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【结 构 式】 
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【药物名称】Fosinopril sodium, SQ-28555, Tenso-stop, Eliten, Fositen, Fozitec, Monopril HCT, Dynacil, Fosinorm, Monopril, Staril 【化学名称】4(S)-Cyclohexyl-1-[2-[(R)-[2-methyl-1(S)-(1-propionyloxy)propoxy](4-phenylbutyl)phosphinyl]acetyl]-L-proline sodium salt 【CA登记号】88889-14-9, 98048-97-6 (free acid) 【 分 子 式 】C30H45NNaO7P 【 分 子 量 】585.65925 |
【开发单位】Bristol-Myers Squibb (Originator), Esteve (Licensee), Lipha (Licensee), Schwarz (Licensee) 【药理作用】CARDIOVASCULAR DRUGS, Heart Failure Therapy, Hypertension, Treatment of, Angiotensin-I Converting Enzyme (ACE) Inhibitors |
合成路线1
The reduction of L-pyroglutamic acid (I) with NaBH4 gives 5(S)-(hydroxymethyl)pyrrolidin-2-one (II), which is cyclized with benzaldehyde (III) by means of p-toluenesulfonic acid yielding the perhydropyrrolooxazolone (IV). The alkylation of (IV) with 2-cyclohexenyl bromide (V) and LDA in THF affords the corresponding cyclohexenyl derivative (VI), which is reduced with LiAlH4 in THF to give 1-benzyl-3(S)-(2-cyclohexenyl)-5(S)-(hydroxymethyl)pyrrolidine (VII). Elimination of the benzyl protecting group of (VII) with H2 over Pd/C yields the pyrrolidine (VIII), which is reprotected with benzyl chloroformate and K2CO3 to afford the carbamate (IX). The oxidation of the carbinol group of (IX) with Jones reagent or oxygen and platinum black gives the protected proline (X), which is finally deprotected with H2 over Pd/C providing the desired intermediate trans-4-cyclohexyl-L-proline (XI).
| 【1】 Thottathil, J.K.; et al.; Conversion of L-pyroglutamic acid to 4-alkyl substituted L-prolines. The synthesis of trans-4-cyclohexyl L-proline. J Org Chem 1986, 51, 16, 3140. |
| 【2】 Thottathil, J.K. (Bristol-Myers Squibb Co.); Process and intermediates for preparing trans-4-substd.-S-prolines. EP 0183390; US 4588819 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| (I) | 32046 | (3aR,4S,5R,6aS)-4-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-one | C29H40O7 | 详情 | 详情 | |
| (II) | 38560 | (5S)-5-(hydroxymethyl)-2-pyrrolidinone | 17342-08-4 | C5H9NO2 | 详情 | 详情 |
| (III) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (IV) | 38561 | (3R,7aS)-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one | 103201-79-2 | C12H13NO2 | 详情 | 详情 |
| (V) | 30800 | 3-bromo-1-cyclohexene | 1521-51-3 | C6H9Br | 详情 | 详情 |
| (VI) | 38562 | (3R,6S,7aS)-6-[(1S)-2-cyclohexen-1-yl]-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one | C18H21NO2 | 详情 | 详情 | |
| (VII) | 38563 | [(2S,4S)-1-benzyl-4-[(1S)-2-cyclohexen-1-yl]pyrrolidinyl]methanol | C18H25NO | 详情 | 详情 | |
| (VIII) | 38564 | [(2S,4S)-4-cyclohexylpyrrolidinyl]methanol; trans-4-cyhexyl-L-Proline | 90657-55-9 | C11H21NO | 详情 | 详情 |
| (IX) | 38565 | benzyl (2S,4S)-4-cyclohexyl-2-(hydroxymethyl)-1-pyrrolidinecarboxylate | C19H27NO3 | 详情 | 详情 | |
| (X) | 38566 | (2S,4S)-1-[(benzyloxy)carbonyl]-4-cyclohexyl-2-pyrrolidinecarboxylic acid | C19H25NO4 | 详情 | 详情 | |
| (XI) | 38567 | (2S,4S)-4-cyclohexyl-2-pyrrolidinecarboxylic acid | C11H19NO2 | 详情 | 详情 |
合成路线2
The protection of the NH group of trans-4-hydroxy-L-proline (XII) with tert-butoxycarbonyl anhydride and NaOH in tert-butanol/water gives the N-protected proline (XIII), which is esterified with benzyl alcohol and triethylamine to the benzyl ester (XIV). The tosylation of (XIV) with tosyl chloride and pyridine affords the tosylate (XV), which is debenzylated with H2 over Pd/C yielding the tosylated proline (XVI). The arylation of (XVI) with phenyllithium (XVII) and CuBr in ether/THF affords 1-(tert-butoxycarbonyl)-4(S)-phenyl)-L-proline (XVIII), which is deprotected with TFA in chloroform giving 4(S)-phenyl-L-proline (XIX). Finally, this compound is reduced with H2 over PtO2 in ethanol providing the desired intermediate trans-4-cyclohexyl-L-proline (XI).
