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A method for reclaiming and utilizing bedaquiline stereochemical isomers

A technology of stereochemistry and isomers, applied in organic chemistry methods, chemical instruments and methods, organic chemistry, etc., can solve the problem that isomers cannot be reused

Active Publication Date: 2019-02-01
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The purpose of the present invention is to reclaim and utilize the three non-medicinal stereoisomers of Bedaquiline, turn waste into treasure, and solve the problem that the unnecessary isomers in the stereoisomer mixture cannot be reused at present

Method used

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  • A method for reclaiming and utilizing bedaquiline stereochemical isomers
  • A method for reclaiming and utilizing bedaquiline stereochemical isomers
  • A method for reclaiming and utilizing bedaquiline stereochemical isomers

Examples

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Effect test

preparation example

[0049] Preparation of stereoisomers of 6-bromo-α-[2-(dimethylamino)ethyl]-2-methoxy-α-1-naphthyl-β-phenyl-3-quinoline ethanol

[0050] The preparation of step 1 intermediate N-(4-bromophenyl)-3-phenylpropanamide

[0051]

[0052] In a 500ml single-necked bottle, add p-bromoaniline (40g, 0.232mol) and dichloromethane (200ml), stir to dissolve, add triethylamine (32ml), add dropwise phenylpropionyl chloride (37.5g, 0.223mol) under ice cooling Stir the reaction overnight, pour the reaction solution into a large beaker, add an appropriate amount of 10% hydrochloric acid to precipitate a large amount of white flocculent solid, filter with suction, wash the filter cake with a small amount of ether, and dry to obtain a white solid N-(4-bromophenyl) -3-phenylpropanamide 62g, yield 92%. mp103-105°C.

[0053] Step 23- Preparation of Benzyl-6-bromo-2-chloroquinoline

[0054]

[0055] Add anhydrous DMF (32.6ml, 0.420mol) into a 500ml single-necked bottle, slowly add POCl dropwise...

Embodiment 1

[0069]

[0070] Diastereomer B (0.5g, 0.9mmol) was dissolved in 20ml of anhydrous THF, NaOH powder (90mg, 2.3mmol) was added at room temperature, reacted at room temperature for 2 hours, detected by TLC, after the reaction was complete (see attached image 3 ), adding 0.5M hydrochloric acid to adjust the pH to acidity, extracting with ethyl acetate, separating the organic phase and the aqueous phase, evaporating the organic layer to dryness under reduced pressure, and recrystallizing the residue with methanol to obtain 233 mg of 3-benzyl-6 bromo-2 - Methoxyquinoline (X), yield 80.5%. The aqueous phase was adjusted to alkaline with saturated sodium carbonate solution, extracted with ethyl acetate, the organic phase was separated, dried over anhydrous magnesium sulfate, and evaporated to dryness to obtain 168 mg of 3-dimethylamino-1-naphthyl-1-propanone (Y). Yield 82.3%.

[0071] Product 3-benzyl-6 bromo-2-methoxyquinoline (see the attached figure 1 ) and 3-dimethylamino-1...

Embodiment 2

[0075] Using diastereomer A instead of diastereomer B, the procedure of Example 1 was repeated (yield X: 83%, Y: 85%).

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Abstract

The invention relates to a method for recycling and utilizing Bedaquiline stereochemical isomers. The isomers comprise (alpha R, beta R), (alpha S, beta S), and (alpha R, beta S)-6-bromine-alpha-[2-(dimethyl amidogen) ethyl]-2-methoxy-alpha-1-naphthyl-beta-phenyl-3-quinoline ethanol. The recycled isomers can generate X and Y with the high conversion rate, and X and Y can be used for synthesizing Bedaquiline again. According to the process method, the production cost of the Bedaquiline can be greatly lowered, and the utilization rate of raw materials can be improved. See the formula in the specification.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and relates to a process method for recovering and utilizing Bedaquiline stereochemical isomers and the application of the method in Bedaquiline synthesis. Background technique [0002] Mycobacterium tuberculosis is the causative agent of a serious and potentially fatal infection with worldwide distribution. The World Health Organization estimates that more than eight million people are infected with tuberculosis (TB) every year. The top five countries with the highest number of cases are India, China, Indonesia, Nigeria and South Africa. Multidrug-resistant tuberculosis continues to expand with the rise of drug-resistant strains and the emergence of cross-resistance. Of all infectious diseases, only AIDS kills more people than tuberculosis. According to statistics, in 2011, about 8.7 million people suffered from tuberculosis and 1.4 million died of tuberculosis. Millions of new p...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/227C07B57/00
CPCC07B57/00C07B2200/07C07D215/227
Inventor 冯文化孔德龙
Owner INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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