2-(4-bromophenoxy)ethanol

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

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

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

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

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

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 2-(4-bromophenoxy)ethanol (100 mg, 0.46 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (173 mg, 0.50 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (38.0 mg, 0.025 mmol) and potassium acetate (135 mg, 1.38 mmol) in 1,4-dioxane (1 mL) was sealed in a pressure tube and heated to 130° C. for 1 hour. To the mixture was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (100 mg, 0.36 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.7 mg, 0.018 mmol), 2N aqueous potassium carbonate solution (0.5 mL, 1.0 mmol) and EtOH (2 mL). The mixture was sealed and heated to 130° C. for 1 hour. Water (3 mL) was added to the reaction mixture, followed by 1N HCl solution to adjust the pH to 2. The layers were separated and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Column: Waters Sunfire C18 19×100 mm, 5 μm; Mobile phase A: 0.05% Formic acid in water (v/v); Mobile phase B: 0.05% Formic acid in MeCN (v/v); HOLD at 75.0% H2O/25.0% MeCN for 1.0 min. 75.0% H2O/25.0% MeCN linear to 45.0% H2O/55.0% MeCN in 6.75 min, linear to 0% H2O/100% MeCN to 7.0 min. HOLD at 0% H2O/100% MeCN from 7.0 to 8.0 min. Flow: 30 mL/min) to afford the title compound (23.1 mg, 15% yield). MS (ES+) 333.0 (M+H)+. Retention time=2.19 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min). was sealed in a pressure tube The mixture was sealed heated to 130° C. for 1 hour The layers were separated the aqueous layer was extracted with EtOAc (3×5 mL) The combined organic layers were dried over Na2SO4 concentrated in vacuo The crude material was purified by reverse phase HPLC (Column: Waters Sunfire C18 19×100 mm, 5 μm; Mobile phase A: 0.05% Formic acid in water (v/v); Mobile phase B: 0.05% Formic acid in MeCN (v/v); HOLD at 75.0% H2O/25.0% MeCN for 1.0 min. 75.0% H2O/25.0% MeCN linear to 45.0% H2O/55.0% MeCN in 6.75 min, linear to 0% H2O/100% MeCN to 7.0 min. HOLD at 0% H2O/100% MeCN from 7.0 to 8.0 min. Flow: 30 mL/min)

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

Procedure: The title compound was prepared by the procedures of Example 33 from sulfamoyl chloride and 2-(4-bromophenoxy)ethanol as white solid, mp 134°-137° C., in 69% yield.

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

Procedure: In a reactor, 10.0 g of 4-bromophenol, 7.95 g of ethylene bromohydrin, 16.0 g of K2CO3, and 300 ml of acetone were charged, and stirred and refluxed for 50 hours to give a reaction solution. The reaction solution was poured into water, extracted with toluene, washed with water, and thereafter dried over sodium sulfate anhydride, and the solvent was evaporated and the residue was distilled under reduced pressure in GTO (glass tube oven) to give 5.55 g (Y., 44.3%) of 1-bromo-4-(2-hydroxyethoxy)benzene. GC; 96.8% b.p.; 100° C./0.1 mmHg (which was the prescribed temperature of GTO) refluxed for 50 hours to give a reaction solution extracted with toluene washed with water dried over sodium sulfate anhydride the solvent was evaporated the residue was distilled under reduced pressure in GTO (glass tube oven)

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

Procedure: In a reactor, 10.0 g of 4-bromophenol, 7.95 g of ethylene bromohydrin, 16.0 g of K2CO3, and 300 ml of acetone were charged, and stirred and refluxed for 50 hours to give a reaction solution. The reaction solution was poured into water, extracted with toluene, washed with water, and thereafter dried over sodium sulfate anhydride, and the solvent was evaporated and the residue was distilled under reduced pressure in GTO (glass tube oven) to give 5.55 g (Y., 44.3%) of 1-bromo-4-(2-hydroxyethoxy)benzene. GC; 96.8% b.p.; 100° C./0.1 mmHg (which was the prescribed temperature of GTO) refluxed for 50 hours to give a reaction solution extracted with toluene washed with water dried over sodium sulfate anhydride the solvent was evaporated the residue was distilled under reduced pressure in GTO (glass tube oven)

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

Procedure: N-{6-Chloro-2-(2-pyrimidyl)-5-(2-methoxyphenoxy)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide and 2-(4-bromophenoxy)ethanol are treated in the same manner as in Example 192-(1) to give N-{6-{2-(4-bromophenoxy)ethoxy}-2-(2-pyrimidyl)-5-(2-methoxyphenoxy)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide.

