page_title: Discovery and development of beta2 agonists
section_title: Synthesis of β2-adrenoceptor agonists
hierarchical_section_title: Discovery and development of beta2 agonists / Synthesis of β2-adrenoceptor agonists
caption_attribution_description: English: Skidmore, I. F.; Lunts, L. H. C.; Finch, H.; Naylor, A.; German Offen., 1984, 3414752; Chem. Abstr., 1986, 102, 95383.
context_page_description: β₂-adrenoceptor agonists is a group of drugs that act selectively on β₂-receptors in the lungs causing bronchodilation. β₂-agonists are used to treat asthma and COPD, diseases that cause obstruction in the airways. Prior to their discovery, the non-selective beta-agonist isoprenaline was used. The aim of the drug development through the years has been to minimise side effects, achieve selectivity and longer duration of action. The mechanism of action is well understood and has facilitated the development. The structure of the binding site and the nature of the binding is also well known, as is the structure activity relationship.
context_section_description: The β₂-agonsist that are clinically used are all substituted β-phenethylamine (see figure 5) and they have three kinds of phenyl rings shown in figure 4. They are called resorcinol ring, salicyl alcohol ring or N-formamide ring. The alcohol substituents in the phenyl ring are reactive and complicate the synthesis of the β₂-agonists. A protection step is needed while the N-residue is added in position R1 (figure 5). Another thing that complicates the synthesis is obtaining optically pure R (-) enantiomer of the compound. The stereochemistry is very important for activity because only the R (-) enantiomer is able to form the hydrogen bonds necessary to fit in the binding site and activate the β₂-receptor.
  Salbutamol is usually inhaled in racemic mixtures (for example Ventolin). By treating asthma with optically pure (R)-salbutamol the risk of side effects, such as nervous system stimulatory effects and cardiac arrythmia, can be minimized. This is why several ways to obtain optically pure salbutamol have been described but they have not been potent enough to use in the pharmaceutical industry. The most effective way to obtain pure (R)-salbutamol is to produce a racemic mixture and then separate the isomers.
  Stereoselective synthesis of tributalin and salbutamol acetal can be done from O-protected-(R)-cyanohydrins. F. Effenberg, et al. describe a way for the synthesis. The main complications are to perform the deprotection step without racemization and to form a pure salt. A Ritter reaction can be used for an N-tertiary butylation. In this experiment deacetylation of (R)-salbutamol acetal was unsuccessful so it can not be used to obtain pure (R)-salbutamol. Figure 6 shows the main steps in the synthesis of salmeterol and tributalin.
  
  The long acting β₂-agonist salmeterol can be synthesised from phenethyl alcohol. Dibromohexane is used to link the phenethyl alcohol with the salicyl alcohol ethylamine. Figure 7 shows the main steps for the synthesis.
caption: Figure 7: Salmeterol synthesis
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