1-(Diphenylmethyl)azetidin-3-one → (9aS)-8-[1-(diphenylmethyl)azetidin-3-yl]hexahydropyrazino-[2,1-c][1,4]oxazin-4(3H)-one

Participants

Reaction Steps

To a solution of 1-(diphenylmethyl)azetidin-3-one (see Bioorg. Med. Chem. Lett.; 13; 2003; 2191-2194, ˜0.65 mmol) and (9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (0.65 mmol), in methanol (10 mL) was added a solution of sodium cyano borohydride (125 mg, 2.0 mmol) and zinc chloride (135 mg, 1.0 mmol) in methanol (20 mL). The reaction mixture was stirred at RT for 15 min and then the solvent was removed by evaporation. The residue was partitioned between ethyl acetate (50 mL) and water (20 mL). The organic solution was washed with brine and then dried over Na2SO4. The solvent was removed by evaporation and the residue was dissolved in a mixture of acetonitrile (10 mL), acetic acid (100 mg) and water (10 mL). The product was purified by means of reversed phase chromatography using a mixture of acetonitrile and aqueous 0.1 M ammonium acetate. The proper fractions were combined and concentrated on a rotavapor. The aqueous residue was extracted with ethyl acetate and the organic solution was dried over Na2SO4. The solvent was removed by evaporation and there was obtained 170 mg (69%) of (9aS)-8-[1-(diphenylmethyl)azetidin-3-yl]hexahydropyrazino-[2,1-c][1,4]oxazin-4(3H)-one. 1H NMR (400 MHz, CDCl3): 1.6-1.7 (m, 1H), 1.8-1.9 (m, 1H), 2.6 (d, 1H), 2.7-2.8 (m, 21-1), 2.8-2.9 (m, 2H), 3.0 (qn, 1H), 3.3-3.7 (m, 4H), 3.9 (dd, 1H), 4.0-4.2 (qt, 2H), 4.4 (s, 1H), 4.5 (dd, 1H), 7.2 (t, 2H), 7.3 (m, 4H), 7.4 (m, 4H); LCMS: m/z 378 (M+1)+.

Provenance & Evidence