【结 构 式】 |
【药物名称】CRX-395 【化学名称】6-[5-(7-Amino-1H-indol-2-ylcarboxamido)-1-benzofuran-2-ylcarbonyl]-8(S)-(chloromethyl)-2-methyl-4-(4-methylpiperazin-1-ylcarbonyloxy)-3,6,7,8-tetrahydrobenzo[1,2-b:4,3-b']dipyrrole-1-carboxylic acid methyl ester 【CA登记号】477208-10-9 【 分 子 式 】C38H36ClN7O7 【 分 子 量 】738.20632 |
【开发单位】Corixa (Originator) 【药理作用】Oncolytic Drugs |
合成路线1
5-Nitrobenzofuran-2-carboxylic acid (I) is coupled to 4-nitrophenol (II) in the presence of EDC to produce the p-nitrophenyl ester (III). Subsequent acylation of the duocarmycin derivative (IV) with active ester (III) leads to amide (V). Cyclopropane ring opening in (V) with HCl in DMF furnishes the chloromethyl derivative (VI). The nitro group of (VI) is then reduced by catalytic hydrogenation, yielding amine (VII). Acylation of (VII) with 7-nitroindole-2-carboxylic acid (VIII) affords the corresponding amide (IX)
【1】 McGee, D.P.C.; Saunders, O.L.; Martichonok, V.; Wu, G.; Ng, H.P.; Li, Z.; Yarranton, G.T. (Medarex, Inc.); Cytotoxic agents. US 2003050331; WO 0296910 . |
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) | 63365 | 5-nitro-1-benzofuran-2-carboxylic acid | 10242-12-3 | C9H5NO5 | 详情 | 详情 |
(II) | 11236 | 4-Nitrophenol; p-Nitrophenol | 100-02-7 | C6H5NO3 | 详情 | 详情 |
(III) | 63440 | 4-nitrophenyl 5-nitro-1-benzofuran-2-carboxylate | C15H8N2O7 | 详情 | 详情 | |
(IV) | 38365 | methyl (3bR,4aS)-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C14H14N2O3 | 详情 | 详情 | |
(V) | 63441 | methyl 2-methyl-6-[(5-nitro-1-benzofuran-2-yl)carbonyl]-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C23H17N3O7 | 详情 | 详情 | |
(VI) | 63442 | methyl 8-(chloromethyl)-4-hydroxy-2-methyl-6-[(5-nitro-1-benzofuran-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C23H18ClN3O7 | 详情 | 详情 | |
(VII) | 63443 | methyl 6-[(5-amino-1-benzofuran-2-yl)carbonyl]-8-(chloromethyl)-4-hydroxy-2-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C23H20ClN3O5 | 详情 | 详情 | |
(VIII) | 63444 | 7-nitro-1H-indole-2-carboxylic acid | C9H6N2O4 | 详情 | 详情 | |
(IX) | 63445 | methyl 8-(chloromethyl)-4-hydroxy-2-methyl-6-[(5-{[(7-nitro-1H-indol-2-yl)carbonyl]amino}-1-benzofuran-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C32H24ClN5O8 | 详情 | 详情 |
合成路线2
The phenolic hydroxyl group of (IX) is acylated by 4-nitrophenyl chloroformate (X), producing carbonate (XI). Then, displacement of the 4-nitrophenoxy group of (XI) with N-methylpiperazine (XII) yields carbamate (XIII). Finally, nitro group reduction in (XIII) gives rise to the title compound
【1】 McGee, D.P.C.; Saunders, O.L.; Martichonok, V.; Wu, G.; Ng, H.P.; Li, Z.; Yarranton, G.T. (Medarex, Inc.); Cytotoxic agents. US 2003050331; WO 0296910 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(IX) | 63445 | methyl 8-(chloromethyl)-4-hydroxy-2-methyl-6-[(5-{[(7-nitro-1H-indol-2-yl)carbonyl]amino}-1-benzofuran-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C32H24ClN5O8 | 详情 | 详情 | |
(X) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
(XI) | 63446 | methyl 8-(chloromethyl)-2-methyl-6-[(5-{[(7-nitro-1H-indol-2-yl)carbonyl]amino}-1-benzofuran-2-yl)carbonyl]-4-({[(4-nitrophenyl)oxy]carbonyl}oxy)-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C39H27ClN6O12 | 详情 | 详情 | |
(XII) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
(XIII) | 63447 | methyl 8-(chloromethyl)-2-methyl-4-{[(4-methyl-1-piperazinyl)carbonyl]oxy}-6-[(5-{[(7-nitro-1H-indol-2-yl)carbonyl]amino}-1-benzofuran-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C38H34ClN7O9 | 详情 | 详情 |