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【结 构 式】 
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【药物名称】LY-178207(free base), GYKI-14451 【化学名称】tert-Butyloxycarbonyl-D-phenylalanyl-L-prolyl-L-arginine aldehyde sulfate (2:1) 【CA登记号】69201-89-4 (free base) 【 分 子 式 】C50H78N12O14S 【 分 子 量 】1103.31516 |
【开发单位】Gedeon Richter (Originator), Lilly (Originator) 【药理作用】Antiplatelet Therapy, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS |
合成路线1
N2-tert-Butoxycarbonyl-N6-benzyloxycarbonyl-L-arginine (I) is converted by treatment with isobutyl oxycarbonyl chloride (A) and N-methylmorpholine (B) to the lactam (II), and the tert-butoxycarbonyl group is cleaved off to give the aminolactam (III), which is coupled with N-tert-butoxycarbonyl-D-phenylalanyl-L-proline (IV) to the tripeptide (V) using the mixed anhydride method as in the first step. The lactam carbonyl is reduced with LiAlH4 to an aldehyde group present as the cyclic a aminoalcohol (VI). Removal of the benzyloxycarbonyl blocking group provides GYKI-14451. In solution the aldehyde group is either in the cyclic alpha-aminoalcohol form or is hydrated.
| 【1】 Voutilainen, S.; Valkonen, V.P.; Venho, B.; et al.; Magy Kem Lapja 1982, 27, 2, 358-365. |
| 【2】 Bajusz, S.; Szell, E.; Barabas, E.; Bagdy, D. (Gedeon Richter Ltd.); D-Phenylalanyl-L-prolyl-L-arginine aldehyde sulfate and process for the preparation thereof. DE 3200812; FR 2497799; GB 2091270; JP 57181046; US 4399065; US 4478745 . |
| 【3】 Nogradi, M.; GYKI-14451. Drugs Fut 1985, 10, 1, 23. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 13423 | 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate | 543-27-1 | C5H9ClO2 | 详情 | 详情 |
| (B) | 28928 | 4-methylmorpholine | 109-02-4 | C5H11NO | 详情 | 详情 |
| (I) | 28927 | tert-butyl 3-[(amino[[(benzyloxy)carbonyl]imino]methyl)amino]propylcarbamate | C17H26N4O4 | 详情 | 详情 | |
| (II) | 28933 | tert-butyl 1-(amino[[(benzyloxy)carbonyl]imino]methyl)-2-oxo-3-piperidinylcarbamate | C19H26N4O5 | 详情 | 详情 | |
| (III) | 28929 | benzyl (E)-amino(3-amino-2-oxo-1-piperidinyl)methylidenecarbamate | C14H18N4O3 | 详情 | 详情 | |
| (IV) | 28932 | (2S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl]-2-pyrrolidinecarboxylic acid | C19H26N2O5 | 详情 | 详情 | |
| (V) | 28930 | tert-butyl (1R)-2-[(2S)-2-([[1-(amino[[(benzyloxy)carbonyl]imino]methyl)-2-oxo-3-piperidinyl]amino]carbonyl)pyrrolidinyl]-1-benzyl-2-oxoethylcarbamate | C33H42N6O7 | 详情 | 详情 | |
| (VI) | 28931 | tert-butyl (1R)-2-[(2S)-2-([[1-(amino[[(benzyloxy)carbonyl]imino]methyl)-2-hydroxy-3-piperidinyl]amino]carbonyl)pyrrolidinyl]-1-benzyl-2-oxoethylcarbamate | C33H44N6O7 | 详情 | 详情 |