2-phenoxyethyl methanesulfonate

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

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

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

Procedure: To a solution of 2-(phenoxy)ethanol (1.35 g, 9.78 mmoles) and triethytamine (2.04 ml, 14.7 mmoles) in methylene chloride (30 ml) was added methanesulfonyl chloride (0.91 ml, 12 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice-cooling for 10 minutes. The reaction solution was washed with water and the aqueous layer was extracted with methylene chloride (30 ml×3). The methylene chloride layers were combined and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was subjected to column chromatography [eluent:hexane/methyl (1:1)] to obtain crude 1-methanesulfonyloxy-2-(phenoxy)ethane as a pale yellow oily product. cooling the mixture was further stirred under ice- cooling for 10 minutes The reaction solution was washed with water the aqueous layer was extracted with methylene chloride (30 ml×3) dried over anhydrous magnesium sulfate After the solvent was distilled off

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

Procedure: To a solution of 2-(phenoxy)ethanol (1.35 g, 9.78 mmoles) and triethylamine (2.04 ml, 14.7 mmoles) in methylene chloride (30 ml) was added methanesulfonyl chloride (0.91 ml, 12 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice-cooling for 10 minutes. The reaction solution was washed with water and the aqueous layer was extracted with methylene chloride (30 ml×3). The methylene chloride layers were combined and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was subjected to column chromatography [eluent: hexane/methyl (1:1)] to obtain crude 1-methanesulfonyloxy-2-(phenoxy)ethane as a pale yellow oily product. cooling the mixture was further stirred under ice- cooling for 10 minutes The reaction solution was washed with water the aqueous layer was extracted with methylene chloride (30 ml×3) dried over anhydrous magnesium sulfate After the solvent was distilled off

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

Procedure: To a solution of 2-(phenoxy)ethanol (1.35 g, 9.78 mmoles) and triethylamine (2.04 ml, 14.7 mmoles) in methylene chloride (30 ml) was added methanesulfonyl chloride (0.91 ml, 12 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice-cooling for 10 minutes. The reaction solution was washed with water and the aqueous layer was extracted with methylene chloride (30 ml×3). The methylene chloride layers were combined and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was subjected to column chromatography [eluent: hexane/methyl (1:1)] to obtain crude 1-methanesulfonyloxy-2-(phenoxy)ethane as a pale yellow oily product. cooling the mixture was further stirred under ice- cooling for 10 minutes The reaction solution was washed with water the aqueous layer was extracted with methylene chloride (30 ml×3) dried over anhydrous magnesium sulfate After the solvent was distilled off

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

Procedure: Synthesis of N-[1-(2-phenoxyethan-1-yl)piperidin-4-ylmethyl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide Under nitrogen gas, 0.37 ml (4.78 mM) of methanesulfonyl chloride was added to a solution of 0.44 g (3.18 mM) of phenoxyethanol and 0.89 ml (6.39 mM) of triethylamine in methylene chloride (6 ml) at 0° C. and the mixture was stirred at the prevailing temperature for 35 minutes. The reaction was stopped by adding saturated aqueous solution of sodium hydrogen carbonate and the reaction mixture was extracted with diethyl ether. The organic layer was washed serially with water and saturated aqueous solution of sodium chloride and dried over MgSO4. The solvent was then distilled off under reduced pressure to provide 0.6989 g (<3.18 mM) of phenoxyethyl mesylate. To a solution of 0.58 g (1.5 mM) of N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (7.2 mM) of triethylamine in ethanol (6.0 ml) was added 0.6989 g (<3.18 mM) of the above phenoxyethyl mesylate at room temperature and the mixture was refluxed under nitrogen for 17 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The resulting crude product was purified by column chromatography (methanol/ethyl acetate 30-40%) to provide the title compound. the mixture was refluxed under nitrogen for 17 hours The solvent was then distilled off under reduced pressure the residue was diluted with water extracted with chloroform The organic layer was washed with saturated aqueous solution of sodium chloride dried over MgSO4 The resulting crude product was purified by column chromatography (methanol/ethyl acetate 30-40%)

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

Procedure: Synthesis of N-[1-(2-phenoxyethan-1-yl)piperidin-4-ylmethyl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide Under nitrogen gas, 0.37 ml (4.78 mM) of methanesulfonyl chloride was added to a solution of 0.44 g (3.18 mM) of phenoxyethanol and 0.89 ml (6.39 mM) of triethylamine in methylene chloride (6 ml) at 0° C. and the mixture was stirred at the prevailing temperature for 35 minutes. The reaction was stopped by adding saturated aqueous solution of sodium hydrogen carbonate and the reaction mixture was extracted with diethyl ether. The organic layer was washed serially with water and saturated aqueous solution of sodium chloride and dried over MgSO4. The solvent was then distilled off under reduced pressure to provide 0.6989 g (<3.18 mM) of phenoxyethyl mesylate. To a solution of 0.58 g (1.5 mM) of N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (7.2 mM) of triethylamine in ethanol (6.0 ml) was added 0.6989 g (<3.18 mM) of the above phenoxyethyl mesylate at room temperature and the mixture was refluxed under nitrogen for 17 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The resulting crude product was purified by column chromatography (methanol/ethyl acetate 30-40%) to provide the title compound. the reaction mixture was extracted with diethyl ether The organic layer was washed serially with water and saturated aqueous solution of sodium chloride dried over MgSO4 The solvent was then distilled off under reduced pressure

