2-methylsulfonylphenol

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: m-Chloroperbenzoic acid (280 mg, 1.62 mmol) was added to a cold (0-4° C.) solution of 1-methoxy-2-methylsulfanyl-benzene (100 mg, 0.64 mmol) in DCM (3 mL) and stirring was continued for 1 hr. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with saturated brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 110 mg (91.6% Yield) of 1-methanesulfonyl-2-methoxy-benzene. Boron tribromide (370 mg, 1.47 mmol) was added to a cold solution (−70° C.) solution of 1-methanesulfonyl-2-methoxy-benzene (10 mg, 0.591 mmol) in DCM (2 mL) and stirring was continued for 10 minutes. After which the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with saturated brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 65 mg (64.35% Yield) of 2-methanesulfonyl-phenol. 2-Methylsulfonyl-phenol was converted to 4-(2-methanesulfonyl-phenoxy)-piperidine hydrochloride according to Step 1 of the General Scheme). After which the reaction mixture was stirred at ambient temperature overnight extracted with dichloromethane The organic layer was washed with saturated brine solution dried over sodium sulfate concentrated under reduced pressure

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Fluorobenzaldehyde (0.690 mL, 6.4 mmol) and 2-(methylsulfonyl)phenol (1.2 g, 7.0 mmol) were dissolved in N,N-dimethylformamide (15 mL), and potassium carbonate (0.85 g, 6.1 mmol) was added. The mixture was heated at 100° C. for 4 days. The reaction was diluted with ethyl acetate and extracted with water three times. The combined aqueous layers were extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered, and evaporated on the rotovap. The residue was chromatographed on silica gel using a 20–40% ethyl acetate in hexanes. The major component was collected to give a solid (0.942 g, 53%). 1H NMR (400 MHz, CDCl3): δ 9.97 (s, 1H), 8.12 (dd, J=8.0 Hz, J′=1.6 Hz, 1H), 7.92 (dd, J=6.6 Hz, J′=2.1 Hz, 2H), 7.64 (m, 1H), 7.38 (td, J=7.9 Hz, J′=1.0 Hz, 1H), 7.18 (dd, J=6.7 Hz, J′=1.9 Hz, 2H), 7.07 (dd, J=8.8.2 Hz, J′=1.0 Hz, 1H), 3.28 (s, 3H); LCMS found for C14H13O4S (M+H)+: m/z=277.0. extracted with water three times The combined aqueous layers were extracted with ethyl acetate twice The combined organic layers were dried over sodium sulfate filtered evaporated on the rotovap The residue was chromatographed on silica gel using a 20–40% ethyl acetate in hexanes The major component was collected

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Fluorobenzaldehyde (0.690 mL, 6.4 mmol) and 2-(methylsulfonyl)phenol (1.2 g, 7.0 mmol) were dissolved in N,N-dimethylformamide (15 mL), and potassium carbonate (0.85 g, 6.1 mmol) was added. The mixture was heated at 100° C. for 4 days. The reaction was diluted with ethyl acetate and extracted with water three times. The combined aqueous layers were extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered, and evaporated on the rotovap. The residue was chromatographed on silica gel using a 20–40% ethyl acetate in hexanes. The major component was collected to give a solid (0.942 g, 53%). 1H NMR (400 MHz, CDCl3): δ 9.97 (s, 1H), 8.12 (dd, J=8.0 Hz, J′=1.6 Hz, 1H), 7.92 (dd, J=6.6 Hz, J′=2.1 Hz, 2H), 7.64 (m, 1H), 7.38 (td, J=7.9 Hz, J′=1.0 Hz, 1H), 7.18 (dd, J=6.7 Hz, J′=1.9 Hz, 2H), 7.07 (dd, J=8.8.2 Hz, J′=1.0 Hz, 1H), 3.28 (s, 3H); LCMS found for C14H13O4S (M+H)+: m/z=277.0. extracted with water three times The combined aqueous layers were extracted with ethyl acetate twice The combined organic layers were dried over sodium sulfate filtered evaporated on the rotovap The residue was chromatographed on silica gel using a 20–40% ethyl acetate in hexanes The major component was collected

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-(Methylthio)phenol (1.08 g, 7.32 mmol) was dissolved in acetone (20 mL). Oxone® (9.4 g, 15 mmol) was separately dissolved in water (100 mL) and stirred at ambient temperature for 24 h. The acetone was concentrated, extracted with ether, dried over sodium sulfate, filtered, and concentrated to yield a waxy solid (1.2 g, 95%). 1H NMR (400 MHz, CDCl3): δ 8.85 (s, 1H), 7.69 (dd, J=8.4 Hz, J′=1.7 Hz, 1H), 7.54 (m, 1H), 7.05 (m, 2H), 3.12 (s, 3H); LCMS found for C7H9O3S (M+H)+: m/z=173.0. The acetone was concentrated extracted with ether dried over sodium sulfate filtered concentrated

