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Sulmary Synthesis of 24imethylamino-2-phenylbutanol 3,4,5-trimethoxybenzoate (Trimebutine, I) labeled with carbon-14 and deuterium. and of its alcohol-and acid-moiety metabolites labeled with deuterium are described. Carbon-14-labeled I was obtained from K CN in five steps with a radiochemical yield of 31.6% and a specific activity of 2.50 uCi/mg. I and its metabolites labeled with five deuterium atoms in the aromatic ring were synthesized from hexadeuterobenzene as a starting material. Metabolites labeled with three deuterium atoms on the 4-methyl group were obtained from trideuteromethyl iodide as a labeling 2 2 material. The synthetic yields of H5-and H3-2-dimethylamino-2-phenylbutanol were 53.4% and 13.1% respectively, based on the deuterated starting materials. The acid moiety metabolite, 3,4,5-trimethoxybenzoic acid, labeled with nine deuterium atoms in the three rnethoxy groups was obtained from gallic acid and hexadeuterodimethylsulfate in 18.6% yield. 14 Y. Miura et al, by Astier e t at. who measured the unchanged form in plasma after intravenous administration of I to man, but little is known about its metabolic fate. We have investigated the metabolic fate of I in animals using carbon-14and deuterium-labeled I and metabolites. (31, In this paper, we describe the Synthesis of I labeled with carbon44 ( C-I) and five deuterium atoms in the 2-phenyl aromatic ring (G5-I), and of the alcohol-moiety metabolites labeled with five deuterium a t o m in the aromatic ring and those with three deuterium atoms in the 4-methyl group. The synthesis of the acid-moiety metabolite, 3,4,5-trimethoxybenzoic acid, labeled with nine deuterium atoms in the three methoxy groups is also described. The pentadeuterated alcohol-moiety metabolites labeled in the ring and the nonadeuterated acid-moiety metabolite were used as internal standards in G C / m measurement. The alcohol-moiety metabolite, 24irnethylamino-2-phenylbutanol (DPB), labeled with three deuterium atoms was used to assess the amounts of N-demethylated alcohol-moiety metabolites arising via DPB after simultaneous administration of trideuterated DPB and I in the same animal. 14 Wethods and R d t m The synthesis of I has been previously reported in patents by Viennosis (41, Miyoshi e t at. (5) and Claude e t a Z . ( 6 ) . The synthesis of I and the alcohol-moiety metabolites labeled with carbon-14 and deuterium followed the same synthetic route. The synthesis of 14C-I provides carbon-14 at a metabolically inert site. i.e.. at C-1 in 2-dimethylamino-2-phenylbutanol(5) as shown in Fig. 1. The synthesis began with a reaction of d4CN with propiophenone and resultant 5-ethy1-5-phenylhydant0in-4-~~C (2) was then hydrolized in a barium hydroxide solution to 2-amino-2-phenylbutyric acid-l-14C (3) according to the method of Viennosis (4). 2 was reduced with sodium borohydride in the presence of boron trifluoride etherate to 2-amin0-2-phenyl-butanol-l-~~C (4) , which was then methylated with formic acid and formaldehyde to 2-dimethylamino-2-phenyl-b~t a n o l -l -~~C (2). 14C-I...

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