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【结 构 式】 
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【分子编号】64043 【品名】2-iodo-5-(methyloxy)-4-(1,3-oxazol-5-yl)aniline; 2-iodo-5-(methyloxy)-4-(1,3-oxazol-5-yl)phenylamine 【CA登记号】 |
【 分 子 式 】C10H9IN2O2 【 分 子 量 】316.09821 【元素组成】C 38% H 2.87% I 40.15% N 8.86% O 10.12% |
合成路线1
该中间体在本合成路线中的序号：(VI)Oxidation of 4-nitro-2-methoxytoluene (I) by means of chromic anhydride and sulfuric acid in the presence of acetic anhydride gives rise to acylal (II), which is further hydrolyzed to aldehyde (III) under acidic conditions. Reaction of aldehyde (III) with tosylmethyl isocyanide produces the 5-aryl oxazole (IV). Reduction of the nitro group of (IV) by catalytic hydrogenation yields aniline (V). Then, electrophilic iodination of amine (V) with iodine and silver triflate furnishes the aryl iodide (VI).
| 【1】 Pitts, W.J.; Iwanowicz, E.J.; Dhar, T.G.M.; Gu, H.H.; Watterson, S.H. (Bristol-Myers Squibb Co.); Heterocycles that are inhibitors of IMPDH enzyme. EP 1276739; JP 2003531205; WO 0181340 . |
| 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) | 39654 | methyl 2-methyl-5-nitrophenyl ether; 2-methoxy-1-methyl-4-nitrobenzene | 13120-77-9 | C8H9NO3 | 详情 | 详情 |
| (II) | 39655 | (acetoxy)(2-methoxy-4-nitrophenyl)methyl acetate | C12H13NO7 | 详情 | 详情 | |
| (III) | 39656 | 2-methoxy-4-nitrobenzaldehyde | C8H7NO4 | 详情 | 详情 | |
| (IV) | 39657 | methyl 5-nitro-2-(1,3-oxazol-5-yl)phenyl ether; 5-(2-methoxy-4-nitrophenyl)-1,3-oxazole | C10H8N2O4 | 详情 | 详情 | |
| (V) | 39658 | C10H10N2O2 | 详情 | 详情 | ||
| (VI) | 64043 | 2-iodo-5-(methyloxy)-4-(1,3-oxazol-5-yl)aniline; 2-iodo-5-(methyloxy)-4-(1,3-oxazol-5-yl)phenylamine | C10H9IN2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)6-Bromo-1-indanone (VII) is reduced to alcohol (VIII) employing NaBH4. After chlorination of (VIII) with SOCl2, the resultant alkyl chloride (IX) is displaced by heating with ethanolic dimethylamine in a sealed vessel to produce the (dimethylamino)indan (X). Palladium-catalyzed coupling of aryl bromide (X) with trimethylsilyl acetylene (XI) furnishes the silyl acetylene (XII), which is then desilylated to (XIII) with Bu4NF in THF. Finally, condensation between acetylene (XIII), aryl iodide (VI) and carbon monoxide in the presence of palladium catalyst leads to the title quinolone derivative. (1,2)
| 【1】 Dhar, T.G.M.; Watterson, S.H.; Chen, P.; Shen, Z.; Gu, H.H.; Norris, D.; Carlsen, M.; Haslow, K.D.; Pitts, W.J.; Guo, J.; Chorba, J.; Fleener, C.A.; Rouleau, K.A.; Townsend, R.; Hollenbaugh, D.; Iwanowicz, E.J.; Quinolone-based IMPDH inhibitors: Introduction of basic residues on ring D and SAR of the corresponding mono, di and benzofused analogues. Bioorg Med Chem Lett 2003, 13, 3, 547. |
