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【结 构 式】 
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【分子编号】16094 【品名】(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 【CA登记号】16094 |
【 分 子 式 】C10H17NO5 【 分 子 量 】231.24872 【元素组成】C 51.94% H 7.41% N 6.06% O 34.59% |
合成路线1
该中间体在本合成路线中的序号：(XVI)Coupling of primary amine (XI) with 1-(tert-butoxycarbonyl)-4(R)-hydroxy-L-proline (XVI) by means of HATU and DIEA in CH2Cl2 gives dipeptide (XVII), which is treated with TFA in CH2Cl2 to provide the deprotected dipeptide (XVIII). Condensation of peptide (XVIII) with N-(tert-butoxycarbonyl)-3-methyl-L-valine (XIX) using HATU and DIEA in CH2Cl2 affords tripeptide (XX), which is finally condensed with 1,7-dichloro-4-methoxyisoquinoline (XXI) in the presence of LaCl3 and t-BuOK in DMF (1).
1,7-Dichloro-4-methoxyisoquinoline (XXI) is obtained by cyclization of 3-(4-chlorophenyl)-3-methoxyacrylic acid (XXII) with (PhO)2PON3 by means of of Et3N in benzene, resulting in 7-chloro-4-methoxyisoquinolin-1(2H)-one (XXIII), which is then chlorinated with POCl3 in refluxing DMF .
| 【1】 Campbell, J.A., Wang, X.A., Sin, N. et al. (Bristol-Myers Squibb Co.). Hepatitis C virus inhibitors. EP 1505963, EP 2340830, JP 2005533028, KR 2010093140, US 200410659, US 6995174, US 2011311482, WO 200309974. |
| 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) | 68243 | tert-butyl ((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamate hydrochloride | C14H22N2O5S.HCl | 详情 | 详情 | |
| (XVI) | 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 |
| (XVII) | 68248 | (2S,4R)-tert-butyl 2-(((1S,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylate | C19H29N3O7S | 详情 | 详情 | |
| (XVIII) | 68247 | (2S,4R)-N-((1S,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-4-hydroxypyrrolidine-2-carboxamide 2,2,2-trifluoroacetate | C14H21N3O5S.C2HF3O2 | 详情 | 详情 | |
| (XIX) | 22251 | (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyric acid;2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid;N-(tert-butoxycarbonyl)-3-methyl-L-valine | 62965-35-9 | C11H21NO4 | 详情 | 详情 |
| (XX) | 68246 | tert-butyl (1-((2S,4R)-2-(((1S,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate | C25H40N4O8S | 详情 | 详情 | |
| (XXI) | 68249 | 1,7-dichloro-4-methoxyisoquinoline | C10H7Cl2NO | 详情 | 详情 | |
| (XXII) | 68250 | 3-(4-chlorophenyl)-3-methoxyacrylic acid | C10H9ClO3 | 详情 | 详情 | |
| (XXIII) | 68251 | 7-chloro-4-methoxyisoquinolin-1(2H)-one | C10H8ClNO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVI)Alternatively, condensation of 1,7-dichloro-4-methoxyisoquinoline (XXI) with 1-(tert-butoxycarbonyl)-4(R)-hydroxy-L-proline (XVI) in the presence of t-BuOK in DMSO gives 1-(tert-butoxycarbonyl)-4(R)-[(7-chloro-4-methoxyisoquinolin-1-yl)oxy]-L-proline (XXIV), which is then coupled with 1(R)-amino-2(S)-vinylcyclopropanecarboxamide (XI) by means of EDC, HOBt and DIEA , or HATU and DIEA in CH2Cl2 , to yield the corresponding dipeptide derivative (XXV). NBoc cleavage by means of HCl in i-PrOH (1) or refluxing MeOH provides amine hydrochloride (XXVI), which is finally condensed with N-(tert-butoxycarbonyl)-3-methyl-L-valine (XIX) using HATU and DIEA in .
