Novel method for preparing atazanavir monomer

A new method and monomer technology, applied in the field of medicine, can solve the problems of eye and skin irritation, complicated product separation and purification, unsuitable for industrial production, etc., and achieve the effects of easy separation and purification, high product yield and low price.

Active Publication Date: 2015-02-18
NORTHEAST PHARMA GRP
View PDF12 Cites 1 Cited by
  • 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 conden

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Novel method for preparing atazanavir monomer
  • Novel method for preparing atazanavir monomer
  • Novel 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)-hydroxy-5(S)-2,5-diamino-6-phenyl-2-azahexyl 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%.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention discloses a method for preparing an atazanavir monomer. The method is applied to the technical field of medicines and comprises steps as follows: at the proper temperature, weak base is used as an acid-binding agent, under a certain organic solvent condition, N-methoxycarbonyl-L-tert-leucine firstly reacts with thionyl chloride to produce N-methoxycarbonyl-L-tert-leucine acyl chloride, then the N-methoxycarbonyl-L-tert-leucine acyl chloride and 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxyl-5(S)-2,5-diamino-6-phenyl-2-azahexane have an amide formation reaction at the room temperature, and the atazanavir monomer is obtained. The method has the advantages as follows: (1), the thionyl chloride is cheap, so that the costs of raw materials are effectively reduced, and the method is suitable for industrialization; (2), the produced pollution is less and is converted into soluble effluent brine after after-treatment, so that the method is relatively environment-friendly; (3), the operation is simple, the product yield is high, separation and purification are easy, and the method 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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
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
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap