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【结 构 式】 
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【药物名称】SY-726, SSY-726 【化学名称】(-)-(R)-3-Methyl-3-(methylsulfonyl)-1-(1,2,4-triazol-1-yl)-2-[4-(trifluoromethyl)phenyl]-2-butanol 【CA登记号】136067-88-4 【 分 子 式 】C15H18F3N3O3S 【 分 子 量 】377.38821 |
【开发单位】Mitsubishi Pharma (Originator), SSP (Originator) 【药理作用】Antifungal Agents, ANTIINFECTIVE THERAPY |
合成路线1
The intermediate 2-(methylsulfanyl)-4'-(trifluoromethyl)isobutyrophenone (IV) was prepared by two alternative procedures. Reaction of bromo ketone (I) with sodium methanethiolate provided sulfide (II). Subsequent two step dimethylation of acetophenone (II) with CH3I and NaI gave rise to the isobutyrophenone (IV), through the intermediate propiophenone (III).
| 【1】 Tokizawa, M.; Kanamaru, Y.; Matsumoto, M.; Asaoka, T.; Matsuda, H.; Kuraishi, T.; Maebashi, K.; Taido, N.; Kawahara, R. (SSP Co., Ltd.); Triazole derivs.. EP 0435081; JP 1991223266; US 5147886 . |
| 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) | 56163 | 4-(Trifluoromethyl)phenacyl bromide | C9H6BrF3O | 详情 | 详情 | |
| (II) | 56164 | 2-(methylsulfanyl)-1-[4-(trifluoromethyl)phenyl]-1-ethanone | C10H9F3OS | 详情 | 详情 | |
| (III) | 56165 | 2-(methylsulfanyl)-1-[4-(trifluoromethyl)phenyl]-1-propanone | C11H11F3OS | 详情 | 详情 | |
| (IV) | 56166 | 2-methyl-2-(methylsulfanyl)-1-[4-(trifluoromethyl)phenyl]-1-propanone | C12H13F3OS | 详情 | 详情 |
合成路线2
In a different approach, addition of isopropylmagnesium bromide to 4-(trifluoromethyl)benzaldehyde (V) afforded alcohol (VI), which was further oxidized to the corresponding ketone (VII) by treatment with pyridinium chlorochromate. Bromination of 4'-(trifluoromethyl)isobutyrophenone (VII) in HOAc provided bromo ketone (VIII). Sulfide (IV) was then obtained by displacement of the bromide group of (VIII) with sodium methanethiolate.
| 【1】 Tokizawa, M.; Kanamaru, Y.; Matsumoto, M.; Asaoka, T.; Matsuda, H.; Kuraishi, T.; Maebashi, K.; Taido, N.; Kawahara, R. (SSP Co., Ltd.); Triazole derivs.. EP 0435081; JP 1991223266; US 5147886 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 56166 | 2-methyl-2-(methylsulfanyl)-1-[4-(trifluoromethyl)phenyl]-1-propanone | C12H13F3OS | 详情 | 详情 | |
| (V) | 13380 | 4-(Trifluoromethyl)benzaldehyde; alpha,alpha,alpha-Trifluoro-p-tolualdehyde | 455-19-6 | C8H5F3O | 详情 | 详情 |
| (VI) | 56167 | 2-methyl-1-[4-(trifluoromethyl)phenyl]-1-propanol | C11H13F3O | 详情 | 详情 | |
| (VII) | 56168 | 2-methyl-1-[4-(trifluoromethyl)phenyl]-1-propanone | C11H11F3O | 详情 | 详情 | |
| (VIII) | 56169 | 2-bromo-2-methyl-1-[4-(trifluoromethyl)phenyl]-1-propanone | C11H10BrF3O | 详情 | 详情 |
合成路线3
Condensation of isobutyrophenone (IV) with the lithium derivative of (S)-methyl p-tolyl sulfoxide (IX) produced alcohol (X) as a diastereomeric mixture. After chromatographic separation of the desired diastereoisomer, the methylsulfanyl group was selectively oxidized to sulfone (XI) with m-chloroperbenzoic acid. Reduction of the tolyl sulfoxide moiety of (XI) by means of NaI in the presence of acetyl chloride led to the corresponding sulfide (XII). Cyclization of the hydroxy sulfide (XII) to epoxide (XIII) was accomplished via S-alkylation with triethyloxonium tetrafluoroborate. Finally, opening of the chiral epoxide (XIII) with triazole (XIV) in the presence of K2CO3 furnished the title compound.
| 【1】 Tokizawa, M.; Kanamaru, Y.; Matsumoto, M.; Asaoka, T.; Matsuda, H.; Kuraishi, T.; Maebashi, K.; Taido, N.; Kawahara, R. (SSP Co., Ltd.); Triazole derivs.. EP 0435081; JP 1991223266; US 5147886 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Xa) | 56171 | (2R)-3-methyl-1-[(4-methylphenyl)sulfinyl]-3-(methylsulfanyl)-2-[4-(trifluoromethyl)phenyl]-2-butanol | C20H23F3O2S2 | 详情 | 详情 | |
| (Xb) | 56172 | (2S)-3-methyl-1-[(4-methylphenyl)sulfinyl]-3-(methylsulfanyl)-2-[4-(trifluoromethyl)phenyl]-2-butanol | C20H23F3O2S2 | 详情 | 详情 | |
| (IV) | 56166 | 2-methyl-2-(methylsulfanyl)-1-[4-(trifluoromethyl)phenyl]-1-propanone | C12H13F3OS | 详情 | 详情 | |
| (IX) | 56170 | methyl 4-methylphenyl sulfoxide; methyl(4-methylphenyl)oxo-lambda~4~-sulfane | C8H10OS | 详情 | 详情 | |
| (XI) | 56173 | (2R)-3-methyl-1-[(4-methylphenyl)sulfinyl]-3-(methylsulfonyl)-2-[4-(trifluoromethyl)phenyl]-2-butanol | C20H23F3O4S2 | 详情 | 详情 | |
| (XII) | 56174 | (2R)-3-methyl-1-[(4-methylphenyl)sulfanyl]-3-(methylsulfonyl)-2-[4-(trifluoromethyl)phenyl]-2-butanol | C20H23F3O3S2 | 详情 | 详情 | |
| (XIII) | 56175 | methyl 1-methyl-1-{(2R)-2-[4-(trifluoromethyl)phenyl]oxiranyl}ethyl sulfone; (2R)-2-[1-methyl-1-(methylsulfonyl)ethyl]-2-[4-(trifluoromethyl)phenyl]oxirane | C13H15F3O3S | 详情 | 详情 | |
| (XIV) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |