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【结 构 式】

【药物名称】Kahalalide F, PM-92102

【化学名称】5-Methylhexanoyl-D-valyl-L-threonyl-L-valyl-D-valyl-D-prolyl-L-ornithyl-D-alloisoleucyl-D-allothreonyl-D-alloisoleucyl-D-valyl-L-phenylalanyl-[2-amino-2(Z)-butenoyl]-L-valine C-1.13-O-3.8-lactone

【CA登记号】149204-42-2

【 分 子 式 】C75H124N14O16

【 分 子 量 】1477.90873

【开发单位】PharmaMar (Originator)

【药理作用】Liver Cancer Therapy, Oncolytic Drugs, Prostate Cancer Therapy

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 anchoring of Fmoc-D-Val-OH (I) to Cl-TrtCl-RESIN (II) by means of DIEA, followed by cleavage of the Fmoc protecting group with piperidine in DMF, gives the resin-bonded valine (III), which is submitted to successive deprotection/coupling cycles with Fmoc-D-allo-Ile-OH (IV), Fmoc-D-allo-Thr-OH (VI) and again Fmoc-D-allo-Ile-OH (IV) to yield peptide resins (V), (VII) and (VIII), respectively. The coupling of Alloc-L-Val-OH (IX) to the free OH group of the Thr amino acid of peptide resin (VII) by means of DIPCDI and DMAP affords peptide resin (X), which is submitted to successive deprotection/coupling cycles with Fmoc-L-Orn(Boc)-OH (XI), Fmoc-D-Pro-OH (XIII) and Fmoc-D-Val-OH (I) to provide peptide resins (XII), (XIV) and (XV), respectively.

参考文献 中间体
【1】 Royo, M.; Manzanares, I.; Lopez, A.; Jimenez, J.C.; Albericio, F.; Giralt, E.; Rodrigues, I. (PharmaMar, SA); Kahalalide cpds.. WO 0158934 .
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) 43354 (2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-methylbutyric acid C20H21NO4 详情 详情
(III) 49374 (2-chlorophenyl)(diphenyl)methyl (2R)-2-amino-3-methylbutanoate C24H24ClNO2 详情 详情
(IV) 49375 (2R,3S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-methylpentanoic acid C21H23NO4 详情 详情
(V) 49376 (2-chlorophenyl)(diphenyl)methyl (2R)-2-[[(2R,3S)-2-amino-3-methylpentanoyl]amino]-3-methylbutanoate C30H35ClN2O3 详情 详情
(VI) 49377 (2R,3R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-hydroxybutyric acid C19H19NO5 详情 详情
(VII) 49378 (2-chlorophenyl)(diphenyl)methyl (2R)-2-[((2R,3S)-2-[[(2R,3R)-2-amino-3-hydroxybutanoyl]amino]-3-methylpentanoyl)amino]-3-methylbutanoate C34H42ClN3O5 详情 详情
(VIII) 49379 (2-chlorophenyl)(diphenyl)methyl (5R,8R,11R,14R)-1-(9H-fluoren-9-yl)-8-[(1R)-1-hydroxyethyl]-14-isopropyl-5,11-bis[(1S)-1-methylpropyl]-3,6,9,12-tetraoxo-2-oxa-4,7,10,13-tetraazapentadecan-15-oate C55H63ClN4O8 详情 详情
(IX) 49380 (2S)-2-[[(allyloxy)carbonyl]amino]-3-methylbutyric acid C9H15NO4 详情 详情
(X) 49381 (2-chlorophenyl)(diphenyl)methyl (2R,5R,8R,9R,12S)-8-[[(2R,3S)-2-amino-3-methylpentanoyl]amino]-2,12-diisopropyl-9-methyl-5-[(1S)-1-methylpropyl]-4,7,11,14-tetraoxo-10,15-dioxa-3,6,13-triaza-17-octadecen-1-oate C49H66ClN5O9 详情 详情
(XI) 49382 (2S)-5-[(tert-butoxycarbonyl)amino]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]pentanoic acid C25H30N2O6 详情 详情
(XII) 49383 (2-chlorophenyl)(diphenyl)methyl (9S,12R,15R,18R,21R)-15-[(1R)-1-[((2S)-2-[[(allyloxy)carbonyl]amino]-3-methylbutanoyl)oxy]ethyl]-9-amino-21-isopropyl-2,2-dimethyl-12,18-bis[(1S)-1-methylpropyl]-4,10,13,16,19-pentaoxo-3-oxa-5,11,14,17,20-pentaazadoc C59H84ClN7O12 详情 详情
(XIII) 34762 (2S)-1-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-pyrrolidinecarboxylic acid 71989-31-6 C20H19NO4 详情 详情
(XIV) 49384 (2-chlorophenyl)(diphenyl)methyl (9S,12R,15R,18R,21R)-15-[(1R)-1-[((2S)-2-[[(allyloxy)carbonyl]amino]-3-methylbutanoyl)oxy]ethyl]-21-isopropyl-2,2-dimethyl-12,18-bis[(1S)-1-methylpropyl]-4,10,13,16,19-pentaoxo-9-[(2-pyrrolidinylcarbonyl)amino]-3-oxa-5,11,14,17,20-pentaazadocosan-22-oate C64H91ClN8O13 详情 详情
(XV) 49385 (2-chlorophenyl)(diphenyl)methyl (9S,12R,15R,18R,21R)-15-[(1R)-1-[((2S)-2-[[(allyloxy)carbonyl]amino]-3-methylbutanoyl)oxy]ethyl]-9-[([1-[(2R)-2-amino-3-methylbutanoyl]-2-pyrrolidinyl]carbonyl)amino]-21-isopropyl-2,2-dimethyl-12,18-bis[(1S)-1-methylpropyl]-4,10,13,16,19-pentaoxo-3-oxa-5,11,14,17,20-pentaazadocosan-22-oate C69H100ClN9O14 详情 详情