| 【1】 Perrone, R.K., Wang, C., Ying, W., Song, A.I. (Bristol-Myers Squibb Co.).Crystalline forms of N-(tert-butoxycarbonyl)-3-methyl-L-valyl-(4R)-4-((7-cholor-4-methoxy-1-isoquino linyl)oxy)-N-((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-L-prolinamide. CN 101903371, EP 2231639, JP 2011507869, KR 2010099703, WO 2009085659. |
| 【2】 Sun, L.Q., Wang, A.X., Chen, J. et al. Design and optimization of a series of potent and novel HCV NS3 protease inhibitors leading to the discovery of BMS-650032. 241st ACS Natl Meet (March 27-30, Anaheim) 2011, Abst MEDI 73. |
| 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) | 68243 | tert-butyl ((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamate hydrochloride | C14H22N2O5S.HCl | 详情 | 详情 | |
| (XVI) | 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 |
| (XIX) | 22251 | (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyric acid;2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid;N-(tert-butoxycarbonyl)-3-methyl-L-valine | 62965-35-9 | C11H21NO4 | 详情 | 详情 |
| (XXI) | 68249 | 1,7-dichloro-4-methoxyisoquinoline | C10H7Cl2NO | 详情 | 详情 | |
| (XXIV) | 68254 | 1-(tert-butoxycarbonyl)-4(R)-[(7-chloro-4-methoxyisoquinolin-1-yl)oxy]-L-proline;(2S,4R)-1-(tert-butoxycarbonyl)-4-((7-chloro-4-methoxyisoquinolin-1-yl)oxy)pyrrolidine-2-carboxylic acid | C20H23ClN2O6 | 详情 | 详情 | |
| (XXV) | 68253 | (2S,4R)-tert-butyl 4-((7-chloro-4-methoxyisoquinolin-1-yl)oxy)-2-(((1S,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidine-1-carboxylate | C29H35ClN4O8S | 详情 | 详情 | |
| (XXVI) | 68252 | (2S,4R)-4-((7-chloro-4-methoxyisoquinolin-1-yl)oxy)-N-((1S,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)pyrrolidine-2-carboxamide hydrochloride | C24H27ClN4O6S.HCl | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIII)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4
该中间体在本合成路线中的序号：(V)The protection of the amino group of L-(2-naphthyl)alanine (I) with di-tert-butyl dicarbonate and triethylamine gives N-tert-butoxycarbonyl-L-(2-naphthyl)alanine (II), which is amidated with benzylmethylamine by means of hydroxybenzotriazole (HOBT) and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (WSC) in dichloromethane yielding N-tert-butoxycarbonyl-L-(2-naphthyl)alanine N-benzyl-N-methylamide (III). Elimination of the tert-butoxycarbonyl group of (III) with HCl in dioxane affords L-(2-naphthyl)alanine N-benzyl-N-methylamide (IV), which is condensed with N-(tert-butoxycarbonyl)-[4(R)-hydroxy]-L-proline (V) by means of HOBT an WSC as before giving the protected dipeptide (VI). Elimination of the protecting group of (VI) with HCl in dioxane as before yields the dipeptide (VII) with the free amino group, which is finally acylated with 1-methylindole-3-carboxylic acid (VIII) by means of HOBT and WSC as before.
| 【1】 Leeson, P.A.; Rabasseda, X.; Castaner, J.; FK-888. Drugs Fut 1997, 22, 4, 353. |
| 【2】 Matsuo, M.; Hagiwara, D.; Miyake, H. (Fujisawa Pharmaceutical Co., Ltd.); Peptides having tachykinin antagonist activity, a process for preparation thereof and pharmaceutical compsns. comprising the same. EP 0443132; JP 1992210996; US 5468731 . |
| 【3】 Hagiwara, D.; Miyake, H.; Igari, N.; Karino, M.; Maeda, Y.; Fujii, T.; Matsuo, M.; Studies on neurokinin antagonists. 4. Synthesis and structure-activity relationships of novel dipeptide substance P antagonists. J Med Chem 1994, 37, 13, 2090-9. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11975 | Ethyl (E)-3-amino-2-butenoate | 7318-00-5 | C6H11NO2 | 详情 | 详情 | |
| (I) | 15060 | L-3-(2-Naphthyl)alanine; (S)-2-amino-3-(2-naphthyl)propionic acid | 58438-03-2 | C13H13NO2 | 详情 | 详情 |
| (II) | 15061 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-naphthyl)propionic acid; N-T-BOC-L-3-(2-NAPHTHYL)ALANINE | 58438-04-3 | C18H21NO4 | 详情 | 详情 |