| 【2】 Pitts, W.J.; Iwanowicz, E.J.; Dhar, T.G.M.; Gu, H.H.; Watterson, S.H. (Bristol-Myers Squibb Co.); Heterocycles that are inhibitors of IMPDH enzyme. EP 1276739; JP 2003531205; WO 0181340 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 64043 | 2-iodo-5-(methyloxy)-4-(1,3-oxazol-5-yl)aniline; 2-iodo-5-(methyloxy)-4-(1,3-oxazol-5-yl)phenylamine | C10H9IN2O2 | 详情 | 详情 | |
| (VII) | 64044 | 6-bromo-2,3-dihydro-1H-inden-1-one | C9H7BrO | 详情 | 详情 | |
| (VIII) | 64045 | 6-bromo-2,3-dihydro-1H-inden-1-ol | C9H9BrO | 详情 | 详情 | |
| (IX) | 64046 | 6-bromo-1-chloro-2,3-dihydro-1H-indene | C9H8BrCl | 详情 | 详情 | |
| (X) | 64047 | 6-bromo-N,N-dimethyl-2,3-dihydro-1H-inden-1-amine; N-(6-bromo-2,3-dihydro-1H-inden-1-yl)-N,N-dimethylamine | C11H14BrN | 详情 | 详情 | |
| (XI) | 23897 | ethynyl(trimethyl)silane；trimethylsilyl acetylene | 1066-54-2 | C5H10Si | 详情 | 详情 |
| (XII) | 64048 | N,N-dimethyl-6-[2-(trimethylsilyl)ethynyl]-2,3-dihydro-1H-inden-1-amine; N,N-dimethyl-N-{6-[2-(trimethylsilyl)ethynyl]-2,3-dihydro-1H-inden-1-yl}amine | C16H23NSi | 详情 | 详情 | |
| (XIII) | 64049 | N-(6-ethynyl-2,3-dihydro-1H-inden-1-yl)-N,N-dimethylamine; 6-ethynyl-N,N-dimethyl-2,3-dihydro-1H-inden-1-amine | C13H15N | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Condensation of iodoaniline (I) with ethyl 2-(methylsulfanyl)acetate (II) in the presence of sulfuryl chloride gives rise to the oxindole derivative (III). Desulfuration of (III) by means of Raney-nickel then affords (IV). The Vilsmeier-Haack reaction of oxindole (IV) with POBr3 and DMF leads to the bromo aldehyde (V). This is finally subjected to Suzuki coupling with 3-benzothienylboronic acid (VI) to furnish the title compound.
| 【1】 Watterson, S.H.; Dhar, T.G.M.; Ballentine, S.K.; Shen, Z.; Barrish, J.C.; Cheney, D.; Fleener, C.A.; Rouleau, K.A.; Townsend, C.; Hollenbaugh, D.L.; Iwanowicz, E.J.; Novel indole-based inhibitors of IMPDH: Introduction of hydrogen bond acceptors at indole C-3. Bioorg Med Chem Lett 2003, 13, 7, 1273. |
| 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) | 64043 | 2-iodo-5-(methyloxy)-4-(1,3-oxazol-5-yl)aniline; 2-iodo-5-(methyloxy)-4-(1,3-oxazol-5-yl)phenylamine | C10H9IN2O2 | 详情 | 详情 | |
| (II) | 48543 | Ethyl methylthioacetate; (Methylthio)acetic acid ethyl ester; ethyl 2-(methylsulfanyl)acetate | 4455-13-4 | C5H10O2S | 详情 | 详情 |
| (III) | 64333 | 6-(methyloxy)-3-(methylsulfanyl)-5-(1,3-oxazol-5-yl)-1,3-dihydro-2H-indol-2-one | C13H12N2O3S | 详情 | 详情 | |
| (IV) | 64334 | 6-(methyloxy)-5-(1,3-oxazol-5-yl)-1,3-dihydro-2H-indol-2-one | C12H10N2O3 | 详情 | 详情 | |
| (V) | 64335 | 2-bromo-6-(methyloxy)-5-(1,3-oxazol-5-yl)-1H-indole-3-carbaldehyde | C13H9BrN2O3 | 详情 | 详情 | |
| (VI) | 64336 | 1-benzothiophen-3-ylboronic acid | C8H7BO2S | 详情 | 详情 |