butyl 2-bromoacetate

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

Procedure: This compound is prepared by the reaction of butyl bromoacetate with 5-chloro-2-tosylaminophenyl cyclohexyl ketone, followed by cyclization in the presence of sodium methylate in butanol.

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

Procedure: To a solution of compound 8.3 methyl 1-(4-(3-amino-6-bromoquinolin-4-ylamino)-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (60 mg, 0.115 mmol, 1 equiv.) in anhydrous DMF (3 mL) at 0° C. was added sodium hydride (60%, 5.0 mg, 0.126 mmol, 1.1 equiv.). After the mixture solution was stirred for 15minutes, tent-Butyl bromoacetate (19 mL, 0.126 mmol, 1.1 equiv.) was added. The resulting mixture was stirred overnight at room temperature under argon. Upon quenching with water, the mixture was concentrated under vacuum, diluted with EtOAc (20 mL), and washed with water (20 mL) and brine (20 mL). The organic phase was dried over Na2SO4. After removal of solvent under vacuum, the resulting residue was purified via flash chromatography (CH2Cl2:MeOH=35:1) to afford the desired product 8.4 methyl 1-(4-(9-bromo-3-oxo-3,4-dihydropyrazino[2,3-c]quinolin-1(2H)-yl)-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (61 mg; 94%). LC-MS (M+H): 563.15 The resulting mixture was stirred overnight at room temperature under argon Upon quenching with water the mixture was concentrated under vacuum diluted with EtOAc (20 mL) washed with water (20 mL) and brine (20 mL) The organic phase was dried over Na2SO4 After removal of solvent under vacuum the resulting residue was purified via flash chromatography (CH2Cl2:MeOH=35:1)

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

Procedure: 1RS, 2RS, 3RS)-3-(2-Carbo-t-butoxymethoxy-4-methoxyphenyl)-2-cyanomethyl-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane. To a solution of 1RS, 2RS, 3RS)-2-cyanomethyl-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (250 mg, 0.55 mmol) in DMF (4 ml) stirred at 0° C. under argon added NaH (21 mg of 80% oil dispersion, 0.7 mmol). The mixture stirred at 0° C. for 15 min then t -butylbromoacetate (107 mg, 0.55 mmol) was added. The cooling bath was removed and the mixture was stirred for 3 h at room temperature then partitioned between EtOAc and 3N HCl. The organic extract was washed with H2O, saturated NaHCO3 solution, H2O, then brine, dried (Na2SO4) and solvent removed in vacuo. The residue was purified by flash chromatography on silica gel, (eluent 25-50% Et2O/hexanes) to afford the title compound as an oil (247 mg, 79%). was added The cooling bath was removed the mixture was stirred for 3 h at room temperature then partitioned between EtOAc and 3N HCl The organic extract was washed with H2O, saturated NaHCO3 solution, H2O brine, dried (Na2SO4) and solvent removed in vacuo The residue was purified by flash chromatography on silica gel, (eluent 25-50% Et2O/hexanes)

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

Procedure: 1RS,2RS,3RS)-3-(2-Carbo-t-butoxymethoxy-4-methoxyphenyl)-2-cyanomethyl-1-(3,4methylenedioxyphenyl)-5-(prop-1-yloxy)indane. To a solution of 1RS,2RS,3RS)-2-cyanomethyl-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (250 mg, 0.55 mmol) in DMF (4 ml) stirred at 0° C. under argon added NaH (21 mg of 80% oil dispersion, 0.7 mmol). The mixture stirred at 0° C. for 15 min then t -butylbromoacetate (107 mg, 0.55 mmol) was added. The cooling bath was removed and the mixture was stirred for 3 h at room temperature then partitioned between EtOAc and 3N HCl. The organic extract was washed with H2O, saturated NaHCO3 solution, H2O, then brine, dried (Na2SO4) and solvent removed in vacuo. The residue was purified by flash chromatography on silica gel, (eluent 25-50% Et2O/hexanes) to afford the title compound as an oil (247 mg, 79%). was added The cooling bath was removed the mixture was stirred for 3 h at room temperature then partitioned between EtOAc and 3N HCl The organic extract was washed with H2O, saturated NaHCO3 solution, H2O brine, dried (Na2SO4) and solvent removed in vacuo The residue was purified by flash chromatography on silica gel, (eluent 25-50% Et2O/hexanes)

