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New synthesis route and method of bedaquiline racemate

A bedaquiline racemate and methoxyquinoline technology, which is applied in the field of medicine, can solve the problems of harsh reaction conditions, lengthy synthesis routes, lengthy synthesis steps and the like, and achieves mild and easily controllable reaction conditions, simple and convenient reaction steps, The effect of easy product separation

Active Publication Date: 2015-12-23
CHONGQING SHENGHUAXI PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The synthetic route is tedious, the total yield is low, the cost is high, precious metals such as osmium tetroxide with high toxicity are used, the reaction conditions are harsh, and it is not suitable for industrial production
[0016] The above-mentioned preparation methods of bedaquiline all have harsh reaction conditions, lengthy synthesis steps, low yield and high cost, which are unfavorable for industrialized production

Method used

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  • New synthesis route and method of bedaquiline racemate
  • New synthesis route and method of bedaquiline racemate
  • New synthesis route and method of bedaquiline racemate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Preparation of 3-bromobenzyl-6-bromo-2-methoxyquinoline (Ⅱ)

[0034]

[0035] A. Add 30g (0.091mol) of 3-benzyl-6-bromo-2-methoxyquinoline, 16.2g (0.091mol) of NBS, 1g (0.004mol) of BPO and CCl into a 500ml single-necked bottle 4 200ml, stirred and warmed up to 78°C for 2h, filtered while hot to remove insoluble matter, evaporated the solvent under reduced pressure, added 200ml of DCM to dissolve the solid, washed three times with 10% sodium carbonate, dried the organic layer with anhydrous magnesium sulfate, filtered, and spun Dry to obtain white solid 34g, yield 92%, purity 99%.

[0036] [M+H] + :408; 1 HNMR (500MHz, CDCl 3 )δ8.13(d, J =11.6Hz,2H),7.90(d, J =4.5Hz, 2H), 7.41-7.29(m, 4H), 7.28(s, 1H), 6.36(s, 1H), 4.10(s, 3H). B. Add 50g (0.152mol) of 3-benzyl-6-bromo-2-methoxyquinoline, 27g (0.152mol) of NBS, 2.0g (0.008mol) of BPO, and CCl into a 1000ml single-necked bottle 4 400ml, stirred and raised to 78°C and refluxed for 2h, filtered while hot to remov...

Embodiment 2

[0038] Preparation of (6-bromo-2-methoxyquinolin-3-yl)-1-(naphthalene-1-yl)-2-phenylethanol (Ⅳ)

[0039]

[0040]A. Add 2.5g (0.104mol) of magnesium powder to a dry 250ml three-necked bottle, add an appropriate amount of dry ether to cover the magnesium powder, and slowly add 3-bromobenzyl-6-bromo-2 dissolved in 100ml of dry ether -Methoxyquinoline 15g (0.037mol), you can add a few drops of 1,2-dibromoethane to initiate the reaction, keep the reaction system slightly boiling until the addition is complete, keep warm and reflux for 1h; slowly add 1-naphthaldehyde 6.3g (0.040mol), after the dropwise addition, continue to keep warm and reflux for 1h. Cool down to 0°C, add 100ml of saturated ammonium chloride dropwise, adjust pH to 6, filter to remove insoluble matter, extract with dichloromethane, combine organic layers, wash with saturated brine, add anhydrous magnesium sulfate to dry, filter, and reduce pressure The solvent was evaporated to obtain 14.5 g of off-white solid...

Embodiment 3

[0044] Preparation of 2-(6-bromo-2-methoxyquinolin-3-yl)-1-(naphthalene-1-yl)-2-phenylethanone (Ⅴ)

[0045]

[0046] A. Add 13.5ml (0.16mol) oxalyl chloride to a 1000ml dry three-neck flask, cool down to -78°C, slowly add 22ml (0.31mol) dry DMSO dissolved in 100ml DCM into the reaction flask, and keep the temperature to continue After stirring for 30 min, 64.5 g (0.133 mol) of (6-bromo-2-methoxyquinolin-3-yl)-1-(naphthalene-1-yl)-2-phenylethanol dissolved in 30 ml of DMSO was added dropwise, Continue to stir for 1 hour after the dropwise addition, then add 110ml of triethylamine dropwise, and continue to maintain the low temperature reaction for half an hour after the addition. Rise to room temperature and add 400ml of water, let stand to separate the layers, separate the dichloromethane layer, continue to extract the water layer with dichloromethane, combine the dichloromethane layers with 1% hydrochloric acid solution, 5% sodium carbonate solution, water Wash, add anhydr...

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PUM

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Abstract

The invention relates to a new synthesis route and method of a bedaquiline racemate, and belongs to the medical technical field. The method comprises the steps: (1) carrying out a reaction of a starting material 3-bromobenzyl-6-bromo-2-methoxyquinoline (II) with metal magnesium in THF to prepare a Grignard reagent, then adding 1-naphthaldehyde (III) in the prepared Grignard reagent, carrying out a reflux reaction to obtain a compound (IV) 2-(6-bromo-2-methoxyquinoline-3-yl)-1-(naphthalen-1-yl)-2-phenylethanol; (2) undergoing swern oxidation of the compound (IV) to obtain a carbonyl compound 2-(6-bromo-2-methoxyquinoline-3-yl)-1-(naphthalen-1-yl)-2-phenyl ethyl ketone (a compound V); and (3) carrying out a Grignard reaction of the compound (V) with the Grignard reagent (VI) to obtain the bedaquiline racemate (I). The method is simple in route, is mild in reaction conditions, low in cost, high in yield, and suitable for industrialized production application.

Description

technical field [0001] The invention relates to the field of medicine, in particular to bedaquiline, a new anti-tuberculosis drug, and in particular to a new preparation method of bedaquiline racemate. Background technique [0002] Bedaquiline is a novel ATP synthase inhibitor targeting Mycobacterium tuberculosis. The chemical name is (1R,2S)-1-(6-bromo-2-methoxy-3-quinolyl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-2 - Butanol, molecular formula: C 32 h 31 BrN 2 o 2 , Molecular weight: 555.504, its structure is as follows. [0003] [0004] Bedaquiline was developed by Johnson & Johnson Pharmaceutical Co., Ltd. of the United States. It was approved by the Food and Drug Administration of the United States on December 28, 2012. It is clinically used for the treatment of drug-resistant tuberculosis. The drug is the first anti-tuberculosis drug with a new mechanism of action approved for clinical use in more than 40 years, and it is also currently the only drug for the t...

Claims

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Application Information

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IPC IPC(8): C07D215/227
Inventor 翁明君王忠玉
Owner CHONGQING SHENGHUAXI PHARMA CO LTD
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