4-Methylmorpholine → [4-(4-Methylpiperazinylmethyl)-2-phenylbenzoyl]methionine methyl ester

Participants

Reaction Steps

A solution of 4-chloromethyl-2-phenylbenzoic acid methyl ester (0.521 g, 2.00 mmol), prepared as in Example 286A, 1-methylpiperazine (0.607 g, 6.00 mmol), K2CO3 (0.663 g, 4.80 mmol), KI (0.332 g, 2.00 mmol), and Bu4NBr (0.032 g, 0.10 mmol) in DMF (5 mL) was stirred for 2 hours at ambient temperature and then concentrated under reduced pressure. The residue was treated with a saturated LiOH-methanol (10 mL) and then heated at reflux for 5 hours. The mixture was concentrated and the residue was dissolved in H2O. This solution was extracted with ethyl acetate (5×), and the aqueous phase was then acidified by the addition of 3 M HCl and lyopholized. The resulting white foam was dissolved in DMF (20 mL) and the solution was treated with L-methionine, methyl ester hydrochloride (0.807 g, 4.00 mmol), 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (1.33 g, 8.00 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.56 g, 8.00 mmol), and N-methylmorpholine (1.23 g, 12.0 mmol). The reaction mixture was stirred at ambient temperature for 20 hours, diluted with ethyl acetate, and extracted with a 2:1 mixture of H2O and saturated aqueous NaHCO3 (2×), 1:1 mixture of the same (2×) and brine (2×). The organic phase was dried (MgSO4) and concentrated to provide a gold oil. Radial chromatography (30% methanol-ethyl acetate) afforded the desired compound (0.321 g, 35%).

Provenance & Evidence