2-bromo-N,N-dimethylacetamide

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:0.00; pressure:0.00; stir:

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

Procedure: (-)-(1R)-1-[4-Benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylamino)ethanol (450 mg) was dissolved in 4 ml of methylene chloride, 860 μl of 5 N aqueous sodium hydroxide solution and 143 mg of 2-bromo-N,N-dimethylacetamide were added to the solution with stirring at room temperature in that order, and the mixture was subjected to 3 hours of reaction at room temperature. Then, 143 mg of 2-brorno-N,N-dimethylacetamide was additionally added to the reaction solution, and the mixture was subjected to 1 hour of reaction at room temperature. Then, 267 μl of diethylamine was added and the mixture was stirred for 30 minutes. Brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by aminopropylated silica gel medium pressure liquid column chromatography (eluent: ethyl acetate) to give 410 mg of (-)-2-[(2S)-2-[[(2R)-2-[4-benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-hydroxyethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy)-N,N-dimethylacetamide in an oily form. the mixture was subjected to 3 hours of reaction at room temperature the mixture was subjected to 1 hour of reaction at room temperature the mixture was stirred for 30 minutes the mixture was extracted with ethyl acetate The extract was washed with brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the resulting residue was purified by aminopropylated silica gel medium pressure liquid column chromatography (eluent: ethyl acetate)

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

Procedure: (S)-2-(Benzyloxycarbonylamino)-7-hydroxytetralin (13.4 g) was dissolved in 120 ml of N,N-dimethylformamide, 8.27 g of 2-bromo-N,N-dimethylacetamide and 22.0 g of cesium carbonate were added to the solution, and the mixture was stirred at room temperature for 6 hours. The reaction solution was poured into ice-water, the mixture was extracted with ethyl acetate, and the extract was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was crystallized by adding diethyl ether to give 14.0 g of (S)-2-[2-(benzyloxycarbonylamino)-1,2,3,4-tetrahydronaphthalen-7-yloxy]-N,N-dimethylacetamide having a melting point of 117 to 118° C. the mixture was extracted with ethyl acetate the extract was washed with water dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the resulting residue was crystallized by adding diethyl ether

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

Procedure: 2-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenoxy)-N,N-dimethylacetamide was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) and following the procedure described for Example 139, but using 2-bromo-N,N-dimethylacetamide. 1H NMR (Acetone-d6): δ 8.75 (s, 1H), 8.70 (s, 1H), 8.28 (d, 1H), 7.40 (s, 1H), 7.18 (t, 3H), 6.87 (d, 2H), 6.56 (br, 2H), 4.72 (s, 2H), 3.20 (t, 2H), 3.07 (s, 3H), 3.05 (t, 2H), 2.87 (s, 3H), 2.45 (s, 3H). LRMS [M+H]=415.2

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

Procedure: To a solution of 3-methyl-4-nitropyrazole (Apollo, Cheshire, UK, 500 mg, 3.93 mmol) in DMF (10 ml) was added 55% NaH in oil (198 mg, 4.54 mmol) and the reaction mixture was stirred for 30 min at rt. Then to the reaction mixture was added a solution of 2-bromo-N,N-dimethylacetamide (stage L.3, 720 mg, 4.34 mmol) in DMF (3 ml). The reaction mixture was stirred for 1 h at it then quenched with saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organic layers were washed with water (2×), brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by Prep. HPLC (H2O (0.1% TFA)/CH3CN 97:2 to 75:25; reverse phase silica gel). The fractions containing product were collected together, basified with NaHCO3 and concentrated before being extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give the title compound as a white solid (HPLC tR 2.06 min (Method A); M+H=213 MS-ES). The reaction mixture was stirred for 1 h at it then quenched with saturated aqueous NaHCO3 extracted with EtOAc (2×) The combined organic layers were washed with water (2×), brine dried over Na2SO4 filtered evaporated The crude product was purified by Prep The fractions containing product were collected together concentrated before being extracted with EtOAc (3×) The combined organic layers were washed with brine dried over Na2SO4 filtered evaporated

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

Procedure: To a solution of 3-methyl-4-nitropyrazole (Apollo, Cheshire, UK, 500 mg, 3.93 mmol) in DMF (10 ml) was added 55% NaH in oil (198 mg, 4.54 mmol) and the reaction mixture was stirred for 30 min at rt. Then to the reaction mixture was added a solution of 2-bromo-N,N-dimethylacetamide (stage L.3, 720 mg, 4.34 mmol) in DMF (3 ml). The reaction mixture was stirred for 1 h at it then quenched with saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organic layers were washed with water (2×), brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by Prep. HPLC (H2O (0.1% TFA)/CH3CN 97:2 to 75:25; reverse phase silica gel). The fractions containing product were collected together, basified with NaHCO3 and concentrated before being extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give the title compound as a white solid (HPLC tR 2.06 min (Method A); M+H=213 MS-ES). The reaction mixture was stirred for 1 h at it then quenched with saturated aqueous NaHCO3 extracted with EtOAc (2×) The combined organic layers were washed with water (2×), brine dried over Na2SO4 filtered evaporated The crude product was purified by Prep The fractions containing product were collected together concentrated before being extracted with EtOAc (3×) The combined organic layers were washed with brine dried over Na2SO4 filtered evaporated

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

Procedure: (-)-(1R)-1-[4-Benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylamino)ethanol (450 mg) was dissolved in 4 ml of methylene chloride, 860 μl of 5 N aqueous sodium hydroxide solution and 143 mg of 2-bromo-N,N-dimethylacetamide were added to the solution with stirring at room temperature in that order, and the mixture was subjected to 3 hours of reaction at room temperature. Then, 143 mg of 2-brorno-N,N-dimethylacetamide was additionally added to the reaction solution, and the mixture was subjected to 1 hour of reaction at room temperature. Then, 267 μl of diethylamine was added and the mixture was stirred for 30 minutes. Brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by aminopropylated silica gel medium pressure liquid column chromatography (eluent: ethyl acetate) to give 410 mg of (-)-2-[(2S)-2-[[(2R)-2-[4-benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-hydroxyethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy)-N,N-dimethylacetamide in an oily form. the mixture was subjected to 3 hours of reaction at room temperature the mixture was subjected to 1 hour of reaction at room temperature the mixture was stirred for 30 minutes the mixture was extracted with ethyl acetate The extract was washed with brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the resulting residue was purified by aminopropylated silica gel medium pressure liquid column chromatography (eluent: ethyl acetate)