Réaction #45464

Équation de réaction

N,O-Dimethylhydroxylamine hydrochloride

thiocarbamic acid S-methyl ester

N,N-diisopropylethylamine

1-(2-hydroxyethyl)piperazine

Methyl chlorothiolformate

N-[4-(7-Amino-4-{[(1E)-(dimethylamino)methylene]amino}thieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide

→

title compound

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

Solvants

pyridine

Conditions de réaction

Traitement

1. 1
   workup.STIRRINGthe solution was stirred at 50° C. for 4 h, at which point LCMS analysis
2. 2
   TempératureThe reaction mixture was cooled to ambient temperature
3. 3
   workup.STIRRINGThe mixture was stirred at 70° C. for 12 h
4. 4
   Températurewas cooled to ambient temperature
5. 5
   Concentrationconcentrated
6. 6
   workup.ADDITIONThe residue was diluted with aqueous sodium carbonate (0.5 M, 10 mL)
7. 7
   Extractionthe mixture was extracted with dichloromethane (3×20 mL)
8. 8
   Séchagedried over magnesium sulfate
9. 9
   Concentrationconcentrated
10. 10
    AutrePurification of the residue on silica gel which

Mode opératoire

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.

Source