LARGE-SCALE SYNTHESIS OF ENANTIOSTEREOMERICALLY AND DIASTEREOMERICALLY PURE (R,R)-FORMOTEROL

(R,R)-Formoterol (1) is a long-acting, very potent Pz-agonist, which i s used as a bronchodilator in the therapy of asthma and chronic bronch itis. Highly convergent synthesis of enantio-and diastereomerically pu re (R,R)-formoterol fumarate is achieved by a chromatography-free proc ess with an overall yield of 44%. Asymmetric catalytic reduction of br omoketone 4 using as catalyst oxazaborolidine derived from (1R, 2S)-1- amino-2-indanol and resolution of chiral amine 3 are the origins of ch irality in this process. Further enrichment of enantio-and diastereome ric purity is accomplished by crystallizations of the isolated interme diates throughout the process to give (R,R)-formoterol (1) as the pure stereoisomer (ee, de >99.5%).