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Preparation method of bedaquiline and intermediate thereof

A technology of quinoline racemate and betadine, which is applied in the field of pharmaceutical synthesis, can solve the problems of low reaction temperature, high energy consumption, expensive reaction conditions of reagents, etc., and achieves a technology that reduces production cost, improves reaction yield, and is easy to crystallize and purify. Effect

Pending Publication Date: 2020-09-01
ANHUI BIOCHEM BIO PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

For example, the first method is not suitable for industrial production due to long steps, expensive reagents and harsh reaction conditions.
Both the second and third methods inevitably require reaction under ultra-low temperature conditions, which are not suitable for industrial production
In addition, the two substrates—compound 1 and compound 3—react with large steric hindrance, require low reaction temperature, long reaction time, and huge energy consumption
At present, many domestic pharmaceutical companies do not have large-scale ultra-low temperature reactors. Such low reaction temperatures are easy to achieve in laboratories or 100L-200L reactors, but it is very difficult to implement them in large reactors of thousands of liters.
In the fourth method, although the ultra-low temperature reaction is avoided, two Grignard reactions are required
Especially for the first Grignard reaction, there are two bromines on the reaction substrate, the selectivity will be relatively poor under the condition of magnesium powder, resulting in low yield and difficult removal of impurities
Therefore, the current technology limits the large-scale production of bedaquiline to a certain extent

Method used

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  • Preparation method of bedaquiline and intermediate thereof
  • Preparation method of bedaquiline and intermediate thereof
  • Preparation method of bedaquiline and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0124] Embodiment 1: the preparation of N-(4-aminophenyl) phthalimide (compound I)

[0125]

[0126] Referring to the method recorded in the document CN103834051A (see the synthesis of amines in page 3 (2) of the description), it is prepared by the following method:

[0127] Dissolve phthalic anhydride (14.g) in DMF, add p-phenylenediamine (14g, 1.3eq) in batches, raise the temperature to 150°C for reaction, maintain the temperature for 3 hours, and cool down after the reaction is complete. The reaction mixture was slowly poured into ice water, and a solid precipitated out, which was filtered by suction to obtain compound I (17.1 g, yield 72%). 1 H NMR (400MHz, DMSO-d 6 )δ: 7.86-7.93 (m, 4H), 7.02 (d, J = 8.0Hz, 2H), 6.64 (d, J = 8.0Hz, 2H), 5.33 (s, br, 2H); Ms (+C, ESI): M=238, measured value: (239, M+1).

Embodiment 2

[0128] Example 2: Preparation of N-(4-(1,3-diketoisoindol-2-yl)phenyl)-3-phenylpropanamide (compound II)

[0129]

[0130] Compound I (23.8g, 1.1eq) was dissolved in 70ml of toluene, triethylamine (20.9ml, 1.5eq) was added, and the reaction mixture was cooled in ice water. Phenylpropanoyl chloride (17.6g, 1.05eq) was slowly added dropwise to the toluene solution of compound I, and after the addition was completed, the temperature was raised naturally, and stirred overnight at room temperature. After the reaction was completed, 200ml of water was added to the reaction mixture at room temperature, stirred for 2h, filtered, and the filter cake was washed with 20ml*3 water and 20ml of toluene, and dried to obtain compound II (33g, yield 89%).

[0131] 1 H NMR (400MHz, DMSO-d 6 )δ10.09(s,1H),7.87-7.97(m,5H),7.71(d,J=8.0Hz,2H),7.36(d,J=8.0Hz,2H),7.19-7.32(m,2H ), 7.03(d, J=8.0Hz, 1H), 6.67(d, J=8.0Hz, 1H), 2.94(t, J=8.0Hz, 2H), 2.67(t, J=8.0Hz, 2H); Ms(+C, ESI): M=370, measur...

Embodiment 3

[0132] Example 3: Preparation of 2-(3-benzyl-2-chloro-quinolin-6-yl)isoindole-1,3-dione (compound III)

[0133]

[0134] DMF (29ml, 5eq) was placed in a round bottom flask, POCl was added dropwise under ice water cooling 3 (50ml, 7eq), after the dropwise addition, continue to stir in ice water for 10min. The ice-water bath was removed, and stirring was continued at room temperature for 10 min. Add 80ml of acetonitrile and solid compound II (37g, 1eq), and heat to 80°C for 8h. After the reaction was completed, the reaction solution was poured into a sodium carbonate solution mixed with ice and water, stirred for 30 min, filtered with suction, washed with water, crystallized with ethanol, and dried to obtain compound III (27.1 g, yield 68%).

[0135] 1 H NMR (400MHz, DMSO-d 6 )δ8.43(s,1H),8.10-8.11(m,2H),8.02-8.03(m,2H),7.94-7.96(m,2H),7.89-7.90(m,1H),7.25-7.34( m, 5H), 4.27 (s, 2H); Ms (+C, ESI): M=398, found value: (399, M+1).

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PUM

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Abstract

The invention discloses a preparation method of a bedaquiline racemate and a key intermediate compound used in the preparation method. According to the method for preparing the bedaquiline racemate, the ultra-low temperature reaction in the prior art is changed, and the ultra-low temperature reaction which is difficult to realize in the prior art is carried out at the conventional temperature, sothat large-scale industrialization becomes possible. Besides, the method provided by the invention greatly improves the conversion rate of the reaction substrate, improves the reaction yield, makes the product more easily crystallized and purified, and reduces the production cost at the same time.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular, the invention relates to a preparation method of bedaquiline and an intermediate thereof. Background technique [0002] Bedaquiline was developed by Johnson & Johnson Pharmaceutical Co., Ltd., and was approved by the US Food and Drug Administration on December 28, 2012 for the treatment of 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. [0005] Bedaquiline prevents Mycobacterium tuberculosis from using ATP to generate energy by inhibiting the proton transfer chain of ATP synthase of Mycobacterium, thereby exerting an anti-tuberculosis effect. This is a brand-new pathway of action against Mycobacterium tuberculosis. Bedaquiline is the first anti-tuberculosis drug with a new mechanism of action approved for clinical use in mor...

Claims

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Application Information

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IPC IPC(8): C07D215/227C07D401/04
CPCC07D215/227C07D401/04C07B2200/13
Inventor 郑国君王亚平郭立新王志邦王哲陈小峰裴冉冉胡凯凯高亮高鹏鹏张法魁刘安友
Owner ANHUI BIOCHEM BIO PHARMA
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