|
【结 构 式】 
|
【分子编号】42131 【品名】2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]acetic acid 【CA登记号】29022-11-5 |
【 分 子 式 】C17H15NO4 【 分 子 量 】297.31044 【元素组成】C 68.68% H 5.09% N 4.71% O 21.53% |
合成路线1
该中间体在本合成路线中的序号：(III)The title compound was obtained by solid-phase peptide synthesis starting from N-Boc-S-(4-methylbenzyl)cysteine linked to PAM resin (I). The protected peptide template (XVII) was synthesized by sequential coupling-deprotection cycles using the appropriate combination of either Boc- or Fmoc- N-alpha-protected amino acids. The following side-chain-protected amino acid residues were assembled: Gly (III), Lys(Boc) (V), Glu(cyclohexyl ester) (VII), Lys(Boc) (V), Pro (X), Gly (III), Lys(Boc) (V), Lys(chlorobenzyloxycarbonyl) (XIV) and Lys(Boc) (XVI) to produce the peptide resins (IV), (VI), (VIII), (IX), (XI), (XII), (XIII), (XV) and (XVII), respectively. Subsequent removal of the N-terminal and the four side-chain Boc protecting groups by means of trifluoroacetic acid yielded the peptide resin (XVIII).
| 【1】 Callebaut, C.; et al.; Inhibition of HIV infection by pseudopeptides blocking viral envelope glycoprotein-mediated membrane fusion and cell death. Virology 1996, 218, 1, 181. |
| 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) | 42129 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-[(4-methylbenzyl)sulfanyl]propionic acid | C16H23NO4S | 详情 | 详情 | |
| (II) | 42130 | (2R)-2-amino-3-[(4-methylbenzyl)sulfanyl]propionic acid | 42294-52-0 | C11H15NO2S | 详情 | 详情 |
| (III) | 42131 | 2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]acetic acid | 29022-11-5 | C17H15NO4 | 详情 | 详情 |
| (IV) | 42132 | (2R)-2-[(2-aminoacetyl)amino]-3-[(4-methylbenzyl)sulfanyl]propionic acid | C13H18N2O3S | 详情 | 详情 | |
| (V) | 18854 | (2S)-6-[(tert-butoxycarbonyl)amino]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]hexanoic acid | C26H32N2O6 | 详情 | 详情 | |
| (VI) | 42133 | (10S,16R)-10-amino-2,2-dimethyl-16-[[(4-methylbenzyl)sulfanyl]methyl]-4,11,14-trioxo-3-oxa-5,12,15-triazaheptadecan-17-oic acid | C24H38N4O6S | 详情 | 详情 | |
| (VII) | 42134 | (2S)-5-(cyclohexyloxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-oxopentanoic acid | 150047-85-1 | C26H29NO6 | 详情 | 详情 |
| (VIII) | 42135 | (10R,16R)-10-[(3S)-3-amino-6-(cyclohexyloxy)-2,6-dioxohexyl]-2,2-dimethyl-16-[[(4-methylbenzyl)sulfanyl]methyl]-4,11,14-trioxo-3-oxa-5,12,15-triazaheptadecan-17-oic acid | C36H56N4O9S | 详情 | 详情 | |
| (IX) | 42136 | (10S,13S,16R,22R)-10-amino-16-[4-[(tert-butoxycarbonyl)amino]butyl]-13-[3-(cyclohexyloxy)-3-oxopropyl]-2,2-dimethyl-22-[[(4-methylbenzyl)sulfanyl]methyl]-4,11,14,17,20-pentaoxo-3-oxa-5,12,18,21-tetraazatricosan-23-oic acid | C47H76N6O12S | 详情 | 详情 | |
| (X) | 34762 | (2S)-1-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-pyrrolidinecarboxylic acid | 71989-31-6 | C20H19NO4 | 详情 | 详情 |
| (XI) | 42137 | (10S,13S,16R,22R)-16-[4-[(tert-butoxycarbonyl)amino]butyl]-13-[3-(cyclohexyloxy)-3-oxopropyl]-2,2-dimethyl-22-[[(4-methylbenzyl)sulfanyl]methyl]-4,11,14,17,20-pentaoxo-10-[[(2S)pyrrolidinylcarbonyl]amino]-3-oxa-5,12,18,21-tetraazatricosan-23-oic acid | C52H83N7O13S | 详情 | 详情 | |
| (XII) | 42138 | (10S,13S,16R,22R)-10-([[(2S)-1-(2-aminoacetyl)pyrrolidinyl]carbonyl]amino)-16-[4-[(tert-butoxycarbonyl)amino]butyl]-13-[3-(cyclohexyloxy)-3-oxopropyl]-2,2-dimethyl-22-[[(4-methylbenzyl)sulfanyl]methyl]-4,11,14,17,20-pentaoxo-3-oxa-5,12,18,21-tetraaz | C54H86N8O14S | 详情 | 详情 | |
| (XIII) | 42139 | (10S,13S,16R,22R)-10-[([(2S)-1-[2-([(2S)-2-amino-6-[(tert-butoxycarbonyl)amino]hexanoyl]amino)acetyl]pyrrolidinyl]carbonyl)amino]-16-[4-[(tert-butoxycarbonyl)amino]butyl]-13-[3-(cyclohexyloxy)-3-oxopropyl]-2,2-dimethyl-22-[[(4-methylbenzyl)sulfanyl] | C65H106N10O17S | 详情 | 详情 | |
