Use of (S)-(trifloxymethyl)oxirane in the synthesis of a chiral beta-adrenoceptor antagonist, (R)- and (S)-9-[[3-(tert-butylamino)-2-hydroxypropyl]oximino]fluorene.
Two synthetic approaches were used to prepare, in chirally pure form, the beta-adrenoceptor antagonist 9-[[3-(tert-butylamino)-2-hydroxypropyl]oximino]fluorene (1a). One of these employed the oxazolidine (S)-6 generated from D-mannitol, while the other utilized (S)-[[(trifluoromethanesulfonyl)oxy]methyl]oxirane (4) as the chiral three-carbon fragment. This latter synthesis was designed to incorporate the amino function in the last step. In vitro, a beta 2 selectivity of only 2.2 was observed for 1a. The example, (S)-9-[[3-(tert-amylamino)-2-hydroxypropyl]oximino]fluorene (1b), was also prepared and found to be selective for the beta 1 receptor by a factor of 2.5. In contrast to other beta-adrenoceptor antagonists, the enantiomers of 1a exhibited no chiral preference; i.e., (S)-1a and (R)-1a possessed a similar order of beta-adrenoceptor antagonistic activity.
D000319:Adrenergic beta-Antagonists / Q000138:chemical synthesis*; D000818:Animals; D001667:Binding, Competitive; D055598:Chemical Phenomena; D002621:Chemistry; D004082:Dihydroalprenolol / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D007202:Indicators and Reagents; D008168:Lung / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D011412:Propanolamines / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism
D000319:Adrenergic beta-Antagonists; D007202:Indicators and Reagents; D011412:Propanolamines; D004082:Dihydroalprenolol; C014898:IPS 339