RESUMEN
With certain amounts of sodium tert-butoxide and tert-butanol as additives, catalytic amounts of an inexpensive and easy-to-handle copper source Cu(OAc)(2)â H(2)O, a commercially available and air-stable non-racemic dipyridylphosphine ligand, as well as the stoichiometric desirable hydride donor polymethylhydrosiloxane (PMHS), formed a versatile in situ catalyst system for the enantioselective reduction of a broad spectrum of prochiral diaryl and aryl heteroarylketones in air, in high yields and with good to excellent enantioselectivities (up to 96 %). In particular, the practical viability of this process was evinced by its successful applications in the asymmetric synthesis of optically enriched potent antihistaminic drugs orphenadrine and neobenodine.
Asunto(s)
Cobre/química , Antagonistas de los Receptores Histamínicos/síntesis química , Cetonas/química , Orfenadrina/análogos & derivados , Orfenadrina/síntesis química , Catálisis , Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/farmacología , Ligandos , Estructura Molecular , Orfenadrina/química , Orfenadrina/farmacología , Estereoisomerismo , Alcohol terc-Butílico/químicaRESUMEN
Desymmetrizations of the prochiral bis(bromoaryl)alcohols 1 and 4 were effected by treatment with iPr2Mg and enantiomerically pure lithium alkoxides. The resulting arylmagnesium compounds were quenched with various electrophiles. The absolute and (if relevant) relative configurations of the resulting products were determined. The best ee/yield combination was obtained for the protonolysis furnishing monobromoalcohol (R)-2 (53 % ee, 51 % yield). The latter was converted into (R)-orphenadrine, an antihistaminic and anticholinergic drug.
Asunto(s)
Alcoholes/química , Antagonistas Colinérgicos/síntesis química , Antagonistas de los Receptores Histamínicos/síntesis química , Orfenadrina/síntesis química , Antagonistas Colinérgicos/química , Antagonistas Colinérgicos/farmacología , Técnicas Químicas Combinatorias , Halógenos , Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/farmacología , Hidrocarburos Bromados/química , Litio/química , Magnesio/química , Estructura Molecular , Orfenadrina/química , Orfenadrina/farmacología , EstereoisomerismoRESUMEN
1. A series of derivatives of 4-methyldiphenhydramine have been examined as potential quaternary radioligands for the histamine H1-receptor. 2. [3H]-(+)-N-methyl-4-methyldiphenhydramine ([3H]-QMDP), 83 Ci mmol-1, was synthesized by methylation of the tertiary analogue and purified by high-voltage electrophoresis. 3. [3H]-QMDP bound to H1-receptors in a washed homogenate from guinea-pig cerebellum with an affinity constant, Ka, of 1.14 +/- 0.03 x 10(9) M-1. The proportion of non-specific binding of 0.3-0.6 nM [3H]-QMDP, defined by 0.4 microM mepyramine, was usually in the range 15-45%, depending on the method of measurement of binding. The affinity of [3H]-QMDP was similar in guinea-pig cerebellum, cerebral cortex and hippocampus, but was lower, 1.4 x 10(8) M-1, in rat cerebral cortex. 4. Evidence was obtained for the presence of a secondary, non-muscarinic, binding site for [3H]-QMDP in guinea-pig cerebellum, approximate Ka 1.5 x 10(7) M-1, accounting for circa 4% of the total binding of 1 nM [3H]-QMDP. 5. There was a very good correlation between the affinities of 15 compounds for the H1-receptor determined from inhibition of [3H]-QMDP binding and from inhibition of [3H]-mepyramine binding. 6. The potential utility of [3H]-QMDP for studies of H1-receptors in the plasma membrane of cells in culture is discussed.