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【结 构 式】 
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【分子编号】21016 【品名】(2R)-2-amino-3-(2-naphthyl)propionic acid; D-3-(2-Naphthyl)alanine 【CA登记号】76985-09-6 |
【 分 子 式 】C13H13NO2 【 分 子 量 】215.25176 【元素组成】C 72.54% H 6.09% N 6.51% O 14.87% |
合成路线1
该中间体在本合成路线中的序号：(I)The acylation of 3-(2-naphthyl)-D-alanine (I) with phenylacetyl chloride (II) and bis(trimethylsilyl)acetamide in THF gives the expected N-phenylacetyl derivative (III), which is methylated with NaH and methyl iodide in THF yielding the N-methyl derivative (IV). The reaction of (IV) with 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (WSC), HOBT and ammonium hydroxide affords the corresponding alaninamide (V), which by reaction with bis(trifluoroacetoxy)iodobenzene (BTI) in acetonitrile is converted into the monoacylated gemdiamine (VI). The condensation of (VI) with cis-2-(1H-indol-3-ylcarboxamido)cyclohexanecarboxylic acid (VII) by means of WSC and HOBT in DMF affords the target compound as a diastereomeric mixture that is separated by preparative RP-HPLC.
| 【1】 Sisto, A.; Fincham, C.; Potier, E.; Manzini, S.; Arcamone, F.; Lombardi, P. (Malesci Ist. Farmacobiol. SpA; Menarini Industrie Farma Riunite srl); Tachykinin antagonists. EP 0731790; JP 1997506348; US 5760248; WO 9515311 . |
| 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) | 21016 | (2R)-2-amino-3-(2-naphthyl)propionic acid; D-3-(2-Naphthyl)alanine | 76985-09-6 | C13H13NO2 | 详情 | 详情 |
| (II) | 25890 | 2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride | 103-80-0 | C8H7ClO | 详情 | 详情 |
| (III) | 25891 | (2R)-3-(2-naphthyl)-2-[(2-phenylacetyl)amino]propionic acid | C21H19NO3 | 详情 | 详情 | |
| (IV) | 25892 | (2R)-2-[methyl(2-phenylacetyl)amino]-3-(2-naphthyl)propionic acid | C22H21NO3 | 详情 | 详情 | |
| (V) | 25893 | (2R)-2-[methyl(2-phenylacetyl)amino]-3-(2-naphthyl)propanamide | C22H22N2O2 | 详情 | 详情 | |
| (VI) | 25894 | N-[(1R)-1-amino-2-(2-naphthyl)ethyl]-N-methyl-2-phenylacetamide | C21H22N2O | 详情 | 详情 | |
| (VII) | 25895 | (1R,2S)-2-[(1H-indol-3-ylcarbonyl)amino]cyclohexanecarboxylic acid | C16H18N2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)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 |