| 【1】 Moniot, J.L.; Thottathil, J.K.; Littium diphenylcuprate reactions with 4-tosyloxy-L-prolines; An interesting stereochemical outcome. A synthesis of trans-4-phenyl-L-proline. Tetrahedron Lett 1986, 27, 2, 151. |
| 【2】 Floyd, D.; Thottathil, J.K.; Brandt, S.; Moniot, J.L. (Bristol-Myers Squibb Co.); Method for making substd. prolines. DE 3434121; US 4501901 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| (XI) | 38567 | (2S,4S)-4-cyclohexyl-2-pyrrolidinecarboxylic acid | C11H19NO2 | 详情 | 详情 | |
| (XII) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (XIII) | 16094 | (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid;1-(tert-butoxycarbonyl)-4®-hydroxy-L-proline;(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid | 16094 | C10H17NO5 | 详情 | 详情 |
| (XIV) | 38568 | 2-benzyl 1-(tert-butyl) (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate | C17H23NO5 | 详情 | 详情 | |
| (XV) | 38569 | 2-benzyl 1-(tert-butyl) (2S,4R)-4-[[(4-methylphenyl)sulfonyl]oxy]-1,2-pyrrolidinedicarboxylate | C24H29NO7S | 详情 | 详情 | |
| (XVI) | 38570 | (2S,4R)-1-(tert-butoxycarbonyl)-4-[[(4-methylphenyl)sulfonyl]oxy]-2-pyrrolidinecarboxylic acid | C17H23NO7S | 详情 | 详情 | |
| (XVII) | 24014 | Phenyllithium | 591-51-5 | C6H5Li | 详情 | 详情 |
| (XVIII) | 38571 | (2S,4S)-1-(tert-butoxycarbonyl)-4-phenyl-2-pyrrolidinecarboxylic acid | C16H21NO4 | 详情 | 详情 | |
| (XIX) | 38572 | (2S,4S)-4-phenyl-2-pyrrolidinecarboxylic acid | C11H13NO2 | 详情 | 详情 |
合成路线3
The Grignard condensation of N-(benzyloxycarbonyl)-4-oxo-L-proline (XXIX) with phenylmagnesium bromide gives the 4-hydroxy-4-phenylproline derivative (XXX), which is dehydrated with TFA yielding the dehydroproline (XXXI). The hydrogenation of (XXXI) with Li in liquid ammonia affords the previously reported trans-4-phenyl-L-proline (XIX), which is hydrogenated to the corresponding cyclohexyl derivative (XI) with H2 over PtO2.
| 【1】 Powell, J.R.; Cushman, D.W.; Krapcho, J.; Turk, C.; DeForrest, J.M.; Spitzmiller, E.R.; Karanewsky, D.S.; Duggan, M.; Rovnyak, G.; Schwartz, J.; et al.; Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines. J Med Chem 1988, 31, 6, 1148. |
| 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 | |
| (XIX) | 38572 | (2S,4S)-4-phenyl-2-pyrrolidinecarboxylic acid | C11H13NO2 | 详情 | 详情 | |
| (XXIX) | 11357 | (2S)-1-[(Benzyloxy)carbonyl]-4-oxotetrahydro-1H-pyrrole-2-carboxylic acid | C13H13NO5 | 详情 | 详情 | |
| (XXX) | 38573 | (2S,4S)-1-[(benzyloxy)carbonyl]-4-hydroxy-4-phenyl-2-pyrrolidinecarboxylic acid | C19H19NO5 | 详情 | 详情 | |
| (XXXI) | 38574 | (2S)-1-[(benzyloxy)carbonyl]-4-phenyl-2,5-dihydro-1H-pyrrole-2-carboxylic acid | C19H17NO4 | 详情 | 详情 |
合成路线4
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 |