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Intermediate compound of Lefamulin and application of intermediate compound in preparation of Lefamulin

A compound and intermediate technology, applied in the preparation of organic compounds, carbamic acid derivatives, thiols, etc., can solve the problems of low yield and high cost of Lefamulin preparation

Active Publication Date: 2020-05-19
郑州依米花手性药物研究有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The technical problem to be solved by the present invention is to provide a novel intermediate compound that can be used to prepare Lefamulin, and open up a new synthesis and preparation route about Lefamulin; in order to solve the technology of high cost and low yield of Lefamulin preparation in the prior art question

Method used

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  • Intermediate compound of Lefamulin and application of intermediate compound in preparation of Lefamulin
  • Intermediate compound of Lefamulin and application of intermediate compound in preparation of Lefamulin
  • Intermediate compound of Lefamulin and application of intermediate compound in preparation of Lefamulin

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Embodiment 1: the preparation method of compound Lefamulin

[0075] Using commercially available (1R,3R,4R)-4-bromo-3-hydroxy-cyclohexylcarboxylic acid as the starting material to prepare Lefamulin, the process is as follows:

[0076] ;

[0077] details as follows:

[0078] (1) Preparation of ((1R,3R,4R)-4-bromo-3-hydroxy-cyclohexyl) tert-butoxycarbonylamide

[0079] Add 4.8kg of (1R,3R,4R)-4-bromo-3-hydroxycyclohexylcarboxylic acid (commercially available, see Organic Process Research and Development, 2019, vol. 23, # 4, p. 524-534), toluene 50L, add triethylamine 1.3eq under stirring condition, then add diphenylphosphoryl azide 1.1eq, then heat to reflux, when the reaction is finished, cool down to 80°C, dropwise add tert-butanol 5L, Then add catalyst cuprous halide 5g, continue to react for 2 hours. Purified to obtain 3.1 kg of the target compound ((1R,3R,4R)-4-bromo-3-hydroxy-cyclohexyl) tert-butoxycarbonyl amide (formula A).

[0080] Similarly, benzyloxycarb...

Embodiment 2

[0091] Embodiment 2: the preparation method of compound Lefamulin

[0092] Adopting commercially available commercially available (1R,3R,4R)-4-bromo-3-hydroxy-cyclohexyl formic acid to prepare Lefamulin, the process is:

[0093] ;

[0094] details as follows:

[0095] (1) Preparation of (1R,3R,4R)-4-bromo-3-((tert-butyldimethylsilyl)oxy)cyclohexylcarboxylic acid

[0096] Add 60L of dichloromethane and 4.8kg of (1R,3R,4R)-4-bromo-3-hydroxycyclohexylcarboxylic acid (commercially available, see Organic Process Research and Development, 2019, vol. 23, # 4, p.524-534) and 1.2eq of tert-butyldimethylchlorosilane, add 1.3eq of triethylamine dropwise under stirring condition, stir the reaction to the end after adding, wash the reaction system with water, concentrate dichloromethane, 6.4 kg of the product (1R,3R,4R)-4-bromo-3-((tert-butyldimethylsilyl)oxy)cyclohexylcarboxylate (formula 1) was obtained. The yield is 98%.

[0097] Similarly, reacting with trimethylchlorosilane, tr...

Embodiment 3

[0109] Embodiment 3: the preparation method of compound Lefamulin

[0110] Adopting commercially available commercially available (1R,3R,4R)-4-bromo-3-hydroxy-cyclohexyl formic acid to prepare Lefamulin, the process is:

[0111] ;

[0112] (1) Preparation of (1R,3R,4R)-4-bromo-3-(benzyloxy)cyclohexylcarboxylic acid

[0113] Add 100 ml of DMF, 30 g of (1R,3R,4R)-4-bromo-3-hydroxycyclohexylcarboxylic acid, 1.2 eq of benzyl bromide, and 1.3 eq of sodium hydrogen into a 250 ml three-necked flask. The reaction system was quenched with water and extracted with dichloromethane to obtain 21.4 g of the target compound (ie Formula 1).

[0114] Similarly, with p-methoxybenzyl chloride, methoxychloromethyl ether or methoxybromomethyl ether, 3,4-dihydro-2H-pyran, 2-(trimethylsilyl)ethoxymethyl Chlorine, allyl chloride, 3,4-dihydro-2H-pyran, 2-(trimethylsilyl) ethoxymethyl chloride, allyl chloride and other reactions can obtain other alkanes of formula 1' Ether protected analogues. W...

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Abstract

The invention discloses an intermediate compound of Lefamulin and application of the intermediate compound in preparation of Lefamulin, and aims to solve the technical problems of high preparation cost and low yield of Lefamulin in the prior art. The invention provides theintermediate compound and a preparation method thereof, andapplication of the intermediate compound in preparation of Lefamulinor a pharmaceutical intermediate related to Lefamulin. The method overcomes the defects that chiral oxidation lacks chiral induction in the production process in the prior art, the conversion rate ofa target compound is very low, the cost is very high, and industrial production is difficult; during industrial application, the production cost can be effectively reduced, generation of three wastescan be effectively controlled, and remarkable economic benefits and social benefits are achieved.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to an intermediate compound of Lefamulin and its application in the preparation of Lefamulin. Background technique [0002] Lefamulin (acetate) is an antibiotic developed by Nabriva Therapeutics and approved by the U.S. Food and Drug Administration (FDA) on August 19, 2019. The product name is Xenleta. Lefamulin is a pleuromutilin antibacterial drug indicated for the treatment of community-acquired pneumonia (CABP) in adults with susceptible organisms. The antibacterial mechanism of Lefamulin is to inhibit bacterial protein synthesis by interacting with the A-site and P-site of the peptidyl transferase center (PTC) in the 23s RNA domain of the 50S subunit of the bacterial ribosome. This makes it less prone to lead to the development of drug resistance. Compared with β-lactams, quinolones, glycopeptides, macrolides and tetracycline antibiotics, Lefamulin has no cross-res...

Claims

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Application Information

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IPC IPC(8): C07C271/24C07C269/00C07C323/61C07C319/20C07C323/43C07C319/06
CPCC07C271/24C07C269/00C07C319/06C07C319/20C07C2601/14C07C2603/82C07B2200/07C07C323/43C07C323/61Y02P20/55
Inventor 张俊杰白晓光
Owner 郑州依米花手性药物研究有限公司
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