合成路线2

Successive deprotection/coupling cycles of peptide resin (XV) with Fmoc-L-Val-OH (XVI), Fmoc-L-Thr(tBu)-OH (XVIII), Fmoc-D-Val-OH (I) and 5-methylhexanoic acid (XXI) give peptide resins (XVII), (XIX), (XX) and (XXII), respectively.

参考文献 中间体
【1】 Royo, M.; Manzanares, I.; Lopez, A.; Jimenez, J.C.; Albericio, F.; Giralt, E.; Rodrigues, I. (PharmaMar, SA); Kahalalide cpds.. WO 0158934 .
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) 43354 (2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-methylbutyric acid C20H21NO4 详情 详情
(XV) 49385 (2-chlorophenyl)(diphenyl)methyl (9S,12R,15R,18R,21R)-15-[(1R)-1-[((2S)-2-[[(allyloxy)carbonyl]amino]-3-methylbutanoyl)oxy]ethyl]-9-[([1-[(2R)-2-amino-3-methylbutanoyl]-2-pyrrolidinyl]carbonyl)amino]-21-isopropyl-2,2-dimethyl-12,18-bis[(1S)-1-methylpropyl]-4,10,13,16,19-pentaoxo-3-oxa-5,11,14,17,20-pentaazadocosan-22-oate C69H100ClN9O14 详情 详情
(XVI) 19932 (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-methylbutyric acid C20H21NO4 详情 详情
(XVII) 49386 (2-chlorophenyl)(diphenyl)methyl (9S,12R,15R,18R,21R)-15-[(1R)-1-[((2S)-2-[[(allyloxy)carbonyl]amino]-3-methylbutanoyl)oxy]ethyl]-9-([[1-((2R)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-3-methylbutanoyl)-2-pyrrolidinyl]carbonyl]amino)-21-isopropyl-2,2-dimethyl-12,18-bis[(1S)-1-methylpropyl]-4,10,13,16,19-pentaoxo-3-oxa-5,11,14,17,20-pentaazadocosan-22-oate C74H109ClN10O15 详情 详情
(XVIII) 18847 (2S,3R)-3-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]butyric acid C23H27NO5 详情 详情
(XIX) 49387 (2-chlorophenyl)(diphenyl)methyl (9S,12R,15R,18R,21R)-15-[(1R)-1-[((2S)-2-[[(allyloxy)carbonyl]amino]-3-methylbutanoyl)oxy]ethyl]-9-[[(1-[(2R)-2-[((2S)-2-[[(2S)-2-amino-3-(tert-butoxy)butanoyl]amino]-3-methylbutanoyl)amino]-3-methylbutanoyl]-2-pyrrolidinyl)carbonyl]amino]-21-isopropyl-2,2-dimethyl-12,18-bis[(1S)-1-methylpropyl]-4,10,13,16,19-pentaoxo-3-oxa-5,11,14,17,20-pentaazadocosan-22-oate C82H124ClN11O17 详情 详情
(XX) 49388 　 C87H133ClN12O18 详情 详情
(XXI) 27649 5-methylhexanoic acid 628-46-6 C7H14O2 详情 详情
(XXII) 49389 (2-chlorophenyl)(diphenyl)methyl (9S,12R,15R,18R,21R)-15-[(1R)-1-[((2S)-2-[[(allyloxy)carbonyl]amino]-3-methylbutanoyl)oxy]ethyl]-9-[[(1-[(2R,5S,8S,11R)-8-[1-(tert-butoxy)ethyl]-2,5,11-triisopropyl-17-methyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazaoctadec-1-anoyl]-2-pyrrolidinyl)carbonyl]amino]-21-isopropyl-2,2-dimethyl-12,18-bis[(1S)-1-methylpropyl]-4,10,13,16,19-pentaoxo-3-oxa-5,11,14,17,20-pentaazadocosan-22-oate C94H145ClN12O19 详情 详情

合成路线3

Elimination of the Alloc protecting group of resin (XXII) by means of Pd(PPh3)4 and PhSiH3 gives peptide resin (XXIII), which is coupled successively with Fmoc-L-Thr-OH (XXIV) and Alloc-L-Phe-OH (XXVI) to yield peptide resins (XXV) and (XXVII), respectively.

