1-bromo-3-diethoxyphosphorylpropane

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:

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

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

Procedure: Diethyl 3-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)propylphosphonate was prepared following an analogous procedure to the preparation described for Example 139, but using 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol (from Example 50) with diethyl 3-bromopropylphosphonate. 1H NMR (Acetone-d6): δ 9.52 (s, 1H), 9.47 (s, 1H), 9.03 (d, 1H), 8.21 (s, 1H), 7.93 (d, 1H), 7.84 (d, 1H), 7.60 (br, 2H), 7.53 (s, 1), 7.45 (d, 1H), 4.76-4.91 (m, 6H), 3.93 (t, 2H), 3.81 (t, 2H), 3.24 (s, 3H), 3.06 (s, 3H), 2.76-2.86 (m, 2H), 2.61-2.72 (m, 2H), 2.07 (t, 6H). LRMS [M+H]=522.2

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

Procedure: To a solution of ethyl 3-{2-fluoro-4-[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy]phenyl}propanoate (315 mg, 0.74 mmol) in N,N-dimethylformamide (4 mL) was added sodium hydride (60%, 31 mg, 0.78 mmol) at 0° C. with stirring, and the mixture was stirred at room temperature for 30 min. Diethyl (3-bromopropyl)phosphonate (578 mg, 2.23 mmol) and potassium iodide (37 mg, 0.22 mmol) were added, and the mixture was further stirred overnight at 60° C. The reaction mixture was concentrated under reduced pressure. Brine was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-1/4) and then by preparative HPLC (gradient cycle A) to give the title compound (0.22 g, yield 50%) as a colorless oil. the mixture was stirred at room temperature for 30 min the mixture was further stirred overnight at 60° C The reaction mixture was concentrated under reduced pressure Brine was added to the residue the mixture was extracted with ethyl acetate The extract was dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-1/4)

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

Procedure: To a solution of ethyl 3-{2-fluoro-4-[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy]phenyl}propanoate (315 mg, 0.74 mmol) in N,N-dimethylformamide (4 mL) was added sodium hydride (60%, 31 mg, 0.78 mmol) at 0° C. with stirring, and the mixture was stirred at room temperature for 30 min. Diethyl (3-bromopropyl)phosphonate (578 mg, 2.23 mmol) and potassium iodide (37 mg, 0.22 mmol) were added, and the mixture was further stirred overnight at 60° C. The reaction mixture was concentrated under reduced pressure. Brine was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-1/4) and then by preparative HPLC (gradient cycle A) to give the title compound (0.22 g, yield 50%) as a colorless oil. the mixture was stirred at room temperature for 30 min the mixture was further stirred overnight at 60° C The reaction mixture was concentrated under reduced pressure Brine was added to the residue the mixture was extracted with ethyl acetate The extract was dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-1/4)

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

Procedure: A mixture of 2-(4-octyloxy-phenyl)-morpholine (1.04 g; 3.6 mmol), diethyl (3-bromopropyl)phosphonate (0.82 mL; 4.3 mmol), NaI (0.11 g; 0.7 mmol), and K2CO3 (0.99 g; 7.1 mmol) in CH3CN (10 mL) was heated under reflux for 2 hours. After cooling to RT the mixture was partitioned between 5% aqueous NaHCO3 solution and Et2O. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, EtOAc: MeOH 90:10) to afford {2-[2-(4-octyloxy-phenyl)morpholin-4-yl]-propyl}-phosphonic acid diethyl ester (1.13 g). was heated under reflux for 2 hours was partitioned between 5% aqueous NaHCO3 solution and Et2O The organic layer was dried (Na2SO4) filtered concentrated in vacuo The residue was purified by column chromatography (SiO2, EtOAc: MeOH 90:10)