-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】(7bR,8aS)-7-Bromo-2-[3-(4-methoxyphenyl)-2(E)-propanoyl]-6-methyl-2,5,8,8a-tetrahydro-1H-cyclopropa[c]pyrrolo[3,2-e]indol-4-one

【CA登记号】205050-73-3

【分子式】C₂₂H₁₉BrN₂O₃

【分子量】439.31233

【开发单位】Kyowa Hakko (Originator)

【药理作用】Antibiotics and Alkaloids, Antineoplastic Antibiotics, Oncolytic Drugs

合成路线1 合成路线2

合成路线1

Protection of the phenolic group of duocarmycin B2 (I) with tert-butyldimethylsilyl chloride and imidazole afforded silyl ether (II). The methyl ester group of (III) was then converted to either allyl ester (III) or benzyl ester (IV) upon treatment with the respective alcohols and K2CO3 at 0 C. Reduction of (III) or (IV) with NaBH4 in allyl alcohol provided the 3alpha-hydroxy compounds (V) and (VI). Subsequent BF3-catalyzed Wagner-Meerwein type rearrangement in (V) or (VI) produced the indole-3-carboxylates (VII) and (VIII). Carboxylic acid (IX) was then obtained by deprotection of the allyl group of (VII) using Pd(PPh3)4/dimedone or the benzyl group of (VIII) using Pd/C in the presence of ammonium formate.

参考文献中间体

【1】 Saito, H.; Konayashi, E.; Gomi, K.; Asai, A.; Nagamura, S.; Kanda, Y.; Wagner-Meerwein rearangement of duocarmycins. Chem Pharm Bull 1996, 44, 5, 933-939.
【2】 Okabe, M.; Tamaoki, T.; Saito, H.; Okamoto, A.; Amishiro, N.; Murakata, C.; Synthesis and antitumor activity of duocarmycin derivatives: Modification of segment-A of A-ring pyrrole compounds. J Med Chem 1999, 42, 15, 2946-60.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	33739	methyl (2R,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)	33740	methyl (2R,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)	33741	allyl (2R,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	C₃₄H₄₂BrN₃O₈Si	详情	详情
(IV)	33742	benzyl (2R,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	C₃₈H₄₄BrN₃O₈Si	详情	详情
(V)	33743	allyl (1R,2R,8S)-8-(bromomethyl)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-2-methyl-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,6,7,8-hexahydropyrrolo[3,2-e]indole-2-carboxylate	C₃₄H₄₄BrN₃O₈Si	详情	详情
(VI)	33744	benzyl (1R,2R,8S)-8-(bromomethyl)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-2-methyl-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,6,7,8-hexahydropyrrolo[3,2-e]indole-2-carboxylate	C₃₈H₄₆BrN₃O₈Si	详情	详情
(VII)	33745	allyl (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	C₃₄H₄₂BrN₃O₇Si	详情	详情
(VIII)	33746	benzyl (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	C₃₈H₄₄BrN₃O₇Si	详情	详情
(IX)	33747	(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-carboxylic acid	C₃₁H₃₈BrN₃O₇Si	详情	详情

合成路线2

Decarboxylation of (IX) in refluxing bromobenzene yielded (X), which was converted to the 3-bromoindole (XI) by reaction with N-bromosuccinimide in the presence of silicagel. Desilylation of (XI) with tetrabutylammonium fluoride gave phenol (XII), and further intramolecular cyclization of (XII) with simultaneous amide hydrolysis by treatment with NaOMe produced the cyclopropyl cyclohexadienone (XIII). Finally, the 4-methoxycinnamoyl group was introduced in (XIII) by condensation with the 4-nitrophenyl ester (XIV) in the presence of NaH at -20 C.

参考文献中间体

【1】 Okabe, M.; Tamaoki, T.; Saito, H.; Okamoto, A.; Amishiro, N.; Murakata, C.; Synthesis and antitumor activity of duocarmycin derivatives: Modification of segment-A of A-ring pyrrole compounds. J Med Chem 1999, 42, 15, 2946-60.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IX)	33747	(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-carboxylic acid	C₃₁H₃₈BrN₃O₇Si	详情	详情
(X)	33748	[(1S)-1-(bromomethyl)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-methyl-1,6-dihydropyrrolo[3,2-e]indol-3(2H)-yl](5,6,7-trimethoxy-1H-indol-2-yl)methanone	C₃₀H₃₈BrN₃O₅Si	详情	详情
(XI)	33749	[(1S)-8-bromo-1-(bromomethyl)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-methyl-1,6-dihydropyrrolo[3,2-e]indol-3(2H)-yl](5,6,7-trimethoxy-1H-indol-2-yl)methanone	C₃₀H₃₇Br₂N₃O₅Si	详情	详情
(XII)	33750	[(1S)-8-bromo-1-(bromomethyl)-5-hydroxy-7-methyl-1,6-dihydropyrrolo[3,2-e]indol-3(2H)-yl](5,6,7-trimethoxy-1H-indol-2-yl)methanone	C₂₄H₂₃Br₂N₃O₅	详情	详情
(XIII)	33751	(3bR,4aS)-3-bromo-2-methyl-4,4a,5,6-tetrahydrocyclopropa[c]pyrrolo[3,2-e]indol-8(1H)-one	C₁₂H₁₁BrN₂O	详情	详情
(XIV)	33752	4-nitrophenyl (E)-3-(4-methoxyphenyl)-2-propenoate	C₁₆H₁₃NO₅	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)