参考文献 中间体
【1】 Royo, M.; Manzanares, I.; Lopez, A.; Jimenez, J.C.; Albericio, F.; Giralt, E.; Rodrigues, I. (PharmaMar, SA); Kahalalide cpds.. WO 0158934 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXII) 49389 (2-chlorophenyl)(diphenyl)methyl (9S,12R,15R,18R,21R)-15-[(1R)-1-[((2S)-2-[[(allyloxy)carbonyl]amino]-3-methylbutanoyl)oxy]ethyl]-9-[[(1-[(2R,5S,8S,11R)-8-[1-(tert-butoxy)ethyl]-2,5,11-triisopropyl-17-methyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazaoctadec-1-anoyl]-2-pyrrolidinyl)carbonyl]amino]-21-isopropyl-2,2-dimethyl-12,18-bis[(1S)-1-methylpropyl]-4,10,13,16,19-pentaoxo-3-oxa-5,11,14,17,20-pentaazadocosan-22-oate C94H145ClN12O19 详情 详情
(XXIII) 49390 (2-chlorophenyl)(diphenyl)methyl (9S,12R,15R,18R,21R)-15-((1R)-1-[[(2S)-2-amino-3-methylbutanoyl]oxy]ethyl)-9-[[(1-[(2R,5S,8S,11R)-8-[1-(tert-butoxy)ethyl]-2,5,11-triisopropyl-17-methyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazaoctadec-1-anoyl]-2-pyrrolidinyl)carbonyl]amino]-21-isopropyl-2,2-dimethyl-12,18-bis[(1S)-1-methylpropyl]-4,10,13,16,19-pentaoxo-3-oxa-5,11,14,17,20-pentaazadocosan-22-oate C90H141ClN12O17 详情 详情
(XXIV) 49391 (2S,3R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-hydroxybutyric acid C19H19NO5 详情 详情
(XXV) 49392 (2-chlorophenyl)(diphenyl)methyl (9S,12R,15R,18R,21R)-15-[(1R)-1-[((2S)-2-[[(2S,3R)-2-amino-3-hydroxybutanoyl]oxy]-3-methylbutanoyl)oxy]ethyl]-9-[[(1-[(2R,5S,8S,11R)-8-[1-(tert-butoxy)ethyl]-2,5,11-triisopropyl-17-methyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazaoctadec-1-anoyl]-2-pyrrolidinyl)carbonyl]amino]-21-isopropyl-2,2-dimethyl-12,18-bis[(1S)-1-methylpropyl]-4,10,13,16,19-pentaoxo-3-oxa-5,11,14,17,20-pentaazadocosan-22-oate C94H147ClN12O20 详情 详情
(XXVI) 49393 (2S)-2-[[(allyloxy)carbonyl]amino]-3-phenylpropionic acid C13H15NO4 详情 详情
(XXVII) 49394 　 C107H160ClN13O23 详情 详情

合成路线4

The dehydration of peptide resin (XXVII) by means of EDC and CuCl in DMF/dichloromethane, followed by elimination of the Alloc protecting group with Pd(PPh3)4 and PhSiH3, gives the peptide resin (XXVIII). The cleavage of the protected peptide from the resin was performed with TFA in dichloromethane to yield peptide (XXIX), which is cyclized by means of DIEA and benzotriazol-1-yl-N-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) and finally deprotected with TFA in water to afford the target kahalalide F.

参考文献 中间体
【1】 Royo, M.; Manzanares, I.; Lopez, A.; Jimenez, J.C.; Albericio, F.; Giralt, E.; Rodrigues, I. (PharmaMar, SA); Kahalalide cpds.. WO 0158934 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXVII) 49394 　 C107H160ClN13O23 详情 详情
(XXVIII) 49395 (2-chlorophenyl)(diphenyl)methyl (9S,12R,15R,18R,21R)-15-[(1R)-1-([(2S)-2-[((Z)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-2-butenoyl)oxy]-3-methylbutanoyl]oxy)ethyl]-9-[[(1-[(2R,5S,8S,11R)-8-[1-(tert-butoxy)ethyl]-2,5,11-triisopropyl-17-methyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazaoctadec-1-anoyl]-2-pyrrolidinyl)carbonyl]amino]-21-isopropyl-2,2-dimethyl-12,18-bis[(1S)-1-methylpropyl]-4,10,13,16,19-pentaoxo-3-oxa-5,11,14,17,20-pentaazadocosan-22-oate C103H154ClN13O20 详情 详情
(XXIX) 49396 (9S,12R,15R,18R,21R)-15-[(1R)-1-([(2S)-2-[((Z)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-2-butenoyl)oxy]-3-methylbutanoyl]oxy)ethyl]-9-[[(1-[(2R,5S,8S,11R)-8-[1-(tert-butoxy)ethyl]-2,5,11-triisopropyl-17-methyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazaoctadec-1-anoyl]-2-pyrrolidinyl)carbonyl]amino]-21-isopropyl-2,2-dimethyl-12,18-bis[(1S)-1-methylpropyl]-4,10,13,16,19-pentaoxo-3-oxa-5,11,14,17,20-pentaazadocosan-22-oic acid C84H141N13O20 详情 详情
Extended Information