Acetic Acid → Dimethyl 4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydropyridine-3,5-dicarboxylate

Participants

Reaction Steps

To a stirred solution of 2-methyl-2-propanol (92.8g, 1252 mmol; 2.1 eq.) in anhydrous THF (1100 ml) was added a 1.0M solution of EtMgBr in THF (1192 ml, 1192 mmol; 2.0 eq.) dropwise slowly at 0° C. under nitrogen atmosphere for 2 h period. The resulting solution was stirred at room temperature for 1 h. Then to the mixture was added a solution of dimethyl 3-amino-2-pentenedioate (113.5 g, 655 mmol; 1.1 eq.) in anhydrous THF (550 ml) dropwise slowly at 0° C. for 20 min. The resulting pale yellow solution was stirred at the same temperature for 1 h, then a solution of methyl 3-(2,6-dichlorophenyl)-2-[(1,3-thiazol-2-yl)propanoyl]-2-propenoate (219.9 g, 594 mmol; 1.0 eq.) in anhydrous THF (550 ml) was added at 0° C. for 30 min. The reaction mixture was stirred at room temperature for 16 h under nitrogen atmosphere, then acetic acid (170 ml; 5.0 eq.) was added at 0° C. The resulting mixture was stirred at room temperature for 6 h. The mixture was poured into 2N NaOHaq. (1000 ml), the organic phase was separated and the aqueous phase was extracted with EtOAc (2000 ml). The combined organic phase was washed with H2O (1000 ml) and brine (1000 ml), dried (Na2SO4) and concentrated to give a crude mixture. Purification on silica gel column chromatography (3 times 1700 g) eluted with hexane/EtOAc (2/1 to 1/2) to afford 246.0 g (85%) of dimethyl 4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydropyridine-3,5-dicarboxylate as a brown oil

Provenance & Evidence