Synthesis of nucleoside-based antiviral drugs in ionic liquids Vineet Kumar, Sanjay V. Malhotra * Laboratory of Synthetic Chemistry, SAIC-Frederick Inc., National Cancer Institute-Frederick, 1050 Boyles Street, Frederick, MD 21702, USA article info Article history: Received 24 June 2008 Revised 23 August 2008 Accepted 26 August 2008 Available online 29 August 2008 Keywords: Nucleoside Antiviral drugs Ionic liquid HIV HSV abstract Nucleoside-based antiviral drugs have been synthesized using imidazolium-based ionic liquids as reaction medium. The ionic liquids were proved to be better solvents for all the nucleoside in terms of solubility and reaction medium as compared to conventional molecular solvents. Ó 2008 Elsevier Ltd. All rights reserved. Nucleosides analogs are prominent drugs used for treatment of several viral infections, including HSV (herpes simplex virus), HIV (human immunodeficiancy virus), HBC (hepatitis B virus), HCV (hepatitis C virus), and HCMV (human cytomegalovirus) infections. Some well-known examples of nucleoside-based antiviral drugs al- ready in the market are: AZT (Zidovudine), ddC (2 0 ,3 0 -dideoxycyti- dine), d4T (Stavudine), BVDU (Brivudine), TFT (Trifluridine), IDU (Idoxuridine), etc. 1 Several structural modifications have been achieved on the heterocyclic bases and/or on the sugar moiety of natural nucleosides in search of antiviral nucleoside analogs. 1,2 However, the synthesis of modified nucleosides presents a major challenge, which is further aggravated by poor solubility of these compounds in common organic solvents. Solvents commonly used in nucleoside chemistry, viz. pyridine, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA) and N-methylpyrrolidone (NMP), are hazardous for human health and environment. More- over, these solvents are difficult to remove and often get contami- nated with reaction products making the workup procedures more tedious and time consuming. Hence, there is a great need for the development of new methodologies for nucleoside chemistry using environmentally benign media which could replace the conven- tional solvents and provide sufficient solubility to nucleosides. Ionic liquids (ILs) have emerged as attractive alternatives to conventional organic solvents due to their advantageous proper- ties viz. negligible vapor pressure, recyclability, high thermal sta- bility, and their ability to dissolve wide range of compounds. 3 The possibilities of their structural variations help in designing ideal solvents suitable for any particular process. 4 Despite their attractive properties, there are only handful of reports where ILs have been used for nucleoside reactions. 5 Our earlier studies in this area have led to designing of ILs which provide high solubility for nucleosides and found to be efficient reaction medium for selective modifications, giving high yields under ambient conditions. 5e,5f Herein, we are reporting the utility of ILs 1-methoxyethyl-3-meth- ylimidazolium methanesulfonate ([MoeMIm][Ms]), 1-methoxy- ethyl-3-methylimidazolium trifluoroacetate ([MoeMIm][TFA]) and 1-butyl-3-methylimidazolium trifluoroacetate ([BMIm][TFA]) (Fig. 1) 5e,5f as reaction medium for some of the key steps involved in the synthesis of antiviral nucleoside drugs d4T, BVDU and TFT. Stavudine (2), also known as 2 0 ,3 0 -didehydro-3 0 -deoxythymi- dine (d4T) is an anti-HIV drug which act as a reverse transcriptase inhibitor. 6 Although several methods for its synthesis are reported, they are associated with limitations such as tedious reaction con- ditions and workup, longer reaction time, use of expensive re- agents, poor yields, and use of harmful solvents. 6,7 In one of 0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2008.08.090 * Corresponding author. Tel.: +1 301 846 5141; fax: +1 301 846 5206. E-mail address: malhotrasa@mail.nih.gov (S.V. Malhotra). N N O + N N + N N O + CH 3 SO 3 - CF 3 COO - CF 3 COO - [BMIm][TFA] [MoeMIm][Ms] [MoeMIm][TFA] Figure 1. Structures of ILs used. Bioorganic & Medicinal Chemistry Letters 18 (2008) 5640–5642 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl