ethyl 3-(4-hydroxyphenyl)-2-methylpropanoate

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

Procedure: To a solution of ethyl 3-(4-hydroxyphenyl)-2-methylpropanoate (672) (150 mg, 0.72 mmol), potassium carbonate (149.3 mg, 1.08 mmol) in toluene (7 mL) was added N,N-dimethylmethylideneammonium iodide (173.2 mg, 0.94 mmol) and stirred for 72 hours. Water was added and the reaction was extracted with ethyl acetate and the combined organic layers dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (50%) to give ethyl 3-(3-((dimethylamino)methyl)-4-hydroxyphenyl)-2-methylpropanoate (673). the reaction was extracted with ethyl acetate the combined organic layers dried over sodium sulfate filtered concentrated in vacuo The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (50%)

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

Procedure: To a solution of ethyl 3-(4-hydroxyphenyl)-2-methylpropanoate (672) (150 mg, 0.72 mmol), potassium carbonate (149.3 mg, 1.08 mmol) in toluene (7 mL) was added N,N-dimethylmethylideneammonium iodide (173.2 mg, 0.94 mmol) and stirred for 72 hours. Water was added and the reaction was extracted with ethyl acetate and the combined organic layers dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (50%) to give ethyl 3-(3-((dimethylamino)methyl)-4-hydroxyphenyl)-2-methylpropanoate (673). the reaction was extracted with ethyl acetate the combined organic layers dried over sodium sulfate filtered concentrated in vacuo The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (50%)

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

Procedure: 3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.056 g, 0.24 mmol) obtained in Step C of Preparation Example 8 and 3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester obtained in Step B of Preparation Example 3 A were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.035 g, 40%). 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-isopropylsulfanyl-pyridine (0.063 g, 0.31 mmol) obtained in Step C of Preparation Example 1 and 3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (0.065 g, 0.31 mmol) obtained in Step B of Preparation Example 3 were reacted in the same manner as in Step A of Example 1 to obtain the title compound (0.062 g, 53%). were reacted 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-isopropylsulfanyl-5-methyl-pyridine (0.02 g, 0.09 mmol) obtained in Step D of Preparation Example 30 and 3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester obtained in Step B of Preparation Example 3 were reacted in the same manner as in Step A of Example 1 to obtain the title compound (0.012 g, 33%). were reacted 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-cyclopentylsulfanyl-pyridine (0.056 g, 0.24 mmol) obtained in Step C of Preparation Example 8 and 3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester obtained in Step B of Preparation Example 3 A were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.035 g, 40%). 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-isopropylsulfanyl-pyridine (0.063 g, 0.31 mmol) obtained in Step C of Preparation Example 1 and 3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (0.065 g, 0.31 mmol) obtained in Step B of Preparation Example 3 were reacted in the same manner as in Step A of Example 1 to obtain the title compound (0.062 g, 53%). were reacted 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-isopropylsulfanyl-5-methyl-pyridine (0.02 g, 0.09 mmol) obtained in Step D of Preparation Example 30 and 3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester obtained in Step B of Preparation Example 3 were reacted in the same manner as in Step A of Example 1 to obtain the title compound (0.012 g, 33%). were reacted 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 following Steps 5 and 6 by coupling (3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxyphenyl)-2-methyl-propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ: 7.71 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.16 (d, J=8.4 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 5.09 (s, 2H), 2.93-2.98 (m, 1H), 2.63-2.74 (m, 2H), 1.15 (d, J=6.8 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C21H17ClF3NO3S, 454.0 (M−H). found 454.0. The title compound was prepared followed by hydrolysis

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

Procedure: The reaction mixture of compound A (30.0 mg, 97.8 μmol), compound 12.3 (22.4 mg, 108 μmol) and cesium carbonate (38.2 mg, 117 μmol) in DMF (1.0 mL) was stirred at room temperature overnight. The resulting reaction mixture was treated with lithium hydroxide (23.4 mg, 978 μmol) in water (0.5 mL), and stirred at room temperature for 5 hours. The reaction mixture was purified by reverse phase preparative HPLC to give the title compound. MS ESI (neg.) m/e: 449 (M−H). 1H NMR (CD3CN) δ 7.61(d, 1H), 7.41(d, 1H), 7.11(d, 2H), 7.06(m, 2H), 6.93(m, 1H), 6.89(d, 2H), 6.81(d, 1H), 5.02(s, 2H), 3.77 (s, 3H), 2.86(dd, 1H), 2.63(m, 2H), 1.21(s, 9H), 1.09(d, 3H). The resulting reaction mixture stirred at room temperature for 5 hours The reaction mixture was purified by reverse phase preparative HPLC

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

Procedure: The reaction mixture compound 12.2 (2.80 g, 9.45 mmol) and Pd/C (0.40 g, wt 10% on activated carbon) in EtOH (35 mL) was purged with hydrogen three times and stirred under hydrogen at ambient temperature overnight. The catalyst was removed by filtration. The filtrate was evaporated to give the crude compound 12.3 which was used in the next step without further purification. MS ESI (pos.) m/e: 209 (M+H). 1H NMR (CDCl3) δ 7.02(d, 2H), 6.75(d, 2H), 4.11(q, 2H), 2.93(dd, 1H), 2.68(m, 2H), 1.21(t, 3H), 1.16(d, 3H). The catalyst was removed by filtration The filtrate was evaporated

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

Procedure: To a solution of ethyl 3-(4-hydroxyphenyl)-2-methylpropanoate (672) (150 mg, 0.72 mmol), potassium carbonate (149.3 mg, 1.08 mmol) in toluene (7 mL) was added N,N-dimethylmethylideneammonium iodide (173.2 mg, 0.94 mmol) and stirred for 72 hours. Water was added and the reaction was extracted with ethyl acetate and the combined organic layers dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (50%) to give ethyl 3-(3-((dimethylamino)methyl)-4-hydroxyphenyl)-2-methylpropanoate (673). the reaction was extracted with ethyl acetate the combined organic layers dried over sodium sulfate filtered concentrated in vacuo The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (50%)