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【结 构 式】

【分子编号】15063

【品名】(2S)-2-amino-N-benzyl-N-methyl-3-(2-naphthyl)propanamide

【CA登记号】

【 分 子 式 】C21H22N2O

【 分 子 量 】318.41856

【元素组成】C 79.21% H 6.96% N 8.8% O 5.02%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(IV)

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:(IV)

The reaction of N-(tert-butoxycarbonyl)-L-(2-naphthyl)alanine (I) with N-methylbenzyamine (II) by means of isobutyl chloroformate and NMM in dichloromethane gives the corresponding amide (III), which is deprotected with HCl in dioxane yielding (IV) with a free amino group. Finally, this compound is condensed with 1-[N-(2-nitrophenyl)carbamoyl]-L-proline (V) by means of HOBT and DCC in THF. The intermediate 1-[N-(2-nitrophenyl)carbamoyl]-L-proline (V) has been obtained by reaction of L-proline (VI) with 2-nitrophenyl isocyanate (VII) by means of NMM in THF/water.

1 Prashad, M.; et al.; Process development of (2-nitrophenylcarbamoyl)-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzyl-N-methylamide (SDZ NKT343). Org Process Res Dev 1999, 3, 6, 409.
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) 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
(II) 11969 N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine 103-67-3 C8H11N 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) 32772 (2S)-1-[(2-nitroanilino)carbonyl]-2-pyrrolidinecarboxylic acid C12H13N3O5 详情 详情
(VI) 16731 L-proline 147-85-3 C5H9NO2 详情 详情
(VII) 32771 1-isocyanato-2-nitrobenzene; 2-nitrophenyl isocyanate 3320-86-3 C7H4N2O3 详情 详情
Extended Information