A kind of preparation method of purification and stable crystal form of bedaquiline

A bedaquiline and crystal form technology, which is applied in the field of purification and stable crystal form preparation, can solve the problems of easy agglomeration, inconspicuous removal of impurities, and difficulty in removing, and achieves the effects of convenient storage, simple operation and convenient process.

Active Publication Date: 2021-06-25
WUHAN WUYAO SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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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  • A kind of preparation method of purification and stable crystal form of bedaquiline
  • A kind of preparation method of purification and stable crystal form of bedaquiline
  • A kind of preparation method of purification and stable crystal form of bedaquiline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] 1200 g of Baddaquinoline-zonetheol phosphate salt, 12L toluene, potassium carbonate aqueous solution (1.2 kg of anhydrous potassium carbonate was stirred with a purified water) to stir the 30 L of the reaction kettle, warmed to 75 ~ 85 ° C. 1 hour, standing, hot separation of the organic layer into another 30L reactor, add 10% aqueous potassium carbonate solution (stirred 1.2 kg anhydrous anhydrous potassium carbonate to about 10.8 kg purified water), warmed to 75 ~ 85 ° C After stirring for 15 minutes, it was allowed to stand for 15 minutes, separated from the organic layer, and 0.5 kg was dried for 3 hours, filtered, and the filtrate was divided into 12 parts to concentrate to be purified. Sampling detection HPLC purity was 96.1%.

Embodiment 2

[0030] A concentrate (equivalent to Ba Davanozoline-strawnaphenol phosphate) obtained in Example 1 was taken in Example 1, 150 ml of acetone was added, and the mixture was stirred to 50 to 60 ° C to completely dissolve, and the temperature of 50 to 60 ° C was controlled. 150 ml of ethanol was added dropwise, and stirring was stirred after 15 minutes after drying, 150 ml of purified water was 0.0 mL, cooled to 30 to 40 ° C, filtered, the resulting solid was dried at 50 ± 5 ° C for 10 hours, 55.8 g White solid is Bearda quinoline, yield: 90.7%, purity: 99.7%.

Embodiment 3

[0032] The concentrate (equivalent to the Paddanquinoline-zerohydla phosphate salt 100g) obtained in Example 1 was taken, 250 ml of acetone was added, and the mixture was stirred to 50 to 60 ° C to completely dissolve, the temperature of 50 to 60 ° C, 250 ml of ethanol was added dropwise, and stirred after 15 minutes after drying, the temperature was 50 to 60 ° C to purify the water 250 ml, the temperature was lowered to 30 to 40 ° C, filtered, the resulting solid was dried at 50 ± 5 ° C for 10 hours, 52.9 G white solid is Bearda quinoline, 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. After dissociating the bedaquiline-binaphthol phosphate salt obtained by the resolution with alkaline water to remove the resolution reagent, extract and concentrate with toluene to obtain an oily substance, add ketone and stir to dissolve; then add alcohol and purified water dropwise, and stir evenly , Precipitating powdery crystals of bedaquiline free base. The method of the invention refines and purifies the bedaquiline free base by using a mixed solvent, so that the impurity content is significantly reduced, the quality requirement of the finished product is met, and a stable crystal form is obtained, which is convenient for storage and a subsequent salt-forming process. The process of the invention has the advantages of simple and convenient operation, high product yield and good quality, and is suitable for industrialized production.

Description

Technical field [0001] The present invention relates to the field of medicine, and more particularly to the purification of Padda Quinoline Tour and the preparation method of stabilizing crystalline form. Background technique [0002] Bedaquiline has been successfully developed by American Johnson & Johnson. It is a new type of diryquinoline anti-reneganica drug, clinical for tuberculosis treatment. It is called (1R, 2S) -1- (6-bromo-2-methoxy-3-quinolinyl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-phenyl- 2-butanol, structural formula is as follows: [0003] [0004] Bedaquinoline is a single anti-tuberculosis new drug for the listing in the nearly 40 years. Johnson & Johnson production was made of oral solid preparation with its fumanrate, and the trade name is Sirturo, which is a new type of diaryl quinoline anti-reneganiobacillus drug, by inhibiting myocardium ATP synthetase. The activity of the proton pump affects the ATP synthesis of the Nuclear Pyrogen, thereby plays an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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