ETHYL 2-CHLORO-3-CYANO-6-(TRIFLUOROMETHYL)-PYRIDINE-5-CARBOXYLATE synthesis

Yield:175277-73-3 95%

Reaction Conditions:

with oxalyl dichloride;N,N-dimethyl-formamide in dichloromethane at 50;Product distribution / selectivity;Heating / reflux;

Steps:

3.a; 5.a

Example 3Ethyl 6-(4-{[(benzylsulfonyl)amino]carbonyl}piperidin-l-yl)-5-cyano-2- 2₅ (trifluoromethyl)nicotinate(a) Ethyl 6-chloro-5-cyano-2-(trifluoromethyl)nicotinateOxalylchloride (12.20 g, 96.1 mmol) and DMF (0.744 mL) were added to a solution of 30 ethyl 5-cyano-6-oxo-2-(trifluoromethyl)-l,6-dihydropyridine-3-carboxylate (5 g, 19.22 mmol) (prepared essentially according to the method described in Mosti, L et al, Farmaco, VoI 47, No 4, 1992, pp. 427-437) and the reaction was heated to 5O⁰C over night. The 90reaction was evaporated and the crude was dissolved in EtOAc and water. The phases was separated and the organic phase was washed with Brine and NaHCO₃ (aq,sat). The aqueous phase was extracted with EtOAc (3 times) and the combined organic phase was dried (Na₂CO₃), filtered and concentrated to give ethyl 6-chloro-5-cyano-2- 5 (trifluoromethyl)nicotinate as a brown solid which was used without further purification. Yield: 5.21 g (95 %).¹HNMR (400 MHz, DMSO-de) δ 1.31 (3H, t, J= 7.2 Hz)₃ 4.38 (2H, q, J= 6.9 Hz), 9.07 (IH, s)Example 5 93Ethyl 6-(3- { [(benzylsulf onyl)amino] carbonyl} azetidin -l-yl)-5 -cyano -2- (trifluoromethyl)nicotinate(a) Ethyl β-chloro-S-cyano^-^rifluoromethytynicotinate5Oxalylchloride (8.13 mL, 96.1 mmol) and DMF (0.744 mL, 9.61 mmol) were added to a solution of ethyl 5-cyano-6-oxo-2-(trifluoromethyl)- l,6-dihydropyridine-3-carboxylate (5.0 g, 19.22 mmol, prepared essentially according to the procedure described by Mosti L, et. al. Farmaco, VoI 47, No 4, 1992, pp. 427-437) and the reaction was heated to reflux io over nightThe solvent was evaporated and the residue was dissolved in EtO Ac/water. The phases were separated and the organic phase was washed with Brine and NaHCO₃ (aq) (twice). The aqueous phase was extracted with EtOAc (three times) and the combinec organic phases was dried (Na₂CO₃), filtered and concentrated to give ethyl 6-chloro-5- cyano-2-(trifluoromethyl)nicotinate which was used without further purification. Yield: is 5.21 g (95%).¹H NMR (400 MHz, DMSO-de) δ 1.31 (3H, t, J= 7 Hz), 4.38 (2H, q, J= 7 Hz), 9.07 (IH, s).

References:

WO2008/4946,2008,A1 Location in patent:Page/Page column 89-90; 93