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 2-(4-bromophenoxy)ethanol (100 mg, 0.46 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (173 mg, 0.50 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (38.0 mg, 0.025 mmol) and potassium acetate (135 mg, 1.38 mmol) in 1,4-dioxane (1 mL) was sealed in a pressure tube and heated to 130° C. for 1 hour. To the mixture was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (100 mg, 0.36 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.7 mg, 0.018 mmol), 2 N aqueous potassium carbonate solution (0.5 mL, 1.0 mmol) and EtOH (2 mL). The mixture was sealed and heated to 130° C. for 1 hour. Water (3 mL) was added to the reaction mixture, followed by 1 N HCl solution to adjust the pH to 2. The layers were separated and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Column: Waters Sunfire C18 19×100 mm, 5 μm; Mobile phase A: 0.05% Formic acid in water (v/v); Mobile phase B: 0.05% Formic acid in MeCN (v/v); HOLD at 75.0% H2O/25.0% MeCN for 1.0 min. 75.0% H2O/25.0% MeCN linear to 45.0% H2O/55.0% MeCN in 6.75 min, linear to 0% H2O/100% MeCN to 7.0 min. HOLD at 0% H2O/100% MeCN from 7.0 to 8.0 min. Flow: 30 ml/min) to afford the title compound (23.1 mg, 15% yield). MS (ES+) 333.0 (M+H)+. Retention time=2.19 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min). was sealed in a pressure tube The mixture was sealed heated to 130° C. for 1 hour The layers were separated the aqueous layer was extracted with EtOAc (3×5 mL) The combined organic layers were dried over Na2SO4 concentrated in vacuo The crude material was purified by reverse phase HPLC (Column: Waters Sunfire C18 19×100 mm, 5 μm; Mobile phase A: 0.05% Formic acid in water (v/v); Mobile phase B: 0.05% Formic acid in MeCN (v/v); HOLD at 75.0% H2O/25.0% MeCN for 1.0 min. 75.0% H2O/25.0% MeCN linear to 45.0% H2O/55.0% MeCN in 6.75 min, linear to 0% H2O/100% MeCN to 7.0 min. HOLD at 0% H2O/100% MeCN from 7.0 to 8.0 min. Flow: 30 ml/min)

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 2-(4-bromophenoxy)ethanol (100 mg, 0.46 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (173 mg, 0.50 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (38.0 mg, 0.025 mmol) and potassium acetate (135 mg, 1.38 mmol) in 1,4-dioxane (1 mL) was sealed in a pressure tube and heated to 130° C. for 1 hour. To the mixture was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (100 mg, 0.36 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.7 mg, 0.018 mmol), 2 N aqueous potassium carbonate solution (0.5 mL, 1.0 mmol) and EtOH (2 mL). The mixture was sealed and heated to 130° C. for 1 hour. Water (3 mL) was added to the reaction mixture, followed by 1 N HCl solution to adjust the pH to 2. The layers were separated and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Column: Waters Sunfire C18 19×100 mm, 5 μm; Mobile phase A: 0.05% Formic acid in water (v/v); Mobile phase B: 0.05% Formic acid in MeCN (v/v); HOLD at 75.0% H2O/25.0% MeCN for 1.0 min. 75.0% H2O/25.0% MeCN linear to 45.0% H2O/55.0% MeCN in 6.75 min, linear to 0% H2O/100% MeCN to 7.0 min. HOLD at 0% H2O/100% MeCN from 7.0 to 8.0 min. Flow: 30 ml/min) to afford the title compound (23.1 mg, 15% yield). MS (ES+) 333.0 (M+H)+. Retention time=2.19 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min). was sealed in a pressure tube The mixture was sealed heated to 130° C. for 1 hour The layers were separated the aqueous layer was extracted with EtOAc (3×5 mL) The combined organic layers were dried over Na2SO4 concentrated in vacuo The crude material was purified by reverse phase HPLC (Column: Waters Sunfire C18 19×100 mm, 5 μm; Mobile phase A: 0.05% Formic acid in water (v/v); Mobile phase B: 0.05% Formic acid in MeCN (v/v); HOLD at 75.0% H2O/25.0% MeCN for 1.0 min. 75.0% H2O/25.0% MeCN linear to 45.0% H2O/55.0% MeCN in 6.75 min, linear to 0% H2O/100% MeCN to 7.0 min. HOLD at 0% H2O/100% MeCN from 7.0 to 8.0 min. Flow: 30 ml/min)