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The oil comprising 2-Phenoxyethyl methanesulfonate was prepared as described above in Example 1. The acylation and workup procedure was identical to that of Example 1 with the exception that 30.26 g (220 mmol) 2-phenylacetic acid was reacted instead of the 2-phenylbutyric acid. The organic layer obtained by the workup procedure was cooled to 25° C. and stirred at this temperature for 1 hour. The resulting crystallized product was filtered, washed with toluene and dried under vacuum at 40° C. to yield 53.18 g (159 mmol) of the 4-(2-mesyloxyethoxy)phenyl benzylketone as a tan colored solid. Yield: 80% on 2-phenoxyethanol. was prepared The organic layer obtained by the workup procedure The resulting crystallized product was filtered washed with toluene dried under vacuum at 40° C.

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

Procedure: To a solution of 2-(phenoxy)ethanol (1.35 g, 9.78 mmoles) and triethylamine (2.04 ml, 14.7 mmoles) in methylene chloride (30 ml) was added methanesulfonyl chloride (0.91 ml, 12 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice-cooling for 10 minutes. The reaction solution was washed with water and the aqueous layer was extracted with methylene chloride (30 ml×3). The methylene chloride layers were combined and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was subjected to column chromatography [eluent: hexane/methyl (1:1)] to obtain crude 1-methanesulfonyloxy-2-(phenoxy)ethane as a pale yellow oily product. cooling the mixture was further stirred under ice- cooling for 10 minutes The reaction solution was washed with water the aqueous layer was extracted with methylene chloride (30 ml×3) dried over anhydrous magnesium sulfate After the solvent was distilled off

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

Procedure: To a solution of methyl 4-[(1S)-1-[[(2R)-2-hydroxy-3-methyl-butanoyl]amino]ethyl]benzoate (3.0 g, 10.7 mmol) and 2-phenoxyethyl methanesulfonate (2.32 g, 10.7 mmol) in dry THF (25 mL) is added sodium hydride (440 mg, 10.7 mmol). The mixture is stirred at room temperature overnight and partitioned between 1N HCl and EtOAc. The aqueous layer is extracted with EtOAc. The combined EtOAc layers are washed with brine, dried with MgSO4, filtered, and concentrated. The crude material (4.7 g) is purified using silica gel column chromatography (120 g cartridge; 30 to 100% ethyl acetate in heptane) to provide the title compound as a white solid (1.41 g, 33%). MS (m/z): 400.2 (M+1). partitioned between 1N HCl and EtOAc The aqueous layer is extracted with EtOAc The combined EtOAc layers are washed with brine dried with MgSO4 filtered concentrated The crude material (4.7 g) is purified

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-phenoxyethanol (10.0 mL, 80.0 mmol) and triethylamine (13.5 mL, 96.9 mmol) in anhydrous CH2Cl2 (250 mL) at 0° C. is added methanesulfonyl chloride (6.80 mL, 87.9 mmol). The resulting cloudy mixture is stirred at 0° C. for 2 h. The mixture is diluted with water (75 mL) and extracted. The organic layer is washed with 1N HCl (75 mL) then saturated NaHCO3/brine (1:1; 75 mL) dried (Na2SO4), filtered, and concentrated. The residue is dried to constant weight under reduced pressure to provide the title compound as a pale yellow oil (17.1 g, 99%). This material is used in the next step without further purification. extracted The organic layer is washed with 1N HCl (75 mL) saturated NaHCO3/brine (1:1; 75 mL) dried (Na2SO4) filtered concentrated The residue is dried to constant weight under reduced pressure

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

Procedure: To a solution of 2-(phenoxy)ethanol (1.35 g, 9.78 mmoles) and triethytamine (2.04 ml, 14.7 mmoles) in methylene chloride (30 ml) was added methanesulfonyl chloride (0.91 ml, 12 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice-cooling for 10 minutes. The reaction solution was washed with water and the aqueous layer was extracted with methylene chloride (30 ml×3). The methylene chloride layers were combined and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was subjected to column chromatography [eluent:hexane/methyl (1:1)] to obtain crude 1-methanesulfonyloxy-2-(phenoxy)ethane as a pale yellow oily product. cooling the mixture was further stirred under ice- cooling for 10 minutes The reaction solution was washed with water the aqueous layer was extracted with methylene chloride (30 ml×3) dried over anhydrous magnesium sulfate After the solvent was distilled off