ethyl 3-(3,5-difluoro-4-hydroxyphenyl)-2-methylpropanoate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of ethyl 3-(3,5-difluoro-4-hydroxyphenyl)-2-methylpropanoate (9) (930 mg, 3.81 mmol) and potassium carbonate (1.05 g, 7.62 mmol) in DMF (8 mL) was added benzyl chloride (0.53 mL, 4.57 mmol) and stirred overnight at 50° C. The reaction was diluted with water and extracted with ethyl acetate (3×25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with hexanes and EtOAc to afford ethyl 3-(4-(benzyloxy)-3,5-difluorophenyl)-2-methylpropanoate (752). extracted with ethyl acetate (3×25 mL) The organic layer was dried over sodium sulfate filtered concentrated in vacuo The residue was purified by flash column chromatography on silica gel with hexanes and EtOAc

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

Procedure: To a solution (E)-ethyl 3-(4-(benzyloxy)-3,5-difluorophenyl)-2-methylacrylate (8) (1.4 g, 4.21 mmol) in ethanol (25 mL) was added Pd/C (140 mg, 10% Degussa type). A balloon of hydrogen gas was added and the reaction was evacuated and back-filled with hydrogen three times. The reaction was stirred under a hydrogen balloon overnight at room temperature, filtered through a pad of celite and concentrated in vacuo to give ethyl 3-(3,5-difluoro-4-hydroxyphenyl)-2-methylpropanoate (9). the reaction was evacuated back-filled with hydrogen three times filtered through a pad of celite concentrated in vacuo

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

Procedure: 3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.045 g, 0.21 mmol) obtained in Step C of Preparation Example 23 and 3-(3,5-difluoro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (49 mg, 0.21 mmol) obtained in Step B of Preparation Example 34 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.026 g, 31%). to react sequentially in the same manner as in Steps A and B of Example 1

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

Procedure: 3-Chloromethyl-2-propylsulfanyl-pyridine (0.031 g, 0.15 mmol) obtained in Step C of Preparation Example 14 and 3-(3,5-difluoro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (35 mg, 0.15 mmol) obtained in Step B of Preparation Example 34 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.04 g, 68%). to react sequentially in the same manner as in Steps A and B of Example 1

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

Procedure: 2-sec-Butylsulfanyl-6-chloromethyl-pyridine (28 mg, 0.13 mmol) in Step C of Preparation Example 5 and 3-(3,5-difluoro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (30 mg, 0.13 mmol) in Step B of Preparation Example 34 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (50 mg, 96%). in Step B of Preparation Example 34 to react in the same manner as in Step A of Example 1

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

Procedure: 3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.045 g, 0.21 mmol) obtained in Step C of Preparation Example 23 and 3-(3,5-difluoro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (49 mg, 0.21 mmol) obtained in Step B of Preparation Example 34 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.026 g, 31%). to react sequentially in the same manner as in Steps A and B of Example 1

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

Procedure: 3-Chloromethyl-2-propylsulfanyl-pyridine (0.031 g, 0.15 mmol) obtained in Step C of Preparation Example 14 and 3-(3,5-difluoro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (35 mg, 0.15 mmol) obtained in Step B of Preparation Example 34 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.04 g, 68%). to react sequentially in the same manner as in Steps A and B of Example 1

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

Procedure: 2-sec-Butylsulfanyl-6-chloromethyl-pyridine (28 mg, 0.13 mmol) in Step C of Preparation Example 5 and 3-(3,5-difluoro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (30 mg, 0.13 mmol) in Step B of Preparation Example 34 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (50 mg, 96%). in Step B of Preparation Example 34 to react in the same manner as in Step A of Example 1

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

Procedure: The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(2-fluoro-4-methylphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methanol and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)-2-methylpropanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 7.29 (t, J=7.8 Hz, 1H), 7.10 (d, J=7.5 Hz, 1H), 7.07 (d, J=11.4 Hz, 1H), 6.73 (d, J=9.7 Hz, 2H), 5.13 (s, 2H), 2.94-2.85 (m, 1H), 2.54-2.44 (m, 2H), 2.44 (s, 3H), 1.09 (d, J=6.3 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C22H17F6NO3S, 488.1 (M−H). found 488.1. The title compound was prepared followed by hydrolysis

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

Procedure: The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(4-ethylphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)-2-methylpropanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 7.69 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 6.82-6.88 (m, 2H), 5.19 (s, 2H), 2.89-2.97 (m, 1H), 2.75 (q, J=7.6 Hz, 2H), 2.58-2.65 (m, 2H), 1.30 (t, J=7.6 Hz, 3H), 1.14 (d, J=6.4 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C23H20F5NO3S, 486.1 (M+H). found 486.1. The title compound was prepared followed by hydrolysis

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

Procedure: The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)-2-methylpropanoate (prepared according to PCT Application WO2010/048207A2) followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD): δ 7.76 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 6.81 (d, J=9.6 Hz, 2H), 5.18 (s, 2H), 2.88-2.93 (m, 1H), 2.51-2.59 (m, 2H), 1.11 (d, J=6.3 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for: C21H15ClF5NO3S: 492.0 (M+H). found 492.0. The title compound was prepared followed by hydrolysis