Iodoethane → 4-Isopropoxy-3-methylbenzaldehyde

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%).

1. stirringthe reaction mixture was stirred overnight
2. extractionthe aqueous layer was extracted with ethyl acetate (2×10 mL)
3. washThe combined organic layer was washed with water (5 mL)
4. dry with materialdried over MgSO4
5. filtrationfiltered
6. concentrationconcentrated in vacuo
7. washeluting with 30% EtOAc/DCM
8. concentrationThe solvent was concentrated in vacuo
9. dissolutionthe residue was dissolved in N,N-dimethylformamide (1.3 mL) under an atmosphere of nitrogen
10. temperaturecooled to 0° C.
11. stirringThe reaction mixture was stirred at 0° C. for 10 minutes
12. waitat room temperature for 5 minutes
13. stirringthe reaction mixture stirred for 1 hour
14. custommicrofiltered and purified by preparative LCMS (10-99% ACN/Water, 5 mM HCl modifier)

ORD record

ord-eee5d832ee6a4ce1b572cdf524f399eb

Source dataset

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08828996B2