The Third-generation Quinolone Antibacterial Drug Cyproterone Preparation, Enoxacin

In this thesis, the desired intermediate, 2, 6-dihydroxyl-5-fluoro-pyridine-3-cabonitrile is obtained through the condensation and cyclization reaction using methyl fluoroacetate, ethyl formate and eastgate cyanoacetamide as raw materials. 2, 6-dichloro-5-fluoro-pyridine-3-caboxylic acid is gotten after chlorination and hydrolysis reaction. Then 2, 6-dichloro-5-fluoro-pyridine-3-caboxyl chloride is given after acylation reaction. 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate is gained after substitution, condensation and cyclization reaction. Finally, the target chemical compound is obtained after condensation, hydrolysis and acidity with piperazine. Though more simple craft, 2, 6-dichloro-5-fluoro-pyridine-3-caboxylic acid is possessed. This article is a research on the catalysis effect of different catalyst in the period of chlorination reaction, and research on the green synthesis process of piperazine condensation reaction as well as the influence of the final product's crystallization condition on the crystal form of the finished product.The experimental work of this article consist of seven parts:First, preparation of 2,6-dihydroxyl-5-fluoro-pyridine-3-cabonitrile (intermediate Ⅰ)The condensation reaction is developped by using methyl fluoroacetate, ethyl formateand eastgate cyanoacetamide as raw materials. Eastgate cyanoacetamide is added toobtained product after diluting with methanol. The reaction mixture was acidified withhydrochloric acid after cyclization reaction and crystallized at room temperature to give 2,6-dihydroxyl-5-fluoro-pyridine-3-cabonitrile.Second, preparation of 2, 6-dichloro-5-fluoro-pyridine-3-caboxylic acid(intermediate Ⅱ)After the condensation reaction of intermediate Ⅰ and chlorinating agent-POCl₃ with theaid of catalyst, the obtained product was hydrolyzed and extracted. Then it wascontinuous hydrolyzed with concentrated sulfuric acid to produce 2,6-dichloro-5-fluoro-pyridine-3-caboxylic acid.Third, preparation of 2, 6-dichloro-5-fluoro-pyridine-3-caboxyl chloride(intermediate Ⅲ)The intermediate Ⅱ reacts with SOCl₂ under the catalysis of DMF using toluene assolvent to obtain 2, 6-dichloro-5-fluoro-pyridine-3-caboxyl chloride.Fourth, preparation of ethyl(2,6-dichloro-5-fluoro-pyridine-3-cabonxyI)-acetate(intermediate IV)After the reaction of intermediate III with fresh alcohol magnesium, water and4-toluenesulfonic acid were added to reflux for some time to produceethyl(2,6-dichloro-5-fluoro-pyridine-3-cabonxyl)-acetate.Fifth, preparation of ethyl 2(2,6-dichloro-5-fluoro-pyridine-3-cabonxyl)-3-cyclopropylaminoacrylate (intermediate V)The condensation reaction of intermediate IV and triethyl orthoformate was carried on,an oily liquid was obtained, the oily liquid was distilled and then the cyclopropylaminewas dropped at low temperature to give ethyl 2-(2,6-dichloro-5-fluoro-pyridine-3-cabonxyl)-3-cyclopropylaminoacrylate.Sixth, preparation of ethyl 7-chloro-l-cycIopropyI-6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate(intermediate VI)The cyclization reaction of intermediate V and K2CO3 is developped in the solvent ofDMF. The reaction mixture was filtered with the aid of vacuum and washed with water toproduce 7-chloro-1 -cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate(intermediate VI).Seventh, preparation of l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(l-piperazinyl)-l,8-naphthyridine-3-carboxylie acidThe condensation reaction of intermediate VI is carried out in water. After filter,hydrolysis, acidification and filter to give coarse product, the coarse product wasdissolved in alkali solution to decolorize, and filtered, acidified, filtered again and driedto produce desired chemical compound-finished cyclopropyl enoxacin.