Condensation of epichlorohydrin (I) with N-benzylethanolamine (II) in the presence of sulfuric acid afforded the (chloromethyl)morpholine (III). Halogen displacement in (III) by potassium phthalimide (IV) provided the substituted phthalimide (V). Further hydrazinolysis of (V) furnished racemic (aminomethyl)morpholine (VI) (1). The desired (S) enantiomer (VII) was obtained by crystallization of (VI) as the dibenzoyl-D-tartaric acid salt, followed by liberation of the base with NaOH. Eschweiler-Clarke reductive methylation of (VII) with formaldehyde and formic acid produced the dimethylamino derivative (VIII). The N-benzyl groupof (VIII) was then cleaved by transfer hydrogenation in the presence of hydrazine and Pd/C yielding chiral morpholine (IX). Finally, coupling of this morpholine (IX) with the difluoroqyuinolone boron chelate (X) provided the title morpholino quinolone.

Condensation of epichlorohydrin (I) with N-benzylethanolamine (II) in the presence of sulfuric acid afforded the (chloromethyl)morpholine (III). Halogen displacement in (III) by potassium phthalimide (IV) provided the substituted phthalimide (V). Further hydrazinolysis of (V) furnished racemic (aminomethyl)morpholine (VI) (1). The desired (S) enantiomer (VII) was obtained by crystallization of (VI) as the dibenzoyl-D-tartaric acid salt, followed by liberation of the base with NaOH. Eschweiler-Clarke reductive methylation of (VII) with formaldehyde and formic acid produced the dimethylamino derivative (VIII). The N-benzyl groupof (VIII) was then cleaved by transfer hydrogenation in the presence of hydrazine and Pd/C yielding chiral morpholine (IX). Finally, coupling of this morpholine (IX) with the difluoroqyuinolone boron chelate (X) provided the title morpholino quinolone.