Syntheses Of Cefozopran And Its Intermediates

Cefozopran, the fourth generation of injection cephalosporins, has the advantagesof low toxicity and high activity, which played an important role in the treatment ofvarious diseases caused by bacteria in clinical medical field. This article focused onthe synthetic works of the C-3, C-7side-chains of Cefozopran, succeeded insynthesizing2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(Z) methoxyimino amino acid andimidazo [1,2-b] pyridazine, these two intermediates reacted with the nucleus，7-aminocephalosporanic acid (7-ACA) which produced Cefozopran, the wholesynthesis process was introduced.This paper chooses the synthetic route which introduce methoxy imino functionalgroup after the formation of thiadiazole ring to produce the C-7side chain(Z)-2-(5-amino-1,2,4-thiadiazole oxadiazole3-yl)-2-methoxy imino acid.Malononitrile was used as the starting material and reacted with HCl and methanol toproduce3-methoxy-3-imino propionitrile. The following reaction produced3,3,3-trimethoxy-propionitrile which can loose one methanol molecule to generate3,3-dimethoxy-acrylonitrile.5-methoxy-3-amino-isoxazole was got by cyclized withhydroxylamine, with substitution reaction, cyclization, oxidation and hydrolysis toproduce (Z)-2-(5-amino-1,2,4-thiadiazole oxadiazole3-yl)-2-methoxy imino acid.Compared with the route which introduces methoxy imino route functional groupprior to the formation of thiadiazole ring, this route improved the yield and theefficiency of the reaction, total yield exceeded40%.2,2-Dibenzothiazole, disulfide (DM) is the protecting group for the synthesis ofC-7side chains of variety of cephalosporins. This paper chose the mixed solvent torefine2-Mercaptobenzothiazole (M), used oxygen as the oxidant, nitric oxide as theoxygen carrier, produced medicine grade DM in fluidized bed reactor. The oxidationof M is a kind of free radical reaction. The mixed solvent has good solubility towardsM, DM is the only solid phase which precipitated from the reaction system. Thismixed solvent reduced the phase numbers and shorten the mass transfer path; Nitricoxide gas is the oxygen carrier which can carry oxygen between gas-liquid bi-phase toachieve rapid transmission; the application of fluidized bed reactor eliminated the reactant diffusion effects. All of the factors mentioned above in this article werecombined together, Bring in the ‘explosive crystallization of DM’ in industry. The DMwhich produced under the conditions of ‘explosive crystallization’ appeared rod-like,easy to wash, the melting point reached183°C, the purity was98.8%, in accordancewith the needs of the pharmaceutical industry.This paper used maleic anhydride as the starting material, synthesized imidazo [1,2-b] pyridazine through hydrazinolysis, halogenation, ammonolysis, cyclization anddehalogenation. Strong acids were applied as the reaction medium in first step, theyield of maleic hydrazide can be reached up to96%.3,6-dichloro-pyridazine wassynthesized by a new one-pot method which increased the yield from74.4%to88%.3-amino-6-chloro pyridazine could be synthesized by microwave-assistedammonolysis, which could shorten the reaction time from17hours to0.5hours.During the formation of imidazole ring, with ethanol as the solvent, the use oflow-cost chloroacetaldehyde could simplify the reaction process. In the hydrogenationof the6-chloro-imidazo [1,2-b] pyridazine, palladium carbon was used as the catalyst,the reaction could be accomplished under atmospheric pressure. Since eachsingle-step yield was higher than80%, the total yield achieved69%, this syntheticroute was considered to be practical in industry.Hydrochloric Cefozopran was synthesized by using domestic produced7-ACA,self-made (Z)-2-(5-amino-1,2,4-thiadiazole oxadiazole3-yl)-2-methoxy imino acidbenzothiazole thioesters and imidazole [1,2-b] pyridazine, which characteristicparameters were consistent with literature values.