DPP-NH[psi], -Drug Synthesis Database

【结构式】

【药物名称】DPP-NH[psi]

【化学名称】2,6-Dimethyltyrosyl-(1,2,3,4-tetrahydroisoquinolin-3-ylmethyl)-phenylalanyl-phenylalaninamide

【CA登记号】

【分子式】C₃₉H₄₅N₅O₄

【分子量】647.8246

【开发单位】AstraZeneca (Originator)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, IMMUNOMODULATING AGENTS, Immunosuppressants, Opioid Analgesics, delta-Opioid Antagonists, mu-Opioid Agonists

合成路线1 合成路线2

合成路线1

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.

参考文献中间体

【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

The intermediate 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carbaldehyde (V) has been obtained as follows: The reaction of 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (XI) with N,O-dimethylhydroxylamine (XII) by means of BOP gives the corresponding N-methoxy-N-methylamide (XIII), which the reduced to the target aldehyde (V) with LiAlH4.

参考文献中间体

【1】 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
(V)	40873	tert-butyl 3-formyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate		C₁₅H₁₉NO₃	详情	详情
(XI)	40879	2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid		C₁₅H₁₉NO₄	详情	详情
(XII)	13361	(Methoxyamino)methane; N,O-Dimethylhydroxylamine	1117-97-1	C₂H₇NO	详情	详情
(XIII)	40880	tert-butyl 3-[[methoxy(methyl)amino]carbonyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate		C₁₇H₂₄N₂O₄	详情	详情

Extended Information