4-bromo-2-fluoro-1-methylsulfonylbenzene

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

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

Procedure: To 4-bromo-2-fluoro-1-methylsulfonyl-benzene (2 g, 7.9 mmol) in DMF (15 mL) is added 2-methanesulfonyl-ethanol (1.47 g, 11.85 mmol). Sodium hydride (948.16 mg, 23.71 mmol) is added in portions at 0° C. The reaction mixture is allowed to come to r.t. and is added dropwise into cooled aq. hydrochloric acid. The aq. layer is extracted with ethyl acetate. The organic layer is dried over MgSO4, filtered and concentrated. The crude residue is purified by reversed phase HPLC. Yield 86%, m/z 251/253[M+H]+, rt 0.42 min, LC-MS Method X018_S01. to come to r.t. is added dropwise The aq. layer is extracted with ethyl acetate The organic layer is dried over MgSO4 filtered concentrated The crude residue is purified by reversed phase HPLC Yield 86%, m/z 251/253[M+H]+, rt 0.42 min, LC-MS Method X018_S01

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

Procedure: To 4-bromo-2-fluoro-1-methylsulfonyl-benzene (2 g, 7.9 mmol) in DMF (15 mL) is added 2-methanesulfonyl-ethanol (1.47 g, 11.85 mmol). Sodium hydride (948.16 mg, 23.71 mmol) is added in portions at 0° C. The reaction mixture is allowed to come to r.t. and is added dropwise into cooled aq. hydrochloric acid. The aq. layer is extracted with ethyl acetate. The organic layer is dried over MgSO4, filtered and concentrated. The crude residue is purified by reversed phase HPLC. Yield 86%, m/z 251/253[M+H]+, rt 0.42 min, LC-MS Method X018_S01. to come to r.t. is added dropwise The aq. layer is extracted with ethyl acetate The organic layer is dried over MgSO4 filtered concentrated The crude residue is purified by reversed phase HPLC Yield 86%, m/z 251/253[M+H]+, rt 0.42 min, LC-MS Method X018_S01

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

Procedure: Dissolve 4-bromo-2-fluoro-1-methanesulfonyl-benzene (340 mg, 1.34 mmol) into DMF (8 mL) and treat with sodium thiomethoxide (103 mg, 9.8 mmol). Stir at room temperature for 2 days. Add water (10 mL) and CH2Cl2 (20 mL). Separate the layers and wash the organic layer with aqueous lithium chloride (10%), then dry (magnesium sulfate) and evaporate in vacuo. Chromatograph the residue on a SiO2 column eluting with EtOAc (20%) in hexane to give 286 mg (76%) of the title compound. Separate the layers wash the organic layer with aqueous lithium chloride (10%) dry (magnesium sulfate) evaporate in vacuo Chromatograph the residue on a SiO2 column eluting with EtOAc (20%) in hexane

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

Procedure: Combine 4-bromo-2-fluorothioanisole (U.S. Pat. No. 6,307,047, 2.7 g, 12 mmol), oxone (38 g, 62 mmol) and methanol (200 mL) and stir for 12 hours. Filter through a pad of silica gel and elute with ethyl acetate (500 mL). Evaporate solvent and partition between dichloromethane (200 mL) and water (100 mL). Separate the layers, wash the organic layer with saturated aqueous NaHCO3 (10 mL), brine (10 mL), dry with MgSO4, filter, and concentrate in vacuo. Wash the crude solid with hexane (20 mL), ether (10 mL) and dry in vacuo to obtain 2.4 g of 4-bromo-2-fluoro-1-methanesulfonyl-benzene (78%). Filter through a pad of silica gel elute with ethyl acetate (500 mL) Evaporate solvent and partition between dichloromethane (200 mL) and water (100 mL) Separate the layers wash the organic layer with saturated aqueous NaHCO3 (10 mL), brine (10 mL) dry with MgSO4 filter concentrate in vacuo Wash the crude solid with hexane (20 mL), ether (10 mL) dry in vacuo

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

Procedure: Dissolve 4-bromo-2-fluoro-1-methanesulfonyl-benzene (340 mg, 1.34 mmol) into DMF (8 mL) and treat with sodium thiomethoxide (103 mg, 9.8 mmol). Stir at room temperature for 2 days. Add water (10 mL) and CH2Cl2 (20 mL). Separate the layers and wash the organic layer with aqueous lithium chloride (10%), then dry (magnesium sulfate) and evaporate in vacuo. Chromatograph the residue on a SiO2 column eluting with EtOAc (20%) in hexane to give 286 mg (76%) of the title compound. Separate the layers wash the organic layer with aqueous lithium chloride (10%) dry (magnesium sulfate) evaporate in vacuo Chromatograph the residue on a SiO2 column eluting with EtOAc (20%) in hexane

