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 17186

반응식

HRID 17186 반응식
[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.ClC1C=CSC=1C(OC)=O.CS[C:49](=[O:51])[NH2:50].Cl.CNOC.C(N(CC)C(C)C)(C)C.[OH:66][CH2:67][CH2:68][N:69]1[CH2:74][CH2:73]N[CH2:71][CH2:70]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:49]([N:50]2[CH2:73][CH2:74][N:69]([CH2:68][CH2:67][OH:66])[CH2:70][CH2:71]2)=[O:51])=[CH:7][N:6]=1

참가 물질

8

반응물 6

HCID 76771-(2-Hydroxyethyl)piperazineHCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 81531DiisopropylethylamineHCID 179359Carbamothioic acid, S-methyl esterHCID 2777566Methyl 3-chlorothiophene-2-carboxylateHCID 178487773HCID 178487773, 화합물

생성물 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

시약·촉매·용매 1

HCID 1049Pyridine용매

실험 절차

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 chlorothiolformate (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: (MH)+ 600.

후처리

  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

출처 및 근거

ORD 기록
ord-b0b3c8cc7c814a238d9a72296e9281d4
출처 데이터셋
uspto-grants-2010_06
특허 번호
US07737160B2

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