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【结 构 式】 
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【分子编号】16860 【品名】4-(1H-1,2,4-triazol-1-ylmethyl)aniline; 4-(1H-1,2,4-triazol-1-ylmethyl)phenylamine 【CA登记号】 |
【 分 子 式 】C9H10N4 【 分 子 量 】174.20536 【元素组成】C 62.05% H 5.79% N 32.16% |
合成路线1
该中间体在本合成路线中的序号：(I)1) The iodination of 4-(1,2,4-triazol-1-ylmethyl)aniline (I) with ICl and CaCO3 in methanol/water gives the 2-iodoaniline (II), which is cyclized with 1-(triethylsilyl)-4-(triethylsilyloxy)-1-butyne (III) by means of paladium acetate and Na2CO3 in hot DMF yielding 5-(1,2,4-triazol-1-ylmethyl)-3-[2-(triethylsilyloxy)ethyl]-1H-indole (IV). The desilylation of (IV) with HCl in methanol affords the corresponding alcohol (V), which is condensed with dimethylamine by means of methanesulfonyl chloride and triethylamine to give MK-0462 free base (VI). Finally, this compound is treated with benzoic acid in isopropyl alcohol/isopropyl acetate solution.
| 【1】 Castañer, J.; Mealy, N.; Rabassseda, X.; MK-0462. Drugs Fut 1995, 20, 7, 676. |
| 【2】 Lieberman, D.R.; Reamer, R.A.; Reider, P.J.; Cottrell, I.F.; Chen, C.-Y.; Verhoeven, T.R.; Larsen, R.D.; Houghton, P.G.; Synthesis of the 5-HT1D receptor agonist MK-0462 via a Pd-catalyzed coupling reaction. Tetrahedron Lett 1994, 35, 38, 6981-4. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10202 | Benzoic acid | 65-85-0 | C7H6O2 | 详情 | 详情 | |
| (I) | 16860 | 4-(1H-1,2,4-triazol-1-ylmethyl)aniline; 4-(1H-1,2,4-triazol-1-ylmethyl)phenylamine | C9H10N4 | 详情 | 详情 | |
| (II) | 16861 | 2-iodo-4-(1H-1,2,4-triazol-1-ylmethyl)phenylamine; 2-iodo-4-(1H-1,2,4-triazol-1-ylmethyl)aniline | C9H9IN4 | 详情 | 详情 | |
| (III) | 16862 | triethylsilyl 4-(triethylsilyl)-3-butynyl ether; triethyl[[4-(triethylsilyl)-3-butynyl]oxy]silane | 160194-28-5 | C16H34OSi2 | 详情 | 详情 |
| (IV) | 16863 | 2-[5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethyl triethylsilyl ether; 5-(1H-1,2,4-triazol-1-ylmethyl)-3-[2-[(triethylsilyl)oxy]ethyl]-1H-indole | C19H28N4OSi | 详情 | 详情 | |
| (V) | 16864 | 2-[5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]-1-ethanol | C13H14N4O | 详情 | 详情 | |
| (VI) | 16865 | N,N-dimethyl-2-[5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]-1-ethanamine; N,N-dimethyl-N-[2-[5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethyl]amine | C15H19N5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)2) The condensation of 4-nitrobenzyl bromide (VI) with 1,2,4-triazole sodium salt (VII) in DMF gives 1-(4-nitrobenzyl)-1,2,4-triazole (VIII), which is reduced with H2 over Pd/C in ethanol/ethyl acetate yielding the aniline (I). The diazotization of (I) with NaNO2/HCl followed by reduction with SnCl2 affords the corresponding hydrazine (IX), which is cyclized with 4-chlorobutanal dimethylacetal (X) by means of HCl in refluxing ethanol/water to afford 2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl] ethylamine (XI). Finally, this amine is methylated with formaldehyde, sodium cyanoborohydride and acetic acid in methanol.
| 【1】 Castañer, J.; Mealy, N.; Rabassseda, X.; MK-0462. Drugs Fut 1995, 20, 7, 676. |
| 【2】 Baker, R.; Matassa, V.G.; Street, L.J. (Merck Sharp & Dohme Ltd.); Imidazole, triazole and tetrazole derivs. EP 0497512; EP 0778275; US 5298520; US 5451588; US 5602162; US 5602163 . |
| 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) | 16860 | 4-(1H-1,2,4-triazol-1-ylmethyl)aniline; 4-(1H-1,2,4-triazol-1-ylmethyl)phenylamine | C9H10N4 | 详情 | 详情 | |
| (VI) | 16866 | 1-(Bromomethyl)-4-nitrobenzene; para-Nitrobenzyl bromide | 100-11-8 | C7H6BrNO2 | 详情 | 详情 |
| (VII) | 13104 | 1,2,4-Triazole, sodium derivative | 41253-21-8 | C2H2N3Na | 详情 | 详情 |
| (VIII) | 16868 | 1-(4-nitrobenzyl)-1H-1,2,4-triazole | C9H8N4O2 | 详情 | 详情 | |
| (IX) | 16869 | 1-(4-hydrazinobenzyl)-1H-1,2,4-triazole | C9H11N5 | 详情 | 详情 | |
| (X) | 16870 | 4-Chlorobutyraldehyde dimethylacetal; 4-Chloro-1-methoxybutyl methyl ether; 4-Chloro-1,1-dimethoxybutane | C6H13ClO2 | 详情 | 详情 | |
| (XI) | 16871 | 2-[5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine; 2-[5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]-1-ethanamine | C13H15N5 | 详情 | 详情 |