Diisopropylethylamine → 3-chloro-6-((2R,6R)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-5-carbaldehyde

Temperature

85 °C

To an ice cooled solution of 3-chloro-6,7-difluoro-1,2-benzoxazole-5-carbaldehyde (prepared according to the procedure described in International Application Publication No. WO 2010/043893, 10.0 g, 46.0 mmol) in anhydrous acetonitrile (50 mL) was added diisopropylethylamine (11.9 g, 91.9 mmol) followed by (2R,6R)-2,6-dimethylmorpholine (5.2 g, 46.0 mmol) and the mixture was heated at 85° C. for 12 hours in a sealed tube. After cooling to room temperature, the volatiles were removed under vacuum. The residue was dissolved in ethyl acetate (50 mL), washed with water (2×15 mL) followed by brine and then dried over anhydrous Na2SO4. Removal of solvent under vacuum afforded the crude product that was purified over silica gel column using a gradient of ethyl acetate in pet. ether to give title compound as solid. Yield: 11.0 g (76%). 1H NMR (400 MHz, DMSO-d6) δ: 1.2 (d, 6H), 3.0 (m, 2H), 3.4 (m, 2H), 4.1 (m, 2H), 8.0 (s, 1H), 10.3 (s, 1H). ES MH+: 313.3 for C14H14ClFN2O3.

1. temperatureAfter cooling to room temperature
2. customthe volatiles were removed under vacuum
3. dissolutionThe residue was dissolved in ethyl acetate (50 mL)
4. washwashed with water (2×15 mL)
5. dry with materialdried over anhydrous Na2SO4
6. customRemoval of solvent under vacuum
7. customafforded the crude product that
8. customwas purified over silica gel column

ORD record

ord-2fa983e2f4834ed795865eceea2aa6a7

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09187495B2