Methyl 4-methylbenzoate → Methyl 4-(morpholin-4-ylmethyl)benzoate

Participants

Reaction Conditions

Reaction Steps

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.

Provenance & Evidence