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【结 构 式】 
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【分子编号】27902 【品名】N,N-dimethyl-4-[3-[(trimethylsilyl)oxy]propyl]-1H-imidazole-1-carboxamide 【CA登记号】 |
【 分 子 式 】C12H23N3O2Si 【 分 子 量 】269.41914 【元素组成】C 53.5% H 8.6% N 15.6% O 11.88% Si 10.42% |
合成路线1
该中间体在本合成路线中的序号：(IV)The synthesis of [14C]-fadrozole hydrochloride has been described: The reaction of 4-bromotoluene (I) with [14C]-copper cyanide in hot DMF gives [14C]-4-methylbenzonitrile (II), which is brominated with N-bromosuccinimide (NBS) and benzoyl peroxide in CCl4 yields the corresponding bromomethyl derivative (III). The condensation of (III) with N,N-dimethyl-4-[3-(trimethylsilyloxy)propyl]imidazole-1-carboxamide (IV) by means of ammonia, followed by desilylation with HCl affords labeled 4-[5-(3-hydroxypropyl)imidazol-1-ylmethyl]benzonitrile (V). The reaction of (V) with SOCl2 in dichloromethane gives the corresponding chloropropyl derivative (VI), which is finally cyclized by means of potassium tert-butoxide in THF and treated with dry HCl in ethanol/ethyl acetate to obtain the corresponding hydrochloride.
| 【1】 Allentoff, A.J.; Chaudhuri, N.K.; Markus, B.; Duelfer, T.; Desai, M.; Synthesis of 14C--labelled CGS 16949A (fadrozole HCl), a potent aromatase inhibitor. J Label Compd Radiopharm 1997, 39, 11, 885. |
| 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) | 14044 | 4-Bromotoluene; 1-Bromo-4-methylbenzene | 106-38-7 | C7H7Br | 详情 | 详情 |
| (II) | 15458 | 4-methylbenzonitrile; p-tolunitrile | 104-85-8 | C8H7N | 详情 | 详情 |
| (II) | 45171 | 4-methylbenzonitrile | C8H7N | 详情 | 详情 | |
| (III) | 14200 | 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile | 17201-43-3 | C8H6BrN | 详情 | 详情 |
| (III) | 45172 | 4-(bromomethyl)benzonitrile | C8H6BrN | 详情 | 详情 | |
| (IV) | 27902 | N,N-dimethyl-4-[3-[(trimethylsilyl)oxy]propyl]-1H-imidazole-1-carboxamide | C12H23N3O2Si | 详情 | 详情 | |
| (V) | 21248 | 4-[[5-(3-hydroxypropyl)-1H-imidazol-1-yl]methyl]benzonitrile | C14H15N3O | 详情 | 详情 | |
| (V) | 45173 | 4-[[5-(3-hydroxypropyl)-1H-imidazol-1-yl]methyl]benzonitrile | C14H15N3O | 详情 | 详情 | |
| (VI) | 21249 | 4-[[5-(3-chloropropyl)-1H-imidazol-1-yl]methyl]benzonitrile | C14H14ClN3 | 详情 | 详情 | |
| (VI) | 45174 | 4-[[5-(3-chloropropyl)-1H-imidazol-1-yl]methyl]benzonitrile | C14H14ClN3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)14C-Radiolabeled fadrozole has been obtained by two similar ways: 1) The condensation of 4-[3-(methanesulfonyloxy)propyl]-N,N-dimethylimidazole-1-carboxamide (VI) with 14C-labeled 4-(bromomethyl)benzonitrile (IX) by means of NH3 followed by hydrolysis with HCl gives radiolabeled 4-[5-(3-hydroxypropyl)imidazol-1-ylmethyl]benzonitrile (X), which is treated with SOCl2 yielding the chloropropyl derivative (XI). Finally, this compound is cyclized to the target compound by means of potassium tert-butoxide. The intermediate compounds imidazole (VI) and radiolabeled benzonitrile (IX) have been obtained as follows: a) Imidazole (VI): The esterification of 3-(4-imidazolyl)-2(E)-propenoic acid (I) with SOCl2 and methanol gives the methyl ester (II), which is reduced with H2 over Pd/C yielding the propionic ester (III). The reduction of (III) with LiAlH4 affords 3-(4-imidazolyl)-1-propanol (IV), which is treated with N,N-dimethyl chloroformamide to afford 4-(3-hydroxypropyl)-N,N-dimethylimidazole-1-carboxamide (V). Finally, this compound is mesylated with methanesulfonyl chloride to give the desired intermediate (VI). b) Radiolabeled benzonitrile (IX): The reaction of 4-bromotoluene (VII) with radiolabeled potassium cyanide gives the radiolabeled 4-methylbenzonitrile (VIII), which is brominated with NBS and benzoylperoxide yielding intermediate (IX).
