RESUMO
3D-printed flow reactors were designed, fabricated from different materials (PLA, HIPS, nylon), and used for a catalytic stereoselective Henry reaction. The use of readily prepared and tunable 3D-printed reactors enabled the rapid screening of devices with different sizes, shapes, and channel dimensions, aimed at the identification of the best-performing reactor setup. The optimized process afforded the products in high yields, moderate diastereoselectivity, and up to 90 % ee. The method was applied to the continuous-flow synthesis of biologically active chiral 1,2-amino alcohols (norephedrine, metaraminol, and methoxamine) through a two-step sequence combining the nitroaldol reaction with a hydrogenation. To highlight potential industrial applications of this method, a multistep continuous synthesis of norephedrine has been realized. The product was isolated without any intermediate purifications or solvent switches.
Assuntos
Metaraminol/síntese química , Metoxamina/síntese química , Fenilpropanolamina/síntese química , Impressão Tridimensional , Catálise , Desenho de Equipamento , Compostos Heterocíclicos com 3 Anéis/química , Hidrogenação , Metaraminol/química , Metoxamina/química , Estrutura Molecular , Nitrocompostos/química , Fenilpropanolamina/química , EstereoisomerismoRESUMO
New duplicated analogs of the alpha 1-selective agonist methoxamine and of its cyclic derivative 5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthylamine have been synthesized and tested for their adrenergic properties. All the compounds prepared, presenting a polymethylene spacer of varying length between two units of the active structure, turned out to be completely devoid of any alpha-stimulating activity. Surprisingly, some of them showed a marked beta-adrenergic agonistic effect, being the most interesting compound active at nanomolar concentration.
Assuntos
Metoxamina/análogos & derivados , Metoxamina/farmacologia , Sistema Nervoso Simpático/efeitos dos fármacos , Agonistas alfa-Adrenérgicos/síntese química , Agonistas alfa-Adrenérgicos/farmacologia , Antagonistas Adrenérgicos alfa/síntese química , Antagonistas Adrenérgicos alfa/farmacologia , Agonistas Adrenérgicos beta/síntese química , Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/síntese química , Antagonistas Adrenérgicos beta/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Cobaias , Técnicas In Vitro , Masculino , Metoxamina/síntese química , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Ratos , Traqueia/efeitos dos fármacos , Ducto Deferente/efeitos dos fármacosRESUMO
A series of phenylethylamines related to methoxamine has been prepared and evaluated for direct alpha 1-receptor agonist activity. It has been observed that for open-chain compounds such as methoxamine, in which the amine-containing portion is free to adopt numerous conformations, an hydroxyl group is necessary for direct alpha 1-adrenergic activity. When the hydroxyl is removed, however, the direct component of activity is greatly reduced unless the amine is incorporated into a more sterically defined structure. From our studies we have concluded that in order for a phenylethylamine to be active as a direct alpha 1-receptor agonist it should have a beta nitrogen in a fully extended conformation relative to a substituted phenyl ring. For optimum potency, the nitrogen should be exocyclic to a saturated six-membered ring. It may be further incorporated exocyclic or endocyclic into an additional ring as long as the amine occupies a well-defined region of space relative to the aromatic portion of a molecule. The ED50 values of some of the more potent compounds as alpha 1-receptor agonists are on the order of 1 X 10(-7) M.
