Sodium hydride → 2-(4-((2'-Chloro-4',4'-difluoro-4,5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-1-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)-pyridine

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Reaction Conditions

Reaction Steps

To a solution of acetamide oxime (154 mg, 2.1 mmol) in 7 mL tetrahydrofuran, are added under argon 139 mg of grinded 4A molecular sieves and sodium hydride (2.1 mmol; 84 mg as 60% in mineral oil). The mixture is allowed to stir for 30 min at 50° C. After cooling to room temperature, 2-(4-((2′-chloro-4′,4′-difluoro-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]-1-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-nicotinic acid methyl ester (309 mg, 0.6 mmol) is added and then the mixture is heated at 50° C. for 40 min. Quenched after cooling with water and extracted with dichloromethane. After drying the organic phase with magnesium sulfate and evaporation of the solvent, the residue is diluted in methanol and purified using a 5 g SCX cartridge. The resulting residue is further purified by semipreparative reverse phase HPLC_MS using a XBridge column (Sum, 19×100 mm) and a gradient between 60 and 80% of B in A in 5 min at flow 25 mL/min (basic conditions A: ammonium bicarbonate 20 mM pH9 and B: acetonitrile) to give 71 mg of the title compound. MS (m/z): 533 (M+1).

Provenance & Evidence