Fluconazole Synthetic Organic Quantitative Structure - Property Relationship

The preparation of Fluconazole (2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol) was discussed. And a new topological index was advanced.(1) 1,3-dichloroacetone has been prepared by oxidation of 1,3-dichloro-2-propanol with sodium dichromate/sulfuric acid. The solution of sulfuric acid was added dropwise to the reaction vessel containing 1,3-dichloro-2-propanol, sodium dichromate and water. The mixture with 1:2 of molar ratio of sodium dichromate to1,3-dichloro-2-propanol was stirred at 23-27 ℃ for 5 hours.Under the above conditions, pure 1,3-dichloroacetone was obtained with a yield of 79.6%. The obtained product is a colorless crystal and the melting point is 40-42℃.The results of IR spectrum show that the synthesized product accords with the target. The disposal method of the waste solution containing Cr³⁺ was given and Cr(OH)₃ was obtained.(2) 1,2,4-triazole has been prepared from hydrazine hydrate, formic acid and formamide. The first step was the preparation of N,N'-diformylhydrazine from hydrazine hydrate and formic acid, and the second was the reaction of N,N'-diformylhydrazine and formamide to prepare 1,2,4-triazole. The molar ratio of hydrazine hydrate, formic acid and formamide was 1:2.4:2. The temperature of the second step was 170-180℃. Pure 1,2,4-triazole was obtained with a yield of 73.6%. It's a white crystal and the melting point was 117-119℃. The results of IR spectrum show that the synthesized product accords with the target.(3) Fluconazole has been prepared from 1,2,4-triazole, 1,3-dichloroacetone and 1-Br-2,4-difluorobenze.The first step was the preparation of 1,3-bis-(1H-1,2,4-triazol-1-yl)-propan-2-one from 1,2,4-triazole and 1,3-dichloroacetone by using N,N-dimethylformamide as the solvent and triethylamine as pH modifying addition at pH value of 10. The molar ratio of the two reactants was 1:1 and the temperature of the reaction was 80℃. After stirred for 12 hours, 1,3-bis-(1H-1,2,4-triazol-1-yl)-propan-2-one was obtained with a yield of 58.1%. It's a yellow crystal and its melting pointwas 192-195°C. The mechanism of the reaction was also been discussed.The second step was the preparation of fluconazole from 1,3-bis-(lH-l,2,4-triazol-l-yl)-propan-2-one and l-Br-2,4-difluorobenze. 1-Br-2,4-difluorobenzene was transformed to its Grignard reagent with the powder of Mg in diethyl ether , then reacted with 1,3-bis-(lH-1,2,4-triazol-l-yl)-propan-2-one. The production was hydrolyzed by 10% NH4CI solution at last. The molar ratio of l,3-bis-(lH-l,2,4-triazol-l-yl)-propan-2-one and l-Br-2,4-difluorobenze was 1:1.2. After stirred for 1 hour, fluconazole was obtained with a yield of 43.2%.The total yield was 25.1%(calculated from 1,3-dichloroacetone). The production was a white crystal. It was then chromatographed on silica (300-400 mesh),using 5% methanol in chloroform as the eluant. The production was gray powder, while its melting point was 138-140°C. The results of *HNMR and IR spectrum show that the synthesized product accords with the target.(4) A new topological index was developed to research the quantitative structure-activity relationship of organic compounds. The topological index was obtained from the adjacent matrix of the compound. The relationship between the properties of several organic compounds and the index was studied. The organic compounds were the alkanes, the alkenes, the alkines, the alcohols, the aldehydes and ketones, the mercaptans and thioethers. The regression coefficient of all the liner regressions were larger than 0.98.