methyl 4-(morpholin-4-ylmethyl)benzoate

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

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

Procedure: Commercially available 4-bromomethylbenzoic acid (300 mg) was dissolved in acetonitrile (10 ml). Potassium carbonate (30 mg) and morpholine (130 μl) were added to the solution, and the mixture was stirred at room temperature for one hr. The reaction layer was subjected to separation with chloroform and a saturated aqueous sodium hydrogencarbonate solution. The organic layer was then concentrated to give methyl 4-(morpholinomethyl)benzoate. Methanol (1 ml), water (150 μl), and potassium hydroxide (15 mg) were added to the residue, and the mixture was heated at 60° C. for one hr. After the completion of the reaction, the solvent was removed by distillation to give 4-(morpholinomethyl)benzoic acid. Toluene (20 ml) and thionyl chloride (1 ml) were added to the residule, and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 4-(morpholinomethyl)-1-benzenecarbonyl isothiocyanate was prepared using the resultant 4-(morpholinomethyl)-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-(morpholinomethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (74 mg, yield 78%). The reaction layer was subjected to separation with chloroform The organic layer was then concentrated

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

Procedure: Commercially available 4-bromomethylbenzoic acid (300 mg) was dissolved in acetonitrile (10 ml). Potassium carbonate (30 mg) and morpholine (130 μl) were added to the solution, and the mixture was stirred at room temperature for one hr. The reaction layer was subjected to separation with chloroform and a saturated aqueous sodium hydrogencarbonate solution. The organic layer was then concentrated to give methyl 4-(morpholinomethyl)benzoate. Methanol (1 ml), water (150 μl), and potassium hydroxide (15 mg) were added to the residue, and the mixture was heated at 60° C. for one hr. After the completion of the reaction, the solvent was removed by distillation to give 4-(morpholinomethyl)benzoic acid. Toluene (20 ml) and thionyl chloride (1 ml) were added to the residule, and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 4-(morpholinomethyl)-1-benzenecarbonyl isothiocyanate was prepared using the resultant 4-(morpholinomethyl)-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-(morpholinomethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (74 mg, yield 78%). The reaction layer was subjected to separation with chloroform The organic layer was then concentrated

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

Procedure: To a solution of 66.6 g of morpholine and 269 mL of triethylamine in 1.5 L of abs. EtOH under N2 at 0° C. was added dropwise over 30 min a solution of methyl 4-bromomethylbenzoate (from the previous reaction) in 450 mL of abs. EtOH. The resulting solution was stirred at 0° C. for 2 hours at which point the reaction was slowly warmed up to r.t over 4 hours and stirred at r.t overnight. The HPLC showed no unreacted methyl 4-bromomethylbenzoate but the remaining methyl p-toluate from the previous reaction. The solvent was removed under reduced pressure and the residue was taken up in 2 L of 1.5 N HCl. The acidic phase was washed with 3×350 mL diethyl ether and then with 1×350 mL EtOAc then neutralized to pH 7 with NaOH and then to pH 7.5 with 10% NaHCO3 in water. The product was then extracted with 3×700 mL of EtOAc. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduce pressure, affording an orange oil. The excess EtOAc was removed by toluene distillation. The title compound was used in the next step without ether purification. from the previous reaction) in 450 mL of abs was slowly warmed up to r.t over 4 hours stirred at r.t overnight The solvent was removed under reduced pressure The acidic phase was washed with 3×350 mL diethyl ether The product was then extracted with 3×700 mL of EtOAc The organic phase was dried over anhydrous Na2SO4 filtered concentrated affording an orange oil The excess EtOAc was removed by toluene distillation The title compound was used in the next step without ether purification

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

Procedure: To a solution of 66.6 g of morpholine and 269 mL of triethylamine in 1.5 L of abs. EtOH under N2 at 0° C. was added dropwise over 30 min a solution of methyl 4-bromomethylbenzoate (from the previous reaction) in 450 mL of abs. EtOH. The resulting solution was stirred at 0° C. for 2 hours at which point the reaction was slowly warmed up to r.t over 4 hours and stirred at r.t overnight. The HPLC showed no unreacted methyl 4-bromomethylbenzoate but the remaining methyl p-toluate from the previous reaction. The solvent was removed under reduced pressure and the residue was taken up in 2 L of 1.5 N HCl. The acidic phase was washed with 3×350 mL diethyl ether and then with 1×350 mL EtOAc then neutralized to pH 7 with NaOH and then to pH 7.5 with 10% NaHCO3 in water. The product was then extracted with 3×700 mL of EtOAc. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduce pressure, affording an orange oil. The excess EtOAc was removed by toluene distillation. The title compound was used in the next step without ether purification. from the previous reaction) in 450 mL of abs was slowly warmed up to r.t over 4 hours stirred at r.t overnight The solvent was removed under reduced pressure The acidic phase was washed with 3×350 mL diethyl ether The product was then extracted with 3×700 mL of EtOAc The organic phase was dried over anhydrous Na2SO4 filtered concentrated affording an orange oil The excess EtOAc was removed by toluene distillation The title compound was used in the next step without ether purification

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

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of acetonitrile (1.35 ml) in tetrahydrofuran (80 ml), cooled to 5° C., was added sodium hydride (0.94 g, 60% dispersion in oil). The mixture was stirred for 30 minutes before the addition of a solution of methyl 4-(morpholin-4-ylmethyl)benzoate (5.53 g) in tetrahydrofuran (20 ml). The resulting mixture was heated to 70° C. for 5 h. The mixture was cooled, quenched with saturated ammonium chloride (20 ml) and extracted with ethyl acetate. The organic extracts were dried (MgSO4) and evaporated to give a gum which was purified by column chromatography eluting with a 20–100% ethyl acetate/iso-hexane gradient to give 3-[4-(morpholin-4-ylmethyl)phenyl]-3-oxopropanenitrile (0.97 g). The mixture was cooled quenched with saturated ammonium chloride (20 ml) extracted with ethyl acetate The organic extracts were dried (MgSO4) evaporated to give a gum which was purified by column chromatography eluting with a 20–100% ethyl acetate/iso-hexane gradient

