Production Method 1 of Fluconazole: 1H-1,2,4-triazole can be obtained from formamide, hydrazine hydrate and 85% formic acid. From the m-phenylenediamine, m-difluorobenzene can be obtained, followed by bromination to give 2,4-difluorobromobenzene. Magnesium was dissolved in anhydrous diethyl ether, and a solution of 2,4-difluorobromobenzene in diethyl ether was added dropwise under ultrasonic irradiation, and then a solution of 1,3-dichloroacetone in diethyl ether was added dropwise under ice-cooling, and stirred at room temperature overnight. Add glacial acetic acid and water. The separated organic layer was dried and concentrated. The concentrate and triazole, potassium carbonate, and PEG 600 were dissolved in dry ethyl acetate and refluxed. Filter, wash to neutral and dry. The solvent was evaporated, and then crystallised from ethyl acetate-hexanes (1:1) to give fluconazole, the total yield was 33.6%, and the melting point was 138.5-140 °C.
The last step can also be carried out in propionitrile. 1,3-Dihalo (x=Br or Cl)-2-(2,4-difluorophenyl)-2-propanol and 1H-1,2,4-triazole in propionitrile, catalyzed by sodium hydroxide And PEG 600 phase transfer catalysis reflux, can obtain crude fluconazole. The crude product is dissolved in a fatty alcohol (such as propanol, isopropanol or butanol, etc.), dissolved by heating, decolorized with a small amount of activated carbon, and cooled to obtain crystals, which is a fluconazole fine, melting point 139-140 ° C.
Fluconazole Production Method 2: Methyl 2,4-difluorobenzoate is reacted with 1-chloromethyl-1,2,4-triazole Grignard reagent and hydrolyzed to obtain fluconazole.
Fluconazole Production Method 3: Difluorobenzene is brominated to form 1-bromo-2,4-difluorobenzene, which is then converted to its Grignard reagent. The Grignard reagent obtained above is reacted with 1,3-bis(1H-1,2,4-triazolyl)acetone, followed by hydrolysis to obtain fluconazole.
Fluconazole production method
