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A synthetic route and method of a bentelinoline anti -rotor body

A technology of bedaquiline racemate and methoxyquinoline, which is applied in the field of medicine, can solve the problems of harsh reaction conditions, lengthy synthesis steps, lengthy synthesis routes, etc., and achieve mild and easy-to-control reaction conditions, easy product separation, The effect of simple reaction steps

Active Publication Date: 2017-09-19
CHONGQING SHENGHUAXI PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] 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
[0013] 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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  • A synthetic route and method of a bentelinoline anti -rotor body
  • A synthetic route and method of a bentelinoline anti -rotor body
  • A synthetic route and method of a bentelinoline anti -rotor body

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Preparation of 3-bromobenzyl-6-bromo-2-methoxyquinoline (Ⅱ)

[0031]

[0032] 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, stir and heat up to 78°C for 2h, filter while hot to remove insoluble matter, evaporate the solvent under reduced pressure, add 200ml DCM to dissolve the solid, wash with 10% sodium carbonate three times, dry the organic layer with anhydrous magnesium sulfate, filter, Spin dry to obtain 34g of white solid, yield 92%, purity 99%.

[0033] [M+H] + :408; 1 H NMR (500 MHz, CDCl 3 ) δ 8.13 (d, J = 11.6 Hz, 2H), 7.90(d, J = 4.5 Hz, 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 remove...

Embodiment 2

[0035] Preparation of (6-bromo-2-methoxyquinolin-3-yl)-1-(naphthalene-1-yl)-2-phenylethanol (Ⅳ)

[0036]

[0037]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

[0041] Preparation of 2-(6-bromo-2-methoxyquinolin-3-yl)-1-(naphthalene-1-yl)-2-phenylethanone (Ⅴ)

[0042]

[0043] 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 maintain the temperature After continuing to stir for 30min, 64.5g (0.133mol ), continue to stir for 1 hour after the dropwise addition, then add 110ml 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 anhydrous magnesium sulfate to dry, and spin dry under reduced pressure to obtain 56.4 g of light yellow solid, yield: 88%, puri...

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Abstract

The invention relates to a new synthesis route and method of a bedaquiline racemate, belonging to the technical field of medicine. Its steps include: (1) starting material 3-bromobenzyl-6-bromo-2-methoxyquinoline (II) reacts with metal magnesium in THF to prepare Grignard reagent, and then 1-naphthaldehyde (III ) is added in the prepared Grignard reagent, and the reflux reaction obtains the compound (Ⅳ) "2-(6-bromo-2-methoxyquinoline-3-yl)-1-(naphthalene-1-yl)-2- Phenyl alcohol "; (2) make compound (IV) undergo swern oxidation to obtain carbonyl compound 2-(6-bromo-2-methoxyquinoline-3-yl)-1-(naphthalene-1-yl)-2 ‑Phenyl ethyl ketone (compound V); (3) Compound (V) reacts with Grignard reagent (VI) to obtain bedaquiline racemate (I). The method of the invention has simple and convenient route, mild reaction conditions, low cost and high yield, and is suitable for industrial production and 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,2 S) -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] Bedaquiline was developed by Johnson & Johnson Pharmaceutical Co., Ltd. of the United States and was approved by the US Food and Drug Administration on December 28, 2012. It is clinically used for the treatment of drug-resistant tuberculosis. The drug is the first anti-TB drug with a new mechanism of action approved for clinical use in more than 40 years, and it is currently the only drug to treat MDR-TB. Mycobacterium tuberculosis is the p...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/227
Inventor 翁明君王忠玉
Owner CHONGQING SHENGHUAXI PHARMA CO LTD
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