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A method for separating bedaquiline diastereomer a

A technology of diastereoisomers and bedaquiline, applied in the field of separation of bedaquiline diastereomer A, can solve the problem of low purity of diastereomer A and difficult control of reaction conditions , Inability to purify and separate products, etc., to achieve high purity and yield, high purity, and the effect of easy raw material residue

Active Publication Date: 2021-04-02
ZHEJIANG HISUN PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Actual studies have found that due to the difficulty in controlling the reaction conditions for preparing bedaquiline, the control conditions for moisture, temperature, and dripping speed are harsh, the reaction is unstable, and the conversion rate cannot be guaranteed to reach more than 80% in each batch. When the ratio is between 60-80%, the ratio of diastereomer B and diastereomer A obtained by the method is between 1: 1-1: 3, which is helpful for the next step of chiral resolution. Scores matter; and conversion rates can even be as low as 50% or so at times
When the conversion rate is as low as 50%, due to the small amount of product in the reaction solution, if the method of patent WO2006125769 is used, the isolated product can hardly be purified. Even if the product is separated and purified by the purification method disclosed in this patent, the final product Diastereomer A was also obtained in low purity

Method used

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  • A method for separating bedaquiline diastereomer a
  • A method for separating bedaquiline diastereomer a

Examples

Experimental program
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Effect test

Embodiment 1

[0043] Reaction materials 3-benzyl-6-bromo-2-methoxyquinoline (10g) and 3-dimethylamino-1-(naphthalene-5-yl)acetone (10g), in tetrahydrofuran (80ml) with LDA (20g) reaction, one-step reaction obtains the bedaquiline reaction liquid of racemization. The conversion of the reaction was 56% as analyzed by HPLC. After the reaction was quenched, n-heptane (40ml) was added to the reaction solution, and the unnecessary diastereoisomer B was precipitated at 0°C in an ice-water bath, and the non-enantiomer B was removed by filtration. The obtained filtrate was washed with 50% acetic acid aqueous solution to remove the raw material 3-dimethylamino-1-(naphthalene-5-yl) acetone, and 15% hydrochloric acid aqueous solution was added to the organic layer to stir, so that the product was formed into a salt in the aqueous layer. Precipitate in. After filtration, the filtrate was separated into layers, at which point the product was transferred to the aqueous layer, and the starting material 3...

Embodiment 2

[0048] Starting material 3-benzyl-6-bromo-2-methoxyquinoline (10g) and 3-dimethylamino-1-(naphthalene-5-yl)acetone (10g), in tetrahydrofuran (80ml) and LDA ( 20g) reaction, one-step reaction obtains the bedaquiline reaction liquid of racemization. The conversion of the reaction was 65% as analyzed by HPLC. After the reaction was quenched, diisopropyl ether (160ml) was added to the reaction solution, and the unnecessary diastereoisomer B was precipitated in an ice-water bath at 5°C, and the non-enantiomer B was removed by filtration. The obtained filtrate was washed with 10% formic acid aqueous solution to remove the raw material 3-dimethylamino-1-(naphthalene-5-yl) acetone, and 5% sulfuric acid aqueous solution was added to the organic layer and stirred to make the product salted in the aqueous layer Precipitate in. After filtration, the filtrate was separated into layers. At this time, the product was transferred to the water layer, and the raw material 3-benzyl-6-bromo-2-m...

Embodiment 3

[0053] Starting material 3-benzyl-6-bromo-2-methoxyquinoline (10g) and 3-dimethylamino-1-(naphthalene-5-yl)acetone (10g), in tetrahydrofuran (80ml) and LDA ( 20g) reaction, one-step reaction obtains the bedaquiline reaction liquid of racemization. The conversion of the reaction was 75% by HPLC analysis. After the reaction was quenched, diisopropyl ether (400ml) was added to the reaction solution, and the unnecessary diastereoisomer B was precipitated in an ice-water bath at 2°C, and the non-enantiomer B was removed by filtration. The obtained filtrate was washed with 60% propionic acid aqueous solution to remove the raw material 3-dimethylamino-1-(naphthalene-5-yl) acetone, and 40% methanesulfonic acid aqueous solution was added to the organic layer and stirred to make the product into a salt Precipitate in the water layer. After filtration, the filtrate was separated into layers, at which point the product was transferred to the aqueous layer, and the starting material 3-be...

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Abstract

Disclosed is a method for separating a diastereoisomer A of Bedaquiline. The method comprises the following steps: (1) adding a reversed-phase solvent into a Bedaquiline reaction liquid comprising diastereoisomers A and B, so as to precipitate out the diastereoisomer B; and (2) removing the diastereoisomer B precipitated out in step (1), so as to obtain the diastereoisomer A. The separation method of the present invention is easy to operate and is stable, and has higher industrialization value compared with separation and purification in a conventional column chromatography method, and can resolve the problems of difficulty in purifying and separating Bedaquiline due to the small amount of a product caused by an excessively low conversion rate because preparation condition of Bedaquiline is harsh and the conversion rate is difficult to ensure; raw material residuals can be easily removed, the yield is high, and the purity of the diastereoisomer A is high, which facilitates the split; split can be further carried out to obtain a qualified Bedaquiline product with a purity greater than or equal to 99.0%, wherein the impurities of the diastereoisomers are lower than or equal to 0.1%.

Description

technical field [0001] The invention relates to the field of medicines, more specifically, to a method for separating bedaquiline diastereoisomer A. Background technique [0002] Bedaquiline (Bedaquiline) is a kind of anti-tuberculosis drug, and its structural formula is as shown in 1: [0003] [0004] The chemical name of bedaquiline is (1R,2S)-1-(6-bromo-2-methoxy-3-quinolyl)-4-dimethylamino-2-(1-naphthyl)-1 -Phenyl-2-butanol is the first drug that inhibits mycobacterial adenosine triphosphate (ATP) synthetase developed by Johnson & Johnson. The trade name is Sirturo. Bedaquiline has strong selectivity to ATP synthase of Mycobacterium tuberculosis, and its new mechanism of action makes it have no cross-resistance with other anti-tuberculosis drugs, which will greatly reduce the drug resistance of Mycobacterium tuberculosis. It showed good activity against multidrug-resistant tuberculosis bacteria in macrophages, suggesting that it has the effect of shortening the tr...

Claims

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Application Information

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IPC IPC(8): C07D215/227C07F1/02
CPCC07D215/227C07F1/02
Inventor 张福利潘林玉朱津津王新增赵立任重宋颖
Owner ZHEJIANG HISUN PHARMA CO LTD
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