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【结 构 式】 
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【分子编号】45571 【品名】(2S)-1-(2,4-difluorophenyl)-2-hydroxy-1-propanone 【CA登记号】 |
【 分 子 式 】C9H8F2O2 【 分 子 量 】186.1581264 【元素组成】C 58.07% H 4.33% F 20.41% O 17.19% |
合成路线1
该中间体在本合成路线中的序号：(XVIII)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 |
合成路线2
该中间体在本合成路线中的序号：(XV)The known chiral epoxide (IX) can be synthesized by several different ways shown in the following: 1) 2(S)-Acetoxypropionic acid (XII) is treated first with oxalyl chloride in DMF/CH2Cl2, and then the resultant acyl chloride is submitted to a Friedel-Crafts reaction with 1,3-difluorobenzene (XIII) by means of AlCl3 to provide a 1:1 mixture of a(S)-acetoxypropiophenone (XIV) and a(S)-hydroxy-propiophenone (XV). This mixture is treated with H2SO4 in MeOH to give the pure alcohol (XV). Tosylation of alcohol (XV) with p-toluenesulfonyl chloride in pyridine furnishes tosylate (XVI), which is converted into a(R)-hydroxypropiophenone (XVII) by an SN2 displacement reaction with LiOH in DMF/H2O. Reaction of the hydroxy group of (XVII) with 2,3-dihydropyran (XVIII) and pyridi-nium p-toluenesulfonate (PPTS) in CH2Cl2 gives the protected compound (XIX), which is converted into the silyl alcohol (XXI) by a Grignard reaction with (chloro-methyl)dimethylisopropoxysilane (XX) in the presence of Mg and a small amount of MeI. Oxidative desilylation of (XXI) by means of NaHCO3 and H2O2 in THF/MeOH, followed by hydrolysis with TsOH in MeOH, affords the triol (XXII), which is then mesylated with methanesulfonyl chloride in pyridine to provide the dimesylate (XXIII). Finally, nucleofilic substitution of one mesylate group of (XXIII) with 1H-1,2,4-triazole (XXIV) by means of NaH in DMF with concomitant epoxide formation affords the desired intermediate (IX).
| 【1】 Sorbera, L.A.; del Fresno, M.; Rabasseda, X.; CS-758. Drugs Fut 2003, 28, 3, 217. |
| 【2】 Konos, T.; Miyaoka, T.; Tajima, Y.; Oida, S.; Triazole antifungals. III. Stereocontrolled synthesis of an optically active triazolylmethyloxirane precursor to antifungal oxazolodine derivatives. Chem Pharm Bull 1991, 39, 9, 2241. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 31738 | 1-[[(2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole | C12H11F2N3O | 详情 | 详情 | |
| (XII) | 10142 | (2R)-2-(Acetoxy)propionic acid | 18668-00-3 | C5H8O4 | 详情 | 详情 |
| (XIII) | 13095 | m-Difluorobenzene; 1,3-Difluorobenzene | 372-18-9 | C6H4F2 | 详情 | 详情 |
| (XIV) | 59948 | (1S)-2-(2,4-difluorophenyl)-1-methyl-2-oxoethyl acetate | C11H10F2O3 | 详情 | 详情 | |
| (XV) | 45571 | (2S)-1-(2,4-difluorophenyl)-2-hydroxy-1-propanone | C9H8F2O2 | 详情 | 详情 | |
| (XVI) | 59949 | (1S)-2-(2,4-difluorophenyl)-1-methyl-2-oxoethyl 4-methylbenzenesulfonate | C16H14F2O4S | 详情 | 详情 | |
| (XVII) | 13100 | (2R)-1-(2,4-Difluorophenyl)-2-hydroxy-1-propanone | C9H8F2O2 | 详情 | 详情 | |
| (XVIII) | 13684 | 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran | 110-87-2 | C5H8O | 详情 | 详情 |
| (XIX) | 13102 | (2R)-1-(2,4-Difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone | C14H16F2O3 | 详情 | 详情 | |
| (XX) | 59950 | (chloromethyl)(dimethyl)silyl isopropyl ether; (chloromethyl)(isopropoxy)dimethylsilane | C6H15ClOSi | 详情 | 详情 | |
| (XXI) | 59951 | (2S,3R)-2-(2,4-difluorophenyl)-1-[isopropoxy(dimethyl)silyl]-3-(tetrahydro-2H-pyran-2-yloxy)-2-butanol | C20H32F2O4Si | 详情 | 详情 | |
| (XXII) | 59952 | (2R,3R)-2-(2,4-difluorophenyl)-1,2,3-butanetriol | C10H12F2O3 | 详情 | 详情 | |
| (XXIII) | 59953 | (1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-[(methylsulfonyl)oxy]propyl methanesulfonate | C12H16F2O7S2 | 详情 | 详情 | |
| (XXIV) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |