H. Scott Wilkinson

PALLADIUM CATALYZED AMINATION OF 2-CHLORO-1,3-AZOLE DERIVATIVES : MILD ENTRY TO POTENT H1- ANTIHISTAMINIC NORASTEMIZOLE

Abstract Palladium-catalyzed selective amination of 4-fluorobenzyl-2-chlorobenzimidazole with 4-aminopiperidine provided a simple solution for the norastemizole synthesis. Pd-catalyzed amination of other 2-chloro-1,3-Azole derivatives are exploited.

Chemoselective reductions of nitroarenes: bromoethanol-assisted phthalocyanatoiron/NaBH4 reductions

Abstract Porphyrinatoiron/NaBH 4 and a novel phthalocyanatoiron/NaBH 4 catalyst systems were investigated for the reductions of nitroarenes. The phthalocyanatoiron/NaBH 4 system was superior to the porphyrinatoiron/NaBH 4 system. The reductions were performed in good yields and excellent chemoselectivities. The rate of reduction by the PcFe/NaBH 4 system increased upon the addition of 2-bromoethanol.

Properly tuned first fluoride-catalyzed TGME-mediated amination process for chloroimidazoles: inexpensive technology for antihistaminic norastemizole

Abstract Fluoride-catalyzed amination process of chloroimidazole 1 proved to be a practical and inexpensive procedure for the preparation of the antihistaminic, norastemizole.

An efficient and facile synthesis of racemic and optically active fexofenadine

Abstract An efficient and practical method for the synthesis of racemic and optically active (96% ee) fexofenadine is described. The key racemic or optically active lactol intermediate 2 is prepared from readily available tolyl derivative 3 .

Absorption, distribution, metabolism, and excretion of [14C]‐dasotraline in humans

Dasotraline is a dopamine and norepinephrine reuptake inhibitor, and the early clinical trials show a slow absorption and long elimination half‐life. To investigate the absorption, distribution, metabolism, and excretion of dasotraline in humans, a single dose of [14C]‐dasotraline was administered to eight healthy male adult volunteers. At 35 days, 90.7% of the dosed radioactivity was recovered in the urine (68.3%) and feces (22.4%). The major metabolic pathways involved were: (1) amine oxidation to form oxime M41 and sequential sulfation to form M42 or glucuronidation to form M43; (2) N‐hydroxylation and sequential glucuronidation to form M35; (3) oxidative deamination to form (S)‐tetralone; (4) mono‐oxidation of (S)‐tetralone and sequential glucuronidation to form M31A and M32; and (5) N‐acetylation to form (1R,4S)‐acetamide M102. A total of 8 metabolites were detected and structurally elucidated with 4 in plasma (M41, M42, M43, and M35), 7 in urine (M41, M42, M43, M31A, M32, M35, and (S)‐tetralone), and 3 in feces (M41, (S)‐tetralone, and (1R,4S)‐acetamide). The 2 most abundant circulating metabolites were sulfate (M42) and glucuronide (M43) conjugates of the oxime of dasotraline, accounting for 60.1% and 15.0% of the total plasma radioactivity, respectively; unchanged dasotraline accounted for 8.59%. The oxime M41 accounted for only 0.62% of the total plasma radioactivity and was detected only at early time points. M35 was a minor glucuronide metabolite, undetectable by radioactivity but identified by mass spectrometry. The results demonstrate that dasotraline was slowly absorbed, and extensively metabolized by oxidation and subsequent phase II conjugations. The findings from this study also demonstrated that metabolism of dasotraline by humans did not produce metabolites that may cause a safety concern.