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-(methylsulfonyl)phenol (100 mg, 0.58 mmol) and K2CO3 (276 mg, 2 mmol) in CH3CN (10 mL) was added ethyl 2-bromoacetate (115.2 mg, 0.69 mmol) at 25° C. The mixture was heated at 80° C. for 4 h, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude product was used in the next step without further purification. (140 mg, yield 94%). extracted with ethyl acetate The combined organic layers were washed with brine dried over sodium sulfate concentrated The crude product was used in the next step without further purification

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-(methylsulfonyl)phenol (200 mg, 1.16 mmol) in CH3CN (10 mL) was added ethyl 2-bromo-2-methylpropanoate (232 mg, 1.39 mmol) and K2CO3 (690 mg, 5 mmol) at 25° C. The mixture was refluxed for 16 h and then quenched by addition of water (100 mL). The resulting mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound which was used in next step without further purification. The mixture was refluxed for 16 h quenched by addition of water (100 mL) The resulting mixture was extracted with ethyl acetate (2×50 mL) The combined organic layers were washed with brine (30 mL) dried over Na2SO4 concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2-methanesulfonyl-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[4-(2-methanesulfonyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (15 g, 68%) as a white solid; LC-MS: [M+H+]=407; HPLC (0.17% trifluoroacetic acid in acetonitrile/water, 50%-100% acetonitrile, gradient, 1 mL/min, Venusil MP-C18, C18-15 cm×4.6 mm-5 μm), purity 98%. 1H-NMR (300 MHz, DMSO-d6) δ 1.42 (m, 2H), 1.55 (m, 7H), 1.57 (s, 1H), 1.59 (s, 1H), 3.31 (s, 1H), 5.31 (m, 1H), 7.63 (m, 1H), 7.87 (s, 2H), 7.98 (m, 1H), 8.19 (s, 1H).

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-(methylsulfonyl)phenol (200 mg, 1.16 mmol) in CH3CN (10 mL) was added ethyl 2-bromo-2-methylpropanoate (232 mg, 1.39 mmol) and K2CO3 (690 mg, 5 mmol) at 25° C. The mixture was refluxed for 16 h and then quenched by addition of water (100 mL). The resulting mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound which was used in next step without further purification. The mixture was refluxed for 16 h quenched by addition of water (100 mL) The resulting mixture was extracted with ethyl acetate (2×50 mL) The combined organic layers were washed with brine (30 mL) dried over Na2SO4 concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: m-Chloroperbenzoic acid (280 mg, 1.62 mmol) was added to a cold (0-4° C.) solution of 1-methoxy-2-methylsulfanyl-benzene (100 mg, 0.64 mmol) in DCM (3 mL) and stirring was continued for 1 hr. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with saturated brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 110 mg (91.6% Yield) of 1-methanesulfonyl-2-methoxy-benzene. Boron tribromide (370 mg, 1.47 mmol) was added to a cold solution (−70° C.) solution of 1-methanesulfonyl-2-methoxy-benzene (10 mg, 0.591 mmol) in DCM (2 mL) and stirring was continued for 10 minutes. After which the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with saturated brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 65 mg (64.35% Yield) of 2-methanesulfonyl-phenol. 2-Methylsulfonyl-phenol was converted to 4-(2-methanesulfonyl-phenoxy)-piperidine hydrochloride according to Step 1 of the General Scheme). After which the reaction mixture was stirred at ambient temperature overnight extracted with dichloromethane The organic layer was washed with saturated brine solution dried over sodium sulfate concentrated under reduced pressure

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Fluorobenzaldehyde (0.690 mL, 6.4 mmol) and 2-(methylsulfonyl)phenol (1.2 g, 7.0 mmol) were dissolved in N,N-dimethylformamide (15 mL), and potassium carbonate (0.85 g, 6.1 mmol) was added. The mixture was heated at 100° C. for 4 days. The reaction was diluted with ethyl acetate and extracted with water three times. The combined aqueous layers were extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered, and evaporated on the rotovap. The residue was chromatographed on silica gel using a 20–40% ethyl acetate in hexanes. The major component was collected to give a solid (0.942 g, 53%). 1H NMR (400 MHz, CDCl3): δ 9.97 (s, 1H), 8.12 (dd, J=8.0 Hz, J′=1.6 Hz, 1H), 7.92 (dd, J=6.6 Hz, J′=2.1 Hz, 2H), 7.64 (m, 1H), 7.38 (td, J=7.9 Hz, J′=1.0 Hz, 1H), 7.18 (dd, J=6.7 Hz, J′=1.9 Hz, 2H), 7.07 (dd, J=8.8.2 Hz, J′=1.0 Hz, 1H), 3.28 (s, 3H); LCMS found for C14H13O4S (M+H)+: m/z=277.0. extracted with water three times The combined aqueous layers were extracted with ethyl acetate twice The combined organic layers were dried over sodium sulfate filtered evaporated on the rotovap The residue was chromatographed on silica gel using a 20–40% ethyl acetate in hexanes The major component was collected