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【结 构 式】 
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【药物名称】GYKI-14166, RGH-2958 【化学名称】D-Phenylalanyl-L-prolyl-L-argininal sulfate (1:1) 【CA登记号】83997-16-4, 77481-39-1 (diacetate), 77481-38-0 (diHCl), 60503-05-1 (free base) 【 分 子 式 】C20H32N6O7S 【 分 子 量 】500.57804 |
【开发单位】Gedeon Richter (Originator) 【药理作用】Anticoagulants, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Thrombin Inhibitors |
合成路线1
N2-tert-Butyloxycarbonyl-N5-benzyloxycarbonyl-L-arginine (I) is cyclized by treatment with isobutyloxycarbonyl chloride and N-methylmorpholine to the lactam (II). The tert-butyloxycarbonyl group is removed by hydrochloric acid to give the aminolactam (III), which is coupled with N-benzyloxycarbonyl-D-phenylalanyl-L-proline (IV) using, as in the first step, the mixed anhydride method. The resulting tripeptide lactam (V) is reduced with LiAlH4 to an aldehyde, present as the cyclic alpha-aminoalcohol (VI). Deblocking by hydrogenolysis gives RGH-2958. In solution the aldehyde group is either in the cyclic alpha-aminoalcohol form or is hydrated.
| 【1】 Rabloczky, Gy.; Bagdy, D.; Bajusz, S.; RGH-2958. Drugs Fut 1985, 10, 10, 829. |
| 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) | 29740 | N(5)-[[[(benzyloxy)carbonyl]amino](imino)methyl]-N(2)-(tert-butoxycarbonyl)ornithine | 51219-18-2 | C19H28N4O6 | 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) | 29741 | (2S)-1-((2R)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropanoyl)-2-pyrrolidinecarboxylic acid | 7669-64-9 | C22H24N2O5 | 详情 | 详情 |
| (V) | 29742 | benzyl (E)-amino[3-([[(2S)-1-((2R)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropanoyl)pyrrolidinyl]carbonyl]amino)-2-oxo-1-piperidinyl]methylidenecarbamate | C36H40N6O7 | 详情 | 详情 | |
| (VI) | 29743 | benzyl (E)-amino[3-([[(2S)-1-((2R)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropanoyl)pyrrolidinyl]carbonyl]amino)-2-hydroxy-1-piperidinyl]methylidenecarbamate | C36H42N6O7 | 详情 | 详情 |