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【结 构 式】 
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【药物名称】Pibrozelesin hydrochloride, KW-2189 【化学名称】8(S)-(Bromomethyl)-2-methyl-4-(4-methylpiperazin-1-ylcarbonyloxy)-6-(5,6,7-trimethoxyindol-2-ylcarbonyl)-3,6,7,8-tetrahydrobenzo[1,2-b:4,3-b']dipyrrole-1-carboxylic acid methyl ester hydrochloride 【CA登记号】148778-32-9, 154889-68-6 (free base), 134106-78-8 (undefined stereoch.) 【 分 子 式 】C32H37BrClN5O8 【 分 子 量 】735.03739 |
【开发单位】Kyowa Hakko (Originator), National Cancer Institute (Licensee) 【药理作用】Oncolytic Drugs |
合成路线1
The reaction of 8(S)-(bromomethyl)-4-hydroxy-2-methyl-1-oxo-6-(5,6,7-trimethoxyindol-2-ylcarbonyl)-1,2,3,6,7,8-hexahydrobenzo[1,2-b:4,3-b']dipyrrole-2-carboxylic acid methyl ester (I) with tert-butyl-dimethylsilyl chloride in DMF gives the corresponding O-silyl derivative (II), which is treated with camphorsulfonic acid (CPS) in hot chloroform to afford 8(S)-(bromomethyl)-4-hydroxy-2-methyl-6-(5,6,7-trimethoxyindol-2-ylcarbonyl)-3,6,7,8-tetrahydrobenzo[1,2-b:4,3-b']dipyrrole-1-carboxylic acid methyl ester (III). Finally, this compound is desilylated with tetrabutylammonium fluoride in THF and condensed with N-methylpiperazine (IV) and 4-nitrophenyl chloroformate by means of triethylamine in dichloromethane.
| 【1】 Kanda, Y.; Uosaki, Y.; Saito, H.; Sano, H.; Kobayashi, E.; Morimoto, M.; Nagamura, S. (Kyowa Hakko Kogyo Co., Ltd.); DC-88A derivs. EP 0406749; JP 1991128379; US 5070092; US 5187186 . |
| 【2】 Castaner, J.; Hoshi, A.; KW-2189. Drugs Fut 1993, 18, 12, 1112. |
| 【3】 Saito, H.; Gomi, K.; Nagamura, S.; Kanda, Y.; Asai, A.; Kobayashi, E.; Synthesis, antitumor activity and DNA alkylation of duocarmycin analogs. Development of KW2189. 203rd ACS Natl Meet (April 5-10, San Francisco) 1992, Abst MEDI 44. |
| 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) | 14658 | methyl (8S)-8-(bromomethyl)-4-hydroxy-2-methyl-1-oxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,6,7,8-hexahydropyrrolo[3,2-e]indole-2-carboxylate | C26H26BrN3O8 | 详情 | 详情 | |
| (II) | 14659 | methyl (8S)-8-(bromomethyl)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1-oxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,6,7,8-hexahydropyrrolo[3,2-e]indole-2-carboxylate | C32H40BrN3O8Si | 详情 | 详情 | |
| (III) | 14660 | methyl (8S)-8-(bromomethyl)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C32H40BrN3O7Si | 详情 | 详情 | |
| (IV) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
合成路线2
A synthesis of [3H]-KW-2189 has been published: The condensation of duocarmycin B2 (I) with tert-butoxycarbonylpiperazine (II) and 4-nitrophenyl chloroformate by means of triethylamine in dichloromethane gives the expected piperazinecarboxylate (III), which is reduced with NaBH4 in allyl alcohol to yield the hydroxy-derivative (IV). The treatment of (IV) with camphorsulfonic acid (CSA) in hot toluene affords the isomerized compound (V) along with simultaneous deprotection of the piperazine ring. Finally, compound (V) is methylated with tritiated methyl iodide and NaHCO3 in acetone/methanol.
