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【结 构 式】

【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%

与该中间体有关的原料药合成路线共 3 条

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
Extended Information