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Preparation method of sitafloxacin hydrate

A technology of sitafloxacin and compounds, applied in the field of preparation of sitafloxacin, can solve the problems of long steps, low product yield, easy formation of isomer impurities, etc., and achieve simple steps and low content of isomer impurities , reducing the effect of the reaction step

Active Publication Date: 2019-01-18
SUZHOU DAWNRAYS PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The steps of the synthetic route of the prior art are relatively long, the product yield is low, and isomer impurities are easily generated

Method used

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  • Preparation method of sitafloxacin hydrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Preparation process of sitafloxacin:

[0028] step 1,

[0029] Put 21g of ethyl 4-bromoacetoacetate in a reaction flask, add 120mL of DMF, 37.6g of 1,2-dibromoethane, and 52.5g of potassium carbonate in sequence, control the temperature of the reaction solution at 25-30°C, and react for 20- After 30 hours, after the reaction was completed, it was added to 600 mL of water, extracted with ethyl acetate, concentrated and distilled to dryness to obtain 20.1 g of compound I with a yield of 85.5%.

[0030] Step 2,

[0031] Take 20g of compound I, add 400mL of methyl tert-butyl ether to dissolve, take 12g of carbonyl reductase BgADH3, 2g of NADPH, and 20g of glucose in 200mL of deionized water, mix the two-phase solvents, control the reaction temperature at 40°C, and react for 5-6 hours under stirring After the reaction was completed, the organic phase was separated, concentrated and distilled to dryness to obtain 19.2 g of compound II with a yield of 95.2% and a purity of 9...

Embodiment 2

[0048] Preparation process of sitafloxacin:

[0049] step 1,

[0050]Put 420g of ethyl 4-bromoacetoacetate in a reaction flask, add 2.4L of DMF, 750g of 1,2-dibromoethane, and 1.05kg of potassium carbonate in sequence, control the temperature of the reaction solution at 25-30°C, and react for 20- After 30 hours, after the reaction was completed, it was added to 12 L of water, extracted with ethyl acetate, concentrated and distilled to dryness to obtain 391 g of compound I with a yield of 82.9%.

[0051] Step 2,

[0052] Take 300g of compound I, add 6L of methyl tert-butyl ether to dissolve, take 180g of carbonyl reductase BgADH3, 30g of NADPH, and 300g of glucose, dissolve in 3L of deionized water, mix the two-phase solvents, control the reaction temperature at 40°C, and react for 5-6 hours under stirring After the reaction was completed, the organic phase was separated, concentrated and distilled to dryness to obtain 287 g of compound II with a yield of 94.9% and a purity o...

Embodiment 4

[0072] Carbonyl Reductase Selective Reduction of Carbonyl Comparative Example

[0073] Take 20 g of compound I prepared in Example 1, add 400 mL of n-hexane to dissolve, take 12 g of carbonyl reductase BgADH3, 2 g of NADPH, and 20 g of glucose and dissolve them in 200 mL of deionized water, mix the two-phase solvents, control the reaction temperature at 40°C, and react for 5 -6 hours, after the reaction was completed, the organic phase was separated, concentrated and distilled to dryness to obtain 17.8 g of compound II with a yield of 88.3% and an HPLC purity of 99.7%.

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Abstract

The invention discloses a preparation method of sitafloxacin hydrate. The method comprises the following steps: taking ethyl 4-bromoacetoacetate used as a raw material, enabling ethyl 4-bromoacetoacetate to be fully reacted with 1,2-dibromoethane and preparing the obtained product into a compound II in the presence of carbonyl reduction enzyme; taking the compound II, enabling the compound II to carry out cyclization reaction with benzylamine in a solvent in the presence of cesium carbonate, enabling the obtained product to be reacted with DPPA and preparing a compound IV; reducing nitrine group of the compound IV to prepare a compound V; connecting primary amine group of the compound V with a BOC protection group to obtain a compound VI; reducing the compound VI through Pd / C, enabling theobtained product to be reacted with 8-chlorine-6,7-difluoro-1-[(1R,2s)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester to prepare a compound VIII; and carrying out deprotection of the compound VIII to obtain sitafloxacin hydrate. The sitafloxacin hydrate is few in preparation steps, simple in post-treatment and relatively high in yield.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of sitafloxacin. Background technique [0002] The chemical name of sitafloxacin (sitafloxacin hydrate) is 7-[(7S)-7-amino-5-azaspiro[2.4]hept-5-yl]-8-chloro-6-fluoro-1-[(1R ,2S)-cis-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is a broad-spectrum quinolone developed by Daiichi Sankyo A class of antibacterial drugs, and its monohydrate is clinically used for the treatment of severe and refractory infectious diseases. [0003] The steps of the synthetic route of the prior art are relatively long, the product yield is low, and isomer impurities are easily generated. Contents of the invention [0004] The purpose of the present invention is to solve the defects in the prior art, and provide a method for preparing sitafloxacin with relatively few steps, simple post-treatment and relatively high yield. [0005] In order to achiev...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
CPCC07D401/04Y02P20/55
Inventor 邹晓明仲海进姚益陈琛
Owner SUZHOU DAWNRAYS PHARM CO LTD
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