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

Procedure: Dissolve 4-bromo-2-fluoro-1-methanesulfonyl-benzene (340 mg, 1.34 mmol) into DMF (8 mL) and treat with sodium thiomethoxide (103 mg, 9.8 mmol). Stir at room temperature for 2 days. Add water (10 mL) and CH2Cl2 (20 mL). Separate the layers and wash the organic layer with aqueous lithium chloride (10%), then dry (magnesium sulfate) and evaporate in vacuo. Chromatograph the residue on a SiO2 column eluting with EtOAc (20%) in hexane to give 286 mg (76%) of the title compound. Separate the layers wash the organic layer with aqueous lithium chloride (10%) dry (magnesium sulfate) evaporate in vacuo Chromatograph the residue on a SiO2 column eluting with EtOAc (20%) in hexane

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

Procedure: Combine 4-bromo-2-fluorothioanisole (U.S. Pat. No. 6,307,047, 2.7 g, 12 mmol), oxone (38 g, 62 mmol) and methanol (200 mL) and stir for 12 hours. Filter through a pad of silica gel and elute with ethyl acetate (500 mL). Evaporate solvent and partition between dichloromethane (200 mL) and water (100 mL). Separate the layers, wash the organic layer with saturated aqueous NaHCO3 (10 mL), brine (10 mL), dry with MgSO4, filter, and concentrate in vacuo. Wash the crude solid with hexane (20 mL), ether (10 mL) and dry in vacuo to obtain 2.4 g of 4-bromo-2-fluoro-1-methanesulfonyl-benzene 78%). Filter through a pad of silica gel elute with ethyl acetate (500 mL) Evaporate solvent and partition between dichloromethane (200 mL) and water (100 mL) Separate the layers wash the organic layer with saturated aqueous NaHCO3 (10 mL), brine (10 mL) dry with MgSO4 filter concentrate in vacuo Wash the crude solid with hexane (20 mL), ether (10 mL) dry in vacuo

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

Procedure: Following the General Procedure-1, the titled compound (30 mg) was prepared from Intermediate 8 (100 mg, 0.23 mmol) and 4-bromo-2-fluoro-1-(methylsulfonyl)benzene (70 mg, 0.37 mmol) as an off-white solid. M.P.: 174.3-177.5° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.03 (t, J 7.9, 1H), 7.88 (d, J 1.6, 1H), 7.61-7.51 (m, 3H), 7.46 (dd, J 1.6, 11.1, 1H), 4.15 (d, J 11.2, 2H), 3.26 (s, 3H), 3.20-3.11 (m, 1H), 3.00 (t, J 12.2, 2H), 2.20-2.12 (m, 2H), 1.98-1.84 (m, 2H), 1.48 (s, 9H).

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 50 ml sealable tube is introduced 4-Bromo-2-fluoro-1-methylsulfanyl-benzene (as obtained in preparation 63, 5 g, 22.6 mmol) followed by 4.6 ml AcOH. 9.3 ml of a 30% H2O2 solution in H2O is added at RT. The tube is sealed and the resulting colorless biphasic solution is stirred at 100° C. for 2 h. After cooling, the pH of the medium is set basic with solid NaHCO3 and then extracted with CH2Cl2 several times. The combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The title compound is obtained as a colorless solid, Rt=0.916 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min) The tube is sealed After cooling extracted with CH2Cl2 several times The combined organic layers are washed with brine dried over Na2SO4 filtered the filtrate is concentrated in vacuo

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 50 ml sealable tube is introduced 4-Bromo-2-fluoro-1-methylsulfanyl-benzene (as obtained in preparation 63, 5 g, 22.6 mmol) followed by 4.6 ml AcOH. 9.3 ml of a 30% H2O2 solution in H2O is added at RT. The tube is sealed and the resulting colorless biphasic solution is stirred at 100° C. for 2 h. After cooling, the pH of the medium is set basic with solid NaHCO3 and then extracted with CH2Cl2 several times. The combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The title compound is obtained as a colorless solid, Rt=0.916 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min) The tube is sealed After cooling extracted with CH2Cl2 several times The combined organic layers are washed with brine dried over Na2SO4 filtered the filtrate is concentrated in vacuo

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