【结 构 式】 |
【分子编号】43354 【品名】(2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-methylbutyric acid 【CA登记号】 |
【 分 子 式 】C20H21NO4 【 分 子 量 】339.39108 【元素组成】C 70.78% H 6.24% N 4.13% O 18.86% |
合成路线1
该中间体在本合成路线中的序号:(I)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.
【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
该中间体在本合成路线中的序号:(I)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.
【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
该中间体在本合成路线中的序号:(XVII)The Fmoc protecting group of resin (XI) was removed by treatment with piperidine in DMF to give (XII). This was subsequently coupled with N-Fmoc-3-methyl-L-valine (XIII) to provide, after Fmoc deprotection with piperidine, the dipeptide resin (XIV). Further coupling and deprotection cycles with N-Fmoc-3-(2-methylphenyl)-L-alanine (XV) and N-Fmoc-D-valine (XVII) yielded resins (XVI) and (XVIII), respectively. Resin (XVIII) was then coupled with N-(benzyloxycarbonyl)-L-aspartic acid beta-tert-butyl ester (XIX), and the title compound was finally deprotected and liberated from the resin by means of trifluoroacetic acid in CH2Cl2.
【1】 Dunsdon, R.M.; et al.; Solid phase synthesis of aminoboronic acids: Potent inhibitors of the hepatitis C virus NS3 proteinase. Bioorg Med Chem Lett 2000, 10, 14, 1577. |
【2】 Attwood, M.R.; Hurst, D.N.; Jones, P.S.; Kay, P.B.; Raynham, T.M.; Wilson, F.X. (F. Hoffmann-La Roche AG); Antiviral peptide derivs.. JP 2000508344; WO 9822496 . |
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) | 43348 | 9H-fluoren-9-ylmethyl (1S)-1-[([1-[4-(5-amino-3-methyl-5-oxopentyl)-4,5,5-trimethyl-1,3,2-dioxaborolan-2-yl]propyl]amino)carbonyl]-3-methylbutylcarbamate | C35H50BN3O6 | 详情 | 详情 | |
(XII) | 43349 | (2S)-2-amino-N-[1-[4-(5-amino-3-methyl-5-oxopentyl)-4,5,5-trimethyl-1,3,2-dioxaborolan-2-yl]propyl]-4-methylpentanamide | C20H40BN3O4 | 详情 | 详情 | |
(XIII) | 43350 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3,3-dimethylbutyric acid | 132684-60-7 | C21H23NO4 | 详情 | 详情 |
(XIV) | 43351 | (2S)-2-[[(2S)-2-amino-3,3-dimethylbutanoyl]amino]-N-[1-[4-(5-amino-3-methyl-5-oxopentyl)-4,5,5-trimethyl-1,3,2-dioxaborolan-2-yl]propyl]-4-methylpentanamide | C26H51BN4O5 | 详情 | 详情 | |
(XV) | 22255 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-(2-methylphenyl)propionic acid | C25H23NO4 | 详情 | 详情 | |
(XVI) | 43352 | (2S)-N-[1-[4-(5-amino-3-methyl-5-oxopentyl)-4,5,5-trimethyl-1,3,2-dioxaborolan-2-yl]propyl]-2-[((2S)-2-[[(2S)-2-amino-3-(2-methylphenyl)propanoyl]amino]-3,3-dimethylbutanoyl)amino]-4-methylpentanamide | C36H62BN5O6 | 详情 | 详情 | |
(XVII) | 43354 | (2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-methylbutyric acid | C20H21NO4 | 详情 | 详情 | |
(XVIII) | 43353 | (2S)-2-[((2S)-2-[[(2S)-2-[[(2R)-2-amino-3-methylbutanoyl]amino]-3-(2-methylphenyl)propanoyl]amino]-3,3-dimethylbutanoyl)amino]-N-[1-[4-(5-amino-3-methyl-5-oxopentyl)-4,5,5-trimethyl-1,3,2-dioxaborolan-2-yl]propyl]-4-methylpentanamide | C41H71BN6O7 | 详情 | 详情 | |
(XIX) | 36564 | (2S)-2-[[(benzyloxy)carbonyl]amino]-4-(tert-butoxy)-4-oxobutyric acid | C16H21NO6 | 详情 | 详情 |