Synthesis of 6-chloro 2(-ethylamino)-4-methyl-4-phenyl-[-4-14C]-4H-3,1-benzoxazine (Etifoxine)

Abstract

Carbonation of phenyl lithium with 14CO2 followed by reduction of [14CO2] benzoic acid, led to [α-14C] benzyl alcohol 3, the oxidation of which afforded the [α-14C] benzaldehyde 4. The latter, then condensed with pivoylamide 6 (trimethyl acetamide-N-(2-lithio-4chlorophenyl) gave 5-chloro-2 (t-Butylamide)-α-phenyl-[-α-14C] benzyl alcohol 7 which was then oxidized to ketone 8 which it self were subsequently hydrolysed to 5-chloro-2-amino-[-α-14C]benzophenone 9. Grignard reaction of 9 with methylmagnesium iodide gave 5-chloro-2-amino-α-methyl-α-phenyl-[-α-14C] benzyl alcohol 10. Treatment of the alcohol 10 with ethylthioisocyanate, followed by cyclisation led to 6-chloro-2-(ethylamino)-4-methyl-4-phenyl-[-4-14C]-4H-3,1 benzoxazine 12. The latter was acidified to give rise to Etifoxine hydrochloride 13 in an overall yield of about 31% based on [14C] barium carbonate. © 1997 John Wiley & Sons, Ltd.