Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Method for preparing (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline

A bedaquiline, equivalent technology, applied in the field of preparation of and-bedaquiline, can solve the problems of many reaction steps, high manufacturing cost, increase of high-pressure hydrogenation steps, etc., achieve production efficiency improvement, less residual impurities, The effect of fewer reaction steps

Active Publication Date: 2018-03-30
JIANGSU TIANHE PHARMA CO LTD
View PDF5 Cites 1 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Among the above synthetic methods, there are many problems in the first method, such as many reaction steps and extremely low yield, the manufacturing cost is very high, and there is no practical application value; the four optical isomer mixtures in the original research patent of the second method are separated, The yield of (1R, 2S)-bedaquiline is still very low; there are many reaction steps in method three, and the ratio of the four optical isomers has not been reported; in method four, a high-pressure hydrogenation step is added, which has certain dangers, and Ratio of target optical isomers not improved

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
  • Method for preparing (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline
  • Method for preparing (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline
  • Method for preparing (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034]Add 30mL of anhydrous dichloromethane, 4.44g of (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline into a 500mL three-neck flask, blow nitrogen, stir and cool to -70℃~-78℃ Slowly add 1.36g of boron trifluoride·diethyl ether complex within 10min, keep the temperature constant, add 15mL of 2mol / L sodium hydroxide solution after 15min of reaction, raise the temperature to room temperature, and stir the solution at room temperature for 30min, Remove the water phase, wash the dichloromethane layer with 60mL of saturated sodium chloride solution, and then dry and concentrate the dichloromethane layer to obtain an oily product. The ratio of (B+B') is 62 / 38;

[0035] Then add 25mL of tetrahydrofuran to this oil, heat to reflux, and then cool to room temperature, a white solid and mother liquor are precipitated, the white solid is filtered off, and the filtered solid is (1R, 2R)-bedaquiline and (1S, 2S )-bedaquiline, after concentrating the mother liquor to obtain an oily substance, ...

Embodiment 2

[0046] Add 41mL of anhydrous dichloromethane, 5.99g of (1R,2R)-bedaquiline and (1S,2S)-bedaquiline mixture into a 500mL three-necked flask, blow nitrogen, stir and cool to -70°C~-78°C ℃, slowly add 3.71g of boron trifluoride·diethyl ether complex within 10min, keep the temperature constant, add 28mL of 2mol / L sodium hydroxide solution after 15min of reaction, raise the temperature to room temperature, and stir the solution at room temperature for 30min , remove the water phase, wash the dichloromethane layer with 80mL saturated sodium chloride solution, and then dry and concentrate the dichloromethane layer to obtain an oily product. The ratio of / (B+B') is 63 / 37;

[0047] Then add 25mL of tetrahydrofuran to this oil, heat to reflux, and then cool to room temperature, a white solid and mother liquor are precipitated, the white solid is filtered off, and the filtered solid is (1R, 2R)-bedaquiline and (1S, 2S )-bedaquiline, after concentrating the mother liquor to obtain an oil...

Embodiment 3

[0049] Add 36mL of anhydrous dichloromethane, 5.33g of (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline mixture into a 500mL three-neck flask, blow nitrogen, stir and cool to -70°C ~ -78°C ℃, slowly add 1.63g of boron trifluoride·diethyl ether complex within 10min, keep the temperature constant, add 18mL of 2mol / L sodium carbonate solution after 15min of reaction, raise the temperature to room temperature, and stir the solution at room temperature for 30min, Remove the water phase, wash the dichloromethane layer with 60mL of saturated sodium chloride solution, and then dry and concentrate the dichloromethane layer to obtain an oily product. The ratio of (B+B') is 62 / 38;

[0050] Then add 25mL of tetrahydrofuran to this oil, heat to reflux, and then cool to room temperature, a white solid and mother liquor are precipitated, the white solid is filtered off, and the filtered solid is (1R, 2R)-bedaquiline and (1S, 2S )-bedaquiline, after concentrating the mother liquor to obtain an ...

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 (1R, 2S)-bedaquiline and (1S, 2R)-bedaquiline and belongs to the technical field of chemical synthesis. The method comprises the steps of subjecting (1R,2R)-bedaquiline and (1S, 2S)-bedaquiline to a Lewis acid action to form carbenium ions, then, subjecting the carbenium ions to action by OH<-> in an alkaline solution to form novel chiral tertiary alcohol, and then, carrying out resolution, thereby preparing (1R, 2S)-bedaquiline. According to the method, the number of reaction steps is small, the production efficiency is greatly increased, the (1R, 2S)-bedaquiline of relatively high yield is easy to obtain, and thus, the industrial production is facilitated; and meanwhile, the impurity residual is low, the purity of target products is high, and dangerous steps such as high-pressure hydrogenation are not required to be added, so that the entire production process is high in safety.

Description

Technical field [0001] The present invention belongs to the field of chemical synthesis technology, and specifically relates to a preparation method of (1R, 2S) and (1S, 2R)-bedaquiline. Background technique [0002] Multidrug-resistant TB is caused by bacteria that are resistant to isoniazid and rifampicin, as well as any fluoroquinolone and any second-line anti-tuberculosis injectable drug (amikacin, kanamycin, or capreomycin ) all have drug-resistant tuberculosis. In December 2012, the U.S. FDA accelerated approval of Johnson & Johnson's fumaric acid (1R, 2S)-bedaquiline, fumaric acid (1R, 2S)-bedaquiline, for the treatment of drug-resistant tuberculosis. Daquiline kills Mycobacterium tuberculosis by inhibiting the ATP synthase of Mycobacterium tuberculosis. The time for 50% cure is 13 weeks and the time for 80% cure rate is 6 months. When used in combination with the drug (2-4 Compared with other drugs), the cure rate of this drug is greatly improved and the treatment ...

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
Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/227C07B57/00C07B53/00
Inventor 赵学清赵云德朱林飞郑治尧廖伟科刘磊
Owner JIANGSU TIANHE PHARMA CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com