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【结 构 式】

【分子编号】44736

【品名】tert-butyl 3-cyano-4-methyl-1H-indol-7-ylcarbamate

【CA登记号】

【 分 子 式 】C15H17N3O2

【 分 子 量 】271.319

【元素组成】C 66.4% H 6.32% N 15.49% O 11.79%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(VII)

The synthesis of intermediate (VIII) can be achieved by following two different routes: 1) Treatment of 2-bromo-5-methylnitrobenzene (I) with vinyl magnesium bromide (II) in THF yields bromoindole derivative (III), which is then converted into carboxylic acid (IV) by means of BuLi and CO2 in THF. Treatment of (IV) with diphenylphosphoryl azide (DPPA) and Et3N converts the carboxylic group into an amine intermediate which is then treated with hot t-BuOH to afford derivative (V). Formylation of (V) by means of DMF, POCl3 and aqueous NaOH provides aldehyde (VI), which is then treated with hydroxylamine (NH2OH), pyridine and N,N'-carbonyldiimidazole (CDI) and then heated with Et3N to furnish cyano derivative (VII). Finally, removal of the Boc group of (VII) by treatment with TFA in CH2Cl2 gives intermediate (VIII). 2) Alternatively, conversion of 5-methyl-2-nitroaniline (IX) into hydrazone derivative (XI) is achieved by first reaction with NaNO2 in hydrochloric acid media followed by condensation with ethyl 2-methylacetoacetate (X) in EtOH and aqueous KOH. Treatment of (XI) with refluxing H3PO4 in xylene yields indole derivative (XII), which is hydrolyzed by means of aqueous NaOH in THF to afford carboxylic acid (XIII). Decarboxylation of (XIII) with CuCO3 in 1,3-dimethyl-2-imidazolidinone furnishes 4-methyl-7-nitro-1H-indole (XIV), which is then formylated by means of DMF, POCl3 and aqueous NaOH to give aldehyde (XV). Conversion of formyl derivative (XV) into cyano derivative (XVI) is achieved by treatment with hydroxylamine (NH2OH), pyridine and N,N'-carbonyldiimidazole (CDI) followed by heating with Et3N. Finally, hydrogenation of the nitro group of (XVI) over PtO2 affords the target intermediate (VIII).

1 Kamata, J.; Semba, T.; Nara, K.; Ohwa, T.; Hata, N.; Haneda, T.; Funahashi, Y.; Hamaoka, S.; Tsuruoka, A.; Ueda, N.; Wakabayashi, T.; Ozawa, Y.; Yamamoto, Y.; Okabe, T.; Takahashi, K.; Tsukahara, N. (Eisai Co., Ltd.); Sulfonamide-containing indole cpds.. EP 1074542; JP 2000247949; WO 0050395 .
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) 44784 1-bromo-4-methyl-2-nitrobenzene 5326-34-1 C7H6BrNO2 详情 详情
(II) 16524 bromo(vinyl)magnesium 1826-67-1 C2H3BrMg 详情 详情
(III) 44717 7-bromo-4-methyl-1H-indole C9H8BrN 详情 详情
(IV) 44718 4-methyl-1H-indole-7-carboxylic acid C10H9NO2 详情 详情
(V) 44731 tert-butyl 4-methyl-1H-indol-7-ylcarbamate C14H18N2O2 详情 详情
(VI) 44734 tert-butyl 3-formyl-4-methyl-1H-indol-7-ylcarbamate C15H18N2O3 详情 详情
(VII) 44736 tert-butyl 3-cyano-4-methyl-1H-indol-7-ylcarbamate C15H17N3O2 详情 详情
(VIII) 44742 7-amino-4-methyl-1H-indole-3-carbonitrile C10H9N3 详情 详情
(IX) 44745 5-methyl-2-nitrophenylamine; 5-methyl-2-nitroaniline 578-46-1 C7H8N2O2 详情 详情
(X) 10362 ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate 609-14-3 C7H12O3 详情 详情
(XI) 44754 ethyl 2-[(E)-2-(5-methyl-2-nitrophenyl)hydrazono]propanoate C12H15N3O4 详情 详情
(XII) 44755 ethyl 4-methyl-7-nitro-1H-indole-2-carboxylate C12H12N2O4 详情 详情
(XIII) 44756 4-methyl-7-nitro-1H-indole-2-carboxylic acid C10H8N2O4 详情 详情
(XIV) 44757 4-methyl-7-nitro-1H-indole C9H8N2O2 详情 详情
(XV) 44760 4-methyl-7-nitro-1H-indole-3-carbaldehyde C10H8N2O3 详情 详情
(XVI) 44761 4-methyl-7-nitro-1H-indole-3-carbonitrile C10H7N3O2 详情 详情
Extended Information