|
【结 构 式】 
|
【分子编号】15067 【品名】1-methyl-1H-indole-3-carboxylic acid; N-Methylindole-3-carboxylic acid 【CA登记号】32387-21-6 |
【 分 子 式 】C10H9NO2 【 分 子 量 】175.187 【元素组成】C 68.56% H 5.18% N 8% O 18.27% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The protection of the amino group of L-(2-naphthyl)alanine (I) with di-tert-butyl dicarbonate and triethylamine gives N-tert-butoxycarbonyl-L-(2-naphthyl)alanine (II), which is amidated with benzylmethylamine by means of hydroxybenzotriazole (HOBT) and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (WSC) in dichloromethane yielding N-tert-butoxycarbonyl-L-(2-naphthyl)alanine N-benzyl-N-methylamide (III). Elimination of the tert-butoxycarbonyl group of (III) with HCl in dioxane affords L-(2-naphthyl)alanine N-benzyl-N-methylamide (IV), which is condensed with N-(tert-butoxycarbonyl)-[4(R)-hydroxy]-L-proline (V) by means of HOBT an WSC as before giving the protected dipeptide (VI). Elimination of the protecting group of (VI) with HCl in dioxane as before yields the dipeptide (VII) with the free amino group, which is finally acylated with 1-methylindole-3-carboxylic acid (VIII) by means of HOBT and WSC as before.
| 【1】 Leeson, P.A.; Rabasseda, X.; Castaner, J.; FK-888. Drugs Fut 1997, 22, 4, 353. |
| 【2】 Matsuo, M.; Hagiwara, D.; Miyake, H. (Fujisawa Pharmaceutical Co., Ltd.); Peptides having tachykinin antagonist activity, a process for preparation thereof and pharmaceutical compsns. comprising the same. EP 0443132; JP 1992210996; US 5468731 . |
| 【3】 Hagiwara, D.; Miyake, H.; Igari, N.; Karino, M.; Maeda, Y.; Fujii, T.; Matsuo, M.; Studies on neurokinin antagonists. 4. Synthesis and structure-activity relationships of novel dipeptide substance P antagonists. J Med Chem 1994, 37, 13, 2090-9. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11975 | Ethyl (E)-3-amino-2-butenoate | 7318-00-5 | C6H11NO2 | 详情 | 详情 | |
| (I) | 15060 | L-3-(2-Naphthyl)alanine; (S)-2-amino-3-(2-naphthyl)propionic acid | 58438-03-2 | C13H13NO2 | 详情 | 详情 |
| (II) | 15061 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-naphthyl)propionic acid; N-T-BOC-L-3-(2-NAPHTHYL)ALANINE | 58438-04-3 | C18H21NO4 | 详情 | 详情 |
| (III) | 15062 | tert-butyl N-[(1S)-2-[benzyl(methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl]carbamate | C26H30N2O3 | 详情 | 详情 | |
| (IV) | 15063 | (2S)-2-amino-N-benzyl-N-methyl-3-(2-naphthyl)propanamide | C21H22N2O | 详情 | 详情 | |
| (V) | 16094 | (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid;1-(tert-butoxycarbonyl)-4®-hydroxy-L-proline;(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid | 16094 | C10H17NO5 | 详情 | 详情 |
| (VI) | 15065 | tert-butyl (2S,4R)-2-([[(1S)-2-[benzyl(methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl]amino]carbonyl)-4-hydroxy-1-pyrrolidinecarboxylate | C31H37N3O5 | 详情 | 详情 | |
| (VII) | 15066 | (2S,4R)-N-[(1S)-2-[benzyl(methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl]-4-hydroxytetrahydro-1H-pyrrole-2-carboxamide | C26H29N3O3 | 详情 | 详情 | |
| (VIII) | 15067 | 1-methyl-1H-indole-3-carboxylic acid; N-Methylindole-3-carboxylic acid | 32387-21-6 | C10H9NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)1-Benzyl-4-(aminomethyl)piperidine (I) was protected at the primary amino group as the Boc derivative (II) and the N-benzyl group was subsequently removed by transfer hydrogenolysis with hydrazine and Pd/C to give piperidine (III). Alkylation of (III) with N-(5-bromopentyl)phthalimide (IV) afforded (V), which was subjected to hydrazinolysis of the phthalimido group, yielding primary amine (VI). Coupling of (VI) with 1-methylindole-3-carboxylic acid (VII) by means of EDC and HOBt gave rise to amide (VIII). The Boc protecting group of (VIII) was then cleaved by acidic treatment to furnish amine (IX). Finally, coupling of (IX) with 4-amino-5-chloro-2-methoxybenzoic acid (X) provided the title benzamide.
| 【1】 Haga, K.; Tomozane, H.; Sato, N.; Kawakita, T.; Itoh, K.; Sonda, S.; Asano, K.; Fujimura, M.; Hakira, H.; Synthesis and pharmacological properties of novel benzamide derivatives acting as ligands to the 5-hydroxytryptamine 4 (5-HT4) receptor. Eur J Med Chem 1999, 34, 12, 1101. |
| 【2】 Kawakita, T.; Hakira, H.; Haga, K.; Murozono, T.; Kuroita, T. (Welfide Corporation); Benzoic acid cpd. and use thereof as medicine. EP 0774460; WO 9526953 . |
| 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) | 37901 | (1-benzyl-4-piperidinyl)methylamine; (1-benzyl-4-piperidinyl)methanamine | C13H20N2 | 详情 | 详情 | |
| (II) | 37902 | tert-butyl (1-benzyl-4-piperidinyl)methylcarbamate | C18H28N2O2 | 详情 | 详情 | |
| (III) | 37903 | tert-butyl 4-piperidinylmethylcarbamate | C11H22N2O2 | 详情 | 详情 | |
| (IV) | 37904 | 2-(5-bromopentyl)-1H-isoindole-1,3(2H)-dione | 954-81-4 | C13H14BrNO2 | 详情 | 详情 |
| (V) | 37905 | tert-butyl [1-[5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentyl]-4-piperidinyl]methylcarbamate | C24H35N3O4 | 详情 | 详情 | |
| (VI) | 37906 | tert-butyl [1-(5-aminopentyl)-4-piperidinyl]methylcarbamate | C16H33N3O2 | 详情 | 详情 | |
| (VII) | 15067 | 1-methyl-1H-indole-3-carboxylic acid; N-Methylindole-3-carboxylic acid | 32387-21-6 | C10H9NO2 | 详情 | 详情 |
| (VIII) | 37907 | tert-butyl [1-(5-[[(1-methyl-1H-indol-3-yl)carbonyl]amino]pentyl)-4-piperidinyl]methylcarbamate | C26H40N4O3 | 详情 | 详情 | |
| (IX) | 37908 | N-[5-[4-(aminomethyl)-1-piperidinyl]pentyl]-1-methyl-1H-indole-3-carboxamide | C21H32N4O | 详情 | 详情 | |
| (X) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |