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【结 构 式】

【药物名称】ABT-510

【化学名称】N-Acetyl-N-methyl-glycyl-glycyl-L-valyl-D-alloisoleucyl-L-threonyl-L-norvalyl-L-isoleucyl-L-argininyl-L-proline N-ethylamide

【CA登记号】251579-55-2, 251579-56-3 (monotrifluoroacetate)

【 分 子 式 】C46H83N13O11

【 分 子 量 】994.25491

【开发单位】Abbott (Originator)

【药理作用】Lung Cancer Therapy, Lymphoma Therapy, Oncolytic Drugs, Renal Cancer Therapy, Angiogenesis Inhibitors

合成路线1合成路线2合成路线3合成路线4

合成路线1

The title compound is prepared by solid-phase peptide synthesis using an automatic peptide synthesizer. To the L-proline attached to the resin support (I) is coupled Fmoc-L-Arg(Pmc)-OH (II) under activation with HBTU/HOBt to produce the protected dipeptide resin (III). The N-Fmoc group of (III) is then removed by means of piperidine in DMF, yielding the deprotected amine (IV). Subsequent coupling with N-Fmoc-L-isoleucine (V), followed by deprotection with piperidine in DMF, leads to the tripeptide resin (VI). Further coupling/deprotection cycles with N-Fmoc-L-norvaline (VII) and N-Fmoc-O-t-butyl-L-threonine (IX) produce resins (VIII) and (X) respectively.

参考文献 中间体
【1】 Haviv, F.; Kalvin, D.M.; Henkin, J.; Bradley, M.F.; Schneider, A.J. (Abbott Laboratories Inc.); Peptide antiangiogenic drugs. JP 2002516342; WO 9961476 .
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) 16731 L-proline 147-85-3 C5H9NO2 详情 详情
(II) 49886 (2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]pentanoic acid C35H44N4O7S 详情 详情
(III) 61391 (2S)-1-{(2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-5-[(imino{[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino}methyl)amino]pentanoyl}-2-pyrrolidinecarboxylic acid C40H51N5O8S 详情 详情
(IV) 61392 (2S)-1-{(2S)-2-amino-5-[(imino{[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino}methyl)amino]pentanoyl}-2-pyrrolidinecarboxylic acid C25H41N5O6S 详情 详情
(V) 61393 (2S,3S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-methylpentanoic acid C21H23NO4 详情 详情
(VI) 61394 (2S)-1-{(2S)-2-{[(2S,3S)-2-amino-3-methylpentanoyl]amino}-5-[(imino{[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino}methyl)amino]pentanoyl}-2-pyrrolidinecarboxylic acid C31H52N6O7S 详情 详情
(VII) 61395 (2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}pentanoic acid C20H21NO4 详情 详情
(VIII) 61396 (2S)-1-{(2S)-2-[((2S,3S)-2-{[(2S)-2-aminopentanoyl]amino}-3-methylpentanoyl)amino]-5-[(imino{[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino}methyl)amino]pentanoyl}-2-pyrrolidinecarboxylic acid C36H61N7O8S 详情 详情
(IX) 61397 tert-butyl (2S,3R)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-hydroxybutanoate C23H27NO5 详情 详情
(X) 61398 (2S)-1-{(2S,5S,8S,11S,12R)-11-amino-2-{3-[(imino{[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino}methyl)amino]propyl}-12,14,14-trimethyl-5-[(1S)-1-methylpropyl]-4,7,10-trioxo-8-propyl-13-oxa-3,6,9-triazapentadec-1-anoyl}-2-pyrrolidinecarboxylic acid C44H76N8O10S 详情 详情

合成路线2

To the peptide resin (X) are sequentially coupled N-Fmoc-D-isoleucine (XI), N-Fmoc-L-valine (XIII), and N-Fmoc-glycine (XV) to produce - after the corresponding deprotection steps with piperidine in DMF- the peptide resins (XII), (XIV) and (XVI) respectively.

