A new and efficient enantioselective synthesis of both enantiomers of the calcium channel blocker bepridil

A new and efficient enantioselective synthesis of both enantiomers of the calcium channel blocker bepridil Mohammad Mujahid Organic Chemistry Division CSIR-National Chemical Laboratory Pune-411008 India P.G. Department of Chemistry Jambu Subramanian Organic Chemistry Division CSIR-National Chemical Laboratory Pune-411008 India Viswanadh Nalla Organic Chemistry Division CSIR-National Chemical Laboratory Pune-411008 India Murugesan Sasikumar Department of Chemistry School of Basic Sciences Vels University Chennai-600117 India Sunita Sharad Kunte Organic Chemistry Division CSIR-National Chemical Laboratory Pune-411008 India Murugan Muthukrishnan Organic Chemistry Division CSIR-National Chemical Laboratory Pune-411008 India http://orcid.org/0000-0003-2245-5498

We report a simple enantioselective synthesis of bepridil enantiomers employing hydrolytic kinetic resolution and the Mitsunobu reaction as key steps.
A concise and efficient enantioselective synthesis of both enantiomers of bepridil, a calcium channel blocker, is reported. Jacobsen's hydrolytic kinetic resolution method was utilized to resolve racemic 2-(isobutoxymethyl)oxirane. The incorporation of the succinimide moiety by the Mitsunobu reaction, which was investigated in detail, occurred without any loss of enantioselectivity. Using this strategy, both enantiomers of the target molecule were obtained in good yield and with high enantiopurity (ee > 99%).
2017 824 829 1 10.1039/rsc_crossmark_policy rsc.org true This document is Similarity Check deposited Supplementary Information Murugan Muthukrishnan (ORCID) The Royal Society of Chemistry and the partner society(ies) have an exclusive publication licence for this journal Single-blind Received 17 September 2016; Accepted 16 December 2016; Accepted Manuscript published 16 December 2016; Advance Article published 3 January 2017; Version of Record published 16 January 2017 10.1039/C6NJ02928K 20171121172843 https://xlink.rsc.org/?DOI=C6NJ02928K http://pubs.rsc.org/en/content/articlepdf/2017/NJ/C6NJ02928K Annu. Rev. Med. Schwartz 35 325 1984 10.1146/annurev.me.35.020184.001545 Cardiovasc. Drugs Ther. Opie 1 411 1987 10.1007/BF02209083 J. Pharmacol. Exp. Ther. Li 291 562 1999 Am. J. Cardiol. Prystowsky 55 59 1985 10.1016/0002-9149(85)90808-2 Drugs Hollingshead 44 835 1992 10.2165/00003495-199244050-00009 Naunyn-Schmiedeberg's Arch. Pharmacol. Van Amsterdam 337 213 1988 10.1007/BF00169250 Eur. J. Pharmacol. Winslow 166 241 1989 10.1016/0014-2999(89)90065-4 CHEMTECH Federsel 23 24 1993 Chem. Eng. News Stinson 78 55 2000 10.1021/cen-v078n043.p055 Chem. Eng. News Stinson 71 38 1993 10.1021/cen-v071n039.p038 Chromatographia Ren 50 363 1999 10.1007/BF02490843 Electrophoresis De Lorenzi 20 2739 1999 10.1002/(SICI)1522-2683(19990901)20:13<2739::AID-ELPS2739>3.0.CO;2-N J. Chromatogr. A Zukowski 948 331 2002 10.1016/S0021-9673(01)01473-X J. Neurosci. Mitterreiter 30 8974 2010 10.1523/JNEUROSCI.1199-10.2010 Circ. J. Nakazato 69 44 2005 10.1253/circj.69.44 Sci. Transl. Med. Johansen 7 1 2015 10.1126/scitranslmed.aaa5597 Aziridines and Epoxides in Organic Synthesis 2006 Aziridines and Epoxides in Organic Synthesis, ed. A. Yudin, Wiley-VCH Verlag GmbH & Co. KGaA, 2006 Tetrahedron Lett. Viswanadh 57 861 2016 10.1016/j.tetlet.2016.01.032 Tetrahedron Lett. Viswanadh 56 5269 2015 10.1016/j.tetlet.2015.07.032 Synthesis Reddi 1751 2014 Tetrahedron Lett. Mujahid 55 3223 2014 10.1016/j.tetlet.2014.04.021 Chirality Mujahid 25 965 2013 10.1002/chir.22253 Tetrahedron: Asymmetry Mujahid 23 1512 2012 10.1016/j.tetasy.2012.10.006 Tetrahedron: Asymmetry Muthukrishnan 22 1353 2011 10.1016/j.tetasy.2011.07.024 Tetrahedron: Asymmetry Nikalje 21 2825 2010 10.1016/j.tetasy.2010.11.011 Tetrahedron: Asymmetry Sasikumar 20 2814 2009 10.1016/j.tetasy.2009.11.014 Tetrahedron Muthukrishnan 63 1872 2007 10.1016/j.tet.2006.12.016 Tetrahedron: Asymmetry Joshi 16 3802 2005 10.1016/j.tetasy.2005.10.028 Science Tokunaga 277 936 1997 10.1126/science.277.5328.936 J. Am. Chem. Soc. Schaus 124 1307 2002 10.1021/ja016737l Tetrahedron: Asymmetry Larrow 14 3589 2003 10.1016/j.tetasy.2003.09.018 Tetrahedron Kumar 63 2745 2007 10.1016/j.tet.2006.12.015 Org. Biomol. Chem. Dar 11 6195 2013 10.1039/c3ob40853a Tetrahedron Tripathi 65 2226 2009 10.1016/j.tet.2009.01.062 Org. Biomol. Chem. Ganesan 11 599 2013 10.1039/C2OB27000E