| (III) | 15062 | tert-butyl N-[(1S)-2-[benzyl(methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl]carbamate | C26H30N2O3 | 详情 | 详情 | |
| (IV) | 15063 | (2S)-2-amino-N-benzyl-N-methyl-3-(2-naphthyl)propanamide | C21H22N2O | 详情 | 详情 | |
| (V) | 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 |
| (VI) | 15065 | tert-butyl (2S,4R)-2-([[(1S)-2-[benzyl(methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl]amino]carbonyl)-4-hydroxy-1-pyrrolidinecarboxylate | C31H37N3O5 | 详情 | 详情 | |
| (VII) | 15066 | (2S,4R)-N-[(1S)-2-[benzyl(methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl]-4-hydroxytetrahydro-1H-pyrrole-2-carboxamide | C26H29N3O3 | 详情 | 详情 | |
| (VIII) | 15067 | 1-methyl-1H-indole-3-carboxylic acid; N-Methylindole-3-carboxylic acid | 32387-21-6 | C10H9NO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)A new synthesis of S-4661 has been reported: The protection of trans-4-hydroxy-L-proline with tert-butoxycarbonyl anhydride gives N-(tert-butoxycarbonyl)-4(R)-hydroxy-L-proline (II), which is successively treated with ethyl chloroformate, mesylated with mesyl chloride and reduced with NaBH4 yielding (2S,4R)-1-(tert-butoxycarbonyl)-2-(hydroxymethyl)-4-(methanesulfonyloxy)pyrrolidine (III). The reaction of (III) with potassium thioacetate affords Compound (IV), which is condensed with N-(tert-butoxycarbonyl)sulfamide (V) by means of diethyl azodicarboxylate and triphenylphosphine to give the protected pyrrolidinesulfamide (VI). The deacetylation of (VI) with sodium methoxide yields (2S,4S)-1-(tert-butoxycarbonyl)-2-[N-(tert-butoxycarbonyl)-N-sulfamoylaminomethyl]-4-sulfanylpyrrolidine (VII), which is then condensed with (1R,5S,6S)-2-(diphenoxyphosphoryloxy)-6-[1(R)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid diphenylmethyl ester (VIII) by means of diisopropylethylamine to afford the protected final product (IX). Finally, this compound is deprotected with AlCl3 in anisole.
| 【1】 Motokawa, K.; Nishitani, Y.; Iso, Y.; Kii, M.; Irie, T.; Sendo, Y.; Iwaki, T.; Synthesis and modification of a novel 1beta-methyl carbapenem antibiotic, S-4661. J Antibiot 1996, 49, 5, 478. |
| 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) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (II) | 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 |
| (III) | 16095 | tert-butyl (2S,4R)-2-(hydroxymethyl)-4-[(methylsulfonyl)oxy]tetrahydro-1H-pyrrole-1-carboxylate | C11H21NO6S | 详情 | 详情 | |
| (IV) | 16096 | tert-butyl (2S,4S)-4-(acetylsulfanyl)-2-(hydroxymethyl)tetrahydro-1H-pyrrole-1-carboxylate | C12H21NO4S | 详情 | 详情 | |
| (V) | 16097 | tert-butyl 2,2-dioxo-2lambda(6)-diazathiane-1-carboxylate | 148017-28-1 | C5H12N2O4S | 详情 | 详情 |
| (VI) | 16098 | tert-butyl (2S,4S)-4-(acetylsulfanyl)-2-[[(aminosulfonyl)(tert-butoxycarbonyl)amino]methyl]tetrahydro-1H-pyrrole-1-carboxylate | C17H31N3O7S2 | 详情 | 详情 | |
| (VII) | 16099 | tert-butyl (2S,4S)-2-[[(aminosulfonyl)(tert-butoxycarbonyl)amino]methyl]-4-sulfanyltetrahydro-1H-pyrrole-1-carboxylate | C15H29N3O6S2 | 详情 | 详情 | |
| (VIII) | 16100 | benzhydryl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C35H32NO8P | 详情 | 详情 | |
| (IX) | 16101 | benzhydryl (4R,5S,6S)-3-[[(3S,5S)-5-[[(aminosulfonyl)(tert-butoxycarbonyl)amino]methyl]-1-(tert-butoxycarbonyl)pyrrolidinyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C38H50N4O10S2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)Alkylation of N-Boc-4-(R)-hydroxyproline (I) with 2-(bromomethyl)-naphthalene (II) in the presence of NaH afforded the (naphthylmethyl) ether (III). N-Boc-norvaline (IV) was converted to the benzyl ester (V) by treatment with benzyl bromide and DBU. Subsequent acid cleavage of the Boc group of (V) yielded norvaline benzyl ester (VI). This was coupled with proline derivative (III) using HATU to give the protected dipeptide (VII).
