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【结 构 式】 
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【分子编号】16888 【品名】(2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-thienyl)propionic acid；Boc-D-2-Thienylalanine 【CA登记号】78452-55-8 |
【 分 子 式 】C12H17NO4S 【 分 子 量 】271.33732 【元素组成】C 53.12% H 6.32% N 5.16% O 23.59% S 11.82% |
合成路线1
该中间体在本合成路线中的序号：(XIV)The reaction of N-(tert-butoxycarbonyl [Boc])-4-O-methyl-L-tyrosine (I) with N,O-dimethylhydroxylamine (II) by means of dicyclohexylcarbodiimide (DCC) in THF gives the corresponding amide (III), which is reduced with LiAlH4 in ethyl ether yielding N-(tert-butoxycarbonyl)-4-O-methyl-L-tyrosinal (IV). The reductocondensation of (IV) with Nomega-tosyl-L-arginine (V) in methanol/acetic acid affords Nalpha-[2(S)-(tert-butoxycarbonylamino)-3-(4-methoxyphenyl)propyl]-Nomega-tosyl-L-arginine (VI), which is then attached to a polyestyrene resin (Merrifield resin) by means of DCC and dimethylaminopyridine (DMAP) to give the starting peptide-resin complex (IX). This resin (IX) is introduced into a Beckman 990 peptide synthesizer and submitted to successive amino acid coupling cycles (deprotection with TFA and coupling with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate [BOP]) in order to introduce successively Boc-L-proline (X), Boc-L-serine (XII), Boc-L-(2-thienyl)alanine (XIV), Boc-glycine (XVI), Boc-L-(4-benzyloxy)proline (XVIII), Boc-L-proline (X), and Boc-L-(Nomega-tosyl)arginine (XXI) yielding resins (XI), (XIII), (XV), (XVII), (XIX), (XX), and the final resin (XXII), successively. The final peptide (RMP-7) is liberated from the resin (XXII) and simultaneously deprotected by a treatment with anhydrous HF with a 10% anisole and purified by HPLC over a C18 reverse phase column using trifluoroacetic acid/acetonitrile with a 0-25% gradient. Tritiated RMP-7 is obtained by bromination of RMP-7 with Br2 in acetic acid giving a monobrominated compound (XXIII) (basically the 5-position of the thiophene ring of thienylalanine is brominated), which is then tritiated with 3H2 and Pd/C in water.
| 【1】 Graul, A.; Leeson, P.; Castañer, J.; RMP-7. Drugs Fut 1998, 23, 1, 32. |
| 【2】 Straub, J.A.; Musso, G.F.; Smart, J.L.; Lang, C.; Akiyama, A.; Bromination and subsequent catalytic tritiation of thienylalanine and 4-methyltyrosine residues in the bradykinin analog RMP-7. J Label Compd Radiopharm 1994, 34, 12, 1217-26. |
| 【3】 Malfroy-Camine, B.; Smart, J.L. (Alkermes, Inc.); Method for increasing blood-brain barrier permeability. WO 9116355 . |
| 【4】 Kozarich, J.W.; Musso, G.F.; Malfroy-Camine, B. (Alkermes, Inc.); Increasing blood-brain barrier permeability with permeabilizer peptides. WO 9218529 . |
| 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) | 16875 | (2S)-2-[(tert-Butoxycarbonyl)amino]-3-(4-methoxyphenyl)propionic acid; N-t-BOC-O-Methyl-L-tyrosine | 53267-93-9 | C15H21NO5 | 详情 | 详情 |
| (II) | 13361 | (Methoxyamino)methane; N,O-Dimethylhydroxylamine | 1117-97-1 | C2H7NO | 详情 | 详情 |
| (III) | 16877 | tert-butyl N-[(1S)-1-(4-methoxybenzyl)-2-[methoxy(methyl)amino]-2-oxoethyl]carbamate | C17H26N2O5 | 详情 | 详情 | |
| (IV) | 16878 | tert-butyl N-[(1S)-1-formyl-2-(4-methoxyphenyl)ethyl]carbamate | C15H21NO4 | 详情 | 详情 | |
| (V) | 16879 | (2S)-2-amino-5-[[imino(methylamino)methyl]amino]pentanoic acid | C7H16N4O2 | 详情 | 详情 | |
| (VI) | 16880 | (2S)-2-[[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-methoxyphenyl)propyl]amino]-5-[[imino(methylamino)methyl]amino]pentanoic acid | C22H37N5O5 | 详情 | 详情 | |
