A kind of method for preparing atazanavir monomer

A monomer and phenyl technology, applied in the field of preparation of atazanavir monomer, can solve the problems of eye and skin irritation, complex separation and purification of products, unsuitable for industrial production, etc., achieve easy separation and purification, and high product yield , cheap effect

Active Publication Date: 2017-04-19
NORTHEAST PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] 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

Method used

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  • A kind of method for preparing atazanavir monomer
  • A kind of method for preparing atazanavir monomer
  • A kind of method for preparing atazanavir monomer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Example 1: 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxyl-5(S)-2,5-diamino-6-phenyl-2-azepine Preparation of alkane

[0019] In a clean reaction flask, add 27.45g (48.8mmol) of 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxyl-5(S)-2,5-bis[ (tert-butoxycarbonyl)amino]-6-phenyl-2-azidine and 45mL of dichloromethane, add 22.7g of hydrochloric acid dropwise; after dropping, raise the temperature to 40-45°C and keep it for about 3h; TLC analysis and tracking , the reaction was completed, lowered to room temperature, added 24.4g triethylamine, stirred at this temperature for 2h, layered, the organic layer was dried with anhydrous magnesium sulfate for 2h, filtered, the filter cake was rinsed with a small amount of solvent, and concentrated to dryness under reduced pressure , to obtain 16.92 g of solid product, yield 96.1%.

Embodiment 2

[0020] Embodiment 2: the preparation of atazanavir monomer

[0021] Put 18.9 g (100.0 mmol) of N-methoxycarbonyl-L-tert-leucine in a 500 mL eggplant-shaped bottle, add 200 mL of dichloromethane and stir to dissolve it, then add 70.5 g and 14.2 g of triethylamine ( 112.0 mmol) of thionyl chloride, the temperature was raised to 42°C and the solvent dichloromethane was refluxed, and the temperature was kept for 3 hours. After the reaction was completed, the temperature was lowered to room temperature, and the solid triethylamine hydrochloride was removed by filtration, and the filtrate was set aside.

[0022] Dissolve 32.58 g (90.0 mmol) of the solid product in Example 1 in 50 mL of dichloromethane, slowly drop the filtrate in the above step into the system at room temperature, stir overnight, and the reaction is complete. The reaction solution was successively washed with 10% citric acid, 10% potassium carbonate, 10% sodium chloride and purified water (300mL×2), concentrated und...

Embodiment 3

[0023] Example 3: 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxyl-5(S)-2,5-diamino-6-phenyl-2-azepine Preparation of alkane

[0024]In a clean reaction flask, add 41.175g (73.2mmol) of 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxyl-5(S)-2,5-bis[ (tert-butoxycarbonyl)amino]-6-phenyl-2-azepine and 80mL of ethyl acetate, add 36.3g of hydrochloric acid dropwise; after dropping, raise the temperature to 50°C and keep it for about 2.5h; TLC analysis tracking, After completion of the reaction, drop to room temperature, add 35.1g N-methylmorpholine, stir at this temperature for 2h, separate layers, dry the organic layer with anhydrous sodium sulfate for 2h, filter, rinse the filter cake with a small amount of solvent, and concentrate under reduced pressure to Dry to obtain 25.17g of solid product, yield 95.3%.

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Abstract

A method for preparing atazanavir monomers applied in the field of medical technology, at an appropriate temperature, with a weak base as an acid-binding agent and a certain organic solvent, N-methoxycarbonyl-L-tert-leucine The acid first reacts with thionyl chloride to generate N-methoxycarbonyl-L-tert-leucine acid chloride, and then reacts with 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5 (S)-2,5-diamino-6-phenyl-2-azidine was subjected to an amide reaction at room temperature to obtain atazanavir monomer. The invention has the following advantages (1) thionyl chloride is cheap, effectively reduces the cost of raw materials, and is suitable for industrialization; (2) the pollution produced is less, because it becomes soluble waste brine after post-treatment, and the environment is relatively friendly; ( 3) The operation is simple, the product yield is high, and it is easy to separate and purify, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a novel method for preparing atazanavir monomer. Background technique [0002] Atazanavir sulfate (BMS-232632-05, the English name of the product name is Reyataz, and the Chinese name is Rui Ai Tuo) is a white or light yellow crystalline powder, originally developed by Novartis in Switzerland, and later authorized to Germany's Bristol-Myers Squibb (BMS), and was developed by it to the market. In July 2003, it was first launched in the United States for the treatment of HIV-1 infection, and it is currently on the market in Europe, Japan, France, the United Kingdom, Denmark, the Netherlands, Spain, Sweden, Portugal, Canada and Germany. Atazanavir sulfate capsules are the first approved protease inhibitor in a single daily dose. The atazanavir compound itself was registered in the US and Europe in 2008 and 2010, respectively. In August 2006, FDA approved 300mg capsul...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/42
CPCC07D213/42
Inventor 白跃飞皮昌桥韩晓丹刘丹孙董军
Owner NORTHEAST PHARMA GRP
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