14% |
With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In acetonitrile;Heating / reflux; |
Example 1; 25 Ethyl 6-(4-[(benzylsulfoϖyl)amino]carbonyl}piperidin-l-yl)-5-chloro-2- (difluoromethyl)nicotinate(a) Ethyl 2-(difluoromethyl)-6-oxo-l,6-dihydropyridine-3-carboxylate30 Ethyl 2-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate (2.0 g, 11.04 mmol) ( Sobczak, A et al, Synth. Comrnun, VoL 35, No. 23, 2005, pρ2993-3001) was added to a solution of 2- methoxy-N-(2-merhoxyethyl)-N-(trifiuoro-λ4-sulfanyl)ethanamine (7.82 g, 22.08 mmol) in <n="86"/>85CH3CN under an atmosphere of nitrogen. The reaction was refluxed over night after which further 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-λ4-sulfanyl)ethanamine (2.73 g, 7.7 mmol) was added and the stirring was continued until all starting material was consumed. The reaction was diluted with diethyl ether, filtered to remove black solids, washed with5 water and NaHCO3 (aq,sat). Both phases were filtered again to remove more of black solids. The aqueous phase was extracted with diethyl ether (2 times) and the combined organic phase was dried (MgSO4), filtered and concentrated and slurried in diethyl ether to remove yellow impurities. Drying of the remaining white solid gave ethyl 2- (difluoromethyl)-6-oxo-l,6-dihydropyridine-3-carboxylate. Yield: 370 mg (14 %). io 1H NMR (400 MHz, CDCi) δ 1.38 (3H, t, J= 7.2 Hz), 4.36 (2H, q, J= 7.2 Hz), 6.69 (IH, d, J= 10 Hz), 7.56 (IH, t, J= 54 Hz), 7.99 (IH, d, J= 10 Hz).; |