| (VII) | 16881 | (2S)-2-[benzyl[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-methoxyphenyl)propyl]amino]-5-[[imino(methylamino)methyl]amino]pentanoic acid | C29H43N5O5 | 详情 | 详情 | |
| (IX) | 16883 | methyl (2S)-2-[benzyl[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-methoxyphenyl)propyl]amino]-5-[[imino(methylamino)methyl]amino]pentanoate | C30H45N5O5 | 详情 | 详情 | |
| (X) | 16734 | (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid | C10H17NO4 | 详情 | 详情 | |
| (XI) | 16885 | tert-butyl (2S)-2-[(3S,6S)-5-benzyl-11-imino-3-(4-methoxybenzyl)-6-(methoxycarbonyl)-2,5,10,12-tetraazatridec-1-anoyl]-1-pyrrolidinecarboxylate | C35H52N6O6 | 详情 | 详情 | |
| (XII) | 16886 | (2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid; N-alpha-t-BOC-o-benzyl-L-serine | 23680-31-1 | C15H21NO5 | 详情 | 详情 |
| (XIII) | 16887 | methyl (2S)-2-[benzyl[(2S)-2-[[((2S)-1-[(2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]pyrrolidinyl)carbonyl]amino]-3-(4-methoxyphenyl)propyl]amino]-5-[[imino(methylamino)methyl]amino]pentanoate | C45H63N7O8 | 详情 | 详情 | |
| (XIV) | 16888 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-thienyl)propionic acid；Boc-D-2-Thienylalanine | 78452-55-8 | C12H17NO4S | 详情 | 详情 |
| (XV) | 16889 | methyl (2S)-2-[benzyl[(2S)-2-([[(2S)-1-((2S)-3-(benzyloxy)-2-[[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-thienyl)propanoyl]amino]propanoyl)pyrrolidinyl]carbonyl]amino)-3-(4-methoxyphenyl)propyl]amino]-5-[[imino(methylamino)methyl]amino]pentanoate | C52H70N8O9S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXI)Peptide resin (XX) was subjected to sequential coupling-deprotection cycles with the following amino acids: N-Boc-(2-thienyl)alanine (XXI), N-Boc-glycine (XXIII), N-Boc-4-hydroxyproline (XXV), N-Boc-proline (XXVII), Nalpha-Boc-Ngamma-tosyl-arginine (XXIX) and Nalpha-Boc-Ngamma-nitro-D-arginine (XXXI) to produce peptide resins (XXII), (XXIV), (XXVI), (XXVIII), (XXX) and (XXXII), respectively. The title peptide was finally obtained by deprotection and cleavage from the resin by means of treatment with HF.
| 【1】 Daffix, I.; Bergé, G.; Amblard, M.; et al.; Synthesis and characterization of bradykinin B2 receptor agonists containing constrained dipeptide mimics. J Med Chem 1999, 42, 20, 4193. |
| 【2】 Dodey, P.; Luccarini, J.-M.; Martinez, J.; Amblard, M.; Daffix, I. (Fournier Industrie et Santé); Peptides agonists of bradykinine B2 receptor. FR 2756566; WO 9824809 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XX) | 39383 | (2S)-2-([2-[(3S)-3-[[(2S)-2-amino-3-(benzyloxy)propanoyl]amino]-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetyl]amino)-5-[(amino[[(4-methylphenyl)sulfonyl]imino]methyl)amino]pentanoic acid | C35H43N7O8S2 | 详情 | 详情 | |
| (XXI) | 16888 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-thienyl)propionic acid；Boc-D-2-Thienylalanine | 78452-55-8 | C12H17NO4S | 详情 | 详情 |
| (XXII) | 39385 | (2S)-5-[(amino[[(4-methylphenyl)sulfonyl]imino]methyl)amino]-2-([2-[(3S)-3-[[(2S)-2-[[(2S)-2-amino-3-(2-thienyl)propanoyl]amino]-3-(benzyloxy)propanoyl]amino]-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetyl]amino)pentanoic acid | C42H50N8O9S3 | 详情 | 详情 | |
| (XXIII) | 18066 | N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid | 4530-20-5 | C7H13NO4 | 详情 | 详情 |
| (XXIV) | 39386 | C44H53N9O10S3 | 详情 | 详情 | ||
| (XXV) | 19043 | (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid | C10H17NO5 | 详情 | 详情 | |
| (XXVI) | 39387 | C49H60N10O12S3 | 详情 | 详情 | ||
| (XXVII) | 16734 | (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid | C10H17NO4 | 详情 | 详情 | |
| (XXVIII) | 39388 | C54H67N11O13S3 | 详情 | 详情 |