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【结 构 式】 
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【药物名称】LY-426410 【化学名称】2-Methylalanyl-N-[1-[1(R)-(4-methoxyphenyl)-2-(4-methyl-1-piperidinyl)-2-oxoethyl]-1H-imidazol-4-yl]-O-benzyl-D-serinamide 【CA登记号】220529-82-8 (stereoisomer) 【 分 子 式 】C32H42N6O5 【 分 子 量 】590.72874 |
【开发单位】Lilly (Originator) 【药理作用】ENDOCRINE DRUGS, Pituitary Disorder Therapy, Treatment of Growth Hormone Deficiency, Treatment of Growth Hormone Secretion Disorders, Growth Hormone Secretagogues |
合成路线1
Treatment of N-Boc-D-serine benzyl ether (I) with methyl iodide and NaHCO3 provided methyl ester (II). Subsequent acid cleavage of the Boc group of (II) gave aminoester (III), which was coupled with N-Boc-alpha-aminoisobutyric acid (IV) to afford dipeptide (V). The methyl ester group of (V) was then hydrolyzed to acid (VI) using LiOH.
| 【1】 Growth hormone secretagogues. EP 0933365; WO 9908699 . |
| 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) | 28112 | (2R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid | C15H21NO5 | 详情 | 详情 | |
| (II) | 28100 | methyl (2R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoate | C16H23NO5 | 详情 | 详情 | |
| (III) | 28101 | methyl (2R)-2-amino-3-(benzyloxy)propanoate | C11H15NO3 | 详情 | 详情 | |
| (IV) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (V) | 28102 | methyl (2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propanoate | C20H30N2O6 | 详情 | 详情 | |
| (VI) | 28103 | (2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propionic acid | C19H28N2O6 | 详情 | 详情 |
合成路线2
4-Methoxyphenylacetic acid (VII) was esterified with EtOH and p-toluenesulfonic acid. The resulting ethyl ester (VIII) was brominated by means of N-bromosuccinimide to produce bromoester (IX), which was condensed with 4-nitroimidazole (X) yielding (XI). Reduction of the nitro group of (XI) by catalytic hydrogenation over Pd/C gave amine (XII). This was coupled with acid (VI) by means of EDC and HOBt to afford amide (XIII). Then, hydrolysis of the methyl ester of (XIII) with LiOH gave rise to carboxylic acid (XIV). Finally, coupling of (XIV) with 4-methylpiperidine (XV) generated the title compound.
| 【1】 Growth hormone secretagogues. EP 0933365; WO 9908699 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 28103 | (2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propionic acid | C19H28N2O6 | 详情 | 详情 | |
| (VII) | 34793 | 2-(4-methoxyphenyl)acetic acid; p-Methoxyphenyl formate; Homoanisic acid; p-Methyl benzyl formate; 4-methoxyphenylacetic acid; 4-methoxybenzeneacetic acid; p-methoxyphenylacetic acid | 104-01-8 | C9H10O3 | 详情 | 详情 |
| (VIII) | 38805 | methyl 2-(4-methoxyphenyl)acetate | 23786-14-3 | C10H12O3 | 详情 | 详情 |
| (IX) | 38806 | methyl 2-bromo-2-(4-methoxyphenyl)acetate | C10H11BrO3 | 详情 | 详情 | |
| (X) | 35764 | 4-nitro-1H-imidazole | 3034-38-6 | C3H3N3O2 | 详情 | 详情 |
| (XI) | 38807 | methyl 2-(4-methoxyphenyl)-2-(4-nitro-1H-imidazol-1-yl)acetate | C13H13N3O5 | 详情 | 详情 | |
| (XII) | 38808 | methyl 2-(4-amino-1H-imidazol-1-yl)-2-(4-methoxyphenyl)acetate | C13H15N3O3 | 详情 | 详情 | |
| (XIII) | 38809 | methyl 2-(4-[[(2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propanoyl]amino]-1H-imidazol-1-yl)-2-(4-methoxyphenyl)acetate | C32H41N5O8 | 详情 | 详情 | |
| (XIV) | 38810 | 2-(4-[[(2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propanoyl]amino]-1H-imidazol-1-yl)-2-(4-methoxyphenyl)acetic acid | C31H39N5O8 | 详情 | 详情 | |
| (XV) | 10192 | 4-Methylpiperidine; gamma-Pipecoline | 626-58-4 | C6H13N | 详情 | 详情 |