【结 构 式】 |
【药物名称】Efegatran sulfate hydrate, LY-294468, GYKI-14766 【化学名称】N-Methyl-D-phenylalanyl-L-prolyl-L-arginal sulfate hydrate 【CA登记号】126721-07-1, 105806-66-4 (anhydrous), 105806-65-3 (anhydrous free base) 【 分 子 式 】C21H36N6O8S 【 分 子 量 】532.62047 |
【开发单位】Gedeon Richter (Originator), Institute for Drug Research (Originator), Lilly (Licensee) 【药理作用】Anticoagulants, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Thrombin Inhibitors |
合成路线1
The synthesis of GYKI-14766 is as follows: N2-tert-Butoxycarbonyl-L-arginine (I) was converted to the N6-benzyloxycarbonyl derivative (II). Treatment of (II) with isobutoxycarbonyl chloride and N-methylmorpholine gave the aminolactam (III). Dicyclohexylcarbodiimide-mediated esterification of N-benzyloxycarbonyl-D-phenylalanine (IV) with 2,4,5-trichlorophenol gave the active ester (V), which was coupled with L-proline to the dipeptide (VI). Methylation with iodomethane afforded the N-methyl derivative isolated as the cyclohexylamine salt (VII). The fragments (III) and (VII) were coupled via the mixed anhydride of (VII), generated as in the case of (II), giving the tripeptide lactam (VIII). Reduction with lithium aluminum hydride at low temperature converted (VIII) to the aldehyde (IX), which was finally deprotected to the end product.
【1】 Nogradi, M.; GYKI-14766. Drugs Fut 1992, 17, 12, 1087. |
【2】 Széll, E.; Bagdy, D.; Bajusz, S.; et al.; Highly active and selective anticoagulants: D-Phe-Pro-Arg-H, a free tripeptide aldehyde prone to spontaneous inactivation and its stable N-methyl derivative, D-MePhe-Pro-Arg-H. J Med Chem 1990, 33, 6, 1729-35. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
16126 | 2,4,5-trichlorophenol | 95-95-4 | C6H3Cl3O | 详情 | 详情 | |
(I) | 14073 | (2S)-5-[[Amino(imino)methyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid | 13726-76-6 | C11H22N4O4 | 详情 | 详情 |
(II) | 14074 | (2S)-5-[(Amino[[(benzyloxy)carbonyl]imino]methyl)amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid | C19H28N4O6 | 详情 | 详情 | |
(III) | 14075 | tert-butyl N-[(3S)-1-(amino[[(benzyloxy)carbonyl]imino]methyl)-2-oxotetrahydro-3(2H)-pyridinyl]carbamate | C19H26N4O5 | 详情 | 详情 | |
(IV) | 14076 | (2R)-3-Phenyl-2-[[(2-phenylacetyl)oxy]amino]propionic acid | C17H17NO4 | 详情 | 详情 | |
(V) | 14077 | 2,4,5-trichlorophenyl (2R)-3-phenyl-2-[[(2-phenylacetyl)oxy]amino]propanoate | C23H18Cl3NO4 | 详情 | 详情 | |
(VI) | 14078 | (2S)-1-((2R)-3-Phenyl-2-[[(2-phenylacetyl)oxy]amino]propanoyl)tetrahydro-1H-pyrrole-2-carboxylic acid | C22H24N2O5 | 详情 | 详情 | |
(VII) | 14079 | (2R)-1-((2S)-2-[[(Cyclohexylamino)oxy]carbonyl]pyrrolidinyl)-2-[methyl[(2-phenylacetyl)oxy]amino]-3-phenyl-1-propanone | C29H37N3O5 | 详情 | 详情 | |
(VIII) | 14080 | tert-butyl (1R)-2-((2S)-2-[[((3S)-1-[amino[(tert-butoxycarbonyl)imino]methyl]-2-oxopiperidinyl)amino]carbonyl]pyrrolidinyl)-1-benzyl-2-oxoethyl(methyl)carbamate | C31H46N6O7 | 详情 | 详情 | |
(IX) | 14081 | tert-butyl (E)-amino[((4S)-4-[[((2S)-1-[(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-phenylpropanoyl]pyrrolidinyl)carbonyl]amino]-5-oxopentyl)amino]methylidenecarbamate | C31H48N6O7 | 详情 | 详情 |