4-phenylbutylphosphinic acid -Drug Synthesis Database

【结构式】

【分子编号】20932

【品名】4-phenylbutylphosphinic acid

【CA登记号】

【分子式】C₁₀H₁₅O₂P

【分子量】198.201662

【元素组成】C 60.6% H 7.63% O 16.14% P 15.63%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XXI)

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.

参考文献中间体

合成目标

【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：(VI)

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.

参考文献中间体

合成目标

【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

Extended Information