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

Procedure: 1RS,2RS,3RS)-3-(2-Carbo-t-butoxymethoxy-4-methoxyphenyl)-2-cyanomethyl-1-(3,4methylenedioxyphenyl)-5-(prop-1-yloxy)indane. To a solution of 1RS,2RS,3RS)-2-cyanomethyl-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (250 mg, 0.55 mmol) in DMF (4 ml) stirred at 0° C. under argon added NaH (21 mg of 80% oil dispersion, 0.7 mmol). The mixture stirred at 0° C. for 15 min then t -butylbromoacetate (107 mg, 0.55 mmol) was added. The cooling bath was removed and the mixture was stirred for 3 h at room temperature then partitioned between EtOAc and 3N HCl. The organic extract was washed with H2O, saturated NaHCO3 solution, H2O, then brine, dried (Na2SO4) and solvent removed in vacuo. The residue was purified by flash chromatography on silica gel, (eluent 25-50% Et2O/hexanes) to afford the title compound as an oil (247 mg, 79%). was added The cooling bath was removed the mixture was stirred for 3 h at room temperature then partitioned between EtOAc and 3N HCl The organic extract was washed with H2O, saturated NaHCO3 solution, H2O brine, dried (Na2SO4) and solvent removed in vacuo The residue was purified by flash chromatography on silica gel, (eluent 25-50% Et2O/hexanes)

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

Procedure: This compound is prepared by the reaction of butyl bromoacetate with 5-chloro-2-tosylaminophenyl cyclohexyl ketone, followed by cyclization in the presence of sodium methylate in butanol.

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

Procedure: To a solution of compound 8.3 methyl 1-(4-(3-amino-6-bromoquinolin-4-ylamino)-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (60 mg, 0.115 mmol, 1 equiv.) in anhydrous DMF (3 mL) at 0° C. was added sodium hydride (60%, 5.0 mg, 0.126 mmol, 1.1 equiv.). After the mixture solution was stirred for 15minutes, tent-Butyl bromoacetate (19 mL, 0.126 mmol, 1.1 equiv.) was added. The resulting mixture was stirred overnight at room temperature under argon. Upon quenching with water, the mixture was concentrated under vacuum, diluted with EtOAc (20 mL), and washed with water (20 mL) and brine (20 mL). The organic phase was dried over Na2SO4. After removal of solvent under vacuum, the resulting residue was purified via flash chromatography (CH2Cl2:MeOH=35:1) to afford the desired product 8.4 methyl 1-(4-(9-bromo-3-oxo-3,4-dihydropyrazino[2,3-c]quinolin-1(2H)-yl)-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (61 mg; 94%). LC-MS (M+H): 563.15 The resulting mixture was stirred overnight at room temperature under argon Upon quenching with water the mixture was concentrated under vacuum diluted with EtOAc (20 mL) washed with water (20 mL) and brine (20 mL) The organic phase was dried over Na2SO4 After removal of solvent under vacuum the resulting residue was purified via flash chromatography (CH2Cl2:MeOH=35:1)

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

Procedure: 1RS, 2RS, 3RS)-3-(2-Carbo-t-butoxymethoxy-4-methoxyphenyl)-2-cyanomethyl-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane. To a solution of 1RS, 2RS, 3RS)-2-cyanomethyl-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (250 mg, 0.55 mmol) in DMF (4 ml) stirred at 0° C. under argon added NaH (21 mg of 80% oil dispersion, 0.7 mmol). The mixture stirred at 0° C. for 15 min then t -butylbromoacetate (107 mg, 0.55 mmol) was added. The cooling bath was removed and the mixture was stirred for 3 h at room temperature then partitioned between EtOAc and 3N HCl. The organic extract was washed with H2O, saturated NaHCO3 solution, H2O, then brine, dried (Na2SO4) and solvent removed in vacuo. The residue was purified by flash chromatography on silica gel, (eluent 25-50% Et2O/hexanes) to afford the title compound as an oil (247 mg, 79%). was added The cooling bath was removed the mixture was stirred for 3 h at room temperature then partitioned between EtOAc and 3N HCl The organic extract was washed with H2O, saturated NaHCO3 solution, H2O brine, dried (Na2SO4) and solvent removed in vacuo The residue was purified by flash chromatography on silica gel, (eluent 25-50% Et2O/hexanes)

