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【结 构 式】 
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【分子编号】34634 【品名】2-((diethoxyphosphoryl)[2-[(methylsulfonyl)oxy]ethyl]amino)ethyl methanesulfonate 【CA登记号】 |
【 分 子 式 】C10H24NO9PS2 【 分 子 量 】397.407662 【元素组成】C 30.22% H 6.09% N 3.52% O 36.23% P 7.79% S 16.14% |
合成路线1
该中间体在本合成路线中的序号：(III)Protection of the amino group of diethanolamine (I) with diethyl chlorophosphate in the presence of triethylamine gave N-(diethoxyphosphoryl)ethanolamine (II). Further treatment of (II) with methanesulfonyl chloride yielded the corresponding bis(mesylate) (III). Reaction of 2,6-bis(bromomethyl) pyridine (IV) with NaCN in the presence of cetyl trimethylammonium bromide under phase-transfer conditions produced dinitrile (V), which was hydrogenated over Raney Nickel to afford diamine (VI). Subsequent condensation of (VI) with p-toluenesulfonyl chloride gave bis(sulfonamide) (VII). Cyclization of bis(mesylate) (III) with bis(sulfonamide) (VII) in the presence of Cs2CO3 gave rise to macrocycle (VIII). Selective deprotection of the diethoxyphosphoryl group by means of HBr in AcOH gave (IX). This was dimerized with alpha,alpha'-dibromo-p-xylene (X) in the presence of K2CO3 in refluxing acetonitrile to give the tosyl-protected dimer (XI). Deprotection of the tosyl groups of (XI) was achieved by reductive treatment with sodium amalgam. The title compound was then isolated after conversion to the octahydrobromide tetrahydrate salt.
| 【1】 Witvrouw, M.; Henson, G.W.; Padmanabhan, S.; De Clercq, E.; Struyf, S.; Martellucci, S.A.; Bridger, G.J.; Skerlj, R.T.; Schols, D.; Synthesis and structure-activity relationships of phenylenebis (methylene)-linked bis-azamacrocycles that inhibit HIV-1 and HIV-2 replication by antagonism of the chemokine receptor CXCR4. J Med Chem 1999, 42, 19, 3971. |
| 【2】 Bridger, G.J.; Padmanabhan, S.; Skerlj, R.T. (Johnson Matthey plc); Cyclic polyamines. EP 0739345; JP 1997509407; US 5698546; WO 9518808 . |
| 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) | 24273 | 2-[(2-hydroxyethyl)amino]-1-ethanol | 111-42-2 | C4H11NO2 | 详情 | 详情 |
| (II) | 34633 | C8H20NO5P | 详情 | 详情 | ||
| (III) | 34634 | 2-((diethoxyphosphoryl)[2-[(methylsulfonyl)oxy]ethyl]amino)ethyl methanesulfonate | C10H24NO9PS2 | 详情 | 详情 | |
| (IV) | 34635 | 2,6-bis(bromomethyl)pyridine | 7703-74-4 | C7H7Br2N | 详情 | 详情 |
| (V) | 34636 | 2-[6-(2-nitriloethyl)-2-pyridinyl]acetonitrile | C9H7N3 | 详情 | 详情 | |
| (VI) | 34637 | 2-[6-(2-aminoethyl)-2-pyridinyl]-1-ethanamine; 2-[6-(2-aminoethyl)-2-pyridinyl]ethylamine | C9H15N3 | 详情 | 详情 | |
| (VII) | 34638 | 4-methyl-N-[2-[6-(2-[[(4-methylphenyl)sulfonyl]amino]ethyl)-2-pyridinyl]ethyl]benzenesulfonamide | C23H27N3O4S2 | 详情 | 详情 | |
| (VIII) | 34639 | diethyl 4,10-bis[(4-methylphenyl)sulfonyl]-4,7,10,17-tetraazabicyclo[11.3.1]heptadeca-1(17),13,15-trien-7-ylphosphonate | C31H43N4O7PS2 | 详情 | 详情 | |
| (IX) | 34640 | 4,10-bis[(4-methylphenyl)sulfonyl]-4,7,10,17-tetraazabicyclo[11.3.1]heptadeca-1(17),13,15-triene | C27H34N4O4S2 | 详情 | 详情 | |
| (X) | 18697 | 1,4-bis(bromomethyl)benzene | 623-24-5 | C8H8Br2 | 详情 | 详情 |
| (XI) | 34641 | 7-(4-[[4,10-bis[(4-methylphenyl)sulfonyl]-4,7,10,17-tetraazabicyclo[11.3.1]heptadeca-1(17),13,15-trien-7-yl]methyl]benzyl)-4,10-bis[(4-methylphenyl)sulfonyl]-4,7,10,17-tetraazabicyclo[11.3.1]heptadeca-1(17),13,15-triene | C62H74N8O8S4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)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.
| 【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 |