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Method for high efficiency production of Bedaquiline

A quinoline-based, product-based technology, applied in the field of efficient production of bedaquiline, can solve the problems of material waste, no recycling of the three isomers, and unsuitability for large-scale production

Active Publication Date: 2015-12-30
BEIJING WINSUNNY PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compound A reacts with compound B under the action of lithium diisopropylamide to generate 1-(6-bromo-2-methoxy-3-quinolyl)-4-dimethylamino-2-(1-naphthyl) )-1-phenyl-2-butanol, the product has two chiral carbon atoms, so the product includes a mixture of four optical isomers, which is purified by chiral silica gel column chromatography to obtain bedaquiline , the remaining three isomers are discarded as reaction waste, resulting in a large amount of material waste. There is no report on the recovery and treatment of the three isomers in this patent. This process is not suitable for large-scale production

Method used

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  • Method for high efficiency production of Bedaquiline
  • Method for high efficiency production of Bedaquiline
  • Method for high efficiency production of Bedaquiline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039]Add 0.1kg of 1-(6-bromo-2-methoxy-3-quinolyl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-2-butanol to 2L In tetrahydrofuran, after stirring, 0.1 kg of sodium hydroxide was added, the reaction was stirred at room temperature, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product mixture compound A and compound B.

[0040] The resulting crude product mixture was dissolved in ethyl acetate, hydrochloric acid was added, and the organic layer was spin-dried to obtain 51.06 g of compound A, with a yield of 86.4% and a purity of 97.8%; After ester extraction, the organic layers were combined and dried over anhydrous sodium sulfate to obtain 33.82 g of compound B with a yield of 82.7% and a purity of 94.5%.

Embodiment 2

[0042] Add 0.1kg of 1-(6-bromo-2-methoxy-3-quinolinyl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-2-butanol to 1L In dichloromethane, after stirring, 0.45 kg of cesium hydroxide was added, stirred at room temperature for reaction, dried over anhydrous sodium sulfate, and spin-dried to obtain crude compound A and compound B.

[0043] The resulting crude product mixture was dissolved in toluene, phosphoric acid was added, and the organic layer was spin-dried to obtain 50.7 g of compound A, with a yield of 85.8% and a purity of 97.3%; the acid layer was adjusted to alkaline with potassium bicarbonate, extracted with toluene, and combined The organic layer was dried over anhydrous sodium sulfate to obtain 33.74 g of compound B with a yield of 82.5% and a purity of 94.4%.

Embodiment 3

[0045] Add 0.1kg of 1-(6-bromo-2-methoxy-3-quinolyl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-2-butanol to 4L In acetonitrile, 0.15 kg of sodium ethoxide was added after stirring, the reaction was stirred at room temperature, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product mixture compound A and compound B.

[0046] The resulting crude product mixture was dissolved in dichloromethane, hydrochloric acid was added, and the organic layer was spin-dried to obtain 50.35 g of compound A, with a yield of 85.2% and a purity of 97.6%; Extract, combine the organic layers, and dry over anhydrous sodium sulfate to obtain 33.17 g of compound B, with a yield of 81.1% and a purity of 94.6%.

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Abstract

The invention relates to a method for high efficiency production of Bedaquiline. The method comprises that through optical resolution of 1-(6-bromo-2-methoxy-3-quinolyl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-2-butanol, Bedaquiline and other isomers are obtained, the other isomers undergo a reaction under the action of an alkali to produce key intermediate compounds A and B, and the key intermediate compounds A and B are separated and undergo a reaction to produce Bedaquiline. The method realizes high efficiency production of Bedaquiline, prevents large waste of materials, saves a cost and is suitable for large scale industrial production.

Description

technical field [0001] The invention relates to a production method of anti-tuberculosis drugs, in particular to a method for efficiently producing bedaquiline. Background technique [0002] Bedaquiline is a drug developed by Johnson & Johnson for the treatment of drug-resistant tuberculosis. For drugs against drug-resistant tuberculosis, the 50% cure rate is 13 weeks (2 years for the original combination drug), and the 80% cure rate is 6 months. Compared with the combination drug (2-4 drugs), The cure rate of the drug is greatly improved, and the treatment cycle is greatly shortened. The chemical name of bedaquiline is (1R,2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4- Dimethylamino-2-(1-naphthyl)-1-phenyl-2-butanol, the specific structural formula is: [0003] [0004] Disclosed in CN1325475C is the synthetic method of bedaquiline, at first take p-bromoaniline and phenylpropionyl chloride as raw material, obtain 3-benzyl-6-bromo-2-methoxyquinoline through acylation, cycliz...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/227C07C221/00C07C225/16
Inventor 林国良杨帆韩杰耿玉先郝艳山马贵红闫明丹潘海群
Owner BEIJING WINSUNNY PHARMA CO LTD
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