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

Procedure: Commercially available 4-bromomethylbenzoic acid (300 mg) was dissolved in acetonitrile (10 ml). Potassium carbonate (30 mg) and morpholine (130 μl) were added to the solution, and the mixture was stirred at room temperature for one hr. The reaction layer was subjected to separation with chloroform and a saturated aqueous sodium hydrogencarbonate solution. The organic layer was then concentrated to give methyl 4-(morpholinomethyl)benzoate. Methanol (1 ml), water (150 μl), and potassium hydroxide (15 mg) were added to the residue, and the mixture was heated at 60° C. for one hr. After the completion of the reaction, the solvent was removed by distillation to give 4-(morpholinomethyl)benzoic acid. Toluene (20 ml) and thionyl chloride (1 ml) were added to the residule, and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 4-(morpholinomethyl)-1-benzenecarbonyl isothiocyanate was prepared using the resultant 4-(morpholinomethyl)-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-(morpholinomethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (74 mg, yield 78%). The reaction layer was subjected to separation with chloroform The organic layer was then concentrated

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of acetonitrile (1.35 ml) in tetrahydrofuran (80 ml), cooled to 5° C., was added sodium hydride (0.94 g, 60% dispersion in oil). The mixture was stirred for 30 minutes before the addition of a solution of methyl 4-(morpholin-4-ylmethyl)benzoate (5.53 g) in tetrahydrofuran (20 ml). The resulting mixture was heated to 70° C. for 5 h. The mixture was cooled, quenched with saturated ammonium chloride (20 ml) and extracted with ethyl acetate. The organic extracts were dried (MgSO4) and evaporated to give a gum which was purified by column chromatography eluting with a 20-100% ethyl acetate/iso-hexane gradient to give 3-[4-(morpholin-4-ylmethyl)phenyl]-3-oxopropanenitrile (0.97 g). The mixture was cooled quenched with saturated ammonium chloride (20 ml) extracted with ethyl acetate The organic extracts were dried (MgSO4) evaporated to give a gum which was purified by column chromatography eluting with a 20-100% ethyl acetate/iso-hexane gradient

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of acetonitrile (1.35 ml) in tetrahydrofuran (80 ml), cooled to 5° C., was added sodium hydride (0.94 g, 60% dispersion in oil). The mixture was stirred for 30 minutes before the addition of a solution of methyl 4-(morpholin-4-ylmethyl)benzoate (5.53 g) in tetrahydrofuran (20 ml). The resulting mixture was heated to 70° C. for 5 h. The mixture was cooled, quenched with saturated ammonium chloride (20 ml) and extracted with ethyl acetate. The organic extracts were dried (MgSO4) and evaporated to give a gum which was purified by column chromatography eluting with a 20-100% ethyl acetate/iso-hexane gradient to give 3-[4-(morpholin-4-ylmethyl)phenyl]-3-oxopropanenitrile (0.97 g). The mixture was cooled quenched with saturated ammonium chloride (20 ml) extracted with ethyl acetate The organic extracts were dried (MgSO4) evaporated to give a gum which was purified by column chromatography eluting with a 20-100% ethyl acetate/iso-hexane gradient

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

Procedure: To a solution of methyl 4-bromomethylbenzoate (14.75 g) in dimethylformamide (50 ml), cooled to 5° C., was added rapidly morpholine (13.8 ml). The mixture was stirred at room temperature for 2 h. The mixture was partitioned between diethyl ether and water. The organic layer was washed with water, dried (MgSO4), evaporated and purified by column chromatography eluting with ethyl acetate/iso-hexane (20:80) to give methyl 4-(morpholin-4-ylmethyl)benzoate (14.13 g) as an oil. The mixture was partitioned between diethyl ether and water The organic layer was washed with water dried (MgSO4) evaporated purified by column chromatography eluting with ethyl acetate/iso-hexane (20:80)

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

Procedure: To a solution of 66.6 g of morpholine and 269 mL of triethylamine in 1.5 L of abs. EtOH under N2 at 0° C. was added dropwise over 30 min a solution of methyl 4-bromomethylbenzoate in 450 mL of abs. EtOH. The resulting solution was stirred at 0° C. for 2 h then slowly warmed up to rt over 4 h and stirred at rt overnight. The HPLC showed no unreacted methyl 4-bromomethylbenzoate but the remaining methyl p-toluate from the previous reaction. The solvent was removed under reduced pressure and the residue was taken up in 2 L of 1.5 N HCl. The acidic phase was washed with 3×350 mL of diethyl ether then with 1×350 mL of EtOAc and was neutralized to pH 7 with NaOH and then to pH 7.5 with 10% NaHCO3 in water. The product was extracted with 3×700 mL of EtOAc. The organic phase was dried over anhydrous Na2SO4 and concentrated under reduce pressure, affording an orange oil. The excess EtOAc was removed by toluene distillation. The title compound was used in the next step without further purification. then slowly warmed up to rt over 4 h stirred at rt overnight The solvent was removed under reduced pressure The acidic phase was washed with 3×350 mL of diethyl ether The product was extracted with 3×700 mL of EtOAc The organic phase was dried over anhydrous Na2SO4 concentrated affording an orange oil The excess EtOAc was removed by toluene distillation The title compound was used in the next step without further purification