参考文献 中间体
【1】 Haviv, F.; Kalvin, D.M.; Henkin, J.; Bradley, M.F.; Schneider, A.J. (Abbott Laboratories Inc.); Peptide antiangiogenic drugs. JP 2002516342; WO 9961476 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 61398 (2S)-1-{(2S,5S,8S,11S,12R)-11-amino-2-{3-[(imino{[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino}methyl)amino]propyl}-12,14,14-trimethyl-5-[(1S)-1-methylpropyl]-4,7,10-trioxo-8-propyl-13-oxa-3,6,9-triazapentadec-1-anoyl}-2-pyrrolidinecarboxylic acid C44H76N8O10S 详情 详情
(XI) 49375 (2R,3S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-methylpentanoic acid C21H23NO4 详情 详情
(XII) 61399 (2S)-1-{(2S,5S,8S,11S,14R,15S)-14-amino-11-[(1R)-1-(tert-butoxy)ethyl]-2-{3-[(imino{[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino}methyl)amino]propyl}-15-methyl-5-[(1S)-1-methylpropyl]-4,7,10,13-tetraoxo-8-propyl-3,6,9,12-tetraazaheptadec-1-anoyl}-2-pyrrolidinecarboxylic acid C50H87N9O11S 详情 详情
(XIII) 19932 (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-methylbutyric acid C20H21NO4 详情 详情
(XIV) 61400 (2S)-1-{(2S,5S,8S,11S,14R,17S)-17-amino-11-[(1R)-1-(tert-butoxy)ethyl]-2-{3-[(imino{[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino}methyl)amino]propyl}-18-methyl-5,14-bis[(1S)-1-methylpropyl]-4,7,10,13,16-pentaoxo-8-propyl-3,6,9,12,15-pentaazanonadec-1-anoyl}-2-pyrrolidinecarboxylic acid C55H96N10O12S 详情 详情
(XV) 42131 2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]acetic acid 29022-11-5 C17H15NO4 详情 详情
(XVI) 61401 (2S)-1-{(2S,5S,8S,11S,14R,17S)-20-amino-11-[(1R)-1-(tert-butoxy)ethyl]-2-{3-[(imino{[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino}methyl)amino]propyl}-17-isopropyl-5,14-bis[(1S)-1-methylpropyl]-4,7,10,13,16,19-hexaoxo-8-propyl-3,6,9,12,15,18-hexaazaicos-1-anoyl}-2-pyrrolidinecarboxylic acid C57H99N11O13S 详情 详情

合成路线3

Coupling of resin (XVI) with N-Fmoc-sarcosine (XVII), followed by treatment with piperidine, provides (XVIII). This is treated with acetic acid and HBTU, producing the N-acetylated peptide resin (XIX). Cleavage of (XIX) from the resin in the presence of ethylamine leads to the side-chain protected peptide amide (XX).

参考文献 中间体
【1】 Haviv, F.; Kalvin, D.M.; Henkin, J.; Bradley, M.F.; Schneider, A.J. (Abbott Laboratories Inc.); Peptide antiangiogenic drugs. JP 2002516342; WO 9961476 .
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) 61401 (2S)-1-{(2S,5S,8S,11S,14R,17S)-20-amino-11-[(1R)-1-(tert-butoxy)ethyl]-2-{3-[(imino{[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino}methyl)amino]propyl}-17-isopropyl-5,14-bis[(1S)-1-methylpropyl]-4,7,10,13,16,19-hexaoxo-8-propyl-3,6,9,12,15,18-hexaazaicos-1-anoyl}-2-pyrrolidinecarboxylic acid C57H99N11O13S 详情 详情
(XVII) 52441 2-[{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}(methyl)amino]acetic acid C18H17NO4 详情 详情
(XVIII) 61402 (2S)-1-{(2S,5S,8S,11S,14R,17S)-11-[(1R)-1-(tert-butoxy)ethyl]-2-{3-[(imino{[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino}methyl)amino]propyl}-17-isopropyl-5,14-bis[(1S)-1-methylpropyl]-4,7,10,13,16,19,22-heptaoxo-8-propyl-3,6,9,12,15,18,21,24-octaazapentacos-1-anoyl}-2-pyrrolidinecarboxylic acid C60H104N12O14S 详情 详情
(XIX) 61403 (2S)-1-{(2S,5S,8S,11S,14R,17S)-11-[(1R)-1-(tert-butoxy)ethyl]-2-{3-[(imino{[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino}methyl)amino]propyl}-17-isopropyl-24-methyl-5,14-bis[(1S)-1-methylpropyl]-4,7,10,13,16,19,22,25-octaoxo-8-propyl-3,6,9,12,15,18,21,24-octaazahexacos-1-anoyl}-2-pyrrolidinecarboxylic acid C62H106N12O15S 详情 详情
(XX) 61404 (2S)-1-{(2S,5S,8S,11S,14R,17S)-11-[(1R)-1-(tert-butoxy)ethyl]-2-{3-[(imino{[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino}methyl)amino]propyl}-17-isopropyl-24-methyl-5,14-bis[(1S)-1-methylpropyl]-4,7,10,13,16,19,22,25-oc C64H111N13O14S 详情 详情

合成路线4

The side-chain O-tert-butyl and N-pentamethylchromansulfonyl protecting groups of peptide (XX) are finally removed by treatment with trifluoroacetic acid in the presence of thioanisole and ethanedithiol to furnish the deprotected peptide, which is then purified by preparative HPLC.

参考文献 中间体
【1】 Haviv, F.; Kalvin, D.M.; Henkin, J.; Bradley, M.F.; Schneider, A.J. (Abbott Laboratories Inc.); Peptide antiangiogenic drugs. JP 2002516342; WO 9961476 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XX) 61404 (2S)-1-{(2S,5S,8S,11S,14R,17S)-11-[(1R)-1-(tert-butoxy)ethyl]-2-{3-[(imino{[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino}methyl)amino]propyl}-17-isopropyl-24-methyl-5,14-bis[(1S)-1-methylpropyl]-4,7,10,13,16,19,22,25-oc C64H111N13O14S 详情 详情
Extended Information
Drug NewChemical Entity Original Patent(1)