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【结 构 式】 
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【分子编号】28722 【品名】9H-fluoren-9-ylmethyl carbamate 【CA登记号】84418-43-9 |
【 分 子 式 】C15H13NO2 【 分 子 量 】239.27376 【元素组成】C 75.3% H 5.48% N 5.85% O 13.37% |
合成路线1
该中间体在本合成路线中的序号：(II)The successive condensations of fluorenylmethoxycarbonyl-Rink amide resin (I) with Nalpha-FMOC-Nepsilon-Boc-L-lysine (II), FMOC-D-phenylalanine (IV), FMOC-D-2-naphthylalanine (VI), FMOC-Npi-trityl-L-histidine (VIII), and finally 2-(tert-butoxycarbonylamino)isobutyric acid (X), using the solid phase peptide technique synthesis yielded resins (III), (V), (VII), (IX) and finally (XI). This last resin was then treated with trifluoroacetic acid in order to eliminate the Boc protecting groups and the solid phase resin and isolate the target compound.
| 【1】 Muller, L.; et al.; C-14-labelling of ipamorelin, a growth hormone secretagogue. J Label Compd Radiopharm 1998, 41, 12, 1093. |
| 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) | 28722 | 9H-fluoren-9-ylmethyl carbamate | 84418-43-9 | C15H13NO2 | 详情 | 详情 |
| (III) | 28723 | 9H-fluoren-9-ylmethyl (1S)-1-(aminocarbonyl)-5-[(tert-butoxycarbonyl)amino]pentylcarbamate | C26H33N3O5 | 详情 | 详情 | |
| (IV) | 28730 | (2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-phenylpropionic acid | C24H21NO4 | 详情 | 详情 | |
| (V) | 28724 | 9H-fluoren-9-ylmethyl (1R)-2-([(1S)-1-(aminocarbonyl)-5-[(tert-butoxycarbonyl)amino]pentyl]amino)-1-benzyl-2-oxoethylcarbamate | C35H42N4O6 | 详情 | 详情 | |
| (VI) | 28725 | (2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-(2-naphthyl)propionic acid | C28H23NO4 | 详情 | 详情 | |
| (VII) | 28726 | 9H-fluoren-9-ylmethyl (1R,4R,7S)-7-(aminocarbonyl)-4-benzyl-15,15-dimethyl-1-(2-naphthylmethyl)-2,5,13-trioxo-14-oxa-3,6,12-triazahexadec-1-ylcarbamate | C48H53N5O7 | 详情 | 详情 | |
| (VIII) | 28727 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-(1-trityl-1H-imidazol-5-yl)propionic acid | C40H33N3O4 | 详情 | 详情 | |
| (IX) | 28728 | 9H-fluoren-9-ylmethyl (1S,4R,7R,10S)-10-(aminocarbonyl)-7-benzyl-18,18-dimethyl-4-(2-naphthylmethyl)-2,5,8,16-tetraoxo-1-[(1-trityl-1H-imidazol-5-yl)methyl]-17-oxa-3,6,9,15-tetraazanonadec-1-ylcarbamate | C73H74N8O8 | 详情 | 详情 | |
| (X) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (XI) | 28729 | tert-butyl (4S,7R,10R,13S)-13-(aminocarbonyl)-10-benzyl-1,1,21,21-tetramethyl-7-(2-naphthylmethyl)-2,5,8,11,19-pentaoxo-4-[(1-trityl-1H-imidazol-5-yl)methyl]-20-oxa-3,6,9,12,18-pentaazadocos-1-ylcarbamate | C67H79N9O9 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)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3
该中间体在本合成路线中的序号：(I)The compound was prepared via solid-phase synthesis using Rink-amide resin (I). After initial Fmoc-deprotection of (I) with piperidine in DMF, Fmoc-L-phenylalanine (II) was coupled to the resin by means of N,N'-diisopropyl carbodiimide (DIC) and hydroxybenzotriazole (HOBt) in DMF, yielding the phenylalanine-linked resin (III). Subsequent Fmoc-deprotection and coupling cycles with protected arginine (IV) and cyclohexylalanine (VI) produced the peptide resins (V) and (VII), respectively. Further deprotection of (VII) with piperidine, followed by coupling with 5-bromonicotinic acid (VIII) gave the corresponding amide (IX). Cleavage of the final peptide amide from the resin (IX) was then accomplished by treatment trifluoroacetic acid and anisole.
| 【1】 Addo, M.F.; Hawkins, M.J.; Maryanoff, B.E.; Oksenberg, D.; McComsey, D.F.; Andrade-Gordon, P.; Heterocycle-peptide hybrid compounds. Aminotriazole-containing agonists of the thrombin receptor (PAR-1). Bioorg Med Chem Lett 1999, 9, 10, 1423. |
| 【2】 Hawkins, M.J.; Maryanoff, B.E.; McComsey, D.F. (Ortho-McNeil Pharmaceutical, Inc.); Substd. heterocyclic acyl-tripeptides useful as thrombin receptor modulators. WO 0035942 . |
| 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) | 28722 | 9H-fluoren-9-ylmethyl carbamate | 84418-43-9 | C15H13NO2 | 详情 | 详情 |
| (II) | 19030 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-phenylpropionic acid; N-((9H-fluoren-9-ylmethoxy)carbonyl)-phenylalanine | 35661-40-6 | C24H21NO4 | 详情 | 详情 |
| (III) | 19031 | 9H-fluoren-9-ylmethyl (1S)-2-amino-1-benzyl-2-oxoethylcarbamate | C24H22N2O3 | 详情 | 详情 | |
| (IV) | 30825 | (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]pentanoic acid | C35H44N4O7S | 详情 | 详情 | |
| (V) | 30826 | 9H-fluoren-9-ylmethyl (1S)-1-([[(1S)-2-amino-1-benzyl-2-oxoethyl]amino]carbonyl)-4-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]butylcarbamate | C44H54N6O7S | 详情 | 详情 | |
| (VI) | 30827 | (2S)-3-cyclohexyl-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | C24H27NO4 | 详情 | 详情 | |
| (VII) | 30828 | 9H-fluoren-9-ylmethyl (1S)-2-([(1S)-1-([[(1S)-2-amino-1-benzyl-2-oxoethyl]amino]carbonyl)-4-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]butyl]amino)-1-(cyclohexylmethyl)-2-oxoethylcarbamate | C53H69N7O8S | 详情 | 详情 | |
| (VIII) | 17913 | 5-Bromonicotinic acid | 20826-04-4 | C6H4BrNO2 | 详情 | 详情 |
| (IX) | 30829 | N-[(1S)-2-([(1S)-1-([[(1S)-2-amino-1-benzyl-2-oxoethyl]amino]carbonyl)-4-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]butyl]amino)-1-(cyclohexylmethyl)-2-oxoethyl]-5-bromonicotinamide | C44H61BrN8O7S | 详情 | 详情 |