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【结 构 式】 
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【分子编号】17152 【品名】1H-Indole-3-carboxylic acid; Indole-3-Carboxylic acid; 3-Indolecarboxylic acid 【CA登记号】771-50-6 |
【 分 子 式 】C9H7NO2 【 分 子 量 】161.16012 【元素组成】C 67.08% H 4.38% N 8.69% O 19.86% |
合成路线1
该中间体在本合成路线中的序号：(IV)Alkylation of isonipecotamide (I) with n-butyl bromide in the presence of potassium carbonate gives the amide (II), which is reduced with lithium aluminum hydride to afford 1-butyl-4-piperidinylmethylamine (III). Conversion of indole-3-carboxylic acid (IV) to the acid chloride (V) is carried out with oxalyl chloride in dichloromethane containing N,N-dimethylformamide (DMF). Coupling of the amine (III) with the acid chloride (V) in dichloromethane in the presence of triethylamine gives N-[(1-butyl-4-piperidinyl)methyl]indole-3-carboxamide (VI). N-[(1-butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]-oxazino[3,2-a] indole-10-carboxamide (VIII) is formed by treatment of the amide (VI) with N-chlorosuccinimide in chloroform followed by reaction with 3-bromopropanol and cyclization of the intermediate ether (VII) with potassium carbonate in acetone. Conversion to N-[(1-butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a] indole-10-carboxamide hydrochloride (SB-207266) is effected by treatment of (VIII) with anhydrous HCl in ethanol.
| 【1】 Gaster, L.M.; Sanger, G.J.; SB-204070: 5-HT4 receptor antagonists and their potential therapeutic utility. Drugs Fut 1994, 19, 109-21. |
| 【2】 Ford, A.P.D.W.; Clarke, D.E.; The 5-HT4 receptor. Med Res Rev 1993, 13, 633-62. |
| 【3】 Gaster, L.; SB-207266A. Drugs Fut 1997, 22, 12, 1325. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12573 | 3-Bromo-1-propanol; 3-Bromopropanol | 627-18-9 | C3H7BrO | 详情 | 详情 | |
| (I) | 11762 | 4-Piperidinecarboxamide; Isonipecotamide | 39546-32-2 | C6H12N2O | 详情 | 详情 |
| (II) | 17150 | 1-butyl-4-piperidinecarboxamide | C10H20N2O | 详情 | 详情 | |
| (III) | 17151 | (1-butyl-4-piperidinyl)methanamine; (1-butyl-4-piperidinyl)methylamine | C10H22N2 | 详情 | 详情 | |
| (IV) | 17152 | 1H-Indole-3-carboxylic acid; Indole-3-Carboxylic acid; 3-Indolecarboxylic acid | 771-50-6 | C9H7NO2 | 详情 | 详情 |
| (V) | 17153 | 1H-indole-3-carbonyl chloride | C9H6ClNO | 详情 | 详情 | |
| (VI) | 17154 | N-[(1-butyl-4-piperidinyl)methyl]-1H-indole-3-carboxamide | C19H27N3O | 详情 | 详情 | |
| (VII) | 17155 | 2-(3-bromopropoxy)-N-[(1-butyl-4-piperidinyl)methyl]-1H-indole-3-carboxamide | C22H32BrN3O2 | 详情 | 详情 | |
| (VIII) | 17156 | N-[(1-butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide | C22H31N3O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)3-Indolylcarboxylic acid (I) was converted to acid chloride (II) with oxalyl chloride in refluxing CH2Cl2, and subsequently condensed with cis 1,2-cyclohexanediamine (III) to provide racemic amide (IV). Coupling of (4-methylphenyl)acetyl chloride (VI) with D-3-(2-naphthyl)alanine (V) was carried out via previous silylation of the amino acid with bis(trimethylsilyl)acetamide in THF. The resulting amide (VII) was N-alkylated with ICH3 in the presence of NaH to provide (VIII). Then, the chiral acyl amino acid (VIII) was coupled to racemic amine (IV) using 1-ethyl-3-(3-dimethylaminopropyl)- carbodiimide-HCl (EDC) and 7-aza-1-hydroxybenzotriazole (HOAt) to furnish the corresponding amide as a diastereomeric mixture, from which the desired isomer was isolated by reverse phase chromatography.
| 【1】 Potier, E.; Fincham, C.; Sisto, A.; Terracciano, R. (Menarini Industrie Farma Riunite srl); Pseudo-peptide cpds. as antagonists of neurokinines. WO 9845262 . |
| 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) | 17152 | 1H-Indole-3-carboxylic acid; Indole-3-Carboxylic acid; 3-Indolecarboxylic acid | 771-50-6 | C9H7NO2 | 详情 | 详情 |
| (II) | 17153 | 1H-indole-3-carbonyl chloride | C9H6ClNO | 详情 | 详情 | |
| (III) | 21014 | cis-1,2-Diaminocyclohexane; (1R,2S)-1,2-cyclohexanediamine; (1R,2S)-2-aminocyclohexylamine | 1436-59-5 | C6H14N2 | 详情 | 详情 |
| (IV) | 21015 | N-[(1S,2R)-2-aminocyclohexyl]-1H-indole-3-carboxamide | C15H19N3O | 详情 | 详情 | |
| (V) | 21016 | (2R)-2-amino-3-(2-naphthyl)propionic acid; D-3-(2-Naphthyl)alanine | 76985-09-6 | C13H13NO2 | 详情 | 详情 |
| (VI) | 21017 | 2-(4-methylphenyl)acetyl chloride | 35675-44-6 | C9H9ClO | 详情 | 详情 |
| (VII) | 21018 | (2R)-2-[[2-(4-methylphenyl)acetyl]amino]-3-(2-naphthyl)propionic acid | C22H21NO3 | 详情 | 详情 | |
| (VIII) | 21019 | (2R)-2-[methyl[2-(4-methylphenyl)acetyl]amino]-3-(2-naphthyl)propionic acid | C23H23NO3 | 详情 | 详情 |