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【结 构 式】 
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【分子编号】34762 【品名】(2S)-1-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-pyrrolidinecarboxylic acid 【CA登记号】71989-31-6 |
【 分 子 式 】C20H19NO4 【 分 子 量 】337.3752 【元素组成】C 71.2% H 5.68% N 4.15% O 18.97% |
合成路线1
该中间体在本合成路线中的序号：(XIII)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：(IV)The compound was prepared by solid-phase peptide synthesis on a poliethylene glycol amino resin. Coupling with N(alpha)-Fmoc-N(G)-Boc-lysine (I) using O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) and N-methylmorpholine (NMM) afforded the protected lysine-linked resin (II), and subsequent Fmoc deprotection provided resin (III). This was submitted to further coupling and deprotection cycles with the N(alpha)-Fmoc-protected amino acids proline (IV), N(G)-(2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl)arginine (VI), D-alanine (VIII), N(G)-Pbf-arginine (VI), and again N(G)-Pbf-arginine (VI) yielding peptide resins (V), (VII), (IX), (X) and (XI).
| 【1】 Aldrich, J.V.; Murray, T.F.; Wan, Q.; A novel acetylated analogue of dynorphin A-(1-11) amide as a kappa-opioid receptor antagonist. J Med Chem 1999, 42, 16, 3011. |
| 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) | 18854 | (2S)-6-[(tert-butoxycarbonyl)amino]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]hexanoic acid | C26H32N2O6 | 详情 | 详情 | |
| (II) | 28723 | 9H-fluoren-9-ylmethyl (1S)-1-(aminocarbonyl)-5-[(tert-butoxycarbonyl)amino]pentylcarbamate | C26H33N3O5 | 详情 | 详情 | |
| (III) | 34761 | tert-butyl (5S)-5,6-diamino-6-oxohexylcarbamate | C11H23N3O3 | 详情 | 详情 | |
| (IV) | 34762 | (2S)-1-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-pyrrolidinecarboxylic acid | 71989-31-6 | C20H19NO4 | 详情 | 详情 |
| (V) | 34763 | tert-butyl (5S)-6-amino-6-oxo-5-[[(2S)pyrrolidinylcarbonyl]amino]hexylcarbamate | C16H30N4O4 | 详情 | 详情 | |
| (VI) | 34764 | (2S)-5-[[[[(9H-fluoren-9-ylmethoxy)carbonyl]amino](imino)methyl]amino]-2-[[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]amino]pentanoic acid | C34H40N4O7S | 详情 | 详情 | |
| (VII) | 34765 | tert-butyl (5S)-6-amino-5-[[((2S)-1-[(2S)-2-amino-5-[(imino[[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]amino]methyl)amino]pentanoyl]pyrrolidinyl)carbonyl]amino]-6-oxohexylcarbamate | C35H58N8O8S | 详情 | 详情 | |
| (VIII) | 19926 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | C18H17NO4 | 详情 | 详情 | |
| (IX) | 34766 | tert-butyl (5S)-6-amino-5-[[((2S)-1-[(2S)-2-[[(2R)-2-aminopropanoyl]amino]-5-[(imino[[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]amino]methyl)amino]pentanoyl]pyrrolidinyl)carbonyl]amino]-6-oxohexylcarbamate | C38H63N9O9S | 详情 | 详情 | |
| (X) | 34767 | tert-butyl (5S)-6-amino-5-[[((2S)-1-[(2S)-2-[[(2R)-2-([(2S)-2-amino-5-[(imino[[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]amino]methyl)amino]pentanoyl]amino)propanoyl]amino]-5-[(imino[[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]amino]methyl)amino]pentanoyl]pyrrolidinyl)carbonyl]amino]-6-oxohexylcarbamate | C57H91N13O13S2 | 详情 | 详情 | |
| (XI) | 34768 | tert-butyl (5S)-6-amino-5-({[(2S)-1-((2S,5R,8S,11S)-11-amino-16-imino-2,8-bis{3-[(imino{[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]amino}methyl)amino]propyl}-5-methyl-4,7,10-trioxo-16-{[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]amino}-3,6,9,15-tetraazahexadec-1-anoyl)pyrrolidinyl]carbonyl}amino)-6-oxohexylcarbamate | C76H119N17O17S3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The esterification of the silylated resin (II) with the prenyltryptophan derivative (I) by means of HATU, OBT and DIEA in DMF gives the resin-bonded ester (III), which is treated with hydrazine in methanol/dichloromethane to eliminate the protecting phthalimido group and yield the resin-bonded tryptophan ester derivative (IV). The condensation of (IV) with N-(Fmoc)-L-proline (V) by means of HATU, HOBT and DIEA in DMF affords the dipeptide (VI), which is treated with piperidine in N-methylpyrrolidine to eliminate the Fmoc protecting group and yield dipeptide ester (VII). Finally, this compound is submitted to an acid-induced cyclization by means of HOAc in refluxing methanol to afford the target bicyclic diketopiperazine.
