Synthesis Of 1-cyclopropy1-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic Acids

Ciprofloxacin(1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quin-oline-3-carboxylic acid) owns one of the strongest antibacterial activity of the quinolone in all regards. It possesses a broad spectrum of activity against Gram-negative and Gram-positive bacteria and low oral toxicity. To reduce the by-products and manufacture cost of ciprofloxacin, an improvement on synthetic technology was made: it was synthesized from 2, 4-dichloro-5-fluoro-acetophenone and dimethyl carbonate, via condensation, ethoxymethylenation, amination, cyclization, hydrolysis, boric coordination, piperazination, etc. The chemical structure of the compounds and key intermediates was confirmed by 1H NMR. And overall yield was 47.9 %.The Sodium hydride which was dangerous for the operation was substituted by the sodium methylate which was cheap and can be easily got in the first condensation reaction. So the reaction was carried out under moderate condition which suited the industrialization. The yield of the condensation reaction was enhanced from 65 % to 80.6 %.The expensive triethyl orthoformate was replaced by the N,N-dimethyl-formami- dedimethyl acetal in the ethoxymethylenation reaction. As the N,N-dimethyl-formami- dedimethyl acetal could be got by cheap N,N-dimethyl-formamide and dimethylsulfate. So the change could reduce manufacture cost greatly. The chemical structure of the compound synthesized was confirmed by 1H NMR.Boric coordination complex which was preparated by acetic anhydride, boric acid and 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid was used in the piperazination reaction with higher selectivity. And the reaction activity of the 7-position was improved with less by-product. Then the high yield ciprofloxacin was gained via hydrolysis. The HPLC analyse showed that the quality of the product(ciprofloxacin) was improved.Because of its low bioavilability and blood drug level, ciprofloxacin therapeutic effectiveness in body is limited. To resolve the problem, the key is to improve its fatsoluble. According to the relation of construction and biological activity of the known compound, modifications with fatsoluble group at the position of piperazine may increase properly its fatsoluble, improve the character of metabolism dynamics and endow it with some new character. Thus we expect to gain the drugs with broader antibacterial spectrum, better antibacterial effect and less side-effect. This thesis made a modification with a series ofα-bromo-2-arylalkylketones at the position of piperazine and we got 10 new compounds (1-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxo-quinoline-3-carboxylic acid): We usedα-bromo-2-arylalkylketones as alkylating agent in the alkylation reaction. And the mole ratio of ciprofloxacin andα-bromo- 2-arylalkylketones was 1∶2. We could get a series of 1-cyclopropyl-6-fluoro-1,4- dihydro- 4-oxo-quinoline-3-carboxylic acids with the reaction lasting for 3～5 hours. The chemical structure of the target compound was confirmed by 1H NMR. The new compounds of 1-cyclopropyl-6-fluoro-1,4-dihydro4-oxo-quinoline-3- carboxylic acids had better fatsoluble than ciprofloxacin. And the antibacterial activity was still in investigation.