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A method for preparing anti-AIDS drug atazanavir monomer

An anti-AIDS and atazanavir technology, applied in the field of preparing atazanavir monomer, can solve the problems of eye and skin irritation, complex separation and purification of products, unsuitable for industrial production, etc., to achieve easy separation and purification, less pollution , Environmentally friendly effect

Active Publication Date: 2019-09-13
NORTHEAST PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] WO2010146119 discloses a process of using DIC or DCC alone as a condensing agent without using HOBT. Compared with the above process, the safety of this process is improved, but DIC and DCC are still dangerous chemicals, which are irritating to eyes and skin, and have SERIOUS EYE DAMAGE HAZARD AND DIC IS AN EXTREMELY TOXIC CHEMICALS
U.S. patent application US7834043 (assignee: Abbott, application date: on December 9th, 2004) has announced that expensive DEPBT is used as condensation agent to synthesize atazanavir monomer, but yield is only 55%, and its product separation Purification is complicated and needs to be separated by chromatographic columns, which is not suitable for industrial production
In the follow-up patent CN102911113, the method of synthesizing atazanavir monomer using DEPBT as a condensing agent was improved. Although the yield and post-treatment have been greatly improved, the expensive DEPBT still limits the method. wide application of

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  • A method for preparing anti-AIDS drug atazanavir monomer
  • A method for preparing anti-AIDS drug atazanavir monomer
  • A method for preparing anti-AIDS drug atazanavir monomer

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Embodiment 1

[0022] Embodiment one: the preparation of atazanavir monomer

[0023] At 42°C, 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2-nitrogen 36.2g (100mmol) of heterohexane, 41.6g (220.0mmol) of N-methoxycarbonyl-L-tert-leucine, 83.6g (220mmol) of HATU and 71.2g of pyridine were placed in a 500mL eggplant-shaped bottle, and 200mL Stir isopropyl acetate for 1.5 h, TLC detection, the reaction is complete, the reaction solution was washed with saturated brine and purified water in turn 200mL×2, the water layer was discarded, and the organic phase was added to anhydrous magnesium sulfate to dry for 6 hours and then filtered, and then the filtrate Heat to 35°C, add 0.3g activated carbon for decolorization, stir for 20min, cool to 20-30°C and filter, concentrate the organic phase in vacuo to obtain oily atazanavir monomer crude product, add 300mL isopropanol to the above oil, and then Heat to reflux to make it completely dissolved, then add 300mL of n-hexane dropwis...

Embodiment 2

[0024] Embodiment two: the preparation of atazanavir monomer

[0025]At 35°C, 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2-nitrogen 36.2g (100mmol) of heterohexane, 37.8g (200.0mmol) of N-methoxycarbonyl-L-tert-leucine, 76.0g (200mmol) of HATU and 71.2g of pyridine were placed in a 500mL eggplant-shaped bottle, and 200mL Methyl isobutyl ketone was stirred for 1 hour, and detected by TLC. After the reaction was completed, the reaction solution was washed with 10% potassium dihydrogen phosphate and purified water in turn to 200mL×2, the water layer was discarded, and the organic phase was dried by adding anhydrous sodium sulfate for 6 hours. Filtrate, then heat the filtrate to 50°C, add 0.4g injection carbon 767 to decolorize at the same time, stir for 20min, cool to 20-30°C and filter, concentrate the organic phase in vacuo to obtain oily atazanavir monomer crude product, pour into the above oil Add 300mL of ethanol, then heat to reflux at 80°C to disso...

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Abstract

A method for preparing atazanavir monomers applied in the technical field of pharmaceutical synthesis, using HATU as a condensation agent under organic base and organic solvent conditions, N-methoxycarbonyl-L-tert-leucine and 1- [4‑(pyridine‑2‑yl)‑phenyl]‑4(S)‑hydroxy‑5(S)‑2,5‑diamino‑6‑phenyl‑2‑azahexane undergoes an amide reaction, After certain post-processing, atazanavir monomer is obtained. The method of the invention improves the synthesis yield of atazanavir, has high purity, and effectively reduces the cost of raw materials. At the same time, the reaction time is short, the feeding is simple, no nitrogen protection is required, and the feeding temperature can be properly controlled. The by-products of HATU are easier to be washed and removed, which greatly shortens the preparation time and improves work efficiency. It is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, in particular to a method for preparing atazanavir monomer. Background technique [0002] HIV is divided into HIV-1 and HIV-2. HIV-1 is mainly prevalent in the world, and HIV-2 is only distributed in a small amount in the sub-Saharan region. At the same time, in HIV-1, there are also three categories of M group, O group and N group. Among them, the M group virus is the main one, and the M group virus can be subdivided into 9 subtypes of A, B, C, D, F, G, H and J. The large number of HIV subtypes has brought great difficulties to the treatment and prevention of AIDS. At present, there is no drug that can completely cure AIDS, but the existing drugs have transformed AIDS from a dreadful lesion into a chronic infectious disease that can be controlled. The treatment of AIDS must be taken for life. burdened with a heavy financial burden. [0003] Atazanavir sulfate (BMS-232632-05, the Engl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/42
Inventor 白跃飞皮昌桥吴晓璟周宏刘丹祝春艳周凯于河舟
Owner NORTHEAST PHARMA GRP
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