Green Synthesis of (<i>R</i>)-Terbutaline for Recyclable Catalytic Asymmetric Transfer Hydrogenation in Ionic Liquids

Abstract

We synthesize optically active (R)-terbutaline 2, which is an anti-asthmatic drug, through recyclable catalytic asymmetric transfer hydrogenation (RCATH). Various chloroketones 4 were prepared and RCATH was performed on them. The products exhibit moderate to high enantioselectivity. In particular, the hydrogenation of acyl substituted substrates 4c yields chiral secondary alcohols 5c in good yield and enantioselectivity. Furthermore, (R)-terbutaline 2 can be synthesized in one step from the resulting secondary alcohol 5 without racemization.Key words chiral ligand; ionic liquid; recyclable catalytic asymmetric transfer hydrogenation; terbutaline Ionic liquids are ionic compounds that have the liquid form at temperatures below 100°C, or even at room temperature. They are non-volatile and non-flammable. Moreover, they exhibit (1) stability for reaction reagents such as acids or bases; (2) solubility for organic, inorganic, and metal compounds; and (3) recyclability after a work-up process. Ionic liquids have been attracting attention recently as environmentally friendly solvents.1-4) For example, an asymmetric acylation of an allylic alcohol using an enzymatic reaction in an ionic liquid has been reported 5) as well as a reaction system in which the ion liquid can be repeatedly used as a catalyst container, with high catalyst activity, and as a reaction solvent. 6)Catalytic transfer hydrogenation (CTH) is a reduction reaction involving the exchange of hydrogen atoms between organic compounds such as 2-propanol or formic acid in the presence of catalysis agents. [7][8][9] It has several advantages such as (1) the absence of an explosive or flammable hydrogen source, (2) mild reaction conditions, and (3) avoidance of harmful by-products. Catalytic asymmetric transfer hydrogenation (CATH), in particular, is a very useful method for obtaining optically active secondary alcohols from prochiral ketones. CATH has many advantages in terms of safety and convenience over conventional hydrogenation because it uses 2-propanol or formic acid as a hydrogen source. 10,11) In previous work, we showed that recyclable CATH (RCATH) can be performed in an ionic liquid [bmim] [PF 6 ] using an ionic chiral ligand and the Ru(II) catalyst. We prepared several types of ionic ligands, including pyridinium, benzimidazolium, or imidazolium derivatives. Furthermore, by examining the length of the carbon chains and an imidazolium part, we developed chiral ligand 1, which was most suitable for RCATH 12,13) (Fig. 1). Because they can recycle a catalyst and a reaction solvent in RCATH, optically active organic compounds and pharmaceutical products can be synthesized by this method that is inexpensive and environmentally benign.The β-agonist, which is used as a catecholamine-related pharmaceutical drug for asthma treatment, is generally used in the racemic form, although its pharmacologically active compounds are (R)-isomers in many cases (for example, terbutaline 2 and salbutamol 3). 14-18) Terbutaline 2 is used in the racemic form in clinical p...

Enantioselective resolution of Rac‐terbutaline and evaluation of optically pure R‐terbutaline hydrochloride as an efficient anti‐asthmatic drug

“…[6][7][8][9][10][11] Recently, Zhuo Fan et al reported that, S-enantiomer of TBT may activate muscarinic receptors which could generate the airway hyperreactivity of racemic terbutaline. 12 To date, much efforts have been devoted to produce R-TBT 5, either by absolute asymmetric synthesis, 13 or by chemo-enzymatic method in which asymmetric reduction of a substituted α-chloroacetophenone derivative with cultured wholecell biocatalyst of yeast (Williopsis californica JCM 3600), 14 or by catalytic asymmetric synthesis from chloroketones, 15 or using chiral selector (β-cyclodextrin or its derivatives). [16][17][18][19] However, these methods couldn't achieve products with high optical purity for industrial application.…”