| 【1】 Allentoff, A.J.; et al.; Palladium-catalyzed aryl cynations in radiosynthesis: Synthesis of 14C-labeled fadrozole, a potent aromatase inhibitor. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 49. |
| 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) | 27420 | Urocanic acid; (E)-3-(1H-imidazol-4-yl)-2-propenoic acid | 104-98-3 | C6H6N2O2 | 详情 | 详情 |
| (II) | 39976 | methyl (E)-3-(1H-imidazol-4-yl)-2-propenoate | C7H8N2O2 | 详情 | 详情 | |
| (III) | 39977 | methyl 3-(1H-imidazol-4-yl)propanoate | C7H10N2O2 | 详情 | 详情 | |
| (IV) | 21245 | 3-(1H-imidazol-4-yl)-1-propanol | C6H10N2O | 详情 | 详情 | |
| (V) | 39978 | 4-(3-hydroxypropyl)-N,N-dimethyl-1H-imidazole-1-carboxamide | C9H15N3O2 | 详情 | 详情 | |
| (VI) | 27902 | N,N-dimethyl-4-[3-[(trimethylsilyl)oxy]propyl]-1H-imidazole-1-carboxamide | C12H23N3O2Si | 详情 | 详情 | |
| (VII) | 14044 | 4-Bromotoluene; 1-Bromo-4-methylbenzene | 106-38-7 | C7H7Br | 详情 | 详情 |
| (VIII) | 15458 | 4-methylbenzonitrile; p-tolunitrile | 104-85-8 | C8H7N | 详情 | 详情 |
| (VIII) | 45171 | 4-methylbenzonitrile | C8H7N | 详情 | 详情 | |
| (IX) | 14200 | 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile | 17201-43-3 | C8H6BrN | 详情 | 详情 |
| (IX) | 45172 | 4-(bromomethyl)benzonitrile | C8H6BrN | 详情 | 详情 | |
| (X) | 21248 | 4-[[5-(3-hydroxypropyl)-1H-imidazol-1-yl]methyl]benzonitrile | C14H15N3O | 详情 | 详情 | |
| (X) | 45173 | 4-[[5-(3-hydroxypropyl)-1H-imidazol-1-yl]methyl]benzonitrile | C14H15N3O | 详情 | 详情 | |
| (XI) | 21249 | 4-[[5-(3-chloropropyl)-1H-imidazol-1-yl]methyl]benzonitrile | C14H14ClN3 | 详情 | 详情 | |
| (XI) | 45174 | 4-[[5-(3-chloropropyl)-1H-imidazol-1-yl]methyl]benzonitrile | C14H14ClN3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)The esterification of 3-(4-imidazolyl)-2(E)-propenoic acid (I) with SOCl2 and methanol gives the methyl ester (II), which is reduced with H2 over Pd/C yielding the propionic ester (III). The reduction of (III) with LiAlH4 affords 3-(4-imidazolyl)-1-propanol (IV), which is treated with N,N-dimethyl chloroformamide to afford 4-(3-hydroxypropyl)-N,N-dimethylimidazole-1-carboxamide (V). The mesylation of (V) with methanesulfonyl chloride to give the corresponding methanesulfonate (VI), which is condensed with alpha-bromo-4-iodotoluene (XII) by means of NH3 and treated with HCl yielding 3-[1-(4-iodobenzyl)imidazol-5-yl]-1-propanol (XIII). The reaction of (XIII) with SOCl2 affords the 3-chloropropyl derivative (XIV), which is cyclized by means of potassium tert-butoxide to give 5-(4-iodobenzyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (XV). Finally, this compound is condensed with radiolabeled potassium cyanide by means of palladium tetrakis(triphenylphosphine).
| 【1】 Allentoff, A.J.; et al.; Palladium-catalyzed aryl cynations in radiosynthesis: Synthesis of 14C-labeled fadrozole, a potent aromatase inhibitor. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 49. |
| 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) | 27420 | Urocanic acid; (E)-3-(1H-imidazol-4-yl)-2-propenoic acid | 104-98-3 | C6H6N2O2 | 详情 | 详情 |
| (II) | 39976 | methyl (E)-3-(1H-imidazol-4-yl)-2-propenoate | C7H8N2O2 | 详情 | 详情 | |
| (III) | 39977 | methyl 3-(1H-imidazol-4-yl)propanoate | C7H10N2O2 | 详情 | 详情 | |
| (IV) | 21245 | 3-(1H-imidazol-4-yl)-1-propanol | C6H10N2O | 详情 | 详情 | |
| (V) | 39978 | 4-(3-hydroxypropyl)-N,N-dimethyl-1H-imidazole-1-carboxamide | C9H15N3O2 | 详情 | 详情 | |
| (VI) | 27902 | N,N-dimethyl-4-[3-[(trimethylsilyl)oxy]propyl]-1H-imidazole-1-carboxamide | C12H23N3O2Si | 详情 | 详情 | |
| (XII) | 39980 | 1-(bromomethyl)-4-iodobenzene | 16004-15-2 | C7H6BrI | 详情 | 详情 |
| (XIII) | 39979 | 3-[1-(4-iodobenzyl)-1H-imidazol-5-yl]-1-propanol | C13H15IN2O | 详情 | 详情 | |
| (XIV) | 39981 | 5-(3-chloropropyl)-1-(4-iodobenzyl)-1H-imidazole | C13H14ClIN2 | 详情 | 详情 | |
| (XV) | 39982 | 5-(4-iodophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine | C13H13IN2 | 详情 | 详情 |