| (XIV) | 42140 | (2S)-6-([[(4-chlorobenzyl)oxy]carbonyl]amino)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]hexanoic acid | C29H29ClN2O6 | 详情 | 详情 | |
| (XV) | 42141 | (10S,13S,16R,22R)-10-[([(2S)-1-[(5S,8S)-8-amino-5-[4-[(tert-butoxycarbonyl)amino]butyl]-16-(4-chlorophenyl)-4,7,14-trioxo-15-oxa-3,6,13-triazahexadec-1-anoyl]pyrrolidinyl]carbonyl)amino]-16-[4-[(tert-butoxycarbonyl)amino]butyl]-13-[3-(cyclohexyloxy) | C79H123ClN12O20S | 详情 | 详情 | |
| (XVI) | 37991 | (2S)-2,6-bis[(tert-butoxycarbonyl)amino]hexanoic acid | 2483-46-7 | C16H30N2O6 | 详情 | 详情 |
| (XVII) | 42142 | (10S,13S,16R,22R)-10-[[((2S)-1-[(5S,8S,11S)-11-[(tert-butoxycarbonyl)amino]-5-[4-[(tert-butoxycarbonyl)amino]butyl]-8-[4-([[(4-chlorobenzyl)oxy]carbonyl]amino)butyl]-19,19-dimethyl-4,7,10,17-tetraoxo-18-oxa-3,6,9,16-tetraazaicos-1-anoyl]pyrrolidinyl | C95H151ClN14O25S | 详情 | 详情 | |
| (XVIII) | 42143 | (3S,6S,9R,15R)-3,9-bis(4-aminobutyl)-1-[(2S)-1-((5S,8S)-5-(4-aminobutyl)-16-(4-chlorophenyl)-8-[[(2S)-2,6-diaminohexanoyl]amino]-4,7,14-trioxo-15-oxa-3,6,13-triazahexadec-1-anoyl)pyrrolidinyl]-6-[3-(cyclohexyloxy)-3-oxopropyl]-15-[[(4-methylbenzyl)s | C70H111ClN14O15S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I),(II)The cyclic peptide precursor (XIV) was prepared by solid-phase synthesis on a preformed HMPB-MBHA resin. Attachment of N-Fmoc-glycine (I) to the resin by means of DCC and DMAP afforded resin (II). The Fmoc protecting group was then removed with piperidine in DMF, yielding the glycine-bound resin (III). Further couplings with the following protected amino acids: N-Fmoc-3-(aminomethyl)-5-nitrobenzoic acid (IV), N-Fmoc-L-tyrosine(O-t-butyl) (VI) and N-Fmoc-glycine (I), followed by Fmoc deprotection cycles, produced in turn the peptide resins (V), (VII) and (VIII). To peptide resin (VIII) was then coupled N-Fmoc-L-aspartic acid gamma-t-butyl ester (IX), yielding resin (X). Peptide (XI) was then liberated from the resin by means of 1% trifluoroacetic acid in CH2Cl2. The Fmoc group was subsequently removed by treatment with diethylamine in acetonitrile, giving (XII).
| 【1】 Park, H.S.; et al.; Protein surface recognition by synthetic receptors: A route to novel submicromolar inhibitors for alpha-chymotrypsin. J Am Chem Soc 1999, 121, 1, 8. |
| 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),(II) | 42131 | 2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]acetic acid | 29022-11-5 | C17H15NO4 | 详情 | 详情 |
| (X),(XI) | 47339 | 2-([3-[(4S,10S)-4-[4-(tert-butoxy)benzyl]-10-[2-(tert-butoxy)-2-oxoethyl]-14-(9H-fluoren-9-yl)-3,6,9,12-tetraoxo-13-oxa-2,5,8,11-tetraazatetradec-1-yl]-5-nitrobenzoyl]amino)acetic acid | C48H54N6O13 | 详情 | 详情 | |
| (III) | 20436 | glycine | 56-40-6 | C2H5NO2 | 详情 | 详情 |
| (IV) | 47335 | 3-([[(9H-fluoren-9-ylmethoxy)carbonyl]amino]methyl)-5-nitrobenzoic acid | C23H18N2O6 | 详情 | 详情 | |
| (V) | 47336 | 2-[[3-(aminomethyl)-5-nitrobenzoyl]amino]acetic acid | C10H11N3O5 | 详情 | 详情 | |
| (VI) | 18858 | (2S)-3-[4-(tert-butoxy)phenyl]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | C28H29NO5 | 详情 | 详情 | |
| (VII) | 47337 | 2-([3-[([(2S)-2-amino-3-[4-(tert-butoxy)phenyl]propanoyl]amino)methyl]-5-nitrobenzoyl]amino)acetic acid | C23H28N4O7 | 详情 | 详情 | |
| (VIII) | 47338 | 2-([3-[([(2S)-2-[(2-aminoacetyl)amino]-3-[4-(tert-butoxy)phenyl]propanoyl]amino)methyl]-5-nitrobenzoyl]amino)acetic acid | C25H31N5O8 | 详情 | 详情 | |
| (IX) | 22260 | (2S)-4-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-oxobutyric acid | C23H25NO6 | 详情 | 详情 | |
| (XII) | 47340 | 2-[(3-[(4S,10S)-10-amino-4-[4-(tert-butoxy)benzyl]-14,14-dimethyl-3,6,9,12-tetraoxo-13-oxa-2,5,8-triazapentadec-1-yl]-5-nitrobenzoyl)amino]acetic acid | C33H44N6O11 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XV)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.
