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【结 构 式】 
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【药物名称】Ceronapril, Ceranapril, SQ-29852, Novopril 【化学名称】N-[(S)-6-Amino-2-[hydroxy(4-phenylbutyl)phosphinyloxy]-1-oxohexyl]-L-proline 【CA登记号】111223-26-8 【 分 子 式 】C21H33N2O6P 【 分 子 量 】440.48076 |
【开发单位】Bristol-Myers Squibb (Originator) 【药理作用】Antidepressants, CARDIOVASCULAR DRUGS, Cognition Disorders, Treatment of, Hypertension, Treatment of, Mood Disorders, Treatment of, NEUROLOGIC DRUGS, PSYCHOPHARMACOLOGIC DRUGS, Restenosis Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Angiotensin-I Converting Enzyme (ACE) Inhibitors |
合成路线1
This compound can be obtained by two related ways: 1) The reaction of L-lysine (I) with NaNO2 - H2SO4 in water gives 6-amino-2(S)-hydroxyhexanoic acid (II), which is protected with benzyl chloroformate as usual yielding the N-benzyloxycarbonyl compound (III). The condensation of (III) with L-proline benzyl ester (IV) by means of hydroxybenzotriazole (HBT) and dicyclohexylcarbodiimide (DCC) affords the acylated proline ester (V), which is esterified with 4-phenylbutylphosphonous acid (VI) by means of DCC and dimethylaminopyridine (DMAP), and oxidized with NaIO4 to give the protected phosphonic ester (VIII). Finally, this compound is debenzylated by hydrogenation of Pd/C in methanol. The phosphonous acid (VI) is obtained by reaction of 4-phenyl-1-butene (VII) with sodium hypophosphite by means of azobisisobutyronitrile (AIBN). 2) The condensation of acylated proline ester (V) with dibenzyl 4-phenylbutylphosphonate (IX) by means of PCl5, triethylamine and DMAP also gives the protected phosphonic ester (VIII). The dibenzyl phosphonate (IX) is obtained by condensation of 4-phenylbutyl chloride (X) with dibenzyl phosphite (XI) by means of NaH in DMF.
| 【1】 Karanewsky, D.S.; Petrillo, E.W. Jr. (E.R. Squibb & Sons, Inc.); Orally active phosphonyl hydroxyacyl prolines and processes for preparing phosphonyl hydroxyacyl prolines. AU 8666133; EP 0229520; JP 1987164691; US 4745196 . |
| 【2】 Prous, J.; Castaner, J.; SQ-29852. Drugs Fut 1989, 14, 6, 533. |
| 【3】 Powell, J.R.; Karanewsky, D.S.; Dejneka, T.; DeForrest, J.M.; Petrillo, E.W. Jr.; Perri, M.G.; Badia, M.C.; Loots, M.J.; Cushman, D.W.; (Phosphinyloxy)acyl amino acid inhibitors of angiotensin converting enzyme (ACE). 1. Discovery of (S)-1-[6-amino-2-[[hydroxy(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-proline, a novel orally acting inhibitor of ACE. J Med Chem 1988, 31, 1, 204. |
| 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) | 20927 | L-lysine | 56-87-1 | C6H14N2O2 | 详情 | 详情 |
| (II) | 20928 | (2S)-6-amino-2-hydroxyhexanoic acid | C6H13NO3 | 详情 | 详情 | |
| (III) | 20929 | (2S)-6-[[(benzyloxy)carbonyl]amino]-2-hydroxyhexanoic acid | C14H19NO5 | 详情 | 详情 | |
| (IV) | 20930 | benzyl (2S)-2-pyrrolidinecarboxylate | 16652-71-4 | C12H15NO2 | 详情 | 详情 |
| (V) | 20931 | benzyl (2S)-1-((2S)-6-[[(benzyloxy)carbonyl]amino]-2-hydroxyhexanoyl)-2-pyrrolidinecarboxylate | C26H32N2O6 | 详情 | 详情 | |
| (VI) | 20932 | 4-phenylbutylphosphinic acid | C10H15O2P | 详情 | 详情 | |
| (VII) | 20933 | 1-(3-butenyl)benzene | 768-56-9 | C10H12 | 详情 | 详情 |
| (VIII) | 20934 | benzyl (2S)-1-((2S)-6-[[(benzyloxy)carbonyl]amino]-2-[[hydroxy(4-phenylbutyl)phosphoryl]oxy]hexanoyl)-2-pyrrolidinecarboxylate | C36H45N2O8P | 详情 | 详情 | |
| (IX) | 20935 | dibenzyl 4-phenylbutylphosphonate | C24H27O3P | 详情 | 详情 | |
| (X) | 20936 | 1-(4-chlorobutyl)benzene | 4830-93-7 | C10H13Cl | 详情 | 详情 |
| (XI) | 12507 | dibenzyl phosphonate; Dibenzyl phosphite | 17176-77-1 | C14H15O3P | 详情 | 详情 |