Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Preparation method for three-membered ring intermediate of sitafloxacin hydrate

A sitafloxacin and three-membered ring technology, which is applied in the field of preparation of sitafloxacin three-membered ring intermediates, can solve the problems of cis-trans isomerism and low overall yield level, and achieve high product yield and purity, It is easy to scale up to the effect of large-scale production

Inactive Publication Date: 2015-07-29
SUZHOU NACHI BIOTECH CO LTD
View PDF7 Cites 5 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since the intermediate is a chiral molecule, cis-trans isomerism is prone to occur during the synthesis process. In the process of separating the isomers, not only the overall yield level is not high (about 8-20%) ), more critically, the separation needs to be separated by column chromatography, which becomes the bottleneck of large-scale production

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method for three-membered ring intermediate of sitafloxacin hydrate

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0027] A preparation method of sitafloxacin three-membered ring intermediate, comprising the steps of:

[0028] (1) Construction of a three-membered ring: Dissolve dimethyl malonate and 1,1,2-tribromo-2-fluoroethane in anhydrous dimethylformamide, add anhydrous potassium carbonate in batches, and Heating in a water bath at 25-35°C for 55-60 hours, the obtained solution was evaporated to dryness to obtain solid A;

[0029] (2) Debromination: Dissolve solid A in methanol, use palladium carbon as a catalyst to react with hydrogen gas for 20-24 hours, filter, and evaporate the solvent to obtain oily liquid B;

[0030] (3) Debranching: Dissolve the oily liquid B in a mixture of dimethylformamide and saline, reflux for 30-35 hours, evaporate the solvent to dryness, and obtain solid C;

[0031] (4) Hydrolysis: Dissolve solid C in a mixture of tetrahydrofuran and water and place it in an ice-water bath, stir and add lithium hydroxide monohydrate, then add hydrochloric acid dropwise t...

Embodiment 1

[0038] (1) Take 1.32kg dimethyl malonate and 3.7kg 1,1,2-tribromo-2-fluoroethane into a 50L three-necked flask, dissolve with 15L anhydrous dimethylformamide, and place the three-necked flask In a water bath at 25°C, add 4.4kg of anhydrous potassium carbonate in batches under uniform stirring and react for 60 hours. After the reaction, add 30L of ice water first, then extract with ethyl acetate (8L×5), combine the organic phases, and separate the organic The phase was washed with saturated aqueous sodium chloride until neutral, then dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. Then, the residue was added to 3 L of diethyl ether, stirred for 4 hours under ice bath, and finally 1.7 kg of solid A was obtained by filtration.

[0039] (2) Take the obtained solid A and put it into a 10L high-pressure hydrogenation kettle, add 6L of methanol to dissolve, then add 72g of palladium carbon as a catalyst, and replace the air in the kettle with hydrogen f...

Embodiment 2

[0047] (1) Take 1.32kg dimethyl malonate and 3.7kg 1,1,2-tribromo-2-fluoroethane into a 50L three-necked flask, dissolve with 15L anhydrous dimethylformamide, and place the three-necked flask In a water bath at 35°C, add 4.4kg of anhydrous potassium carbonate in batches under uniform stirring and react for 55 hours. After the reaction, add 30L of ice water, then extract with ethyl acetate (8L×5), combine the organic phases, and separate The phase was washed with saturated aqueous sodium chloride until neutral, then dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. Then, the residue was added to 3 L of ether, stirred for 4 hours under ice bath, and finally 1.81 kg of solid A was obtained by filtration.

[0048] (2) Take the obtained solid A and put it into a 10L high-pressure hydrogenation kettle, add 6L of methanol to dissolve, then add 72g of palladium carbon as a catalyst, and replace the air in the kettle with hydrogen for 4 times, then continue...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a preparation method for a three-membered ring intermediate of sitafloxacin hydrate. The preparation method comprises the following steps: dimethyl malonate and 1,1,2-tribromo-2-fluoroethane react to synthesize a solid A, the solid A is subjected to debromination to prepare an oily liquid B, the oily liquid B is subjected to branched chain removal to prepare a solid C, the solid C is hydrolyzed to prepare a solid D, the solid D is subjected to chiral resolution with L-leucinamide and reduced to prepare a solid F, the solid F is introduced to an amino group and combined with p-toluenesulfonic acid to prepare the three-membered ring intermediate of sitafloxacin hydrate. The preparation method has fewer steps for preparing the three-membered ring intermediate of sitafloxacin hydrate, unnecessary isomer is separated by one step with the chiral resolution method, the product yield and purity are higher, and scale production is easier.

Description

technical field [0001] The invention relates to the technical field of biopharmaceuticals, in particular to a method for preparing a sitafloxacin three-membered ring intermediate. Background technique [0002] The chemical name of sitafloxacin (sitafloxacin hydrate) is 7-[(7S)-7-amino-5-azaspiro[2.4]heptane-5-yl]-8-chloro-6-fluoro-1-[( 1R,2S)-cis-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, the structure of which is as follows: [0003] [0004] The compound is a broad-spectrum quinolone antibacterial drug developed by Japan's Daiichi Pharmaceutical Sankyo Co., Ltd., and its monohydrate is used clinically. It is an anti-infection drug, a new oral quinolone antibiotic, and has strong antibacterial activity against methicillin-resistant Staphylococcus aureus and Pseudomonas bacteria. It also has good pharmacokinetic properties, can reduce adverse reactions, and its antibacterial activity in vitro is significantly stronger than most similar drugs. Th...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07C209/56C07C209/00C07C211/37C07C303/32C07C309/30
CPCY02A50/30
Inventor 吴天俊
Owner SUZHOU NACHI BIOTECH CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com