| 【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4
该中间体在本合成路线中的序号：(II)The condensation of ArgoGel-OH resin (I) with N-(Fmoc)-glycine (II) by means of DIC and DMAP gives the resin-bound Fmoc-glycine (III), which is deprotected with piperidine to yield the resin-bound glycine (IV). The reaction of (IV) with 2-nitrophenylsulfonyl chloride (V) affords the sulfonamide (VI), which is alkylated with 2-cyclopentylethanol (VII) by means of DIAD and PPh3 to provide the N-alkylated sulfonamide (VIII). The reaction of (VIII) with Ph-SH, DBU and pyridine gives the N-alkylated resin-bound glycine (IX), which is condensed with 1-(chlorocarbonyl)-L-proline tert-butyl ester (X) to yield the resin-bound dipeptide tert-butyl ester (XI). Hydrolysis of the ester group of (XI) with TFA affords the free resin-bound dipeptide (XII), which is condensed with 4,5-dimethylthiazole-2-amine (XIII) by means of PyBOP and DMAP to provide the corresponding prolinamide (XIV). Finally, this compound is treated with hydroxylamine in order to cleave the title compound from the resin by formation of the desired hydroxamic acid.
| 【1】 Lewis, J.G.; Wu, C.; Jacobs, J.; et al.; Iterative parallel synthesis-derived N-alkyl urea hydroxamic acids: A new class of peptide deformylase inhibitors. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-358. |
| 【2】 Patel, D.V.; Jacobs, J.W.; Lewis, J.; Ni, Z.-J. (Versicor, Inc.); Novel urea cpds., compsns. and methods of use and preparation. WO 0144178 . |
| 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) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (II) | 42131 | 2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]acetic acid | 29022-11-5 | C17H15NO4 | 详情 | 详情 |
| (III) | 54030 | 2-hydroxyethyl 2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}acetate | C19H19NO5 | 详情 | 详情 | |
| (IV) | 54031 | 2-hydroxyethyl 2-aminoacetate | C4H9NO3 | 详情 | 详情 | |
| (V) | 32624 | 2-Nitrobenzenesulfonyl chloride | 1694-92-4 | C6H4ClNO4S | 详情 | 详情 |
| (VI) | 54032 | 2-hydroxyethyl 2-{[(2-nitrophenyl)sulfonyl]amino}acetate | C10H12N2O7S | 详情 | 详情 | |
| (VII) | 54033 | 2-Cyclopentylethanol; 2-Hydroxyethylcyclopentane; alpha-Methylcyclopentanemethanol; Cyclopentylmethylcarbinol | 766-00-7 | C7H14O | 详情 | 详情 |
| (VIII) | 54034 | 2-hydroxyethyl 2-{(2-cyclopentylethyl)[(2-nitrophenyl)sulfonyl]amino}acetate | C17H24N2O7S | 详情 | 详情 | |
| (IX) | 54035 | 2-hydroxyethyl 2-[(2-cyclopentylethyl)amino]acetate | C11H21NO3 | 详情 | 详情 | |
| (X) | 54036 | tert-butyl (2S)-1-(chlorocarbonyl)-2-pyrrolidinecarboxylate | C10H16ClNO3 | 详情 | 详情 | |
| (XI) | 54037 | tert-butyl (2S)-1-({(2-cyclopentylethyl)[2-(2-hydroxyethoxy)-2-oxoethyl]amino}carbonyl)-2-pyrrolidinecarboxylate | C21H36N2O6 | 详情 | 详情 | |
| (XII) | 54038 | (2S)-1-({(2-cyclopentylethyl)[2-(2-hydroxyethoxy)-2-oxoethyl]amino}carbonyl)-2-pyrrolidinecarboxylic acid | C17H28N2O6 | 详情 | 详情 | |
| (XIII) | 54039 | 4,5-dimethyl-1,3-thiazol-2-ylamine; 4,5-dimethyl-1,3-thiazol-2-amine | C5H8N2S | 详情 | 详情 | |
| (XIV) | 54040 | 2-hydroxyethyl 2-{(2-cyclopentylethyl)[((2S)-2-{[(4,5-dimethyl-1,3-thiazol-2-yl)amino]carbonyl}pyrrolidinyl)carbonyl]amino}acetate | C22H34N4O5S | 详情 | 详情 |