【药物名称】FK-888
化学结构式(Chemical Structure):
参考文献No.15754
标题:Peptides having tachykinin antagonist activity, a process for preparation thereof and pharmaceutical compsns. comprising the same
作者:Matsuo, M.; Hagiwara, D.; Miyake, H. (Fujisawa Pharmaceutical Co., Ltd.)
来源:EP 0443132; JP 1992210996; US 5468731
合成路线图解说明:

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.

参考文献No.261342
标题:Studies on neurokinin antagonists. 4. Synthesis and structure-activity relationships of novel dipeptide substance P antagonists
作者:Hagiwara, D.; Miyake, H.; Igari, N.; Karino, M.; Maeda, Y.; Fujii, T.; Matsuo, M.
来源:J Med Chem 1994,37(13),2090-9
合成路线图解说明:

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.

参考文献No.402904
标题:FK-888
作者:Leeson, P.A.; Rabasseda, X.; Casta馿r, J.
来源:Drugs Fut 1997,22(4),353
合成路线图解说明:

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.

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