Green Chemistry Dynamic Article Links Cite this: Green Chem., 2012, 14, 940 www.rsc.org/greenchem PAPER New aspects for biomass processing with ionic liquids: towards the isolation of pharmaceutically active betulin†‡ Anna K. Ressmann, a Katharina Strassl, a Peter Gaertner, a Bin Zhao, b Lasse Greiner b,c and Katharina Bica* a Received 3rd November 2011, Accepted 13th January 2012 DOI: 10.1039/c2gc16389f By utilising ionic liquids the pharmaceutically active triterpene betulin can be extracted from biomass with significantly improved extraction yield and purity. The recovery of the ionic liquid 1-ethyl-3- methylimidazolium acetate via azeotropic distillation of EtOH/H 2 O was successfully demonstrated. Introduction Natural products obtained from plant matter continue to provide a diverse and unique source of bioactive compounds for drug manufacturing. Still, a significant part of drugs approved in the last 25 years owe their existence either directly to a natural product or its semi-synthetic modification. 1 Betulin (lup-20(29)-en-3β,28-diol, 1, Fig. 1) is a naturally occurring triterpene alcohol with a lupane skeleton found in birch bark, but also in roots or leaves of some ash trees. 2 Like many members of the lupane family, betulin exhibits versatile pharmaceutical potential, such as antitumor, anti-HIV, antiviral, antibacterial, anti-inflammatory, and antimalarial properties. Fur- thermore, several derivatives of betulin such as betulinic acid (3β-hydroxylup-20(29)-en-28-oic acid, 2) or bevirimat (3-O- (3′,3′-dimethylsuccinyl)betulinic acid) hold the potential to serve as hits or leads for anti-HIV drug development and are currently in clinical trials. 3,4 To date, the extraction of active ingredients from biomass is mainly performed using solvent extraction processes; however this is always associated with the dangers of handling large volumes of volatile and combustible solvents, human risk and safety issues and poor environmental performance. 5 In the current industrial isolation processes, betulin is extracted with high boiling hydrocarbon solvents, chlorinated solvents or with water azeotropes of alcohols. 6 This is not only a rather time-con- suming process with a limited yield of 10–20%, but suffers from co-extraction of many impurities thus requiring column chrom- atography or several other purification steps to obtain betulin in pharmaceutical purity. Consequently, there is a constant need forcing the pharmaceutical industries to search for more benign alternatives for extraction of active ingredients from biomass while equally taking safety constraints and economic and environmental criteria into account. 7 Recently, there has been increasing interest in the use of ionic liquids (ILs, organic salts liquid below 100 °C) for cost-effective and environmentally benign dissolution and processing of biomass as diverse as cellulose, chitin, and wood. 8 While the growing interest in ILs as solvents for biomass is mostly related to biomass processing and to the degradation towards biofuels, relatively little attention is paid to the extraction of valuable ingredients from crude biomass. Yet, there are several aspects of ILs that are potentially advantageous. Apart from their unique solvent properties and potential environmental benefits compared to organic solvents, the ability of ILs to swell or dissolve biomass can lead to a better access to the valuable ingredient embedded in biopolymer matrices. 9,10 Pioneering work in this area is reported for the extraction of the anti-malaria drug artemisinin from plant material by alterna- tive solvents including ILs. 11 In the past years, HPLC-based strategies for the extraction of several active pharmaceutically ingredients with ILs applying either ultrasound- or microwave- assisted extraction methods have been reported. Examples here include the isolation of the alkaloid piperine from white pepper, 12 the flavonoid rutin, 13 the actives senkyunolide I, sen- kyunolide H and Z-ligustide, 14 or shikonin and β,β′-dimethyl- acrylshikonin 15 from traditional Chinese medical plants. Recently, our group reported an IL-based strategy for essential oil distillation from crude biomass, 16 but also an improved Fig. 1 Structures of betulin 1 and betulinic acid 2. † Electronic supplementary information (ESI) available: See DOI: 10.1039/c2gc16389f ‡ The isolation yield of betulin was defined as: Yield = [(mass of betulin calculated from HPLC)/(mass of crude birch bark)]. a Institute of Applied Synthetic Chemistry, Vienna University of Technology, 1060 Vienna, Austria. E-mail: kbica@ioc.tuwien.ac.at b Institut für Technische und Makromolekulare Chemie, RWTHAachen University, Worringerweg 1, 52056 Aachen, Germany c DECHEMA Karl-Winnacker-Institut, Theodor-Heuss-Allee 25, 60486 Frankfurt am Main, Germany 940 | Green Chem., 2012, 14, 940–944 This journal is © The Royal Society of Chemistry 2012 Downloaded by Technische Universitat Wien on 17 January 2013 Published on 10 February 2012 on http://pubs.rsc.org | doi:10.1039/C2GC16389F View Article Online / Journal Homepage / Table of Contents for this issue