| 【1】 Rancourt, J.; Tsantrizos, Y.; Simoneau, B.; Wernic, D.; Poupart, M.-A.; Llinas-Brunet, M. (Boehringer Ingelheim (Canada) Ltd.); Hepatitis C inhibitor peptides. EP 1003775; WO 9907733 . |
| 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 | |
| (I) | 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 |
| (II) | 35612 | 2-(bromomethyl)naphthalene | 939-26-4 | C11H9Br | 详情 | 详情 |
| (III) | 35613 | (2S,4R)-1-(tert-butoxycarbonyl)-4-(2-naphthylmethoxy)-2-pyrrolidinecarboxylic acid | C21H25NO5 | 详情 | 详情 | |
| (IV) | 35614 | (2S)-2-[(tert-butoxycarbonyl)amino]pentanoic acid | 53308-95-5 | C10H19NO4 | 详情 | 详情 |
| (V) | 35615 | benzyl (2S)-2-[(tert-butoxycarbonyl)amino]pentanoate | C17H25NO4 | 详情 | 详情 | |
| (VI) | 35616 | benzyl (2S)-2-aminopentanoate | C12H17NO2 | 详情 | 详情 | |
| (VII) | 35617 | tert-butyl (2S,4R)-2-[([(1S)-1-[(benzyloxy)carbonyl]butyl]amino)carbonyl]-4-(2-naphthylmethoxy)-1-pyrrolidinecarboxylate | C33H40N2O6 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XII)To the peptide resin (XI) was coupled N-Boc-trans-4-hydroxy-L-proline (XII) to produce resin (XIII). Simultaneous removal of the N-terminal and side-chain protecting groups of (XIII) with trifluoroacetic acid in CH2Cl2 furnished the deprotected peptide resin (XIV). Acylation of (XIV) with the mono-fluorenylmethyl ester of glutaric acid (XV) produced amide (XVI). The desired peptide (XVII) was then liberated from the resin (XVI) employing HF in the presence of anisole.
| 【2】 Garsky, V.M.; Feng, D.-M.; DeFeo-Jones, D. (Merck & Co., Inc.); Conjugates useful in the treatment of prostate cancer. JP 2000509407; WO 9818493 . |
| 【3】 Oliff, A.I.; Jones, R.E.; Defeo-Jones, D. (Merck & Co., Inc.); A method of treating cancer. WO 0059930 . |
| 【1】 Feng, D.-M.; Wai, J.; Ramjit, H.G.; Sardana, M.K.; Lumma, P.K.; DeFeo-Jones, D.; Jones, R.E.; Freidinger, R.M.; Oliff, A.; Garsky, V.M.; The synthesis of a prodrug of doxorubicin designed to provide reduced systemic toxicity and greater target efficacy. J Med Chem 2001, 44, 24, 4216. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI),(XVII) | 53673 | (3S,6S,9S,12S,15S,18S)-12-(3-amino-3-oxopropyl)-9-cyclohexyl-1-{(2S,4R)-1-[5-(9H-fluoren-9-ylmethoxy)-5-oxopentanoyl]-4-hydroxypyrrolidinyl}-6,15-bis(hydroxymethyl)-18-isobutyl-3-methyl-1,4,7,10,13,16-hexaoxo-2,5,8,11,14,17-hexaazanonadecan-19-oic acid | n/a | C52H72N8O15 | 详情 | 详情 |
| (XI) | 53669 | (2S,5S,8S,11S,14S)-14-{[(2S)-2-aminopropanoyl]amino}-5-(tert-butoxymethyl)-11-cyclohexyl-2-isobutyl-17,17-dimethyl-4,7,10,13-tetraoxo-8-[3-oxo-3-(tritylamino)propyl]-16-oxa-3,6,9,12-tetraazaoctadecan-1-oic acid | n/a | C55H79N7O10 | 详情 | 详情 |
| (XII) | 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 |
