Large-Scale Synthesis of Enantio- and Diastereomerically Pure ( R , R )-Formoterol
1998; American Chemical Society; Volume: 2; Issue: 2 Linguagem: Inglês
10.1021/op970116o
ISSN1520-586X
AutoresRobert Hett, Q. Kevin Fang, Yun Gao, Stephen A. Wald, Chris H. Senanayake,
Tópico(s)Chemical Reaction Mechanisms
Resumo(R,R)-Formoterol (1) is a long-acting, very potent β2-agonist, which is used as a bronchodilator in the therapy of asthma and chronic bronchitis. Highly convergent synthesis of enantio- and diastereomerically pure (R,R)-formoterol fumarate is achieved by a chromatography-free process with an overall yield of 44%. Asymmetric catalytic reduction of bromoketone 4 using as catalyst oxazaborolidine derived from (1R, 2S)-1-amino-2-indanol and resolution of chiral amine 3 are the origins of chirality in this process. Further enrichment of enantio- and diastereomeric purity is accomplished by crystallizations of the isolated intermediates throughout the process to give (R,R)-formoterol (1) as the pure stereoisomer (ee, de >99.5%).
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