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Synthesis of 6‐chloro 2(‐ethylamino)‐4‐methyl‐4‐phenyl‐[‐4‐ 14 C]‐4H‐3,1‐benzoxazine (Etifoxine)
Author(s) -
Azim Elmostafa,
Dupuy Jean Michel,
Lepage Françis,
Veyre Annie,
Madelmont Jean Claude
Publication year - 1997
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/(sici)1099-1344(199711)39:11<907::aid-jlcr38>3.0.co;2-2
Subject(s) - chemistry , benzaldehyde , acetamide , benzophenone , medicinal chemistry , benzyl alcohol , hydrochloride , benzoic acid , alcohol , hydrolysis , ketone , yield (engineering) , organic chemistry , iodide , decarboxylation , methyl iodide , catalysis , materials science , metallurgy
Carbonation of phenyl lithium with 14 CO 2 followed by reduction of [ 14 CO 2 ] benzoic acid, led to [α‐ 14 C] benzyl alcohol 3 , the oxidation of which afforded the [α‐ 14 C] benzaldehyde 4 . The latter, then condensed with pivoylamide 6 (trimethyl acetamide‐N‐(2‐lithio‐4chlorophenyl) gave 5‐chloro‐2 (t‐Butylamide)‐α‐phenyl‐[‐α‐ 14 C] benzyl alcohol 7 which was then oxidized to ketone 8 which it self were subsequently hydrolysed to 5‐chloro‐2‐amino‐[‐α‐ 14 C]benzophenone 9 . Grignard reaction of 9 with methylmagnesium iodide gave 5‐chloro‐2‐amino‐α‐methyl‐α‐phenyl‐[‐α‐ 14 C] benzyl alcohol 10 . Treatment of the alcohol 10 with ethylthioisocyanate, followed by cyclisation led to 6‐chloro‐2‐(ethylamino)‐4‐methyl‐4‐phenyl‐[‐4‐ 14 C]‐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 [ 14 C] barium carbonate. © 1997 John Wiley & Sons, Ltd.