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【结 构 式】 
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【药物名称】 【化学名称】1-[1-(Ntau-Methyl-L-histidyl-O-methyl-D-tyrosyl)-4-phenylpiperidin-4-yl]butan-1-one 【CA登记号】457893-92-4 【 分 子 式 】C32H41N5O4 【 分 子 量 】559.71467 |
【开发单位】Bristol-Myers Squibb (Originator) 【药理作用】Antiarthritic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Melanocortin MC1 Agonists |
合成路线1
The title compound has been synthesized by two related methods. Coupling of N-Boc-L-methylhistidine (I) with D-4-methoxyphenylalanine methyl ester (II) employing EDC/HOBt affords the protected dipeptide (III). Subsequent saponification of the methyl ester (III) leads to carboxylic acid (IV). This is then coupled to 4-butyryl-4-phenylpiperidine (V) to furnish amide (VI). Finally, acidic cleavage of the N-Boc protecting group of (VI) provides the title compound.
| 【1】 Poindexter, G.S.; Ruediger, E.H.; Ruel, R.; Lawrence, R.M.; Yu, G.; Macor, J.; Morton, G.C.; Thibault, C.; Herpin, T. (Bristol-Myers Squibb Co.); Cpds. useful as modulators of melanocortin receptors and pharmaceutical compsns. comprising same. EP 1363631; EP 1363898; WO 0270511; WO 0279146 . |
| 【2】 Macor, J.E.; Carlson, K.E. (Bristol-Myers Squibb Co.); Co-administration of melanocortin receptor agonists and phosphodiesterase inhibitor for treatment of cyclic-AMP associated disorders. WO 0269905 . |
| 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) | 63382 | N-{[(1,1-dimethylethyl)oxy]carbonyl}-1-methylhistidine | C12H19N3O4 | 详情 | 详情 | |
| (II) | 32454 | methyl (2S)-2-amino-3-(4-methoxyphenyl)propanoate | C11H15NO3 | 详情 | 详情 | |
| (III) | 63383 | methyl 2-{[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-(1-methyl-1H-imidazol-5-yl)propanoyl]amino}-3-[4-(methyloxy)phenyl]propanoate | C23H32N4O6 | 详情 | 详情 | |
| (IV) | 63384 | N-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-(1-methyl-1H-imidazol-5-yl)propanoyl]-4-(methyloxy)phenylalanine | C22H30N4O6 | 详情 | 详情 | |
| (V) | 63385 | 1-(4-phenyl-4-piperidinyl)-1-butanone | C15H21NO | 详情 | 详情 | |
| (VI) | 63386 | 1,1-dimethylethyl 2-[(2-(4-butanoyl-4-phenyl-1-piperidinyl)-1-{[4-(methyloxy)phenyl]methyl}-2-oxoethyl)amino]-1-[(1-methyl-1H-imidazol-5-yl)methyl]-2-oxoethylcarbamate | C37H49N5O6 | 详情 | 详情 |
合成路线2
Similarly, N-Boc-D-4-methoxyphenylalanine (I) is coupled to 4-butyryl-4-phenylpiperidine (II), yielding amide (III). After acidic Boc group cleavage in (III), the resultant amine (IV) is acylated by N-Boc-L-methylhistidine (V) to provide the dipeptide amide (VI). The N-Boc protecting group of (VI) is finally removed employing trifluoroacetic acid.
| 【1】 Herpin, T.F.; Yu, G.; Carlson, K.E.; Morton, G.C.; Wu, X.; Kang, L.; Tuerdi, H.; Khanna, A.; Tokarski, J.S.; Lawrence, R.M.; Macor, J.E.; Discovery of tyrosine-based potent and selective melanocortin-1 receptor small-molecule agonists with anti-inflammatory properties. J Med Chem 2003, 46, 7, 1123. |
| 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) | 16875 | (2S)-2-[(tert-Butoxycarbonyl)amino]-3-(4-methoxyphenyl)propionic acid; N-t-BOC-O-Methyl-L-tyrosine | 53267-93-9 | C15H21NO5 | 详情 | 详情 |
| (II) | 63385 | 1-(4-phenyl-4-piperidinyl)-1-butanone | C15H21NO | 详情 | 详情 | |
| (III) | 63387 | 1,1-dimethylethyl 2-(4-butanoyl-4-phenyl-1-piperidinyl)-1-{[4-(methyloxy)phenyl]methyl}-2-oxoethylcarbamate | C30H40N2O5 | 详情 | 详情 | |
| (IV) | 63388 | 1-(1-{2-amino-3-[4-(methyloxy)phenyl]propanoyl}-4-phenyl-4-piperidinyl)-1-butanone | C25H32N2O3 | 详情 | 详情 | |
| (V) | 63382 | N-{[(1,1-dimethylethyl)oxy]carbonyl}-1-methylhistidine | C12H19N3O4 | 详情 | 详情 | |
| (VI) | 63386 | 1,1-dimethylethyl 2-[(2-(4-butanoyl-4-phenyl-1-piperidinyl)-1-{[4-(methyloxy)phenyl]methyl}-2-oxoethyl)amino]-1-[(1-methyl-1H-imidazol-5-yl)methyl]-2-oxoethylcarbamate | C37H49N5O6 | 详情 | 详情 |