| 【1】 Wang, B.B.; et al.; Preparation of novel 2-(trialkylsilyl)ethyl linkers and first synthesis of Tryprostatin B on solid phase. Tetrahedron Lett 2001, 42, 8, 1463. |
| 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) | 50024 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-[2-(3-methyl-2-butenyl)-1H-indol-3-yl]propionic acid | C24H22N2O4 | 详情 | 详情 | |
| (II) | 50025 | 2-[dimethyl(phenyl)silyl]-1-ethanol | C10H16OSi | 详情 | 详情 | |
| (III) | 50026 | 2-[dimethyl(phenyl)silyl]ethyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-[2-(3-methyl-2-butenyl)-1H-indol-3-yl]propanoate | C34H36N2O4Si | 详情 | 详情 | |
| (IV) | 50027 | 2-[dimethyl(phenyl)silyl]ethyl (2S)-2-amino-3-[2-(3-methyl-2-butenyl)-1H-indol-3-yl]propanoate | C26H34N2O2Si | 详情 | 详情 | |
| (V) | 34762 | (2S)-1-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-pyrrolidinecarboxylic acid | 71989-31-6 | C20H19NO4 | 详情 | 详情 |
| (VI) | 50028 | 9H-fluoren-9-ylmethyl (2S)-2-[[((1S)-2-[2-[dimethyl(phenyl)silyl]ethoxy]-1-[[2-(3-methyl-2-butenyl)-1H-indol-3-yl]methyl]-2-oxoethyl)amino]carbonyl]-1-pyrrolidinecarboxylate | C46H51N3O5Si | 详情 | 详情 | |
| (VII) | 50029 | 2-[dimethyl(phenyl)silyl]ethyl (2S)-3-[2-(3-methyl-2-butenyl)-1H-indol-3-yl]-2-[[(2S)pyrrolidinylcarbonyl]amino]propanoate | C31H41N3O3Si | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)The deprotection of the resin (I) with piperidine in DMF gives the amino-resin (II), which is condensed with N-Fmoc-L-proline (III) by means of diisopropylcarbodiimide (DIC) in DMF to yield the anchored proline (IV). The deprotection of (IV) with piperidine in DMF affords compound (V) with a free NH group, which is condensed with 2-bromoacetic acid (VI) by means of DIC DMF to provide the bromoacetyl proline resin (VII). The condensation of (VII) with 6-(2-aminoethylamino)pyridine-3-carbonitrile (VIII) in DMSO to give the resin anchored precursor (IX), which is finally cleaved by means of trifluoroacetic anhydride (TFAA) in THF to furnish the target pyrrolidine-carbonitrile. Alternatively, the acylation of L-prolinamide (X) with 2-bromoacetyl bromide (XI) by means of TEA and DMAP in dichloromethane gives the 1-(2-bromoacetyl)-L-prolinamide (XII), which is dehydrated by means of TFAA in dichloromethane to yield the pyrrolidine-carbonitrile (XIII). Finally, this compound is condensed with 6-(2-aminoethylamino)pyridine-3-carbonitrile (VIII) in THF to furnish the target pyrrolidine-carbonitrile.
