Preparation method of bedaquiline racemate and intermediates thereof

A compound and selected technology, applied in the field of drug synthesis, can solve the problems of many side reactions, low reaction temperature, long time and the like

Active Publication Date: 2020-10-09
ANHUI BIOCHEM UNITED PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although the material cost of this process is low and the operation is simple, there are still many problems: Compound 1 and Compound 3 react at -78°C under the action of LDA, the reaction time is long (about 30 hours), the raw materials cannot be converted completely, side reactions Many, the yield is very low (26%); And the resulting product bedaquiline purity is not high, and the total yield after purification is about 6%
In addition, the reaction steric hindrance of the two substrates (compound I and compound VI) is large, the required reaction temperature is low, the time is long, and the energy consumption is huge
In addition, at present, many domestic pharmaceutical companies do not have large-scale ultra-low temperature reactors. Such a low reaction temperature is easy to achieve in a laboratory or a 100L-200L reactor, but it is very difficult to implement in a large reactor of several thousand liters. Therefore, The current process limits the large-scale production of bedaquiline to some extent

Method used

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  • Preparation method of bedaquiline racemate and intermediates thereof
  • Preparation method of bedaquiline racemate and intermediates thereof
  • Preparation method of bedaquiline racemate and intermediates thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Example 1: Compound III-1 (3-benzyl-2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoline) preparation

[0094]

[0095] Compound I (65.6g, 1eq), bis(pinacolate) diboron (53g, 1.05eq), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (7.3 g, 0.05eq), anhydrous sodium acetate (33g, 2eq) was suspended in 500ml of dioxane and replaced with argon. The system was heated up to 100° C. and kept at this temperature for 8 hours. After the reaction was completed, it was extracted with ethyl acetate and the extract was concentrated to about 200ml, stirred and crystallized (ethyl acetate was used as solvent) to obtain compound III-1 (66.8g, yield 89%). 1 H NMR (400MHz, CDCl 3 )δ8.10(s,1H),7.94(dd,J=8.0Hz,J=4Hz,1H),7.81(d,J=4Hz,1H),7.57(s,1H),7.30-7.31(m, 2H), 7.22–7.26(m,3H), 4.11(s,3H), 4.02(s,2H), 1.36(s,12H); Ms(+C,ESI): M=375, measured value: 376( M+1).

Embodiment 2

[0096] Example 2: Compound III-1 (3-benzyl-2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoline) preparation

[0097]

[0098] Mg powder (7.2g, 1.5eq) was added to a 1L three-necked flask, and 50ml of anhydrous THF and 30ml of compound I solution (65.6g of compound I dissolved in 300ml of anhydrous THF, 1eq) were added under argon protection. After heating to reflux temperature, 1,2-dibromoethane (0.5ml) was added dropwise to initiate the reaction. Stir for 2 minutes after the addition, and slowly add the remaining compound I solution (270 ml) dropwise while maintaining slight boiling. After the addition, continue to keep the slight boiling state to react for 1 hour, and cool to room temperature to prepare the Grignard solution. The prepared Grignard solution was slowly added dropwise to methanol pinacol borate (47.4 g, 1.5 eq) and anhydrous THF (50 ml) cooled at 0° C., and the temperature was maintained for 3 hours. After completion of the reaction, extra...

Embodiment 3

[0099] Embodiment 3: the preparation of compound III-2 (3-benzyl-2-methoxy-6-boronic acid quinoline)

[0100]

[0101] Mg powder (7.2g, 1.5eq) was added to a 1L three-necked flask, and 50ml of anhydrous THF and 30ml of compound I solution (65.6g dissolved in 300ml of anhydrous THF, 1eq) were added under argon protection. After heating to reflux temperature, 1,2-dibromoethane (0.5ml) was added dropwise to initiate the reaction. Stir for 2 minutes after the addition, and slowly add the remaining compound I solution (270 ml) dropwise while maintaining slight boiling. After the addition, continue to keep the slight boiling state to react for 1 hour, and cool to room temperature to prepare the Grignard solution. The prepared Grignard solution was slowly added dropwise to trimethyl borate (31.2g, 1.5eq) and anhydrous THF (50ml) cooled at 0°C, and the temperature was maintained for 3 hours. After completion of the reaction, extract with ethyl acetate and concentrate the extract ...

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Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a bedaquiline racemate and intermediates thereof. According to the method disclosed by the invention, convenient, efficient and economical synthesis and industrial production of the bedaquiline and the intermediates thereof are realized. Specifically, the method provided by the invention has the following advantages that: the ultralow-temperature reaction required for preparing bedaquiline from a compound I and a compound II is thoroughly changed, and the original ultralow-temperature reaction which is difficult to realize industrially is changed into the reaction at a conventional temperature, so that large-scale industrial production becomes possible; according to the method disclosed by the invention, the conversion rate of the reaction substrate is greatly improved, the reaction yield is improved, the product is easier to crystallize and purify (recrystallizationof the intermediates can be realized by using a conventional solvent ethyl acetate or methanol), and meanwhile, the production cost is reduced.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and more specifically, the invention relates to a preparation method of a bedaquiline racemate and an intermediate thereof. Background technique [0002] Bedaquiline was developed by Johnson & Johnson Pharmaceutical Co., Ltd. of the United States. It was approved by the U.S. 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, the structure is shown below : [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 appr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02C07D215/227
CPCC07F5/02C07D215/227C07B2200/13
Inventor 郑国君王亚平张伟王哲王志邦库特马丁胡凯凯裴冉冉张法魁
Owner ANHUI BIOCHEM UNITED PHARMA CO LTD
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