4-bromo-2,2-difluoro-1,3-benzodioxole

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: THF (2.0 ml) was added to a solution of 4-bromo-2,2-difluoro-1,3-benzodioxol (1.96 g) in toluene (20 ml). The mixture was cooled to −78° C., and a solution of (±)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c]isoxazole obtained in Preparation Example 1-(2) (500 mg) in toluene-THF (10:1) (10 ml) and a boron trifluoride-diethyl ether complex (990 μl) were added dropwise at the same time. After stirring at the same temperature for two hours, an ammonium chloride solution was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (873 mg). a boron trifluoride-diethyl ether complex (990 μl) were added dropwise at the same time to terminate the reaction The aqueous layer was extracted with ethyl acetate the organic layer was dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: THF (2.0 ml) was added to a solution of 4-bromo-2,2-difluoro-1,3-benzodioxol (1.96 g) in toluene (20 ml). The mixture was cooled to −78° C., and a solution of (±)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c]isoxazole obtained in Preparation Example 1-(2) (500 mg) in toluene-THF (10:1) (10 ml) and a boron trifluoride-diethyl ether complex (990 μl) were added dropwise at the same time. After stirring at the same temperature for two hours, an ammonium chloride solution was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (873 mg). a boron trifluoride-diethyl ether complex (990 μl) were added dropwise at the same time to terminate the reaction The aqueous layer was extracted with ethyl acetate the organic layer was dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (R)-1-chloro-3-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2-propanol was prepared using the same procedure as described for example 2, intermediate (d), but from 4-bromo-2,2-difluoro-benzo[1,3]dioxole and (R)-epichlorohydrin. Example 66 was prepared as described for example 1, intermediate (d), but using (R)-1-chloro-3-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-2-propanol, to obtain the desired morpholine example 66, as a colorless liquid, (0.214 g, 13.6%). Example 66 was prepared

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (R)-1-chloro-3-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2-propanol was prepared using the same procedure as described for example 2, intermediate (d), but from 4-bromo-2,2-difluoro-benzo[1,3]dioxole and (R)-epichlorohydrin. Example 66 was prepared as described for example 1, intermediate (d), but using (R)-1-chloro-3-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-2-propanol, to obtain the desired morpholine example 66, as a colorless liquid, (0.214 g, 13.6%). Example 66 was prepared

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of the title compound of Step B (10.0 g, 42.2 mmol) and the title compound of Step A (4.96 g, 21.1 mmol) in ethylene glycol dimethyl ether (100 mL) were added a solution of sodium carbonate (4.47 g, 42.2 mmol) in water (25 mL) and bis(triphenylphosphine) palladium (II) chloride (740 mg, 1.05 mmol) at room temperature. The mixture was heated at reflux for 2 h and then allowed to come to room temperature. The solvent was removed under reduced pressure and the residue was suspended in water. The aqueous mixture was extracted with ethyl acetate three times. The organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure to obtain a brown liquid. Flash chromatography of the crude product on silica gel eluting with 1:6 ethyl acetate/hexane afforded the title compound of Step C, a compound of the invention, as a yellow oily solid (8 g, 55%). 1H NMR (CDCl3): δ1.12 (s,9H), 2.37 (s,3H), 7.1 (m,2H), 7.12 (s, 1H), 7.2 (t, 1H), 7.25 (m,1H), 7.3 (br s,1H), 7.9 (d, 1H). The mixture was heated at reflux for 2 h to come to room temperature The solvent was removed under reduced pressure The aqueous mixture was extracted with ethyl acetate three times The organic extracts were dried (MgSO4) filtered concentrated under reduced pressure to obtain a brown liquid

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: THF (2.0 ml) was added to a solution of 4-bromo-2,2-difluoro-1,3-benzodioxol (1.96 g) in toluene (20 ml). The mixture was cooled to −78° C., and a solution of (±)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c]isoxazole obtained in Preparation Example 1-(2) (500 mg) in toluene-THF (10:1) (10 ml) and a boron trifluoride-diethyl ether complex (990 μl) were added dropwise at the same time. After stirring at the same temperature for two hours, an ammonium chloride solution was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (873 mg). a boron trifluoride-diethyl ether complex (990 μl) were added dropwise at the same time to terminate the reaction The aqueous layer was extracted with ethyl acetate the organic layer was dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography