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【结 构 式】

【药物名称】SS-750

【化学名称】(-)-2(R)-(2,4-Difluorophenyl)-1-(ethylsulfonyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

【CA登记号】229153-17-7, 229153-16-6 ((+)-(S)-isomer), 229153-10-0 (racemate)

【 分 子 式 】C13H13F4N3O3S

【 分 子 量 】367.32446

【开发单位】SSP (Originator), Aressa Pharmaceuticals (Licensee), Nippon Kayaku (Codevelopment)

【药理作用】Antifungal Agents, ANTIINFECTIVE THERAPY

合成路线1

The acylation of m-difluorobenzene (I) with 2-bromoacetyl bromide (II) by means of AlCl3 gives the phenacyl bromide (III), which is treated with ethylmercaptan (IV) and K2CO3 to yield the sulfanyl derivative (V). The fluorination of (V) with N-fluoro-4-methylpyridinium-2-sulfonate affords the difluoroacetyl derivative (VI). The methylenation of the carbonyl group of (VI) with trimethylsulfoxonium iodide provides the oxiranyl derivative (VII), which is opened with 1,2,4-triazole (VIII) and K2CO3, furnishing the propanol derivative (IX). The oxidation of the sulfanyl group of (IX) by means of H2O2 or MCPBA gives the corresponding sulfonyl derivative (X). Finally, the racemic mixture (X) is submitted to optical resolution by crystallization of the (+)-3-bromocamphorsulfonic acid. Alternatively, intermediate (VI) can be obtained as follows: The reaction of 2-chloro-2,2-difluoroacetic acid ethyl ester (XI) with ethylmercaptan (IV) by means of NaH gives the sulfanyl derivative (XII), which is finally condensed with 2,4-difluorobromobenzene (XIII) by means of BuLi to afford the desired intermediate (VI).

1 Kaneko, Y.; Takeda, S.; Eto, H.; et al.; New antifungal 1,2,4-triazoles with difluoro(substituted sulfonyl)methyl moiety. Chem Pharm Bull 2001, 49, 2, 173.
2 Sato, S.; Kaneko, Y.; Takeda, S.; Eto, H.; Tokizawa, M.; SS750, a new triazole agent: Structure-activity relationship of novel triazole-containing gem-difluoromethylsulfonyl moiety. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1080.
3 Matsumoto, M.; Kaneko, Y.; Maebashi, K.; Takeda, S.; Sato, S.; Tokizawa, M.; Ishida, K.; Eto, H.; Asaoka, T. (SSP Co., Ltd.); Triazole deriv. or salt thereof, preparation process thereof as well as pharmaceutical containing said cpd.. CA 2256060; EP 0927719; JP 1999240871; US 6083968 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 13095 m-Difluorobenzene; 1,3-Difluorobenzene 372-18-9 C6H4F2 详情 详情
(II) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(III) 47646 2-bromo-1-(2,4-difluorophenyl)-1-ethanone C8H5BrF2O 详情 详情
(IV) 23712 1-ethanethiol; ethylhydrosulfide 75-08-1 C2H6S 详情 详情
(V) 47647 1-(2,4-difluorophenyl)-2-(ethylsulfanyl)-1-ethanone C10H10F2OS 详情 详情
(VI) 47648 1-(2,4-difluorophenyl)-2-(ethylsulfanyl)-2,2-difluoro-1-ethanone C10H8F4OS 详情 详情
(VII) 47649 2-(2,4-difluorophenyl)-2-[(ethylsulfanyl)(difluoro)methyl]oxirane; [2-(2,4-difluorophenyl)-2-oxiranyl](difluoro)methyl ethyl sulfide C11H10F4OS 详情 详情
(VIII) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(IX) 47650 2-(2,4-difluorophenyl)-1-(ethylsulfanyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol C13H13F4N3OS 详情 详情
(X) 47651 2-(2,4-difluorophenyl)-1-(ethylsulfonyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol C13H13F4N3O3S 详情 详情
(XI) 47652 Chlorodifluoroacetic acid ethyl ester; Difluorochloroacetic acid ethyl ester; Ethyl chlorodifluoroacetate; ethyl 2-chloro-2,2-difluoroacetate 383-62-0 C4H5ClF2O2 详情 详情
(XII) 47653 ethyl 2-(ethylsulfanyl)-2,2-difluoroacetate C6H10F2O2S 详情 详情
(XIII) 15488 1-bromo-2,4-difluorobenzene 348-57-2 C6H3BrF2 详情 详情
Extended Information