【结 构 式】 |
【分子编号】20261 【品名】S-(2-pyridinyl) (2S)-2-methyl-3-(trityloxy)propanethioate 【CA登记号】 |
【 分 子 式 】C28H25NO2S 【 分 子 量 】439.57804 【元素组成】C 76.51% H 5.73% N 3.19% O 7.28% S 7.29% |
合成路线1
该中间体在本合成路线中的序号:(V)The synthesis of (2S,3S)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1,2,4-triazol-1-yl)butyronitrile (XV), a key intermediate the synthesis of ER-30346 has been described: The tritylation of 3-hydroxy-2(S)-methylpropionic acid methyl ester (I) with trityl chloride in hot pyridine gives the trityl ether (II), which is hydrolyzed with LiOH in H2O/THF/methanol yielding the free acid (III). The esterification of (III) with 2-mercaptopyridine (IV) by means of dicyclohexylcarbodiimide (DCC) in dichloromethane gives the thioester (V), which is treated with 2,4-difluorophenylmagnesium bromide (VI) in THF yielding the propiophenone (VII), which by treatment with methyltriphenylphosphonium bromide/NaH in THF is converted into the methylene derivative (VIII). The oxidation of (VIII) with OsO4 and N-methylmorpholine oxide in acetone affords, after column chromatography, the chiral diol (IX), which is monomesylated with mesyl chloride/triethylamine in dichlormethane giving the monoester (X). The reaction of (X) with 1,2,4-triazol (XI) and NaH in DMF yields (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-1-(1,2,4-triazol-1-yl)-4-(triphenylmethoxy)-2-butanol (XII), which is detritylated with p-toluenesulfonic acid in methanol affording the diol (XIII). The oxidation of (XIII) with oxalyl chloride/DMSO in dichloromethane gives the aldehyde (XIV), which is finally treated with hydroxylamine-O-sulfonic acid in water yielding the desired bytyronitrile intermediate (XV) already referenced.
【1】 Kaku, Y.; et al.; A novel route for chiral synthesis of the triazole antifungal ER-30346. Chem Pharm Bull 1998, 46, 7, 1125. |
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) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
(II) | 17129 | Methyl (2S)-2-methyl-3-(trityloxy)propanoate | C24H24O3 | 详情 | 详情 | |
(III) | 20259 | (2S)-2-methyl-3-(trityloxy)propionic acid | C23H22O3 | 详情 | 详情 | |
(IV) | 20260 | 2-Mercaptopyiridine; 2-pyridinethiol; 2-pyridinylhydrosulfide | 2637-34-5 | C5H5NS | 详情 | 详情 |
(V) | 20261 | S-(2-pyridinyl) (2S)-2-methyl-3-(trityloxy)propanethioate | C28H25NO2S | 详情 | 详情 | |
(VI) | 20262 | bromo(2,4-difluorophenyl)magnesium | C6H3BrF2Mg | 详情 | 详情 | |
(VII) | 17130 | (2S)-1-(2,4-difluorophenyl)-2-methyl-3-(trityloxy)-1-propanone | C29H24F2O2 | 详情 | 详情 | |
(VIII) | 17131 | (2R)-3-(2,4-difluorophenyl)-2-methyl-3-butenyl trityl ether; 2,4-difluoro-1-[1-[(1R)-1-methyl-2-(trityloxy)ethyl]vinyl]benzene | C30H26F2O | 详情 | 详情 | |
(IX) | 17132 | (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-4-(trityloxy)-1,2-butanediol | C30H28F2O3 | 详情 | 详情 | |
(X) | 20266 | (2R,3S)-2-(2,4-difluorophenyl)-2-hydroxy-3-methyl-4-(trityloxy)butyl methanesulfonate | C31H30F2O5S | 详情 | 详情 | |
(XI) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
(XII) | 17135 | (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-(trityloxy)-2-butanol | C32H29F2N3O2 | 详情 | 详情 | |
(XIII) | 17136 | (2S,3R)-3-(2,4-difluorophenyl)-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1,3-butanediol | C13H15F2N3O2 | 详情 | 详情 | |
(XIV) | 17137 | (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanal | C13H13F2N3O2 | 详情 | 详情 | |
(XV) | 17123 | (2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile | C13H12F2N4O | 详情 | 详情 |