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【结 构 式】 
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【分子编号】19031 【品名】9H-fluoren-9-ylmethyl (1S)-2-amino-1-benzyl-2-oxoethylcarbamate 【CA登记号】 |
【 分 子 式 】C24H22N2O3 【 分 子 量 】386.45036 【元素组成】C 74.59% H 5.74% N 7.25% O 12.42% |
合成路线1
该中间体在本合成路线中的序号：(II)Fmoc-protected phenylalanine (I) is attached to Rink resin by means of DCC and HOBt coupling, to give the amino acid-resin complex (II). Then, N-Fmoc protecting group is removed with piperidine in DMF to afford (III). This is submitted to further sequential amino acid coupling and deprotection cycles with Fmoc-phenylalanine (I) and alpha-Fmoc-omega-pmc-D-arginine (VI) to yield in turn resins (V) and (VII), respectively.
| 【1】 Brown, W.; DiMaio, J.; Schiller, P.; Martel, R. (AstraZeneca plc); Novel opioid peptides for the treatment of pain and use thereof. JP 1997509168; WO 9522557 . |
| 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) | 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 |
| (II) | 19031 | 9H-fluoren-9-ylmethyl (1S)-2-amino-1-benzyl-2-oxoethylcarbamate | C24H22N2O3 | 详情 | 详情 | |
| (III) | 19032 | (2S)-2-amino-3-phenylpropanamide | 5241-58-7 | C9H12N2O | 详情 | 详情 |
| (IV) | 19033 | 9H-fluoren-9-ylmethyl (1S)-2-[[(1S)-2-amino-1-benzyl-2-oxoethyl]amino]-1-benzyl-2-oxoethylcarbamate | C33H31N3O4 | 详情 | 详情 | |
| (V) | 19034 | (2S)-2-amino-N-[(1S)-2-amino-1-benzyl-2-oxoethyl]-3-phenylpropanamide | C18H21N3O2 | 详情 | 详情 | |
| (VI) | 19035 | (2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-[(imino[[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]pentanoic acid | 119831-72-0 | C35H42N4O7S | 详情 | 详情 |
| (VII) | 19036 | 9H-fluoren-9-ylmethyl (1R)-1-[[((1S)-2-[[(1S)-2-amino-1-benzyl-2-oxoethyl]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 | C53H63N7O8S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The title compound has been prepared by solid-phase peptide synthesis on a Knorr resin. N-Fmoc-L-Phenylalanine (I) is attached to the resin by means of BOP and HOBt, producing resin (II). Deprotection of the N-Fmoc group of (II) with piperidine in DMF gives the phenylalanine-bound resin (III). Subsequent coupling with N-Fmoc-L-p-fluorophenylalanine (IV) yields the dipeptide resin (V), which is further deprotected to (VI) with piperidine in DMF. Further coupling-deprotection cycles with N-Fmoc-D-alanine (VII) and N-Fmoc-O-tert-butyl-L-tyrosine (IX) provide the peptide resins (VIII) and (X) respectively. Finally, simultaneous cleavage from the resin and side chain deprotection is accomplished by treatment with trifluoroacetic acid.
| 【1】 Wang, W. (AstraZeneca plc); Novel opioid peptides. EP 0845003; JP 1999512086; US 6337319; WO 9707130 . |
| 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) | 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 |
| (II) | 19031 | 9H-fluoren-9-ylmethyl (1S)-2-amino-1-benzyl-2-oxoethylcarbamate | C24H22N2O3 | 详情 | 详情 | |
| (III) | 19032 | (2S)-2-amino-3-phenylpropanamide | 5241-58-7 | C9H12N2O | 详情 | 详情 |
| (IV) | 61042 | (2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-(4-fluorophenyl)propanoic acid | C24H20FNO4 | 详情 | 详情 | |
| (V) | 61043 | 9H-fluoren-9-ylmethyl (1S)-2-{[(1S)-2-amino-1-benzyl-2-oxoethyl]amino}-1-(4-fluorobenzyl)-2-oxoethylcarbamate | C33H30FN3O4 | 详情 | 详情 | |
| (VI) | 61044 | (2S)-2-amino-N-[(1S)-2-amino-1-benzyl-2-oxoethyl]-3-(4-fluorophenyl)propanamide | C18H20FN3O2 | 详情 | 详情 | |
| (VII) | 19926 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | C18H17NO4 | 详情 | 详情 | |
| (VIII) | 61045 | (2S)-N-[(1S)-2-amino-1-benzyl-2-oxoethyl]-2-{[(2R)-2-aminopropanoyl]amino}-3-(4-fluorophenyl)propanamide | C21H25FN4O3 | 详情 | 详情 | |
| (IX) | 18858 | (2S)-3-[4-(tert-butoxy)phenyl]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | C28H29NO5 | 详情 | 详情 | |
| (X) | 61046 | (2S)-2-amino-N-((1R)-2-{[(1S)-2-{[(1S)-2-amino-1-benzyl-2-oxoethyl]amino}-1-(4-fluorobenzyl)-2-oxoethyl]amino}-1-methyl-2-oxoethyl)-3-[4-(tert-butoxy)phenyl]propanamide | C34H42FN5O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)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 |