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 -Drug Synthesis Database

【结构式】

【分子编号】40881

【品名】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

【CA登记号】

【分子式】C₂₆H₂₅N₃O₇

【分子量】491.50052

【元素组成】C 63.54% H 5.13% N 8.55% O 22.79%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(XI)

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.

参考文献中间体

合成目标

【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

合成路线2

该中间体在本合成路线中的序号：(I)

The hydrolysis of DU-86 (I) with NaOMe gives tetracyclic compound (II), which is acylated with the 4-nitrophenyl cinnamate (III) and NaH yielding the adduct (IV). The opening of the cyclopropane ring of (IV) with HBr in acetonitrile affords the aromatic phenol (V), which is activated with 4-nitrophenyl chloroformate (VI) and TEA to provide the activated anhydride (VII). Finally, this compound is condensed with 4-methylpiperazine-1-amine (VIII), and treated with HBr to furnish the target dihydrobromide.

参考文献中间体

合成目标

【1】 Amishiro, N.; Nagamura, S.; Saito, H.; Kobayashi, E.; Okamoto, A.; Gomi, K. (Kyowa Hakko Kogyo Co., Ltd.); DC-89 deriv.. EP 0702014; US 5670492; WO 9526964 .
【2】 Nagamura, S.; Murakata, C.; Amishiro, N.; et al.; Synthesis and antitumor activity of duocarmycin derivatives: Modification at C-8 position of A-ring pyrrole compounds bearing the simplified DNA-binding groups. Bioorg Med Chem 2000, 8, 2, 381.

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)	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
(II)	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
(III)	40887	4-nitrophenyl (E)-3-[3-(dimethylamino)-4-methoxyphenyl]-2-propenoate		C₁₈H₁₈N₂O₅	详情	详情
(IV)	40888	methyl (3bR,4aS)-6-[(E)-3-[3-(dimethylamino)-4-methoxyphenyl]-2-propenoyl]-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate		C₂₆H₂₇N₃O₅	详情	详情
(V)	40889	methyl (8S)-8-(bromomethyl)-6-[(E)-3-[3-(dimethylamino)-4-methoxyphenyl]-2-propenoyl]-4-hydroxy-2-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate		C₂₆H₂₈BrN₃O₅	详情	详情
(VI)	16605	4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene	7693-46-1	C₇H₄ClNO₄	详情	详情
(VII)	40890	methyl (8S)-8-(bromomethyl)-6-[(E)-3-[3-(dimethylamino)-4-methoxyphenyl]-2-propenoyl]-2-methyl-4-[[(4-nitrophenoxy)carbonyl]oxy]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate		C₃₃H₃₁BrN₄O₉	详情	详情
(VIII)	40886	4-methyl-1-piperidinamine; 4-methyl-1-piperidinylamine	19107-42-7	C₆H₁₄N₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

The hydrolysis of DU-86 (I) with NaOMe gives tetracyclic compound (II), which is acylated with the 4-nitrophenyl cinnamate (III) and NaH yielding the adduct (IV). The opening of the cyclopropane ring of (IV) with HBr in acetonitrile affords the aromatic phenol (V), which is activated with 4-nitrophenyl chloroformate (VI) and TEA to provide the activated anhydride (VII). Finally, this compound is condensed with 4-(1-piperidinyl)piperidine-1-amine (VIII), and treated with HBr to furnish the target hydrobromide.

参考文献中间体

合成目标

【1】 Amishiro, N.; Nagamura, S.; Saito, H.; Kobayashi, E.; Okamoto, A.; Gomi, K. (Kyowa Hakko Kogyo Co., Ltd.); DC-89 deriv.. EP 0702014; US 5670492; WO 9526964 .
【2】 Nagamura, S.; Murakata, C.; Amishiro, N.; et al.; Synthesis and antitumor activity of duocarmycin derivatives: Modification at C-8 position of A-ring pyrrole compounds bearing the simplified DNA-binding groups. Bioorg Med Chem 2000, 8, 2, 381.

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)	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
(II)	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
(III)	33752	4-nitrophenyl (E)-3-(4-methoxyphenyl)-2-propenoate		C₁₆H₁₃NO₅	详情	详情
(IV)	40882	methyl (3bR,4aS)-6-[(E)-3-(4-methoxyphenyl)-2-propenoyl]-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate		C₂₄H₂₂N₂O₅	详情	详情
(V)	40883	methyl (8S)-8-(bromomethyl)-4-hydroxy-6-[(E)-3-(4-methoxyphenyl)-2-propenoyl]-2-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate		C₂₄H₂₃BrN₂O₅	详情	详情
(VI)	16605	4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene	7693-46-1	C₇H₄ClNO₄	详情	详情
(VII)	40884	methyl (8S)-8-(bromomethyl)-6-[(E)-3-(4-methoxyphenyl)-2-propenoyl]-2-methyl-4-[[(4-nitrophenoxy)carbonyl]oxy]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate		C₃₁H₂₆BrN₃O₉	详情	详情
(VIII)	40885			C₁₀H₂₁N₃	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

参考文献中间体

合成目标

【1】 Amishiro, N.; Nagamura, S.; Saito, H.; Kobayashi, E.; Okamoto, A.; Gomi, K. (Kyowa Hakko Kogyo Co., Ltd.); DC-89 deriv.. EP 0702014; US 5670492; WO 9526964 .
【2】 Nagamura, S.; Murakata, C.; Amishiro, N.; et al.; Synthesis and antitumor activity of duocarmycin derivatives: Modification at C-8 position of A-ring pyrrole compounds bearing the simplified DNA-binding groups. Bioorg Med Chem 2000, 8, 2, 381.

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)	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
(II)	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
(III)	33752	4-nitrophenyl (E)-3-(4-methoxyphenyl)-2-propenoate		C₁₆H₁₃NO₅	详情	详情
(IV)	40882	methyl (3bR,4aS)-6-[(E)-3-(4-methoxyphenyl)-2-propenoyl]-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate		C₂₄H₂₂N₂O₅	详情	详情
(V)	40883	methyl (8S)-8-(bromomethyl)-4-hydroxy-6-[(E)-3-(4-methoxyphenyl)-2-propenoyl]-2-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate		C₂₄H₂₃BrN₂O₅	详情	详情
(VI)	16605	4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene	7693-46-1	C₇H₄ClNO₄	详情	详情
(VII)	40884	methyl (8S)-8-(bromomethyl)-6-[(E)-3-(4-methoxyphenyl)-2-propenoyl]-2-methyl-4-[[(4-nitrophenoxy)carbonyl]oxy]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate		C₃₁H₂₆BrN₃O₉	详情	详情
(VIII)	40886	4-methyl-1-piperidinamine; 4-methyl-1-piperidinylamine	19107-42-7	C₆H₁₄N₂	详情	详情

Extended Information