tert-butyl 3,5-difluoro-4-(methylsulfonyloxymethyl)benzoate

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

Procedure: A mixture of 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-thiol (60 g, 0.16 mmol), tert-butyl 3,5-difluoro-4-((methylsulfonyloxy)methyl)benzoate (51 g, 0.16 mol, 1.0 eq.) and Cs2CO3 (62 g, 0.19 mol, 1.2 eq.) in MeCN (680 mL) was stirred for 2 h and evaporated to give a residue. The residue was diluted with water (1.5 L) and extracted with CH2Cl2 (1 L). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give tert-butyl 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzoate (95 g, quant). 1H NMR (400 MHz, CDCl3) δ 7.40-7.42 (d, 2H), 7.19 (s, 1H), 7.14-7.16 (d, 1H), 6.76-6.80 (t, 2H), 6.51 (s, 1H), 6.41-6.49 (m, 3H), 4.07 (s, 2H), 3.75 (s, 3H), 1.58 (s, 9H), 1.47 (s, 6H). evaporated to give a residue extracted with CH2Cl2 (1 L) The organic layer was washed with brine dried over MgSO4 filtered concentrated in vacuo

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

Procedure: To a stirred solution of tert-butyl 3,5-difluoro-4-(hydroxymethyl)benzoate (1.9 g, 7.78 mmol) in DCM was added Et3N (3.27 mL, 23.4 mmol, 3 eq) and methanesulfonylchloride (0.72 mL, 9.3 mmol, 1.2 eq) successively at 0° C. After the reaction was stirred for 30 min, it was extracted with CH2Cl2C and water. Organic layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography (Hex/EtOAc=4:1) to give tert-butyl 3,5-difluoro-4-((methylsulfonyloxy)methyl)benzoate (2.25 g, 89% yield) as a ivory solid. it was extracted with CH2Cl2C and water Organic layer was dried over MgSO4 evaporated in vacuo The residue was purified by column chromatography (Hex/EtOAc=4:1)

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

Procedure: To a stirred solution of tert-butyl 3,5-difluoro-4-(hydroxymethyl)benzoate (1.9 g, 7.78 mmol) in DCM was added Et3N (3.27 mL, 23.4 mmol, 3 eq) and methanesulfonylchloride (0.72 mL, 9.3 mmol, 1.2 eq) successively at 0° C. After the reaction was stirred for 30 min, it was extracted with CH2Cl2C and water. Organic layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography (Hex/EtOAc=4:1) to give tert-butyl 3,5-difluoro-4-((methylsulfonyloxy)methyl)benzoate (2.25 g, 89% yield) as a ivory solid. it was extracted with CH2Cl2C and water Organic layer was dried over MgSO4 evaporated in vacuo The residue was purified by column chromatography (Hex/EtOAc=4:1)

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

Procedure: A mixture of tert-butyl 3,5-difluoro-4-((methylsulfonyloxy)methyl)benzoate (355 mg, 1.10 mmol) and 5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazole-2-thiol (402 mg, 0.98 mmol)—prepared in a manner similar to that described for Example 3 from commercially available reagents—was suspended in acetone (4 mL) and treated with K2CO3 (223 mg, 1.6 mmol). The resulting white suspension was stirred at ambient temperature. The reaction mixture rapidly became a thick slurry, and acetone (5 mL) was added to facilitate stirring. After 75 min, the reaction was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford crude product that was purified by flash chromatography (silica gel, EtOAc/Hex, 0:100 to 80:20) to afford the title compound (541 mg, 87% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.49-7.40 (m, 2H), 7.30-7.24 (m, 1H), 7.19 (s, 1H), 7.10 (d, J=2.2 Hz, 1H), 6.87 (ddd, J=10.7, 9.5, 5.4 Hz, 2H), 6.28 (ddd, J=8.5, 3.8, 2.5 Hz, 1H), 5.85 (dd, J=7.5, 2.4 Hz, 1H), 4.20-4.07 (m, 2H), 3.46 (s, 3H), 1.57 (s, 9H), 1.54 (s, 3H), 1.46 (s, 3H); MS (EI) m/z 637 (MH+). was added to facilitate stirring The aqueous layer was extracted with EtOAc The combined extracts were washed with brine dried over Na2SO4 concentrated under reduced pressure to afford crude product that was purified by flash chromatography (silica gel, EtOAc/Hex, 0:100 to 80:20)

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

Procedure: A mixture of 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-thiol (60 g, 0.16 mmol), tert-butyl 3,5-difluoro-4-((methylsulfonyloxy)methyl)benzoate (51 g, 0.16 mol, 1.0 eq.) and Cs2CO3 (62 g, 0.19 mol, 1.2 eq.) in MeCN (680 mL) was stirred for 2 h and evaporated to give a residue. The residue was diluted with water (1.5 L) and extracted with CH2Cl2 (1 L). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give tert-butyl 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzoate (95 g, quant). 1H NMR (400 MHz, CDCl3) δ 7.40-7.42 (d, 2H), 7.19 (s, 1H), 7.14-7.16 (d, 1H), 6.76-6.80 (t, 2H), 6.51 (s, 1H), 6.41-6.49 (m, 3H), 4.07 (s, 2H), 3.75 (s, 3H), 1.58 (s, 9H), 1.47 (s, 6H). evaporated to give a residue extracted with CH2Cl2 (1 L) The organic layer was washed with brine dried over MgSO4 filtered concentrated in vacuo