The Synthesis Of2-aryl-4-substituted Morpholine

Inflammation is a defense response of the body organs or tissues to noxiousstimulation or injury, which is one of the basic physiological and pathological bodyprocesses. The performance of inflammation mainly showed red, swollen, hot, pain，dysfunction, systemic leukocytosis，elevated body temperature and so on.Non-steroidalanti-inflammatory drugs (NSAIDs) is now one of the main drugs, which are thetreatment of inflammatory diseases. The traditional NSAIDs are known asnon-selective COX inhibitor, in inhibiting the biosynthesis of PGs of inflammationsites, it also inhibited the biosynthesis of PGs of gastrointestinal tract which have theprotective effect on the gastric mucosa. It may cause gastrointestinal ulcers and otheradverse reaction if it used for a long time, thus limiting its clinical application.Selectivly inhibiting COX-2may be effective in the treatment of inflammation,while reducing or avoiding the adverse reactions caused by the inhibition of COX-1which is necessary for the human normal physiological function. A new generation ofselective COX-2inhibitors have the following transformations: the introduction ofnitric oxide donor,5-LOX and COX-2inhibitors, the transformation of NSAIDs.Morpholine rings as the parent structure has been extensively studied, such asReboxetine and Viloxazine hetereocyclic drugs have this basic structure. Our researchgroup have finished a series of transformation of traditional NSAIDs. Carboxylprodrugs as the structural modification are designed to introduce morpholine ring, byoccupying the side pockets of COX-2and the introduction of the nitric oxide donors toincrease the inhibition of COX-2, hoping to find the potent highly selective COX-2inhibitors.In this paper, two types of2-aryl-4-substituted morpholine intermediates weresynthesized, which by1H NMR and MS, were characterized.1) The2-aryl-4-hydroxyethyl morpholine hydrochlorides were synthesized by thefollowing way.4-hydroxyacetophenone as the substrate, ethanol as solvent refluxing,potassium iodide and potassium carbonate as catalyst, O-alkylated with differentalkylation reagents, and then the bromination of copper bromide. On the basis of ourgroup research of2-aryl-4-hydroxyethyl morpholine compounds,2-bromoarylalkylketones intermediates and diethanolamine as substrate, mixture ratio of1∶4, reactedat60℃for1~1.5h into the ring system of2-aryl-4-hydroxyethyl-2-morpholinealcohol compounds, and then added88%formic acid, refluxed10h, amination, cyclization, and dehydration,“One pot” to get2-aryl-4-hydroxyethyl morpholine,which by dry HCl gas, a total of seven new2-aryl-4-hydroxyethyl morpholinehydrochlorides were synthesized.2) The4-benzyl-2-aryl-2-hydroxyl morpholine hydrochloric acid salts weresynthesized by the following way. The synthetic route is by2-amino-ethanol in ethanolas solvent, potassium bicarbonate as acid binding agent, reacted with benzyl chlorideunder refluxing conditions, to get benzyl amino ethanol. And then with2-bromo arylalkyl ketones intermediates in acetonitrile as solvent, potassium bicarbonate catalyst,under room temperature stirred overnight, by the cyclization reaction, finally got atotal of five4-benzyl-2-aryl-2-hydroxyl morpholine hydrochloric acid salts.