- Preparation method of fosfluconazole
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The invention provides a preparation method of fosfluconazole. The method comprises the following steps: preparing fluconazole dichlorophosphate: under the protection of nitrogen, controlling the temperature to be-10 DEG C to 0 DEG C, slowly dropwise adding phosphorus oxychloride into a dichloromethane solution of triethylamine, maintaining the temperature to be-10 DEG C to 0 DEG C, performing stirring for 1 hour, slowly dropwise adding a dichloromethane solution of fluconazole, and monitoring the completion of the reaction by TLC; maintaining temperature between-10 DEG C and 0 DEG C, adding water and stirring for 30 minutes, adding inorganic base until the pH value of the water phase is at least 8; and performing standing stratification, separating out the fluconazole, wherein the organicphase contains the fluconazole dichlorophosphate, the fluconazole is prepared through the fluconazole-fluconazole dichlorophosphate-fluconazole dibenzyl phosphate-fosfluconazole ammonium salt-fosfluconazole process, the yield is increased, all intermediates are controllably prepared, the raw materials can be recycled, and raw material waste and organic waste pollution are reduced.
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Paragraph 0063; 0064-0084
(2020/06/17)
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- Compound and preparation method and application thereof
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The invention discloses a compound of 2-(2,4-difluorophenyl)-1,3-di(1H-1,2,4,-triazole-1-yl)-2-propyl di-tert-butylphosphate, a preparation method thereof, and an application of 2-(2,4-difluorophenyl)-1,3-di(1H-1,2,4,-triazole-1-yl)-2-propyl di-tert-butylphosphate to prepare 2,4-difluoro-alpha, alpha-di(1H-1,2,4,-triazole-1-yl methyl) benzyl alcohol dihydrogen phosphate. The method is mild in reaction conditions and can well protect the environment.
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Paragraph 0041; 0042; 0043; 0044; 0045; 0046
(2017/03/22)
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- Triazole derivatives useful in therapy
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The invention provides compounds of formula 1, R1—OP(O)(OH)2??I wherein R1 represents the non-hydroxy portion of a triazole antifungal compound of the type comprising a tertiary hydroxy group; or a pharmaceutically accepta
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- The discovery and process development of a commercial route to the water soluble prodrug, fosfluconazole
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A case history detailing the rationale behind the discovery of 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazole-1-yl)-2-propyl dihydrogen phosphate, fosfluconazole (2), a water-soluble prodrug of Diflucan, and the subsequent development of a commercial route is presented. Particular items to note are (i) that this compound was discovered in the Chemical Research and Development Department, hence Chemical Research and Development can play a key role in prodrug discovery, (ii) the strategy behind the selection of phosphate ester promoiety, by phosphorylation of a sterically hindered tertiary alcohol, (iii) the development of the initial route to remove thermally hazardous reagents and to improve processing to allow scale-up, and (iv) the identification and development of the proposed commercial process.
- Bentley, Arthur,Butters, Michael,Green, Stuart P.,Learmonth, William J.,MacRae, Julie A.,Morland, Matthew C.,O'Connor, Garry,Skuse, Joanne
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p. 109 - 112
(2013/09/06)
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