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【结 构 式】 
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【分子编号】15458 【品名】4-methylbenzonitrile; p-tolunitrile 【CA登记号】104-85-8 |
【 分 子 式 】C8H7N 【 分 子 量 】117.15032 【元素组成】C 82.02% H 6.02% N 11.96% |
合成路线1
该中间体在本合成路线中的序号：(II)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：(VIII)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：(II)Radiolabeled SDZ-FOX-988 has been synthesized as follows: The condensation of 4-bromotoluene (I) with [14C]-cuprous cyanide in DMSO at 180 C gives the labeled 4-methylbenzonitrile (II), which by a Grignard reaction with tert-butylmagnesium chloride in THF yields the ketone (IV). The oxidation of (IV) with KMnO4 in tert-butanol affords the labeled 4-pivaloylbenzoic acid (V), which by reaction with refluxing SOCl2 gives the corresponding acyl chloride (VI). The reaction of (VI) with methoxyamine (VII) and triethylamine in toluene yields the corresponding amide (VIII), which is finally condensed with more acyl chloride (VI), by means of triethylamine in toluene.
| 【1】 Sunay, U.B.; Talbot, K.; Prasad, K.; Lee, G.; Jones, L.; Synthesis of [14C2]SDZ FOX 988, a hypoglycemic agent. J Label Compd Radiopharm 1995, 36, 6, 529-35. |
| 【2】 Mealy, N.; Castaner, J.; SDZ-FOX-988. Drugs Fut 1996, 21, 3, 258. |
| 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) | 15459 | tert-butyl(chloro)magnesium | 677-22-5 | C4H9ClMg | 详情 | 详情 |
| (IV) | 15460 | 2,2-dimethyl-1-(4-methylphenyl)-1-propanone; 2,2,4'-TRIMETHYLPROPIOPHENONE | 30314-44-4 | C12H16O | 详情 | 详情 |
| (IV) | 45250 | 2,2-dimethyl-1-(4-methylphenyl)-1-propanone | C12H16O | 详情 | 详情 | |
| (V) | 15453 | 4-(2,2-dimethylpropanoyl)benzoic acid | C12H14O3 | 详情 | 详情 | |
| (V) | 45251 | 4-(2,2-dimethylpropanoyl)benzoic acid | C12H14O3 | 详情 | 详情 | |
| (VI) | 15454 | 4-(2,2-dimethylpropanoyl)benzoyl chloride | C12H13ClO2 | 详情 | 详情 | |
| (VI) | 45252 | 4-(2,2-dimethylpropanoyl)benzoyl chloride | C12H13ClO2 | 详情 | 详情 | |
| (VII) | 15456 | 4-(2,2-dimethylpropanoyl)-N-methoxybenzamide | C13H17NO3 | 详情 | 详情 | |
| (VIII) | 15455 | (aminooxy)methane; O-methylhydroxylamine | 67-62-9 | CH5NO | 详情 | 详情 |
| (VIII) | 45253 | 4-(2,2-dimethylpropanoyl)-N-methoxybenzamide | C13H17NO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Electrophilic nitration of p-tolunitrile (I) afforded the 3-nitro derivative (II), which was condensed with diethyl oxalate in the presence of sodium ethoxide to produce the sodium enolate of the alpha-keto ester (III). Compound (III) was then subjected to Reissert indole synthesis by means of Zn and HOAc to furnish ethyl 6-cyanoindole-2-carboxylate (IV). N-alkylation of indole (IV) with iodoethane and NaH in DMF gave (V), whose carboxylate group was reduced to alcohol (VI) employing in situ-generated calcium borohydride (obtained from NaBH4 and CaI2 in THF in the presence of NaHCO3). Treatment of alcohol (VI) with PBr3 in methylene chloride yielded the corresponding bromide (VII), which was then converted into the phosphonium salt (VIII) by means of triphenylphosphine in refluxing toluene.
| 【1】 Koo, B.A.; Min, J.K.; Hong, W.S.; Ryu, E.J.; Nam, W.H.; Kim, J.M. (C & C Research Laboratories); Aromatic amidine derivs. useful as selective thrombin inhibitors. EP 0918768; JP 2000504030; US 6201006; WO 9745424 . |
| 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) | 15458 | 4-methylbenzonitrile; p-tolunitrile | 104-85-8 | C8H7N | 详情 | 详情 |
| (II) | 50428 | 4-methyl-3-nitrobenzonitrile | C8H6N2O2 | 详情 | 详情 | |
| (III) | 50429 | sodium (Z)-1-(4-cyano-2-nitrophenyl)-3-ethoxy-3-oxo-1-propen-2-olate | C12H9N2NaO5 | 详情 | 详情 | |
| (IV) | 50430 | ethyl 6-cyano-1H-indole-2-carboxylate | C12H10N2O2 | 详情 | 详情 | |
| (V) | 50431 | ethyl 6-cyano-1-ethyl-1H-indole-2-carboxylate | C14H14N2O2 | 详情 | 详情 | |
| (VI) | 50432 | 1-ethyl-2-(hydroxymethyl)-1H-indole-6-carbonitrile | C12H12N2O | 详情 | 详情 | |
| (VII) | 50433 | 2-(bromomethyl)-1-ethyl-1H-indole-6-carbonitrile | C12H11BrN2 | 详情 | 详情 | |
| (VIII) | 50434 | [(6-cyano-1-ethyl-1H-indol-2-yl)methyl](triphenyl)phosphonium bromide | C30H26BrN2P | 详情 | 详情 |