| 【1】 Mangold, B.L.; Mone, M.D.; Dunning, B.E.; Russell, M.E.; Brinkman, J.A.; Weldon, S.C.; Hughes, T.E.; Naderi, G.B.; Villhauer, E.B.; 1-[2-[(5-Cyanopyridin-2-yl)amino]-ethylamino]acetyl-2-(S)-pyrrolidine-carbonitrile: A potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J Med Chem 2002, 45, 12, 2362. |
| 【2】 Villhauer, E.B. (Novartis AG); N-Substd. 2-cyanopyrrolidines. JP 2000511559; WO 9819998 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V),(X) | 36137 | (2S)-2-pyrrolidinecarboxamide;L-prolinamide | 7531-52-4 | C5H10N2O | 详情 | 详情 |
| (VII),(XII) | 54331 | (2S)-1-(2-bromoacetyl)-2-pyrrolidinecarboxamide | n/a | C7H11BrN2O2 | 详情 | 详情 |
| (I) | 28722 | 9H-fluoren-9-ylmethyl carbamate | 84418-43-9 | C15H13NO2 | 详情 | 详情 |
| (III) | 34762 | (2S)-1-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-pyrrolidinecarboxylic acid | 71989-31-6 | C20H19NO4 | 详情 | 详情 |
| (IV) | 42841 | 9H-fluoren-9-ylmethyl (2R)-2-(aminocarbonyl)-1-pyrrolidinecarboxylate | C20H20N2O3 | 详情 | 详情 | |
| (VI) | 23660 | 2-Bromoacetic acid | 79-08-3 | C2H3BrO2 | 详情 | 详情 |
| (VIII) | 54332 | 6-[(2-aminoethyl)amino]nicotinonitrile | n/a | C8H10N4 | 详情 | 详情 |
| (IX) | 54333 | (2S)-1-[2-({2-[(5-cyano-2-pyridinyl)amino]ethyl}amino)acetyl]-2-pyrrolidinecarboxamide | n/a | C15H20N6O2 | 详情 | 详情 |
| (XI) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (XIII) | 54334 | (2S)-1-(2-bromoacetyl)-2-pyrrolidinecarbonitrile | n/a | C7H9BrN2O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The condensation of protected L-proline (I) with RINK RESIN (II) by means of TBTU, HOBT and DIEA in DMF gives the protected, rein bounded proline (III), which is deprotected by means of piperidine in DMF to yield the resin bounded proline (IV). The condensation of (IV) with 2-bromoacetic acid (V) by means of DIC in the same solvent affords the acyl proline (VI), which is treated with ethylene-1,2-diamine (VII) to provide the aminoacetyl proline (VIII). The condensation of (VIII) with 2-acetyldimedone (IX) gives the regioselectively monoprotected diaminoproline compound (X), which is treated with Boc2O and DIEA in dioxane to protect the secondary amino group of (X) and yield (XI). The selective elimination of the dimedone protecting group with hydrazine in DMF affords compound (XII) selectively monoprotected at the secondary amino group, which is condensed with 6-chloropyridine-3-carbonitrile (XIII) by means of DIEA in NMP to provide the resin adduct (XIV). The cleavage of the resin group of (XIV) by means of TFA and TFAA in dichloromethane takes place with simultaneous dehydration of the carboxamide group and removal of the Boc protecting group affording the trifluoroacetamido derivative (XV). Finally, the trifluoroacetyl group is removed by means of NH3 in aqueous methanol to give rise to the target pyridine carbonitrile derivative.
