Preparation method of Delafloxacin and intermediates thereof
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A technology of delafloxacin and intermediates, applied in the field of medicine, can solve the problems of amidation reaction, high reaction temperature, multiple impurities and the like, and achieve the effects of simple operation, high purity and high product yield
Inactive Publication Date: 2018-05-29
BEIJING VOBAN PHARMA TECH CO LTD
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[0014] The reaction temperature of the intramolecular condensation step from compound W-4 to compound W-5 in this route is high, and more impurities are produced. The hydrolysis of the ester bond of compound W-5 and the deprotection step of the amino group require high temperature reflux, and compound 6 is prone to intermolecular amides reaction
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Embodiment 1
[0042] Preparation of 3-chloro-2,4,5-fluorobenzoyl chloride (compound 2)
[0043] (1) Compound 1 (5g, 23.7mmol) and dichloromethane (50ml) were mixed and stirred, and thionyl chloride (5.6g, 44.4mmol) was added dropwise at 0-20°C. After the addition was complete, DMF (0.2ml ), heated to reflux, monitored by TLC, it took 8 hours to complete the reaction, cooled, and the solvent was removed under reduced pressure to obtain 5.4 g of compound with a yield of 99.5%.
Embodiment 2
[0045] Preparation of ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-(dimethylamino)acrylate (compound 3)
[0046] (1) Mix N,N-ethyl dimethylaminoacrylate (4.2g, 32.7mmol), triethylamine (2.6g, 26.2mmol), dichloromethane (40ml), drop compound 1 (5g, 21.8mmol ) dichloromethane (20ml) mixed solution, heated to 1, TLC monitoring, need 3 hours to complete the reaction, concentrated to give compound 3 7.3g yield 99%.
Embodiment 3
[0048] Preparation of ethyl 3-((6-amino-3,5-difluoro-2-pyridyl)amino)-2-(2,4,5-trifluorobenzoyl)acrylate (compound 4)
[0049] (1) Compound 3 (7g, 20.8mmol); acetonitrile (70ml), glacial acetic acid (3ml) was mixed, and 2,4-diamino-3,5-difluoropyridine (3.3g, 22.8 mmol) of acetonitrile solution, heated to 30-40°C after the dropwise addition, monitored by TLC, it took 1 hour to complete the reaction, cooled, slowly added an appropriate amount of water to the reaction solution, stirred, filtered, and dried to obtain 8.6g of compound 4 with a yield of 94.9% . 1H NMR (400MHz, CDCl3) δ11.31(d,1H),9.04(d,1H),7.41(td,1H),7.25(t,1H),4.65(m,2H),4.17(q,2H) ,1.11(s,3H).
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Abstract
The invention relates to a preparation method of Delafloxacin and intermediates thereof. The method comprises the following steps: firstly, taking 3-chloro-2,4,5-fluorobenzoic acid (compound 1) as a raw material and reacting the raw material with thionyl chloride to obtain a compound 2; secondly, condensing the compound 2 with N,N-dimethylamino ethyl acrylate to obtain a compound 3; thirdly, substituting the compound 3 and 3,5-difluoro-2,6-diaminopyridine to obtain a compound 4; fourthly, cyclizing the compound 4 by using an acid binding agent to obtain a compound 5; fifthly, reacting the compound 5 with 3-hydroxyazetidine hydrochloride to generate a compound 6; sixthly, hydrolyzing the compound 6 to obtain a compound 7; seventhly, salifying the compound 7 with meglumin to obtain the Delafloxacin.
Description
technical field [0001] The invention belongs to the technical field of medicine, in particular to a preparation method of an antibacterial drug delafloxacin and an intermediate thereof. Background technique [0002] Delafloxacin is a new generation of broad-spectrum fluoroquinolone antibiotics. Compared with other quinolone antibacterial agents, this product is more effective against Gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA) resistant to other quinolone antibacterial agents. [0003] Delafloxacin chemical name: D-glucitol-1-deoxy-1-methylamino-,1-(6-amino-3,5-difluoro-2-pyridyl)-8-chloro-6-fluoro -1,4-dihydro-7-(3-hydroxy-1-azetidinyl)-4-oxo-3-quinolinecarboxylic acid, the molecular weight is 635.97, and the structural formula is as follows: [0004] [0005] Delafloxacin is the latest generation of quinolone drugs jointly researched and developed by Wakunaga Pharmaceutical Company of Japan and Melinta Bio Company of the Unite...
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