Facile, Alternative Route to Lubeluzole, Its Enantiomer, and the Racemate CLAUDIO BRUNO, ALESSIA CAROCCI, ALESSIA CATALANO, MARIA M. CAVALLUZZI, FILOMENA CORBO, CARLO FRANCHINI, GIOVANNI LENTINI,* AND VINCENZO TORTORELLA Dipartimento Farmaco-Chimico, Facolta ` di Farmacia, Universita ` degli Studi di Bari, Bari, Italy ABSTRACT Lubeluzole [(S)-9] has been synthesized by a convergent synthesis, alkylation of N-methyl-N-piperidin-4-yl-1,3-benzothiazol-2-amine (4) with (þ)-(R)-1-chloro- 3-(3,4-difluorophenoxy)propan-2-ol [(þ)-(R)-8] being the key step. Alcohol (þ)-(R)-8 was obtained from commercially available (R)-epichlorohydrin [(R)-6], while the thiazole derivative 4 was easily obtained starting from N-protected piperidin-4-one (1) in a three- step procedure. The same method was used in order to obtain both the (R)-stereo- isomer of lubeluzole [(R)-9] and its racemate [(RS)-9]. Overall yields ranged from 20% to 35%. The enantiomeric excess values for (S)-9 and (R)-9 were 97% and 94% respec- tively, as analyzed by chiral HPLC. Chirality 18:227–231, 2006. V V C 2006 Wiley-Liss, Inc. KEY WORDS: stroke; sodium channel; stereospecific synthesis; enantiomers; enantio- meric excess Lubeluzole [(S)-9] is a homochiral benzothiazole deriv- ative that is currently evaluated for its usefulness in the treatment of acute ischemic stroke. 1–3 Previously reported effects of lubeluzole, such as inhibition of glutamate release, inhibition of glutamate-activated NO synthesis, and blockade of voltage-gated Na þ and Ca 2þ channels, suggest that it has neuroprotective potential. 3–5 The (R)- isomer of lubeluzole, 3–6 as well as its racemate, 3 show these effects to a much more modest extent. A recent study has compared the relative antinociceptive proper- ties of a range of drugs capable of blocking voltage-acti- vated Na þ channels. 7 When tested against an acute ther- mal nociceptive stimulus, lubeluzole exhibited antinoci- ceptive effects similar to those displayed by mexiletine, a well-known IB antiarrhythmic and antimyotonic 8 agent that is able to block voltage-dependent Na þ channels in both cardiac and skeletal muscle fibers. Recent data show that lubeluzole produces both tonic and use-dependent block of cardiac sodium channels, mainly acting on chan- nels in the inactivated state. 9 In the last decade, our research group has been involved in a program directed to the synthesis of sodium channel blockers effective as antimyotonic agents. 10,11 We decided to verify whether lubeluzole and its enantiomer exhibit blocking activity also on skeletal muscle sodium channels: a study of the stereoselectivity in lubeluzole sodium channel blocking activity, if detected on skeletal muscle and compared with the patterns displayed on neuronal and cardiac channels, could give useful hints on the possibility of dissociating the plethora of pharmacological activities shown by both lubeluzole and other antiarrhythmic drugs. The first goal was to find a convenient and facile stereospecific route to obtain lubeluzole, its enantiomer, and the corresponding racemate. MATERIALS AND METHODS Chemicals and Reagents (Scheme 1) All chemicals were purchased from Aldrich (Chemical Co., Milwaukee, WI, USA) or Lancaster (Synthesis, Inc., Frankfurt am Main, Germany) at the highest quality com- mercially available. Solvents were RP grade unless otherwise indicated. The preparation of 2-[(3,4-difluorophenoxy)methyl] oxirane (7) was performed as reported in the literature. 12 Instrumentation Yields refer to purified products and were not opti- mized. The structures of the compounds were confirmed by routine spectrometric analyses. Only spectra of com- pounds not previously described are given. Melting points were determined with a Gallenkamp apparatus in open glass capillary tubes and are uncorrected. Infrared spectra were recorded on a PerkinElmer (Norwalk, CT) Spectrum One FT spectrophotometer and band positions are given in reciprocal centimeters (cm À1 ). 1 H and 13 C NMR spectra were recorded on a Bruker 300-MHz spec- trometer (ASPECT 3000), operating at 300 and 75 MHz for 1 H and 13 C, respectively, using CDCl 3 or DMSO-d 6 (where indicated) as solvents. Chemical shifts are re- ported in parts per million (ppm) relative to solvent reso- nance: CDCl 3 , d 7.26 ( 1 H NMR) and d 77.3 ( 13 C NMR); DMSO-d 6 , d 2.50 ( 1 H NMR) and d 39.5 ( 13 C NMR). J val- ues are given in Hz. EIMS spectra were recorded on a V V C 2006 Wiley-Liss, Inc. *Correspondence to: G. Lentini, Prof., Dipartimento Farmaco-Chimico, Facolta ` di Farmacia, Universita ` degli Studi di Bari, via Orabona 4, 70126 Bari, Italy. E-mail: glentini@farmchim.uniba.it Received for publication 25 July 2005; Accepted 21 October 2005 DOI: 10.1002/chir.20240 Published online 6 March 2006 in Wiley InterScience (www.interscience.wiley.com). CHIRALITY 18:227–231 (2006)