carbonyl]-L-valine and thionyl chloride are reacted to produice N(-[N-methyl-N-[(2-isopropyl-4-thiazolyl) methyl] amino-carbonyl]-L-valine acyl chloride, which is not required to be purified and can be directly subjected to amide reaction with (2s, 3s, 5s)-5-amino-2-((i)N( / i)-((5-thiazolyl)-methoxycarbonyl group) amino)-1, 6-diphenyl-3-hydroxy hexane at a room temperature, so as to obtain ritonavir; the mole ratio of the N-[N-methyl-N-[(2-isopropyl-4-thiazolyl) methyl] amino-carbonyl]-L-valine to thionyl chloride is 1:1 to 1:8; the mole ratio of the N-[N-methyl-N-[(2-isopropyl-4-thiazolyl) methyl] amino-carbonyl]-L-valine acyl chloride to weak base is 1:1 to 1:15. The method has the advantages that the price of thionyl chloride is low, the material cost is reduced, the production pollution is low, the pollution can be changed into soluble effluent brine, the method is simple to operate, the product yield is high, and the method is easy for separation and purification, and is applicable to industrial production.

Description

technical field [0001] The invention relates to a method for preparing anti-HIV drug ritonavir in the technical field of medicine. Background technique [0002] In 2011, there were more than 34 million HIV-infected patients worldwide, of which 2.5 million were newly added, and 1.7 million died of related diseases. According to the latest data from the Ministry of Health of my country, the number of AIDS cases in my country reached 20,450 in 2011, a year-on-year increase of 27.96%, and the death toll was 9,224, a year-on-year increase of 19.13%. [0003] At present, the design of anti-HIV drugs is mainly aimed at the three key enzymes in the HIV replication cycle, namely reverse transcriptase, protease, integrase, and the HIV invasion process. According to the different drug targets, it can be divided into six categories, namely: nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), entry inh...

AI Technical Summary

Problems solved by technology

At present, the synthetic route of ritonavir is similar, and the synthetic route mainly includes US5567823 applied by the original research Abbott Company, which uses N -Methylmorpholine as an acid-binding agent, (2S,3S,5S)-5-amino-2-( N -((5-thiazolyl)-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane 2 forms the corresponding ester intermediate with isobutyl chloroformate, and then with N -Hydroxysuccinimide forms a lively imine intermediate, which is finally combined with N -[ N -methyl- N -[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine 1 forms ritonavir, although the operating conditions and yield of this method can be, but due to the need for more expensive of N -Hydroxysuccinimide and isobutyl chloroformate, therefore, consider from the cost of raw material, do not satisfy real suitability for industrialized 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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