AMD-7049(free base), AMD-8664, -Drug Synthesis Database

【结构式】

【药物名称】AMD-7049(free base), AMD-8664

【化学名称】N-(2-Pyridinylmethyl)-N-[4-(1,4,7-triazacyclotetradecan-4-ylmethyl)benzyl]amine tetrahydrochloride

【CA登记号】255383-00-7

【分子式】C₂₅H₄₃Cl₄N₅

【分子量】555.46696

【开发单位】AnorMED (Originator)

【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Chemokine CXCR4 Antagonists

合成路线1 合成路线2

合成路线1

The acylation of 1,7-heptanediamine (I) with 2-nitrobenzenesulfonyl chloride (II) by means of TEA in dichloromethane gives the bis sulfamide (III), which is submitted to macrocyclization with the dimesylate (IV) by means of Cs2CO3 in hot DMF, yielding the protected 1,4,7-triazacyclotetradecane (V). The cleavage of the phosphoryl group of (IV) with HBr in acetic acid affords the secondary amine (VI), which is alkylated with he benzyl chloride (VII) by means of K2CO3 in refluxing acetonitrile, providing the adduct (VIII). This compound is deprotected with K2CO3 in DMF and treated with HCl or HBr to furnish the corresponding target salts.

参考文献中间体

【2】 Bogucki, D.E.; Boehringer, E.M.; Wang, Z.; Bridger, G.J.; Schols, D.; Skerlj, R.T. (AnorMED Inc.); Antiviral macrocyclic cpds.. EP 1095031; WO 0002870 .
【1】 De Clercq, E.; HEnson, G.; Schols, D.; Witvrouw, M.; Macfarland, R.T.; Bridger, G.J.; Skerli, R.T.; Yasuda, N.; An orally bioavailable CXCR4 antagonist for inhibition of HIV replication. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1845.

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)	12941	7-Aminoheptylamine; 1,7-Diaminoheptane; 1,7-Heptanediamine	646-19-5	C₇H₁₈N₂	详情	详情
(II)	32624	2-Nitrobenzenesulfonyl chloride	1694-92-4	C₆H₄ClNO₄S	详情	详情
(III)	46248	2-nitro-N-(7-[[(2-nitrophenyl)sulfonyl]amino]heptyl)benzenesulfonamide		C₁₉H₂₄N₄O₈S₂	详情	详情
(IV)	34634	2-((diethoxyphosphoryl)[2-[(methylsulfonyl)oxy]ethyl]amino)ethyl methanesulfonate		C₁₀H₂₄NO₉PS₂	详情	详情
(V)	46249	diethyl 1,7-bis[(2-nitrophenyl)sulfonyl]-1,4,7-triazacyclotetradecan-4-ylphosphonate		C₂₇H₄₀N₅O₁₁PS₂	详情	详情
(VI)	46250	1,7-bis[(2-nitrophenyl)sulfonyl]-1,4,7-triazacyclotetradecane		C₂₃H₃₁N₅O₈S₂	详情	详情
(VII)	46251	N-[4-(chloromethyl)benzyl]-2-nitro-N-(2-pyridinylmethyl)benzenesulfonamide		C₂₀H₁₈ClN₃O₄S	详情	详情
(VIII)	46252	N-[4-([1,7-bis[(2-nitrophenyl)sulfonyl]-1,4,7-triazacyclotetradecan-4-yl]methyl)benzyl]-2-nitro-N-(2-pyridinylmethyl)benzenesulfonamide		C₄₃H₄₈N₈O₁₂S₃	详情	详情

合成路线2

The intermediate benzyl chloride (VII) is obtained as follows: The reduction of 4-(bromomethyl)benzoic acid methyl ester (IX) with DIBAL in dichloromethane gives 4-(bromomethyl)benzyl alcohol (X), which is condensed with sulfamide (XI) (obtained by sulfonation of 2-(aminomethyl)pyridine (XII) with sulfonyl chloride (II) and TEA), by means of K2CO3 in dichloromethane, yielding the disubstituted sulfamide (XIII). Finally, the hydroxymethyl group of (XIII) is treated with MsCl and TEA in refluxing dichloromethane to afford the target benzyl chloride (VII).

参考文献中间体

【1】 Bogucki, D.E.; Boehringer, E.M.; Wang, Z.; Bridger, G.J.; Schols, D.; Skerlj, R.T. (AnorMED Inc.); Antiviral macrocyclic cpds.. EP 1095031; WO 0002870 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	32624	2-Nitrobenzenesulfonyl chloride	1694-92-4	C₆H₄ClNO₄S	详情	详情
(VII)	46251	N-[4-(chloromethyl)benzyl]-2-nitro-N-(2-pyridinylmethyl)benzenesulfonamide		C₂₀H₁₈ClN₃O₄S	详情	详情
(IX)	14565	methyl 4-(bromomethyl)benzoate	2417-72-3	C₉H₉BrO₂	详情	详情
(X)	46253	[4-(bromomethyl)phenyl]methanol		C₈H₉BrO	详情	详情
(XI)	46254	2-nitro-N-(2-pyridinylmethyl)benzenesulfonamide		C₁₂H₁₁N₃O₄S	详情	详情
(XII)	13582	2-Pyridinylmethanamine; 2-Pyridinylmethylamine; 2-(Aminomethyl)pyridine	3731-51-9	C₆H₈N₂	详情	详情
(XIII)	46255	N-[4-(hydroxymethyl)benzyl]-2-nitro-N-(2-pyridinylmethyl)benzenesulfonamide		C₂₀H₁₉N₃O₅S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)