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Preparation method of bedaquiline

A bedaquiline and compound technology, which is applied to the preparation field of bedaquiline, can solve the problems of long reaction steps, expensive reagents, harsh reaction conditions, etc., achieves simple operation, improves conversion rate and reaction yield, and reduces production cost effect

Pending Publication Date: 2020-08-25
ANHUI BIOCHEM BIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] However, the above-mentioned methods all have the problems of long reaction steps, expensive reagents and harsh reaction conditions.

Method used

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  • Preparation method of bedaquiline
  • Preparation method of bedaquiline
  • Preparation method of bedaquiline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Embodiment 1: Preparation of 6-bromo-3-chlorobenzyl-2-methoxyquinoline

[0053]

[0054]Dissolve 3-benzyl-6-bromo-2-methoxyquinoline (32.7g, 0.01mol, 1eq) in 200ml of 1,2-dichloroethane, add NCS (14.7g, 1.1eq), peroxide Benzoyl (1.5 g, 0.006 mol), replaced with argon. The reaction system was heated to 80° C., and the reaction was continued at this temperature for 5 hours. After the reaction was complete, cool, add water and extract with dichloromethane, anhydrous Na 2 SO 4 After drying, the organic phase was concentrated, and the residue was recrystallized from methanol to obtain compound II-1 (29.3 g, yield 81%). 1 H NMR (400MHz, CDCl 3 )δ7.87(s,1H),7.84(d,J=4.0Hz,1H),7.63-7.70(m,2H),7.29–7.41(m,5H),6.05(s,1H),4.04(s ,3H). Ms(+C,ESI): M=362, found value: 363(M+1).

Embodiment 2

[0055] Embodiment 2: Preparation of 6-bromo-3-bromobenzyl-2-methoxyquinoline

[0056]

[0057] Dissolve 3-benzyl-6-bromo-2-methoxyquinoline (32.7g, 1eq) in 200ml of dichloromethane, add NBS (18.7g, 1.05eq), benzoyl peroxide (1.5g) , argon replacement. It was heated to reflux, and the reaction was continued at this temperature for 5 hours. After the reaction was complete, cool, add water and extract with dichloromethane, anhydrous Na 2 SO 4 After drying, the organic phase was concentrated, and the residue was recrystallized from methanol to obtain compound II-2 (34.6 g, yield 85%). 1 H NMR (400MHz, CDCl 3 )δ8.10(s,1H), 7.87(d,J=4.0Hz,1H), 7.44–7.69(m,4H), 7.26–7.38(m,3H), 6.56(s,1H),4.06(s , 3H); Ms(+C, ESI): M=406, found: (407, M+1).

Embodiment 3

[0058] Embodiment 3: the preparation of bedaquiline (racemate)

[0059]

[0060] Zinc powder (6.5g, 2eq) was suspended in 20ml of anhydrous tetrahydrofuran, trimethylchlorosilane (0.2ml) was slowly added dropwise at room temperature, and stirred for 5min after the addition was complete. Then the temperature was raised to 60°C, and at this temperature, 90ml of anhydrous THF mixed solution prepared by compound II-1 (18.2g, 1eq) and compound III (17g, 1.5eq) was slowly added dropwise, and the addition was completed within 1h. Stirring was continued for 4h after addition. Stop heating, cool to room temperature, extract with ethyl acetate, anhydrous Na 2 SO 4 Dry, stop the concentration when the organic phase is concentrated to 50ml, put it in an ice-water bath and stir, and precipitate the diastereomer B, that is, (S, S)-bedaquiline and (R,R)-bedaquiline non-corresponding The mixture of isomers was suction filtered, washed with a small amount of ethyl acetate, the solid was ...

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Abstract

The invention provides a method for preparing bedaquiline shown as a formula IV (See the specification). The method comprises the step of reacting a compound II with a compound III. According to the method disclosed by the invention, the ultralow-temperature reaction of the original process is changed, and the ultralow-temperature reaction which is difficult to realize industrially in the past iscarried out at the conventional temperature (heating condition), so that large-scale industrial production becomes possible. Besides, the method shortens the reaction route, enhances the conversion rate and reaction yield of the reaction substrate, enables the product to be easier to crystallize and purify, and lowers the production cost.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and more specifically relates to a preparation method of bedaquiline. Background technique [0002] Bedaquiline was developed by Johnson & Johnson Pharmaceutical Co., Ltd. of the United States and was approved by the US Food and Drug Administration on December 28, 2012. It is clinically used to treat drug-resistant tuberculosis. Its chemical name is (1R,2S)-1-(6-bromo-2-methoxy-3-quinolyl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl- 2-butanol. Its structure is as follows: [0003] [0004] Bedaquiline inhibits the proton transfer chain of ATP synthase of mycobacteria and prevents Mycobacterium tuberculosis from using ATP to generate energy, thereby exerting anti-tuberculosis effects. This is a brand-new pathway of action against Mycobacterium tuberculosis. It is the first anti-tuberculosis drug with a new mechanism of action approved for clinical use in more than 40 years, and it is also the only...

Claims

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Application Information

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IPC IPC(8): C07D215/227
CPCC07D215/227
Inventor 王亚平郑国君王哲王志邦陈小峰郭立新高亮裴冉冉高鹏鹏刘安友
Owner ANHUI BIOCHEM BIO PHARMA
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