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【结 构 式】 
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【分子编号】16892 【品名】N(alpha)-[s(S)-[N(alpha)-tert-butoxycarbonyl-N(omega)-tosyl-arginyl-prolyl-[4(R)-benzyloxy]prolyl-glycyl-[3-(2-thienyl)]alanyl-)O-benzyl)seryl-propylamino]-1-(4-methoxyphenyl)propyl]-N(alpha)-benzyl-N(omega)-tosyl-arginine methyl ester 【CA登记号】 |
【 分 子 式 】C84H111N15O16S2 【 分 子 量 】1651.02884 【元素组成】C 61.11% H 6.78% N 12.73% O 15.5% S 3.88% |
合成路线1
该中间体在本合成路线中的序号：(XXII)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.
| 【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 |
|---|---|---|---|---|---|---|
| (XX) | 16890 | tert-butyl (2S)-2-[[(2S,4R)-2-[(6S,9S)-9-([(2S)-2-[(3S,6S)-5-benzyl-11-imino-3-(4-methoxybenzyl)-6-(methoxycarbonyl)-2,5,10,12-tetraazatridec-1-anoyl]pyrrolidinyl]carbonyl)-4,7-dioxo-12-phenyl-6-(2-thienylmethyl)-11-oxa-2,5,8-triazadodec-1-anoyl]-4-(benzyloxy)pyrrolidinyl]carbonyl]-1-pyrrolidinecarboxylate | C71H93N11O13S | 详情 | 详情 | |
| (XXI) | 19064 | (2S)-2-[(tert-butoxycarbonyl)amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid | C18H28N4O6S | 详情 | 详情 | |
| (XXII) | 16892 | N(alpha)-[s(S)-[N(alpha)-tert-butoxycarbonyl-N(omega)-tosyl-arginyl-prolyl-[4(R)-benzyloxy]prolyl-glycyl-[3-(2-thienyl)]alanyl-)O-benzyl)seryl-propylamino]-1-(4-methoxyphenyl)propyl]-N(alpha)-benzyl-N(omega)-tosyl-arginine methyl ester | C84H111N15O16S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXII)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】 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. |
| 【2】 Graul, A.; Leeson, P.; Castañer, J.; RMP-7. Drugs Fut 1998, 23, 1, 32. |
| 【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 |
|---|---|---|---|---|---|---|
| RMP-7 | 41822 | C49H75N15O12S | 详情 | 详情 | ||
| (XXII) | 16892 | N(alpha)-[s(S)-[N(alpha)-tert-butoxycarbonyl-N(omega)-tosyl-arginyl-prolyl-[4(R)-benzyloxy]prolyl-glycyl-[3-(2-thienyl)]alanyl-)O-benzyl)seryl-propylamino]-1-(4-methoxyphenyl)propyl]-N(alpha)-benzyl-N(omega)-tosyl-arginine methyl ester | C84H111N15O16S2 | 详情 | 详情 | |
| (XXIII) | 16893 | (2S)-2-[[(2S)-2-([[(2S)-1-((2S)-2-[[(2S)-2-[(2-[[((2S,4R)-1-[[(2S)-1-((2S)-2-amino-5-[[amino(imino)methyl]amino]pentanoyl)pyrrolidinyl]carbonyl]-4-hydroxypyrrolidinyl)carbonyl]amino]acetyl)amino]-3-(5-bromo-2-thienyl)propanoyl]amino]-3-hydroxypropanoyl)pyrrolidinyl]carbonyl]amino)-3-(4-methoxyphenyl)propyl]amino]-5-[[amino(imino)methyl]amino]pentanoic acid | C49H74BrN15O12S | 详情 | 详情 |