| (XIII) | 53670 | (3S,6S,9S,12S,15S,18S)-1-[(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidinyl]-6,15-bis(tert-butoxymethyl)-9-cyclohexyl-18-isobutyl-3-methyl-1,4,7,10,13,16-hexaoxo-12-[3-oxo-3-(tritylamino)propyl]-2,5,8,11,14,17-hexaazanonadecan-19-oic acid | n/a | C65H94N8O14 | 详情 | 详情 |
| (XIV) | 53671 | (3S,6S,9S,12S,15S,18S)-12-(3-amino-3-oxopropyl)-9-cyclohexyl-6,15-bis(hydroxymethyl)-1-[(2S,4R)-4-hydroxypyrrolidinyl]-18-isobutyl-3-methyl-1,4,7,10,13,16-hexaoxo-2,5,8,11,14,17-hexaazanonadecan-19-oic acid | n/a | C33H56N8O12 | 详情 | 详情 |
| (XV) | 53680 | 5-(9H-fluoren-9-ylmethoxy)-5-oxopentanoic acid | n/a | C19H18O4 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XII)The synthesis of the precursor peptide (XVII) was also reported in solution phase. trans-4-Hydroxy-L-proline (XX) was protected as the N-Boc derivative (XII), which was subsequently activated as the pentafluorophenyl ester (XXI). This was condensed with the dipeptide alanyl-serine (XXII) to furnish the protected tripeptide (XXIII). Acidic cleavage of the Boc protecting group of (XXIII) yielded tripeptide (XXIV).
| 【1】 Kaufman, M.J.; Almarsson, O.; Nerurkar, M.J.; Lynch, J.E.; Karki, S.B.; Cameron, M.; Lieberman, D.R.; Robbins, M.A.; Shi, Y.-J. (Merck & Co., Inc.); Salt form of a conjugate useful in the treatment of prostate cancer. US 6355611; WO 0130804 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 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 |
| (XX) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (XXI) | 53675 | 1-(tert-butyl) 2-(2,3,4,5,6-pentafluorophenyl) (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate | n/a | C16H16F5NO5 | 详情 | 详情 |
| (XXII) | 53676 | (2S)-2-{[(2S)-2-aminopropanoyl]amino}-3-hydroxypropanoic acid | n/a | C6H12N2O4 | 详情 | 详情 |
| (XXIII) | 53677 | (2S)-2-{[(2S)-2-({[(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidinyl]carbonyl}amino)propanoyl]amino}-3-hydroxypropanoic acid | n/a | C16H27N3O8 | 详情 | 详情 |
| (XXIV) | 53678 | (2S)-3-hydroxy-2-{[(2S)-2-({[(2S,4R)-4-hydroxypyrrolidinyl]carbonyl}amino)propanoyl]amino}propanoic acid | n/a | C11H19N3O6 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(V)Condensation of N-Boc-4-hydroxyproline (V) with dimethylamine using BOP as the coupling reagent furnished amide (VI). The N-Boc protecting group of (VI) was then removed under acidic conditions to yield prolinaminde (VII). Alkylation of (VII) with the chloro oxindole (IV) produced the N-indolyl proline derivative (VIII) as a mixture of diastereoisomers, separable by column chromatography. Finally, indole N acylation in (VIII) by means of 2,4-dimethoxybenzenesulfonyl chloride (IX) in the presence of NaH furnished the target sulfonamide.
