Preparation method of sitafloxacin hydrate five-membered ring side chain intermediate

Abstract

The invention relates to a preparation method of a sitafloxacin hydrate five-membered ring side chain intermediate. The preparation method comprises following steps: keto carbonyl groups of a raw material 1 are reacted with sodium cyanoborohydride or sodium triacetoxyborohydride in the presence of ammonium acetate or ammonium chloride; reduction of amide carbonyl groups of an obtained production is realized with lithium aluminum hydride; free amino groups of a reduction product are reacted with di-tert-butyl dicarbonate ester in the presence of an alkali; phenethyl groups of an obtained compound are subjected to reductive destruction with formic acid or a formate in the presence of palladium-carbon so as to obtain the sitafloxacin hydrate intermediate (product 5). Reaction conditions of the preparation method are mild; equipment requirements are low; preparation process is safe; stereoselectivity is excellent; the raw material reagents are cheap and easily available; and production cost is low.

Description

technical field [0001] The invention relates to the fields of pharmacy and chemical synthesis, in particular to a preparation method of a sitafloxacin five-membered ring side chain intermediate. Background technique [0002] The chemical name of sitafloxacin 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 antibacterial developed by Daiichi Sankyo Co., Ltd. It is a medicine, and its monohydrate is clinically used for the treatment of severe and refractory infectious diseases. [0003] Because sitafloxacin contains a cis-fluorocyclopropylamine group in its structure, it has good pharmacokinetic properties and can reduce adverse reactions. Its antibacterial activity in vitro is significantly stronger than most similar drugs. Sitafloxacin not only significantly enhanced the antibacterial activity against Gram-positive bacteria, but also had antibacteri...

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Problems solved by technology

[0010] Among the above two synthetic methods, the first one is through the azide compound intermediate. Although this method has a high yield, the azide compound is easy to explode and has potential safety hazards. This risk is especially prominent in large-scale production; The second method is to introduce chiral nitrogen atoms through condensation of hydroxylamine hydrochloride and ketone carbonyl followed by hydrogenation reduction. The disadvantage of this method is poor selectivity and low yield, resulting in high cost

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