4-(morpholin-4-ylmethyl)benzoyl chloride

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

Conditions: temp:100.01; 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 solvent was removed by distillation, and 4-(morpholinomethyl)-1-benzenecarbonyl isothiocyanate was prepared The reaction solution was concentrated the residue was purified by chromatography on silica gel

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

Procedure: 2.33 g of α-morpholinoparatoluic acid are placed in 30 mL of CH2Cl2 and 3.76 g of SOCl2 are added. The not very homogenous solution is taken to reflux for 48 hours The white precipitate obtained is filtered, washed with CH2Cl2 and dried. 2.65 g of product is obtained (Yield=70%). to reflux for 48 hours The white precipitate obtained is filtered washed with CH2Cl2 dried

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

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

Procedure: A 250 mL, two-neck flask fitted with an addition funnel and thermocouple probe was charged with 1-cyclopropyl-piperazine dihydrochloride (7.1 g, 0.036 mol, 1.0 eq) and toluene (70 mL) and then cooled to 0° C. Aqueous NaOH solution (1.0 M, 70 mL, 2.0 eq) was added at such a rate that the reaction temperature did not exceed 10° C. Na2CO3 powder (7.5 g, 0.071 mol, 2.0 eq) was then added to the reaction mixture. The 4-morpholin-4-ylmethyl-benzoyl chloride, prepared as in Step A above (9.8 g, 0.036 mol, 1.0 eq) was added in portions over 3 minutes, while the temperature of the reaction mixture was maintained below 5° C. The reaction mixture was then stirred for 2 hrs. The reaction mixture was filtered, the layers were separated, the aqueous layer was extracted with toluene (30 mL×2), and the combined organic layers washed with brine (30 mL) and dried over Na2SO4. The solvent was removed in vacuo to yield the title compound as a as pale yellow viscous oil. A 250 mL, two-neck flask fitted with an addition funnel did not exceed 10° C was added in portions over 3 minutes, while the temperature of the reaction mixture was maintained below 5° C The reaction mixture was filtered the layers were separated the aqueous layer was extracted with toluene (30 mL×2) the combined organic layers washed with brine (30 mL) dried over Na2SO4 The solvent was removed in vacuo

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

Procedure: A 200 mL round-bottom flask fitted with a reflux condenser was charged with 4-(4-carboxy-benzyl)-morpholin-4-ium chloride (10.0 g, 0.039 mol, 1.0 eq), toluene (50 mL), DMF (0.3 mL, 0.0039 mol, 0.1 eq), and thionyl chloride (7.1 mL, 0.097 mol, 2.5 eq) under a nitrogen atmosphere. The reaction mixture was heated to 70° C. for 6 h and then cooled to 0° C. The resulting mixture was filtered and the solid washed with pentane to yield 4-morpholin-4-ylmethyl-benzoyl chloride, which was used in the next step without further purification. A 200 mL round-bottom flask fitted with a reflux condenser cooled to 0° C The resulting mixture was filtered the solid washed with pentane

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

Procedure: A 250 mL, two-neck flask fitted with an addition funnel and thermocouple probe was charged with 1-cyclopropyl-piperazine dihydrochloride (7.1 g, 0.036 mol, 1.0 eq) and toluene (70 mL) and then cooled to 0° C. Aqueous NaOH solution (1.0 M, 70 mL, 2.0 eq) was added at such a rate that the reaction temperature did not exceed 10° C. Na2CO3 powder (7.5 g, 0.071 mol, 2.0 eq) was then added to the reaction mixture. The 4-morpholin-4-ylmethyl-benzoyl chloride, prepared as in Step A above (9.8 g, 0.036 mol, 1.0 eq) was added in portions over 3 minutes, while the temperature of the reaction mixture was maintained below 5° C. The reaction mixture was then stirred for 2 hrs. The reaction mixture was filtered, the layers were separated, the aqueous layer was extracted with toluene (30 mL×2), and the combined organic layers washed with brine (30 mL) and dried over Na2SO4. The solvent was removed in vacuo to yield the title compound as a as pale yellow viscous oil. A 250 mL, two-neck flask fitted with an addition funnel did not exceed 10° C was added in portions over 3 minutes, while the temperature of the reaction mixture was maintained below 5° C The reaction mixture was filtered the layers were separated the aqueous layer was extracted with toluene (30 mL×2) the combined organic layers washed with brine (30 mL) dried over Na2SO4 The solvent was removed in vacuo

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

Procedure: A 200 mL round-bottom flask fitted with a reflux condenser was charged with 4-(4-carboxy-benzyl)-morpholin-4-ium chloride (10.0 g, 0.039 mol, 1.0 eq), toluene (50 mL), DMF (0.3 mL, 0.0039 mol, 0.1 eq), and thionyl chloride (7.1 mL, 0.097 mol, 2.5 eq) under a nitrogen atmosphere. The reaction mixture was heated to 70° C. for 6 h and then cooled to 0° C. The resulting mixture was filtered and the solid washed with pentane to yield 4-morpholin-4-ylmethyl-benzoyl chloride, which was used in the next step without further purification. A 200 mL round-bottom flask fitted with a reflux condenser cooled to 0° C The resulting mixture was filtered the solid washed with pentane

Conditions: temp:100.01; 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 solvent was removed by distillation, and 4-(morpholinomethyl)-1-benzenecarbonyl isothiocyanate was prepared The reaction solution was concentrated the residue was purified by chromatography on silica gel

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

Procedure: 2.33 g of α-morpholinoparatoluic acid are placed in 30 mL of CH2Cl2 and 3.76 g of SOCl2 are added. The not very homogenous solution is taken to reflux for 48 hours The white precipitate obtained is filtered, washed with CH2Cl2 and dried. 2.65 g of product is obtained (Yield=70%). to reflux for 48 hours The white precipitate obtained is filtered washed with CH2Cl2 dried