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

Procedure: 1RS,2RS,3RS)-3-(2-Carbo-t-butoxymethoxy-4-methoxyphenyl)-2-cyanomethyl-1-(3,4methylenedioxyphenyl)-5-(prop-1-yloxy)indane. To a solution of 1RS,2RS,3RS)-2-cyanomethyl-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (250 mg, 0.55 mmol) in DMF (4 ml) stirred at 0° C. under argon added NaH (21 mg of 80% oil dispersion, 0.7 mmol). The mixture stirred at 0° C. for 15 min then t -butylbromoacetate (107 mg, 0.55 mmol) was added. The cooling bath was removed and the mixture was stirred for 3 h at room temperature then partitioned between EtOAc and 3N HCl. The organic extract was washed with H2O, saturated NaHCO3 solution, H2O, then brine, dried (Na2SO4) and solvent removed in vacuo. The residue was purified by flash chromatography on silica gel, (eluent 25-50% Et2O/hexanes) to afford the title compound as an oil (247 mg, 79%). was added The cooling bath was removed the mixture was stirred for 3 h at room temperature then partitioned between EtOAc and 3N HCl The organic extract was washed with H2O, saturated NaHCO3 solution, H2O brine, dried (Na2SO4) and solvent removed in vacuo The residue was purified by flash chromatography on silica gel, (eluent 25-50% Et2O/hexanes)

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

Procedure: A solution of diisopropylamine (4.0 mL, 28.5 mmol) in THF (20 mL) was treated with 2.5M n-butyllithium (11.42 mL, 28.5 mmol) at −78° C. The mixture was warmed to RT for 0.5 h, cooled to −78° C., and 2-methylpyrazine (2.0 mL, 21.9 mmol) was added. The reaction mixture was warmed to RT, stirred for 1 h, cooled to −78° C., and butyl bromoacetate (4.25 mL, 26.3 mmol) was added. The reaction mixture was warmed to RT, stirred for 18 h and quenched with water (1 mL). The mixture was concentrated and the residue was purified by flash chromatography (silica gel, 60% ethyl acetate/hexane) to give the title compound (3.06 g, 67%) as a light yellow oil. MS(ES) m/e 209 [M+H]+; 1H NMR (250 MHz) δ8.37-8.57 (m, 3H), 3.10 (t, 2H), 2.74 (t, 2H), 1.43 (s, 9H). cooled to −78° C. The reaction mixture was warmed to RT cooled to −78° C. The reaction mixture was warmed to RT stirred for 18 h quenched with water (1 mL) The mixture was concentrated the residue was purified by flash chromatography (silica gel, 60% ethyl acetate/hexane)

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

Procedure: This compound is prepared by the reaction of butyl bromoacetate with 5-chloro-2-tosylaminophenyl cyclohexyl ketone, followed by cyclization in the presence of sodium methylate in butanol.

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

Procedure: A solution of intermediate 4 (4.00 g, 11.0 mmol), tent-butyl 2-bromoacetate (2.36 g, 12.1 mmol) and potassium carbonate (3.04 g, 22.0 mmol) was stirred at room temperature. After 72 h, the reaction mixture was concentrated under vacuum and the residue was partitioned between CH2Cl2 and water. The organic layer was dried and the residue was reconstituted in CH2Cl2 (20 mL) and TFA (20 mL) was added. After 2 h at room temperature, the reaction mixture was evaporated under vacuum to yield 4.2 g (90%) of {2-[3-cyclohexyl-6-(methoxycarbonyl)-1-methyl-1H-indol-2-yl]phenoxy}acetic acid 5: m/z=422 (M+H)+. the reaction mixture was concentrated under vacuum the residue was partitioned between CH2Cl2 and water The organic layer was dried TFA (20 mL) was added After 2 h at room temperature the reaction mixture was evaporated under vacuum