CGP-64222, -Drug Synthesis Database

【结构式】

【药物名称】CGP-64222

【化学名称】N-(6-Aminohexyl)glycyl-[N-(3-guanidinopropyl)]glycyl-[N-(3-guanidinopropyl)]glycyl-(N-benzyl)glycyl-[N-(3-guanidinopropyl)]glycyl-D-lysyl-D-lysyl-D-arginyl-D-prolinamide

【CA登记号】186380-62-1

【分子式】C₅₈H₁₀₇N₂₅O₉

【分子量】1298.66159

【开发单位】Novartis (Originator)

【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Tat Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

The title compound was prepared by solid-phase peptide synthesis starting from N-Fmoc-D-proline linked to Rink resin (I). Deprotection of the Fmoc group by means of piperidine in DMA afforded proline-resin (II). Coupling of N-alpha-Fmoc-NG-Pmc-D-arginine (III) to proline-resin (II) using diisopropyl carbodiimide (DIC) and HOBt, followed by Fmoc deprotection with piperidine in DMA, furnished dipeptide-resin (IV). Further coupling and deprotection cycles incorporating the amino acid N2-Fmoc-N6-Boc-D-lysine (V) (twice) and the peptoid residue N-Fmoc-N-[3-(3-Pmc-guanidino)propyl]glycine (VIII) yielded the peptide resins (VI), (VII) and (IX), respectively.

参考文献中间体

【1】 Hamy, F.; et al.; An inhibitor of the Tat/TAR RNA interaction that effectively suppresses HIV-1 replication. Proceedings of the National Academy of Sciences of the United States of America 1997, 94, 8, 3548.
【2】 Felder, E.; Hamy, F.; Heizmann, G.; Klimkait, T.; Lazdins, J.K. (Novartis AG); Antiviral peptoid cpds.. EP 0832110; WO 9640759 .

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)	42841	9H-fluoren-9-ylmethyl (2R)-2-(aminocarbonyl)-1-pyrrolidinecarboxylate		C₂₀H₂₀N₂O₃	详情	详情
(II)	37077	(2R)-2-pyrrolidinecarboxamide		C₅H₁₀N₂O	详情	详情
(III)	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
(IV)	42842	(2R)-1-[(2R)-2-amino-5-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]pentanoyl]-2-pyrrolidinecarboxamide		C₂₅H₄₂N₆O₅S	详情	详情
(V)	42847	(2R)-6-[(tert-butoxycarbonyl)amino]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]hexanoic acid		C₂₆H₃₂N₂O₆	详情	详情
(VI)	42843	tert-butyl (5R)-5-amino-6-([(1R)-1-[[(2R)-2-(aminocarbonyl)pyrrolidinyl]carbonyl]-4-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]butyl]amino)-6-oxohexylcarbamate		C₃₆H₆₂N₈O₈S	详情	详情
(VII)	42844	tert-butyl (5R)-5-amino-6-([(1R)-1-[([(1R)-1-[[(2R)-2-(aminocarbonyl)pyrrolidinyl]carbonyl]-4-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]butyl]amino)carbonyl]-5-[(tert-butoxycarbonyl)amino]pentyl		C₄₇H₈₂N₁₀O₁₁S	详情	详情
(VIII)	42845	2-([(9H-fluoren-9-ylmethoxy)carbonyl][3-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]propyl]amino)acetic acid		C₃₅H₄₄N₄O₇S	详情	详情
(IX)	42846	tert-butyl (5R,8R)-5-[([(1R)-1-[[(2R)-2-(aminocarbonyl)pyrrolidinyl]carbonyl]-4-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]butyl]amino)carbonyl]-8-[4-[(tert-butoxycarbonyl)amino]butyl]-17-imino-7		C₆₇H₁₁₄N₁₄O₁₅S₂	详情	详情

合成路线2

Further coupling and deprotection cycles incorporating peptoid N-Fmoc-N-benzylglycine (X), and twice peptoid (VIII), yielded the peptoid-resins (XI) and (XII), respectively. Bromoacetic acid (XIII) was subsequently coupled to resin (XII) to afford the bromoacetamido peptoid-resin (XIV).

参考文献中间体

【1】 Hamy, F.; et al.; An inhibitor of the Tat/TAR RNA interaction that effectively suppresses HIV-1 replication. Proceedings of the National Academy of Sciences of the United States of America 1997, 94, 8, 3548.
【2】 Felder, E.; Hamy, F.; Heizmann, G.; Klimkait, T.; Lazdins, J.K. (Novartis AG); Antiviral peptoid cpds.. EP 0832110; WO 9640759 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	42845	2-([(9H-fluoren-9-ylmethoxy)carbonyl][3-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]propyl]amino)acetic acid		C₃₅H₄₄N₄O₇S	详情	详情
(IX)	42846	tert-butyl (5R,8R)-5-[([(1R)-1-[[(2R)-2-(aminocarbonyl)pyrrolidinyl]carbonyl]-4-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]butyl]amino)carbonyl]-8-[4-[(tert-butoxycarbonyl)amino]butyl]-17-imino-7		C₆₇H₁₁₄N₁₄O₁₅S₂	详情	详情
(X)	42848	2-[benzyl[(9H-fluoren-9-ylmethoxy)carbonyl]amino]acetic acid		C₂₄H₂₁NO₄	详情	详情
(XI)	42849	tert-butyl (5R,8R)-5-[([(1R)-1-[[(2R)-2-(aminocarbonyl)pyrrolidinyl]carbonyl]-4-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]butyl]amino)carbonyl]-12-[2-(benzylamino)acetyl]-8-[4-[(tert-butoxycarbo		C₇₆H₁₂₃N₁₅O₁₆S₂	详情	详情
(XII)	42850			C₁₁₆H₁₈₇N₂₃O₂₄S₄	详情	详情
(XIII)	23660	2-Bromoacetic acid	79-08-3	C₂H₃BrO₂	详情	详情
(XIV)	42851			C₁₁₈H₁₈₈BrN₂₃O₂₅S₄	详情	详情

合成路线3

Displacement of the bromine of (XIV) with N-Boc-1,6-diaminohexane (XV) produced resin (XVI). Finally, the side-chain protecting groups of (XVI) were cleaved and the desired peptoid was liberated from the resin by treatment with trifluoroacetic acid.

参考文献中间体

【1】 Hamy, F.; et al.; An inhibitor of the Tat/TAR RNA interaction that effectively suppresses HIV-1 replication. Proceedings of the National Academy of Sciences of the United States of America 1997, 94, 8, 3548.
【2】 Felder, E.; Hamy, F.; Heizmann, G.; Klimkait, T.; Lazdins, J.K. (Novartis AG); Antiviral peptoid cpds.. EP 0832110; WO 9640759 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIV)	42851			C₁₁₈H₁₈₈BrN₂₃O₂₅S₄	详情	详情
(XV)	31638	tert-butyl 6-aminohexylcarbamate	51857-17-1	C₁₁H₂₄N₂O₂	详情	详情
(XVI)	42852	tert-butyl (23R,26R)-26-[([(1R)-1-[[(2R)-2-(aminocarbonyl)pyrrolidinyl]carbonyl]-4-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]butyl]amino)carbonyl]-16-benzyl-23-[4-[(tert-butoxycarbonyl)amino]but		C₁₂₉H₂₁₁N₂₅O₂₇S₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)