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【结 构 式】 
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【分子编号】40876 【品名】(2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-[(tert-butoxycarbonyl)oxy]-2,6-dimethylphenyl]propionic acid 【CA登记号】 |
【 分 子 式 】C21H31NO7 【 分 子 量 】409.47968 【元素组成】C 61.6% H 7.63% N 3.42% O 27.35% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The condensation of resin bounded L-phenylalanine (I) with N-(tert-butoxycarbonyl)-L-phenylalanine (II) by means of 1,3-diisopropylcarbodiimide (DIC) and HOBT gives the protected, resin bounded dipeptide (III), which is deprotected with TFA to yield the dipeptide (IV). The reductocondensation of (IV) with 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carbaldehyde (V) by means of NaBH3CN affords the protected pseudo tripeptide (VI), which is deprotected with TFA as before yielding the pseudo tripeptide (VII). The condensation of (VII) with the protected L-dimethyltyrosine (VIII) by means of DIC and HOBT affords the protected resin bounded seudotetrapeptide (IX), which is deprotected with TFA as before giving the resin bounded seudotetrapeptide (X). Finally, the target seudotetrapeptide is cleaved from the resin by means of HF and anisole.
| 【1】 Chung, N.N.; Weltrowska, G.; Fundytus, M.E.; Merovitz, L.; Schiller, P.W.; Coderre, T.J.; Nguyen, T.M.D.; Lemieux, C.; The opioid mu agonist/delta antagonist DIPP-NH2[psi] produces a potent analgesic effect, no physical dependence, and less tolerance than morphine in rats. J Med Chem 1999, 42, 18, 3520. |
| 【2】 Schiller, P. (AstraZeneca plc); New peptides. EP 0678099; JP 1996505386; WO 9415959 . |
| 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) | 19032 | (2S)-2-amino-3-phenylpropanamide | 5241-58-7 | C9H12N2O | 详情 | 详情 |
| (II) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (III) | 40872 | tert-butyl (1S)-2-[[(1S)-2-amino-1-benzyl-2-oxoethyl]amino]-1-benzyl-2-oxoethylcarbamate | C23H29N3O4 | 详情 | 详情 | |
| (IV) | 19034 | (2S)-2-amino-N-[(1S)-2-amino-1-benzyl-2-oxoethyl]-3-phenylpropanamide | C18H21N3O2 | 详情 | 详情 | |
| (V) | 40873 | tert-butyl 3-formyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate | C15H19NO3 | 详情 | 详情 | |
| (VI) | 40874 | tert-butyl 3-[[((1S)-2-[[(1S)-2-amino-1-benzyl-2-oxoethyl]amino]-1-benzyl-2-oxoethyl)amino]methyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate | C33H40N4O4 | 详情 | 详情 | |
| (VII) | 40875 | (2S)-3-phenyl-2-([(2S)-3-phenyl-2-[(1,2,3,4-tetrahydro-3-isoquinolinylmethyl)amino]propanoyl]amino)propanamide | C28H32N4O2 | 详情 | 详情 | |
| (VIII) | 40876 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-[(tert-butoxycarbonyl)oxy]-2,6-dimethylphenyl]propionic acid | C21H31NO7 | 详情 | 详情 | |
| (IX) | 40877 | 4-[(2S)-3-[3-[[((1S)-2-[[(1S)-2-amino-1-benzyl-2-oxoethyl]amino]-1-benzyl-2-oxoethyl)amino]methyl]-3,4-dihydro-2(1H)-isoquinolinyl]-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl]-3,5-dimethylphenyl tert-butyl carbonate | C49H61N5O8 | 详情 | 详情 | |
| (X) | 40878 | (2S)-N-[(1S)-2-amino-1-benzyl-2-oxoethyl]-2-[([2-[(2S)-2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]-1,2,3,4-tetrahydro-3-isoquinolinyl]methyl)amino]-3-phenylpropanamide | C39H45N5O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)The title peptide was prepared by solid-phase synthesis using a p-methylbenzhydrylamine resin (II). Coupling of Boc-lysine(2-ClZ) (I) to the resin (II) using diisopropylcarbodiimide (DIC) and 1-hydroxybenzotriazole (HOBt) afforded the amide resin (III). The N-Boc group was then selectively deprotected with trifluoroacetic acid in CH2Cl2, yielding resin (IV). To this were sequentially attached the protected amino acids: Boc-phenylalanine (V), Boc-D-arginine(Ts) (VII) and Boc-2',6'-dimethyltyrosine(Boc) (IX) employing DIC/HOBt and then Boc deprotection with trifluoroacetic acid to provide the peptide resins (VI), (VIII) and (X), respectively. Finally, the desired peptide amide was deprotected and cleaved from the resin (X) by treatment with HF and anisole.
| 【1】 Nguyen, T.M.-D.; Dupuis, S.; Chung, N.N.; Schiller, P.W.; Berezowska, I.; Lemieux, C.; Weltrowska, G.; Synthesis and in vitro opioid activity profiles of DALDA analogues. Eur J Med Chem 2000, 35, 10, 895. |
| 【2】 Schiller, P. (AstraZeneca AB); DALDA analogs and their use. WO 0055189 . |
| 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) | 31374 | (2S)-2-[(tert-butoxycarbonyl)amino]-6-([[(2-chlorobenzyl)oxy]carbonyl]amino)hexanoic acid | C19H27ClN2O6 | 详情 | 详情 | |
| (III) | 45666 | 2-chlorobenzyl (5S)-6-amino-5-[(tert-butoxycarbonyl)amino]-6-oxohexylcarbamate | C19H28ClN3O5 | 详情 | 详情 | |
| (IV) | 45669 | 2-chlorobenzyl (5S)-5,6-diamino-6-oxohexylcarbamate | C14H20ClN3O3 | 详情 | 详情 | |
| (V) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (VI) | 45667 | 2-chlorobenzyl (5S)-6-amino-5-[[(2S)-2-amino-3-phenylpropanoyl]amino]-6-oxohexylcarbamate | C23H29ClN4O4 | 详情 | 详情 | |
| (VII) | 39391 | (2S)-2-[(tert-butoxycarbonyl)amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid | C18H28N4O6S | 详情 | 详情 | |
| (VIII) | 45668 | 2-chlorobenzyl (5S)-6-amino-5-[[(2S)-2-([(2R)-2-amino-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoyl]amino)-3-phenylpropanoyl]amino]-6-oxohexylcarbamate | C36H47ClN8O7S | 详情 | 详情 | |
| (IX) | 40876 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-[(tert-butoxycarbonyl)oxy]-2,6-dimethylphenyl]propionic acid | C21H31NO7 | 详情 | 详情 | |
| (X) | 45670 | 2-chlorobenzyl (5S)-6-amino-5-[[(2S)-2-([(2R)-2-[[(2S)-2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoyl]amino)-3-phenylpropanoyl]amino]-6-oxohexylcarbamate | C47H60ClN9O9S | 详情 | 详情 |