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【结 构 式】 
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【分子编号】12507 【品名】dibenzyl phosphonate; Dibenzyl phosphite 【CA登记号】17176-77-1 |
【 分 子 式 】C14H15O3P 【 分 子 量 】262.245062 【元素组成】C 64.12% H 5.77% O 18.3% P 11.81% |
合成路线1
该中间体在本合成路线中的序号：(XI)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 |
合成路线2
该中间体在本合成路线中的序号：(IV)This compound can be obtained by two related ways: 1) The cyclization of 2-formyl-4-methyl-1,2,3,4-tetrahydroisoquinolone-3-carboxylic acid (I) with 2-chloro-5-hydroxy-1,4-naphthoquinone (II) by means of sodium acetate in hot acetic anhydride gives 9-hydroxy-14-methyl-5,8,13,14-tetrahydrobenz[5,6]isoindolo[2,1-b] isoquinoline-8,13-dione (III), which is condensed with dibenzyl phosphonate (IV) by means of N-chlorosuccinimide (NClS) and NaH in benzene to afford (14-methyl-8,13-dioxo-5,8,13,14-tetrahydrobenz[5,6]isoindolo[2,1-b] isoquinolin-9-yl)phosphoric acid dibenzyl ester (V). Finally, this compound is partially hydrolyzed with NaI in refluxing acetone, and the resulting sodium salt treated with aqueous HCl. 2) The condensation of 5-hydroxy-1,4-naphthoquinone (VI) with phosphonate (IV) by means of Cl2SO2 followed by a treatment with NaHCO3 gives (1,4-naphthoquinon-5-yl)phosphoric acid dibenzyl ester (VII), which is then cyclized with isoquinoline (I) in hot acetic anhydride to compound (V), already obtained.
| 【1】 Phillips, G.H.; Jones, P.S.; Cooper, M.E. (Glaxo Wellcome plc); Dioxobenz[5,6]isoindolo[2,1-b]isoquinoline derivs. AU 8776203; BE 1002110; CH 672489; DE 3725185; FR 2602233; JP 1988093783; JP 1990000187; US 4851399 . |
| 【2】 Phillips, G.H.; Cowley, B.R. (Glaxo Wellcome plc); Preparation of 5,8,13,14-tetrahydrobenz(5,6)isoindolo(2,1-b)isoquinolin-8,13-dione derivs. EP 0323907 . |
| 【3】 Castaner, J.; Pento, J.T.; Fosquidone. Drugs Fut 1993, 18, 10, 891. |
| 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) | 12504 | 2-Formyl-4-methyl-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid | C12H13NO3 | 详情 | 详情 | |
| (II) | 12505 | 2-Chloro-5-hydroxy-2,3-dihydro-1,4-naphthalenedione | C10H7ClO3 | 详情 | 详情 | |
| (III) | 12506 | 9-Hydroxy-14-methyl-5,14-dihydrobenzo[5,6]isoindolo[2,1-b]isoquinoline-8,13-dione | C21H15NO3 | 详情 | 详情 | |
| (IV) | 12507 | dibenzyl phosphonate; Dibenzyl phosphite | 17176-77-1 | C14H15O3P | 详情 | 详情 |
| (V) | 12508 | dibenzyl 14-methyl-8,13-dioxo-5,8,13,14-tetrahydrobenzo[5,6]isoindolo[2,1-b]isoquinolin-9-yl phosphate | C35H28NO6P | 详情 | 详情 | |
| (VI) | 63439 | 5-hydroxynaphthoquinone | C10H6O3 | 详情 | 详情 | |
| (VII) | 12510 | dibenzyl 5,8-dioxo-5,8-dihydro-1-naphthalenyl phosphate | C24H19O6P | 详情 | 详情 |