SYNTHESIS OF O)-4-METHYL-4-PHENYL-[-4-C-14]-4H,-3,1-BENZOXAZINE (ETIFOXINE)

Carbonation of phenyl lithium with (CO2)-C-14, followed by reduction o f [(CO2)-C-14] benzoic acid, led to [alpha-C-14] benzyl alcohol 3, the oxidation of which afforded the [alpha-C-14] benzaldehyde 4. The latt er, then condensed with pivoylamide 6 (trimethyl acetamide-N-(2-lithio -4chlorophenyl) gave 5-chloro-2 (t-Butylamide)-alpha-phenyl-[-alpha-C- 14] benzyl alcohol 2 which was then oxidized to ketone 8 which it self were subsequently hydrolysed to 5-chloro-2-amino-[-alpha-C-14]benzoph enone 9. Grignard reaction of 9 with methylmagnesium iodide gave ro-2- amino-alpha-methyl-alpha-phenyl-[-alpha-C-14] benzyl alcohol 10. Treat ment of the alcohol 10 with ethylthioisocyanate, followed by cyclisati on led to thylamino)-4-methyl-4-phenyl-[-4-C-14]-benzoxazine 12. The l atter was acidified to give rise to Etifoxine hydrochloride 13 in an o verall yield of about 31%based on [C-14] barium carbonate.