| 【1】 Ogasa, T.; Saito, H.; Kinugawa, M.; Nagamura, S.; The synthesis of [H-3]KW-2189, a novel active antitumor antibiotic. J Label Compd Radiopharm 1997, 39, 6, 471. |
| 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) | 17752 | methyl (2S,8S)-8-(bromomethyl)-4-hydroxy-2-methyl-1-oxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,6,7,8-hexahydropyrrolo[3,2-e]indole-2-carboxylate | C26H26BrN3O8 | 详情 | 详情 | |
| (II) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (III) | 17754 | 1-[(2S,8S)-8-(bromomethyl)-2-(methoxycarbonyl)-2-methyl-1-oxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,6,7,8-hexahydropyrrolo[3,2-e]indol-4-yl] 4-(tert-butyl) 1,4-piperazinedicarboxylate | C36H42BrN5O11 | 详情 | 详情 | |
| (IV) | 17755 | 1-[(1R,2S,8S)-8-(bromomethyl)-1-hydroxy-2-(methoxycarbonyl)-2-methyl-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,6,7,8-hexahydropyrrolo[3,2-e]indol-4-yl] 4-(tert-butyl) 1,4-piperazinedicarboxylate | C36H44BrN5O11 | 详情 | 详情 | |
| (V) | 17756 | methyl (8S)-8-(bromomethyl)-2-methyl-4-[(1-piperazinylcarbonyl)oxy]-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C31H34BrN5O8 | 详情 | 详情 |
合成路线3
The acylation of duocarmicin B2 (I) with 4-methylpiperazin-1-ylcarbonyl chloride (II) by means of pyridine in dichloromethane gives the carbamate (III), which is reduced with NaBH4 in methanol as the better solvent, to yield the secondary alcohol (IV). Finally, this compound is submitted to a Wagner-Meerwein rearrangement in acidic medium. CSA, TsOH, MsOH, TfOH and BF3.Et2O have been tested with similar yields and hot 1,2-dichloroethane and toluene have been used as solvents.
| 【1】 Masuda, Y.; Kasai, M.; Saito, H.; Sakaguchi, A.; Kinugawa, M.; Nagamura, S.; Ogasa, T.; Practical synthesis of the high-quality antitumor agent KW-2189 from duocarmycin B2 using a facile one-pot synthesis of an intermediate. Org Process Res Dev 1998, 2, 6, 344. |
| 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) | 42038 | methyl (1S,7R)-1-(bromomethyl)-5-hydroxy-7-methyl-8-oxo-3-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,6,7,8-hexahydrocyclopenta[e]indole-7-carboxylate | C27H27BrN2O8 | 详情 | 详情 | |
| (II) | 30370 | 4-methyl-1-piperazinecarbonyl chloride | C6H11ClN2O | 详情 | 详情 | |
| (III) | 42039 | methyl (1S,7R)-1-(bromomethyl)-7-methyl-5-[[(4-methyl-1-piperazinyl)carbonyl]oxy]-8-oxo-3-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,6,7,8-hexahydrocyclopenta[e]indole-7-carboxylate | C33H37BrN4O9 | 详情 | 详情 | |
| (IV) | 42040 | methyl (1S,7R)-1-(bromomethyl)-8-hydroxy-7-methyl-5-[[(4-methyl-1-piperazinyl)carbonyl]oxy]-3-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,6,7,8-hexahydrocyclopenta[e]indole-7-carboxylate | C33H39BrN4O9 | 详情 | 详情 |
合成路线4
The condensation of indoline (I) with methyl acetoacetate (II) by means of Ts-OH in refluxing benzene gives the adduct (III), which is cyclized by means of Pd(OAc)2 in hot DMA to yield the pyrroloindole (IV). The hydrolysis of the acetate group of (IV) by means of K2CO3 in methanol affords the hydroxymethyl compound (V), which is treated with CCl4 and PPh3 to provide the chloromethyl derivative (VI). The cleavage of the benzyl protecting group of (VI) by means of HCOONH4 and Pd/C in THF gives the hydroxy derivative (VII), which is N-deprotected by means of HCl in ethyl acetate to yield the intermediate (VIII). The condensation of (VIII) with 5,6,7-trimethoxy-1H-indole-2-carboxylic acid (IX) by means of EDC in DMF affords the carboxamide (X), which is treated with DBU in acetonitrile to provide the cyclopropapyrroloindole (XI). The reaction of (XI) with HBr in acetonitrile gives the bromomethyl derivative (XII), which is treated with 4-nitrophenyl chloroformate (XIII) to yield the active carbonate ester (XIV). Finally, this compound is treated with 1-methylpiperazine (XV) to provide the target Pibrozelesin.
