Iodoethane → 4-Isopropoxy-3-methylbenzaldehyde

Participants

Reaction Steps

To 8-(2,2-difluoroethyl)-10-(1H-pyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecane (193 mg, 0.54 mmol), 4-isopropoxy-3-methyl-benzoic acid (110 mg, 0.56 mmol) and HATU (215 mg, 0.56 mmol) was added N,N-dimethylformamide (1.3 mL). The reaction mixture was stirred for 5 minutes at room temperature, then diisopropylethylamine (374 μL, 2.15 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was then diluted with sat. NaHCO3 (5 mL) and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layer was washed with water (5 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was passed through a silica gel plug, eluting with 30% EtOAc/DCM. The solvent was concentrated in vacuo and the residue was dissolved in N,N-dimethylformamide (1.3 mL) under an atmosphere of nitrogen, cooled to 0° C., then treated with NaH (21 mg, 0.54 mmol). The reaction mixture was stirred at 0° C. for 10 minutes, then at room temperature for 5 minutes, then iodoethane (50 μL, 0.63 mmol) was added and the reaction mixture stirred for 1 hour. The reaction mixture was diluted with methanol, microfiltered and purified by preparative LCMS (10-99% ACN/Water, 5 mM HCl modifier) to give 8-(2,2-difluoroethyl)-10-(1-ethylpyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (26 mg, 14%) and 8-(2,2-difluoroethyl)-10-(2-ethylpyrazol-3-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (24 mg, 13%).

Provenance & Evidence