1-(2-Hydroxyethyl)piperazine → N-{4-[4-amino-7-({[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}amino)thieno[3,2-c]pyridin-3-yl]-2-methoxyphenyl}-1-methyl-1H-indole-2-carboxamide

HRID 2390681

反応式

HRID 2390681 の反応式
[NH2:1][C:2]1[C:3]2[S:15][CH:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)[C:4]=2[C:5](/[N:8]=C/N(C)C)=[N:6][CH:7]=1.ClC(OC)=S.CS[C:44](=[O:46])[NH2:45].Cl.CNOC.C(N(CC)C(C)C)(C)C.[OH:61][CH2:62][CH2:63][N:64]1[CH2:69][CH2:68]N[CH2:66][CH2:65]1>N1C=CC=CC=1>[NH2:8][C:5]1[C:4]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)=[CH:14][S:15][C:3]=2[C:2]([NH:1][C:44]([N:45]2[CH2:68][CH2:69][N:64]([CH2:63][CH2:62][OH:61])[CH2:65][CH2:66]2)=[O:46])=[CH:7][N:6]=1

参加物

8

反応物 6

HCID 76771-(2-Hydroxyethyl)piperazineHCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 81531DiisopropylethylamineHCID 179359Carbamothioic acid, S-methyl esterHCID 554404Methyl chloromethanethioateHCID 178487773HCID 178487773、化合物

生成物 1

HCID 18451230N-{4-[4-amino-7-({[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}amino)thieno[3,2-c]pyridin-3-yl]-2-methoxyphenyl}-1-methyl-1H-indole-2-carboxamide

試薬・触媒・溶媒 1

HCID 1049Pyridine溶媒

実験手順

N-[4-(7-Amino-4-{[(1E)-(dimethylamino)methylene]amino}thieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide (0.108 g, 0.217 mmol) was dissolved in pyridine (3 mL). Methyl chlorothioformate (0.020 mL, 0.233 mmol) was added, and the solution was stirred at ambient temperature for 1.5 hours, at which point LCMS analysis indicated that a clean conversion of the 7-amino group to the thiocarbamic acid S-methyl ester had occurred. N,O-Dimethylhydroxylamine hydrochloride (0.106 g, 1.09 mmol) was added, and the solution was stirred at 50° C. for 4 h, at which point LCMS analysis indicated that the 4-(dimethylaminomethyleneamino) group had been cleaved. The reaction mixture was cooled to ambient temperature, and N,N-diisopropylethylamine (0.264 mL, 1.30 mmol) and 1-(2-hydroxyethyl)piperazine (0.057 mL, 1.52 mmol) were added. The mixture was stirred at 70° C. for 12 h, then was cooled to ambient temperature and concentrated. The residue was diluted with aqueous sodium carbonate (0.5 M, 10 mL), and the mixture was extracted with dichloromethane (3×20 mL). The organic fractions were combined, dried over magnesium sulfate, and concentrated. Purification of the residue on silica gel which had been deactivated with triethylamine (10% by volume of silica gel used) afforded the title compound as an off-white powder: 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (s, 1H), 8.48 (s, 1H), 7.99 (d, 1H), 7.71 (d, 1H), 7.64 (s, 1H), 7.59 (d, 1H), 7.50 (s, 1H), 7.35 (s, 1H), 7.33 (t, 1H), 7.20 (s, 1H), 7.15 (t, 1H), 7.08 (d, 1H), 5.40 (br, 2H), 4.47 (br, 1H), 4.04 (s, 3H), 3.91 (s, 3H), 3.55 (m, 2H), 3.46 (m, 4H), 2.45 (m, 6H); MS: (MI)+600.

後処理

  1. stirringthe solution was stirred at 50° C. for 4 h, at which point LCMS analysis
  2. temperatureThe reaction mixture was cooled to ambient temperature
  3. stirringThe mixture was stirred at 70° C. for 12 h
  4. temperaturewas cooled to ambient temperature
  5. concentrationconcentrated
  6. additionThe residue was diluted with aqueous sodium carbonate (0.5 M, 10 mL)
  7. extractionthe mixture was extracted with dichloromethane (3×20 mL)
  8. dry with materialdried over magnesium sulfate
  9. concentrationconcentrated
  10. customPurification of the residue on silica gel which

出典と根拠

ORDレコード
ord-1c724bacb7954fd896449315a46283c3
出典データセット
uspto-grants-2012_09
特許番号
US08273736B2

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