| 【1】 Fukuda, Y.; et al.; Novel syntheses of optically active CC-1065, U-73,975 (adozelesin), U-80,244 (carzelesin), U-77,779 (bizelesin), KW-2189, and DU-86. Heterocycles 1997, 45, 12, 2303. |
| 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) | 59123 | tert-butyl (3S)-3-[(acetyloxy)methyl]-5-amino-6-(benzyloxy)-2,3-dihydro-1H-indole-1-carboxylate | C23H28N2O5 | 详情 | 详情 | |
| (II) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (III) | 61767 | tert-butyl (3S)-3-[(acetyloxy)methyl]-6-(benzyloxy)-5-{[(E)-3-methoxy-1-methyl-3-oxo-1-propenyl]amino}-2,3-dihydro-1H-indole-1-carboxylate | C28H34N2O7 | 详情 | 详情 | |
| (IV) | 61768 | 6-(tert-butyl) 1-methyl (8S)-8-[(acetyloxy)methyl]-4-(benzyloxy)-2-methyl-7,8-dihydropyrrolo[3,2-e]indole-1,6(3H)-dicarboxylate | C28H32N2O7 | 详情 | 详情 | |
| (V) | 61769 | 6-(tert-butyl) 1-methyl (8S)-4-(benzyloxy)-8-(hydroxymethyl)-2-methyl-7,8-dihydropyrrolo[3,2-e]indole-1,6(3H)-dicarboxylate | C26H30N2O6 | 详情 | 详情 | |
| (VI) | 61770 | 6-(tert-butyl) 1-methyl (8S)-4-(benzyloxy)-8-(chloromethyl)-2-methyl-7,8-dihydropyrrolo[3,2-e]indole-1,6(3H)-dicarboxylate | C26H29ClN2O5 | 详情 | 详情 | |
| (VII) | 61771 | 6-(tert-butyl) 1-methyl (8S)-8-(chloromethyl)-4-hydroxy-2-methyl-7,8-dihydropyrrolo[3,2-e]indole-1,6(3H)-dicarboxylate | C19H23ClN2O5 | 详情 | 详情 | |
| (VIII) | 61772 | methyl (8S)-8-(chloromethyl)-4-hydroxy-2-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C14H15ClN2O3 | 详情 | 详情 | |
| (IX) | 61773 | 5,6,7-trimethoxy-1H-indole-2-carboxylic acid | C12H13NO5 | 详情 | 详情 | |
| (X) | 61774 | methyl (8S)-8-(chloromethyl)-4-hydroxy-2-methyl-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C26H26ClN3O7 | 详情 | 详情 | |
| (XI) | 40881 | methyl (3bR,4aS)-2-methyl-8-oxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C26H25N3O7 | 详情 | 详情 | |
| (XII) | 61775 | methyl (8S)-8-(bromomethyl)-4-hydroxy-2-methyl-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C26H26BrN3O7 | 详情 | 详情 | |
| (XIII) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (XIV) | 61776 | methyl (8S)-8-(bromomethyl)-2-methyl-4-{[(4-nitrophenoxy)carbonyl]oxy}-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C33H29BrN4O11 | 详情 | 详情 | |
| (XV) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |