Dimethyl 2-[2-benzyloxy-5-(2-chloroethyl)-4-nitroanilino)malate → Dimethyl 7-benzyloxy-4-(2-chloroethyl)-5-nitroindole-2,3-dicarboxylate

HRID 431711노트

반응식

HRID 431711 반응식
[CH2:1]([O:8][C:9]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]([CH2:30][CH2:31][Cl:32])=[CH:23][C:10]=1[NH:11][C:12]([CH2:18][C:19]([O:21][CH3:22])=[O:20])(O)[C:13]([O:15][CH3:16])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C)C(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]([CH2:30][CH2:31][Cl:32])=[C:23]2[C:10]=1[NH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:18]2[C:19]([O:21][CH3:22])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

참가 물질

4

반응물 1

HCID 18761420Dimethyl 2-[2-benzyloxy-5-(2-chloroethyl)-4-nitroanilino)malate

생성물 1

HCID 18761446Dimethyl 7-benzyloxy-4-(2-chloroethyl)-5-nitroindole-2,3-dicarboxylate수율 23%

시약·촉매·용매 2

HCID 167845palladium(II) acetate촉매HCID 31374Dimethylacetamide용매

실험 절차

2-(5-Amino-4-benzyloxy-2-nitro)phenylethanol was heated at 25-100° C., preferably refluxing, with dimethyl acetylenedicarboxylate in methanol to give dimethyl 2-[2-benzyloxy-5-(2-hydroxyethyl)-4-nitroanilino]malate in 96% yield. Subsequent treatment of dimethyl 2-[2-benzyloxy-5-(2-hydroxyethyl)-4-nitroanilino]malate at 0-50° C., preferably at room temperature, with carbon tetrachloride in methylene chloride and triphenylphosphine provided dimethyl 2-[2-benzyloxy-5-(2-chloroethyl)-4-nitroanilino]malate in 85% yield. Next, dimethyl 2-[2-benzyloxy-5-(2-chloroethyl)-4-nitroanilino]malate was treated with Palladium (II) acetate in N,N-dimethylacetamide at 40-120° C., preferably at 70° C., to give dimethyl 7-benzyloxy-4-(2-chloroethyl)-5-nitroindole-2,3-dicarboxylate in 23% yield. Treatment of dimethyl 7-benzyloxy-4-(2-chloroethyl)-5-nitroindole-2,3-dicarboxylate with 10% palladium-on-carbon in THF at an atmospheric pressure of hydrogen and at 0-35° C., preferably at room temperature, gave an amine intermediate which was directly coupled at 0-50° C., preferably at room temperature, with 5,6,7-trimethoxyindole-2-carboxylic acid and 5-(benzofuran-2-carboxamido)indole-2-carboxylic acid in the presence of EDCI in DMF at room temperature for three days to give the target achiral seco-duocarmycin analogue dimethyl 4-(2-chloroethyl)-7-hydroxy-5-(5,6,7-trimethoxyindole-2-carboxamido)indole-2,3-dicarboxylate and dimethyl 4-(2-chloroethyl)-7-hydroxy-5-[5-(benzofuran-2-carboxamido)indole-2-carboxamido]indole-2,3-dicarboxylate in 20 and 16% yield, respectively.

출처 및 근거

ORD 기록
ord-2ade421cabf54a18b8bf6baa195927b5
출처 데이터셋
uspto-grants-2003_12
특허 번호
US06660742B2

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