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【结 构 式】 
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【分子编号】45565 【品名】1-[(1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]ethyl]-3-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]-1,3-dihydro-2H-imidazol-2-one 【CA登记号】 |
【 分 子 式 】C20H16F2N6O2 【 分 子 量 】410.3830864 【元素组成】C 58.54% H 3.93% F 9.26% N 20.48% O 7.8% |
合成路线1
该中间体在本合成路线中的序号：(XV)The chiral epoxy alcohol (XIII), prepared from methyl (R)-lactate, was converted to triflate (XIV) by treatment with trifluoromethanesulfonic anhydride in the presence of diisopropylethylamine. Condensation of triflate (XIV) with the sodium salt of imidazolone (XII) afforded (XV). Subsequent oxirane ring opening with 1,2,4-triazole (XVI) in the presence of NaH gave the triazolyl alcohol (XVII). The title imidazolidinone was then obtained by catalytic hydrogenation of imidazolone (XVII).
| 【2】 Itoh, K.; Okonogi, K.; Tasaka, A. (Takeda Chemical Industries, Ltd.); Azole cpds., their production and use. EP 0809640; JP 1997183769; WO 9625410 . |
| 【1】 Hosono, H.; Itoh, K.; Kitazaki, T.; Ichikawa, T.; Okonogi, K.; Tasaka, A.; Matsushita, Y.; Hayashi, R.; Optically active antifungal azoles. X. Synthesis and antifungal activity of N-[4-(azolyl)phenyl] and N-[4-(azolylmethyl)phenyl]-N'[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H,1,2,4-triazol-1-yl)propyl]-azolones. Chem Pharm Bull 2000, 48, 12, 1935. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 45562 | 1-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]-1,3-dihydro-2H-imidazol-2-one | C10H8N6O | 详情 | 详情 | |
| (XIII) | 45563 | (1S)-1-[(2S)-2-(2,4-difluorophenyl)oxiranyl]-1-ethanol | C10H10F2O2 | 详情 | 详情 | |
| (XIV) | 45564 | (1S)-1-[(2S)-2-(2,4-difluorophenyl)oxiranyl]ethyl trifluoromethanesulfonate | C11H9F5O4S | 详情 | 详情 | |
| (XV) | 45565 | 1-[(1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]ethyl]-3-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]-1,3-dihydro-2H-imidazol-2-one | C20H16F2N6O2 | 详情 | 详情 | |
| (XVI) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (XVII) | 45566 | 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]-1,3-dihydro-2H-imidazol-2-one | C22H19F2N9O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XV)The preparation of the epoxide precursor (XV) can also be carried out by an alternative route starting from the chiral hydroxypropiophenone (XVIII), obtained from ethyl (S)-lactate. Hydroxy ketone (XVIII) was converted to triflate (XIX), which was condensed with the sodium salt of imidazolone (XII), yielding adduct (XX). Addition of (dimethylisopropoxysilyl)methylmagnesium chloride to the propiophenone (XX) furnished carbinol (XIX). Oxidative desilylation of (XIX) with H2O2 in the presence of NaHCO3 afforded diol (XXII). This was converted to the corresponding mesylate (XXIII) and then cyclized to oxirane (XV) in the presence of K2CO3.
| 【2】 Itoh, K.; Okonogi, K.; Tasaka, A. (Takeda Chemical Industries, Ltd.); Azole cpds., their production and use. EP 0809640; JP 1997183769; WO 9625410 . |
| 【1】 Hosono, H.; Itoh, K.; Kitazaki, T.; Ichikawa, T.; Okonogi, K.; Tasaka, A.; Matsushita, Y.; Hayashi, R.; Optically active antifungal azoles. X. Synthesis and antifungal activity of N-[4-(azolyl)phenyl] and N-[4-(azolylmethyl)phenyl]-N'[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H,1,2,4-triazol-1-yl)propyl]-azolones. Chem Pharm Bull 2000, 48, 12, 1935. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 45562 | 1-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]-1,3-dihydro-2H-imidazol-2-one | C10H8N6O | 详情 | 详情 | |
| (XV) | 45565 | 1-[(1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]ethyl]-3-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]-1,3-dihydro-2H-imidazol-2-one | C20H16F2N6O2 | 详情 | 详情 | |
| (XVIII) | 45571 | (2S)-1-(2,4-difluorophenyl)-2-hydroxy-1-propanone | C9H8F2O2 | 详情 | 详情 | |
| (XIX) | 43510 | (1S)-2-(2,4-difluorophenyl)-1-methyl-2-oxoethyl trifluoromethanesulfonate | C10H7F5O4S | 详情 | 详情 | |
| (XIX) | 45568 | 1-[(1R,2S)-2-(2,4-difluorophenyl)-2-hydroxy-3-[isopropoxy(dimethyl)silyl]-1-methylpropyl]-3-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]-1,3-dihydro-2H-imidazol-2-one | C25H30F2N6O3Si | 详情 | 详情 | |
| (XX) | 45567 | 1-[(1R)-2-(2,4-difluorophenyl)-1-methyl-2-oxoethyl]-3-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]-1,3-dihydro-2H-imidazol-2-one | C19H14F2N6O2 | 详情 | 详情 | |
| (XXII) | 45569 | 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-dihydroxy-1-methylpropyl]-3-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]-1,3-dihydro-2H-imidazol-2-one | C20H18F2N6O3 | 详情 | 详情 | |
| (XXIII) | 45570 | (2S,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]-2,3-dihydro-1H-imidazol-1-yl]butyl methanesulfonate | C21H20F2N6O5S | 详情 | 详情 |