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Method for purifying bedaquiline and preparing stable crystal form of bedaquiline

A bedaquiline and crystal form technology, which is applied in the field of purification and preparation of stable crystal forms, can solve the problems of easy agglomeration, difficult to remove, and inconspicuous removal of impurities, and achieves convenient storage, simple operation and controllable quality. Effect

Active Publication Date: 2019-03-05
WUHAN WUYAO SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

According to the description of the bedaquiline free base precipitation method in the patent CN200680017475, many experiments have been attempted, and the free bedaquiline oily matter is treated with ethanol beating, and the precipitated solid is easy to form agglomerates. From 96.5% to 97.1%, HPLC shows that there are two main impurities that are difficult to remove

Method used

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  • Method for purifying bedaquiline and preparing stable crystal form of bedaquiline
  • Method for purifying bedaquiline and preparing stable crystal form of bedaquiline
  • Method for purifying bedaquiline and preparing stable crystal form of bedaquiline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Add 1200g of bedaquiline-binaphthol phosphate, 12L of toluene, potassium carbonate aqueous solution (dissolve 1.2kg of anhydrous potassium carbonate in about 10.8kg of purified water) into a 30L reactor, heat up to 75-85°C and stir 1 hour, stand still, separate the organic layer while it is hot and transfer it to another 30L reaction kettle, add 10% potassium carbonate aqueous solution (dissolve 1.2kg of anhydrous potassium carbonate in about 10.8kg of purified water with stirring), and heat up to 75-85°C Stir for 15 minutes, let stand for 15 minutes, separate the organic layer, add 0.5 kg of anhydrous sodium sulfate to dry for 3 hours, filter with suction, divide the filtrate into 12 parts by volume and concentrate for purification. Sampling and HPLC purity was 96.1%.

Embodiment 2

[0030] Take a portion of the concentrated solution obtained in Example 1 (equivalent to 100 g of bedaquiline-binaphthol phosphate ester salt), add 150 ml of acetone, stir and heat up to 50-60° C. until completely dissolved, and control the temperature at 50-60° C. Add 150ml of ethanol dropwise, continue stirring for 15 minutes after dropping, add 150ml of purified water dropwise at a controlled temperature of 50-60°C, cool down to 30-40°C, filter with suction, and air-dry the obtained solid at 50±5°C for 10 hours to obtain 55.8 g white solid is bedaquiline, yield: 90.7%, purity: 99.7%.

Embodiment 3

[0032] Get a portion of the concentrated solution obtained in Example 1 (equivalent to 100 g of bedaquiline-binaphthol phosphate ester salt), add 250 ml of acetone, stir and heat up to 50-60° C. until completely dissolved, and control the temperature at 50-60° C. Add 250ml of ethanol dropwise, continue stirring for 15 minutes after dropping, add 250ml of purified water dropwise at a controlled temperature of 50-60°C, cool down to 30-40°C, filter with suction, and air-dry the obtained solid at 50±5°C for 10 hours to obtain 52.9 g white solid is bedaquiline, yield: 86.0%, purity: 99.8%.

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Abstract

The invention relates to a method for purifying bedaquiline and preparing a stable crystal form of bedaquiline. The method comprises the steps: adopting alkaline water to dissociate a resolving agentfrom a bedaquiline-binaphthol phosphate salt obtained after resolution, performing extraction with toluene, performing concentration so as to obtain an oily substance, adding ketone, performing stirring so as to achieve dissolution, then adding alcohol and purified water dropwise, performing uniform stirring so as to precipitate powdery crystal of bedaquiline free base. According to the method, refined purification of the bedaquiline free base is achieved through the mixed solvents, so that the impurity content is reduced significantly, the quality of the finished product is achieved, and a stable crystal form is obtained, so that storage and a subsequent salt forming process are facilitated; and the method has simple and convenient operation, high product yield and good quality, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a method for purifying bedaquiline free base and preparing a stable crystal form. Background technique [0002] Bedaquiline (bedaquiline), successfully developed by Johnson & Johnson, is a new type of diarylquinoline antimycobacterial drug, which is clinically used for the treatment of tuberculosis. Its chemical name is (1R,2S)-1-(6-bromo-2-methoxy-3-quinolyl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl- 2-Butanol, the structural formula is as follows: [0003] [0004] Bedaquiline is the only new anti-tuberculosis drug approved for marketing in the past 40 years. Johnson & Johnson uses its fumarate to make oral solid preparations. The trade name is Sirturo. The activity of the proton pump affects the ATP synthesis of Mycobacterium tuberculosis, thereby exerting antibacterial and bactericidal effects. It is used for the treatment of adult multidrug-resistant pulmonary tuberculosis (MDR-...

Claims

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Application Information

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IPC IPC(8): C07D215/227
CPCC07B2200/13C07D215/227
Inventor 宁东波潘季红朱毅郭亚兵杨波郭婷婷
Owner WUHAN WUYAO SCI & TECH
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