| 【1】 Willand, N.; et al.; Solid and solution phase syntheses of the 2-cyanopyrrolidide DPP-IV inhihitor NVP-DPP728. Tetrahedron 2002, 58, 28, 5741. |
| 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) | 34762 | (2S)-1-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-pyrrolidinecarboxylic acid | 71989-31-6 | C20H19NO4 | 详情 | 详情 |
| (III) | 42841 | 9H-fluoren-9-ylmethyl (2R)-2-(aminocarbonyl)-1-pyrrolidinecarboxylate | C20H20N2O3 | 详情 | 详情 | |
| (IV) | 36137 | (2S)-2-pyrrolidinecarboxamide;L-prolinamide | 7531-52-4 | C5H10N2O | 详情 | 详情 |
| (V) | 23660 | 2-Bromoacetic acid | 79-08-3 | C2H3BrO2 | 详情 | 详情 |
| (VI) | 54331 | (2S)-1-(2-bromoacetyl)-2-pyrrolidinecarboxamide | n/a | C7H11BrN2O2 | 详情 | 详情 |
| (VII) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
| (VIII) | 57168 | (2S)-1-{2-[(2-aminoethyl)amino]acetyl}-2-pyrrolidinecarboxamide | C9H18N4O2 | 详情 | 详情 | |
| (IX) | 57169 | 2-(1-hydroxyethylidene)-5,5-dimethyl-1,3-cyclohexanedione | C10H14O3 | 详情 | 详情 | |
| (X) | 57170 | (2S)-1-{2-[(2-{[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl]amino}ethyl)amino]acetyl}-2-pyrrolidinecarboxamide | C19H30N4O4 | 详情 | 详情 | |
| (XI) | 57171 | tert-butyl 2-[(2S)-2-(aminocarbonyl)pyrrolidinyl]-2-oxoethyl(2-{[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl]amino}ethyl)carbamate | C24H38N4O6 | 详情 | 详情 | |
| (XII) | 57172 | tert-butyl 2-[(2S)-2-(aminocarbonyl)pyrrolidinyl]-2-oxoethyl(2-aminoethyl)carbamate | C14H26N4O4 | 详情 | 详情 | |
| (XIII) | 57164 | 2-Chloro-5-cyanopyridine; 6-Chloro-3-cyanopyridine; 6-Chloronicotinonitrile | 33252-28-7 | C6H3ClN2 | 详情 | 详情 |
| (XIV) | 57173 | tert-butyl 2-[(2S)-2-(aminocarbonyl)pyrrolidinyl]-2-oxoethyl{2-[(5-cyano-2-pyridinyl)amino]ethyl}carbamate | C20H28N6O4 | 详情 | 详情 | |
| (XV) | 57174 | N-{2-[(5-cyano-2-pyridinyl)amino]ethyl}-N-{2-[(2S)-2-cyanopyrrolidinyl]-2-oxoethyl}-2,2,2-trifluoroacetamide | C17H17F3N6O2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(X)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7
该中间体在本合成路线中的序号：(I)The title peptide was originally isolated from the venom of the marine cone snail Conus radiatus in small quantities. The compound has also been obtained by solid-phase peptide synthesis starting from Fmoc-L-proline linked to p-alkoxybenzylalcohol resin (I). Removal of the Fmoc group was effected by treatment with tetrabutylammonium fluoride in DMF. Chain elongation was carried out by coupling with the respective Fmoc-protected amino acids using diisopropyl carbodiimide and 1-hydroxybenzotriazole in CH2Cl2-DMF, followed by deprotection cycles with tetrabutylammonium fluoride. Gamma-carboxy glutamic acid was incorporated as the protected bis-tert-butyl ester. The final protected peptide resin (III) was liberated and deprotected by using a mixture of trifluoroacetic acid, thioanisole, water, ethanedithiol and dichloromethane, and the resulting peptide was air oxidized at a pH of 7.8 to form the required disulfide bridge.
| 【1】 White, H.S.; McCabe, R.T.; Armstrong, H.; et al.; In vitro and in vivo characterization of conantokin-R, a selective NMDA receptor antagonist isolated from the venom of the fish-hunting snail Conus radiatus. The Journal of Pharmacology and Experimental Therapeutics 2000, 292, 1, 425. |
| 【2】 McCabe, R.T.; Zhou, L.-M.; Layer, R.T. (Cognetix, Inc.); Use of conantokins. US 6172041; WO 9803189 . |
| 【3】 Shen, G.S.; Layer, R.T.; Colledge, C.; Abogadie, F.C.; Zhou, L.-M.; Cruz, L.J.; Rivier, J.E.; McCabe, R.T.; Hyllyard, D.R.; Jimenez, E.; Walker, C.; Olivera, B.M. (Cognetix, Inc.; University of Utah); Conantokins. WO 9803541 . |