【结 构 式】 |
【药物名称】MEN-11467 【化学名称】N-[2-(4-Methylphenyl)acetyl]-N-methyl-(3-naphthyl)-L-alanine N-[2-(1H-indol-3-ylcarboxamido)cyclohexyl]amide 【CA登记号】 【 分 子 式 】C38H40N4O3 【 分 子 量 】600.7675 |
【开发单位】Menarini (Originator) 【药理作用】Asthma Therapy, Chronic Obstructive Pulmonary Diseases (COPD), Treatment of, RESPIRATORY DRUGS, Tachykinin NK1 Antagonists |
合成路线1
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 |