ethyl 2-(4,4-difluorocyclohexyl)acetate

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

Procedure: To a solution of ethyl 2-(4,4-difluorocyclohexyl)acetate (0.500 g, 2.424 mmol) in THF (10 mL) was added LDA (2.424 mL, 4.85 mmol, 2M in THF) dropwise at −78° C. and the reaction mixture was stirred at the same temperature for 45 min. MeI (0.606 mL, 9.70 mmol) was then added at −78° C. and the reaction mixture was slowly warmed to RT and stirred for 12 h. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc (2×25 mL). The combined organic layer was dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by silica gel chromatography (12 g REDISEP® column, eluting with 5% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 232A as a pale yellow liquid (0.27 g, 50%). 1H NMR (300 MHz, chloroform-d) δ ppm 4.22-4.08 (m, 1H), 2.32 (quin, J=7.1 Hz, 1H), 2.20-2.02 (m, 2H), 1.88-1.76 (m, 2H), 1.75-1.62 (m, 3H), 1.51-1.35 (m, 2H), 1.33-1.23 (m, 4H), 1.20-1.11 (m, 3H). stirred for 12 h The reaction mixture was quenched with a saturated aqueous solution of NH4Cl extracted with EtOAc (2×25 mL) The combined organic layer was dried over Na2SO4 filtered the filtrate concentrated The crude product was purified by silica gel chromatography (12 g REDISEP® column, eluting with 5% EtOAc in hexane) Fractions containing the product evaporated

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

Procedure: To a solution of ethyl 2-(4-oxocyclohexyl)acetate (0.4 g) in DCM (5 mL) was added Deoxo-Fluor® (0.881 mL) and EtOH (0.038 mL). The reaction mixture was stirred at rt for 16 h and then diluted with sat. NaHCO3 and EtOAc. The organic phase was washed with water, sat. NaCl and dried over anhydrous Na2SO4, filtered and dried to yield ethyl 2-(4,4-difluorocyclohexyl)acetate (0.4 g). To a solution of ethyl 2-(4,4-difluorocyclohexyl)acetate in THF/MeOH (2 mL) was added 1N NaOH (1 mL), and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated, then diluted with EtOAc and acidified with 1N HCl. The organic phase was washed with sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield 2-(4,4-difluorocyclohexyl)acetic acid as a yellow solid. 1H NMR (400 MHz, DMSO-d6) ppm 12.13 (1H, br. s.), 2.06-2.28 (3H, m), 1.92-2.03 (1H, m), 1.72-1.91 (4H, m), 1.31-1.48 (1H, m), 1.10-1.31 (2H, m). The reaction mixture was concentrated diluted with EtOAc The organic phase was washed with sat. NaCl dried over anhydrous Na2SO4 filtered concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a of solution ethyl 2-(4,4-difluorocyclohexyl)acetate (1.44 g, 7.00 mmol) in anhydrous tetrahydrofuran (23 mL) and anhydrous methanol (0.6 mL) was added lithium borohydride (4 M in tetrahydrofuran, 3.5 mL, 16.00 mmol) at 0° C. and the mixture was heated to reflux for 2 hours. The mixture was then cooled to 0° C. and quenched with methanol until gas evolution ceased. The solution was warmed to ambient temperature then poured into water (50 mL). The aqueous layer was separated and extracted with diethyl ether (3×20 mL). The combined organic layers were washed with brine; dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude alcohol (0.98 g), which was dissolved in anhydrous dimethylsulfoxide (6 mL), tert-butyl 5-chloro-2,4-difluorobenzoate (1.64 g, 6.60 mmol) and cesium carbonate (4.11 g, 12.6 mmol) was added. The reaction mixture was heated at 70° C. for 2 hours and then cooled to ambient temperature and diluted with water (60 mL) and extracted with ethyl acetate (4×20 mL). The combined organic layers were washed with brine; dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (0% to 10% ethyl acetate in hexanes) to afford the title compound (0.681 g, 29%): 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J=7.7 Hz, 1H), 6.63 (d, J=12.1 Hz, 1H), 4.08 (t, J=6.6 Hz, 2H), 2.17-2.07 (m, 2H), 1.77-1.62 (m, 5H), 1.57 (s, 9H), 1.42-1.29 (m, 4H). the mixture was heated to reflux for 2 hours quenched with methanol until gas evolution The solution was warmed to ambient temperature then poured into water (50 mL) The aqueous layer was separated extracted with diethyl ether (3×20 mL) The combined organic layers were washed with brine dried over anhydrous sodium sulfate filtered concentrated in vacuo to give the crude alcohol (0.98 g), which The reaction mixture was heated at 70° C. for 2 hours cooled to ambient temperature extracted with ethyl acetate (4×20 mL) The combined organic layers were washed with brine dried over anhydrous sodium sulfate filtered concentrated in vacuo The residue was purified by column chromatography (0% to 10% ethyl acetate in hexanes)

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

Procedure: To a solution of ethyl 2-(4,4-difluorocyclohexyl)acetate (0.500 g, 2.424 mmol) in THF (10 mL) was added LDA (2.424 mL, 4.85 mmol, 2M in THF) dropwise at −78° C. and the reaction mixture was stirred at the same temperature for 45 min. MeI (0.606 mL, 9.70 mmol) was then added at −78° C. and the reaction mixture was slowly warmed to RT and stirred for 12 h. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc (2×25 mL). The combined organic layer was dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by silica gel chromatography (12 g REDISEP® column, eluting with 5% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 232A as a pale yellow liquid (0.27 g, 50%). 1H NMR (300 MHz, chloroform-d) δ ppm 4.22-4.08 (m, 1H), 2.32 (quin, J=7.1 Hz, 1H), 2.20-2.02 (m, 2H), 1.88-1.76 (m, 2H), 1.75-1.62 (m, 3H), 1.51-1.35 (m, 2H), 1.33-1.23 (m, 4H), 1.20-1.11 (m, 3H). stirred for 12 h The reaction mixture was quenched with a saturated aqueous solution of NH4Cl extracted with EtOAc (2×25 mL) The combined organic layer was dried over Na2SO4 filtered the filtrate concentrated The crude product was purified by silica gel chromatography (12 g REDISEP® column, eluting with 5% EtOAc in hexane) Fractions containing the product evaporated

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

Procedure: To a solution of ethyl 2-(4-oxocyclohexyl)acetate (0.4 g) in DCM (5 mL) was added Deoxo-Fluor® (0.881 mL) and EtOH (0.038 mL). The reaction mixture was stirred at rt for 16 h and then diluted with sat. NaHCO3 and EtOAc. The organic phase was washed with water, sat. NaCl and dried over anhydrous Na2SO4, filtered and dried to yield ethyl 2-(4,4-difluorocyclohexyl)acetate (0.4 g). To a solution of ethyl 2-(4,4-difluorocyclohexyl)acetate in THF/MeOH (2 mL) was added 1N NaOH (1 mL), and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated, then diluted with EtOAc and acidified with 1N HCl. The organic phase was washed with sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield 2-(4,4-difluorocyclohexyl)acetic acid as a yellow solid. 1H NMR (400 MHz, DMSO-d6) ppm 12.13 (1H, br. s.), 2.06-2.28 (3H, m), 1.92-2.03 (1H, m), 1.72-1.91 (4H, m), 1.31-1.48 (1H, m), 1.10-1.31 (2H, m). The reaction mixture was concentrated diluted with EtOAc The organic phase was washed with sat. NaCl dried over anhydrous Na2SO4 filtered concentrated