【结 构 式】 |
【分子编号】20933 【品名】1-(3-butenyl)benzene 【CA登记号】768-56-9 |
【 分 子 式 】C10H12 【 分 子 量 】132.20528 【元素组成】C 90.85% H 9.15% |
合成路线1
该中间体在本合成路线中的序号:(XX)The reaction of 4-phenyl-1-butene (XX) with hypophosphorous acid gives 4-phenylbutylphosphinic acid (XXI), which is condensed with chloroacetic acid (XXII) yielding 2-[hydroxy(4-phenylbutyl)phosphoryl]acetic acid (XXIII). The esterifica-tion of (XXII) with benzyl alcohol affords the benzyl acetate (XXIV), which is esterified at the OH group of the phosphinic acid with 2-methyl-1-(propionyloxy)propyl chloride (XXV) giving the completely esterified derivative (XXVI). The debenzylation of (XXVI) with H2 over Pd/C yields the acetic acid derivative (XXVII), which is submitted to optical resolution affording the desired (S)-isomer (XXVIII). Finally, this compound is condensed with the desired intermediate trans-4-cyclohexyl-L-proline (XI) by means of CDI and NaOH.
【1】 Anderson, N.G.; et al.; Generation and fate of regioisomeric side-chain impurities in the preparation of fosinopril sodium. Org Process Res Dev 1997, 1, 4, 315. |
【2】 Anderson, N.G.; et al.; Process development for the preparation of a monopril intermediate by a trimethylsilyl-modified arbuzov reaction. Org Process Res Dev 1997, 1, 3, 211. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XI) | 38567 | (2S,4S)-4-cyclohexyl-2-pyrrolidinecarboxylic acid | C11H19NO2 | 详情 | 详情 | |
(XX) | 20933 | 1-(3-butenyl)benzene | 768-56-9 | C10H12 | 详情 | 详情 |
(XXI) | 20932 | 4-phenylbutylphosphinic acid | C10H15O2P | 详情 | 详情 | |
(XXII) | 11847 | 2-Chloroacetic acid; Chloroacetic Acid | 79-11-8 | C2H3ClO2 | 详情 | 详情 |
(XXIII) | 38575 | 2-[hydroxy(4-phenylbutyl)phosphoryl]acetic acid | C12H17O4P | 详情 | 详情 | |
(XXIV) | 38576 | 2-(benzyloxy)-2-oxoethyl(4-phenylbutyl)phosphinic acid | C19H23O4P | 详情 | 详情 | |
(XXV) | 38577 | 1-chloro-2-methylpropyl propionate | C7H13ClO2 | 详情 | 详情 | |
(XXVI) | 38578 | 1-[[[2-(benzyloxy)-2-oxoethyl](4-phenylbutyl)phosphoryl]oxy]-2-methylpropyl propionate | C26H35O6P | 详情 | 详情 | |
(XXVII) | 38579 | 2-[[2-methyl-1-(propionyloxy)propoxy](4-phenylbutyl)phosphoryl]acetic acid | C19H29O6P | 详情 | 详情 | |
(XXVIII) | 38580 | 2-[[[(1S)-2-methyl-1-(propionyloxy)propyl]oxy](4-phenylbutyl)phosphoryl]acetic acid | C19H29O6P | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(VII)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 |