| 【1】 Wagnon, J.; Tonnerre, B.; Roux, R.; Serradeil-Le Gal, C. (Sanofi-Synthelabo); Novel 1,3-dihydro-2H-indol-2-one derivs., preparation method and pharmaceutical compsns. containing them. EP 1255751; FR 2804114; WO 0155130 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 56073 | 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one | C15H11Cl2NO2 | 详情 | 详情 | |
| (V) | 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 |
| (VI) | 56074 | tert-butyl (2S,4R)-2-[(dimethylamino)carbonyl]-4-hydroxy-1-pyrrolidinecarboxylate | C12H22N2O4 | 详情 | 详情 | |
| (VII) | 56075 | (2S,4R)-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide | C7H14N2O2 | 详情 | 详情 | |
| (VIII) | 56076 | (2S,4R)-1-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide | C22H24ClN3O4 | 详情 | 详情 | |
| (IX) | 56077 | 2,4-dimethoxybenzenesulfonyl chloride | C8H9ClO4S | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(XIV)Tripeptide derivative (VIII) is obtained by coupling of N-Boc-4(R)-hydroxy-L-proline (XIV) with methyl 1(R)-amino-2(S)-vinylcyclopropanecarboxylate (Vb) by means of TBTU and DIEA in DMF to afford amide (XV). Subsequent Mitsunobu condensation of alcohol (XV) with p-nitrobenzoic acid (PNBA) in the presence of PPh3 and DEAD in THF gives the fully protected dipeptide (XVI), from which the N-Boc group is removed by treatment with HCl in dioxane, yielding the corresponding amine (XVII) . Coupling of dipeptide ester (XVII) with N-(cyclopentyloxycarbonyl)-3-methyl-L-valine (XVIII) [prepared by condensation of cyclopentyl succinimidyl carbonate (XX) with 3-methyl-L-valine (XIX) by means of Et3N in THF/H2O in the presence of TBTU and DIEA in CH2Cl2 provides tripeptide derivative (XXI), which by selective hydrolysis of the PNB ester (XXI) by means of LiOH in H2O/THF produces the tripeptide derivative (VIII) .
| 【3】 Bhardwaj, P., Forgione, P., Goudreau, N. et al. (Boehringer Ingelheim International GmbH). Hepatitis C inhibitor compounds. EP 1654261, JP 2006528937, JP 2010043129, US 2005020503, US 2011177030, US 8067438, WO 2004103996. |
| 【1】 Llinas-Brunet, M., Bailey, M.D., Goudreau, N. et al. Discovery of a potent and selective noncovalent linear inhibitor of the hepatitis C virus NS3 protease (BI 201335). J Med Chem 2010, 53(17): 6466-76. |
| 【2】 Llinas-Brunet, M., Bailey, M., Bhardwaj, P. et al. (Boehringer Ingelheim International GmbH & Co. KG). Hepatitis C inhibitor compounds. US 7585845. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Vb) | 68460 | (1R,2R)-methyl 1-amino-2-vinylcyclopropanecarboxylate | C7H11NO2 | 详情 | 详情 | |
| (VIII) | 68436 | (1S,2R)-methyl 1-((2R,4R)-1-(2-(((cyclopentyloxy)carbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate | C24H37N3O7 | 详情 | 详情 | |
| (XIV) | 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 |
| (XV) | 68440 | (4S)-tert-butyl 4-hydroxy-2-(((1R,2S)-1-(methoxycarbonyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidine-1-carboxylate | C17H26N2O6 | 详情 | 详情 | |
| (XVI) | 68441 | (2S,4R)-tert-butyl 2-(((1R,2S)-1-(methoxycarbonyl)-2-vinylcyclopropyl)carbamoyl)-4-((4-nitrobenzyl)oxy)pyrrolidine-1-carboxylate | C24H31N3O8 | 详情 | 详情 | |
| (XVII) | 68439 | (1R,2S)-methyl 1-((2R,4R)-4-((4-nitrobenzyl)oxy)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate hydrochloride | C19H23N3O6.HCl | 详情 | 详情 | |
| (XVIII) | 68442 | 2-(((cyclopentyloxy)carbonyl)amino)-3,3-dimethylbutanoic acid;N-(cyclopentyloxycarbonyl)-3-methyl-L-valine | C12H21NO4 | 详情 | 详情 | |
| (XIX) | 28445 | (2S)-2-amino-3,3-dimethylbutyric acid | C6H13NO2 | 详情 | 详情 | |
| (XX) | 68443 | cyclopentyl succinimidyl carbonate;N-(Cyclopentyloxycarbonyloxy)succinimide;1-[[(cyclopentyloxy)carbonyl]oxy]-2,5-Pyrrolidinedione | 128595-07-3 | C10H13NO5 | 详情 | 详情 |
| (XXI) | 68437 | (1R,2S)-methyl 1-((2S,4R)-1-(2-(((cyclopentyloxy)carbonyl)amino)-3,3-dimethylbutanoyl)-4-((4-nitrobenzyl)oxy)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate | C31H42N4O9 | 详情 | 详情 |