反应详情

To a cooled (ice-bath) solution of 450 mg (1.32 mmol) (S)-morpholin-3-yl-methanol in THF (5 ml) were added at 0° C. 570 μl (2.78 mmol) 1,1,1,3,3,3 hexamethyldisilazane and 33 μl (0.26 mmol) trimethylchlorosilane. The mixture was then stirred at RT for 1 h. Then another 33 μl (0.26 mmol) trimethylchlorosilane was added and stirring was continued at RT for 1 h followed by concentration in vacuo. The residue, 450 mg (1.3 mmol) 6-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section b) of example 2) and 903 μl (5.3 mmol) DIPEA were suspended in NMP (1.5 ml). Then the reaction mixture was heated at 180° C. for 32 h and stirred at RT for 72 h. Subsequently a 1M hydrochlorid acid was added and the mixture was stirred at RT for 15 min. After neutralization with a sat. aq. NaHCO3 sol. EtOAc was added and the layers were separated. The organic layer was washed with water and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (cyclohexane/EtOAc 1:1) provided 70 mg (0.17 mmol, 13%) 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-[(3S)-3-(hydroxymethyl)-morpholin-4-yl]-4-methyl-pyridine-3-carboxylic acid amide (example 263). [M+H]+ 420.2

1. additionwere added at 0° C
2. stirringstirring
3. waitwas continued at RT for 1 h
4. concentrationfollowed by concentration in vacuo
5. temperatureThen the reaction mixture was heated at 180° C. for 32 h
6. stirringstirred at RT for 72 h
7. stirringthe mixture was stirred at RT for 15 min
8. customthe layers were separated
9. washThe organic layer was washed with water and brine
10. dry with materialdried over MgSO4
11. concentrationconcentrated in vacuo
12. customPurification of the residue by CC (cyclohexane/EtOAc 1:1)