Synthesis of the Enantiomers of Thioridazine

Abstract

Thioridazine, a well-known antipsychotic drug, has shown promising effects on several bacterial strains (including Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus). Suppressive effects towards selected cancer cell-lines have also been reported. However, due to adverse effects, the compound is no longer in use for the primary indication. More recent research has demonstrated that these side effects are limited to one of the two enantiomers, (+)-thioridazine. The question arises to whether the beneficial effects of thioridazine are limited to one enantiomer, or if (–)-thioridazine can prove itself to be useful in its pure enantiomeric state. The published procedures on the synthesis of the optically pure enantiomers of thioridazine were found to be unsatisfactory, either due to low optical purity, high cost, or problems scaling up. Herein, we have used an auxiliary-based strategy for the total synthesis of both enantiomers in high optical purity and good overall yield. The strategy can easily be scaled up. Both enantiomers were tested against several bacteria. Comparison of the racemic mixture, (–)-thioridazine and its (+)-antipode revealed that they have the same antimicrobial effects. Thus, the non-toxic enantiomer, (–)-thioridazine, can prove useful in this role and should be investigated further.

Key words

thioridazine - antibacterial - enantiomers - total synthesis - sulfinyl aldimines

• References and Notes

• 1 Fenton M, Rathbone J, Reilly J. Cochrane Database Syst. Rev. 2007; 3: CD001944
• 2 Judah L, Murphree O, Seager L. Am. J. Psychiatry 1959; 115: 1118
• 3 Kinross-Wright J. JAMA, J. Am. Med. Assoc. 1959; 170: 1283
• 4 Fletcher GF, Kazamias TM, Wenger NK. Am. Heart J. 1969; 78: 135
• 5 Harrigan EP, Miceli JJ, Anziano R, Watsky E, Reeves KR, Cutler NR, Sramek J, Shiovitz T, Middle M. J. Clin. Psychopharmacol. 2004; 24: 62
• 6 Hartigan-Go K, Bateman DN, Nyberg G, Martensson E, Thomas SH. L. Clin. Pharmacol. Ther. 1996; 60: 543
• 7 Salih IS. M, Thanacoody RH. K, McKay GA, Thomas SH. L. Clin. Pharmacol. Ther. 2007; 82: 548
• 8 Mehtonen OP, Aranko K, Malkonen L, Vapaatalo H. Acta Psychiatr. Scand. 1991; 84: 58
• 9 Ray WA, Meredith S, Thapa PB, Meador KG, Hall K, Murray KT. Arch. Gen. Psychiatry 2001; 58: 1161
• 10 Reilly JG, Ayis SA, Ferrier IN, Jones SJ, Thomas SH. L. Br. J. Psychiatry 2002; 180: 515
• 11 Hennessy S, Bilker WB, Knauss JS, Margolis DJ, Kimmel SE, Reynolds RF, Glasser DB, Morrison MF, Strom BL. Br. Med. J. 2002; 325: 1070
• 12 Ray WA, Chung CP, Murray KT, Hall K, Stein CM. N. Engl. J. Med. 2009; 360: 225
• 13 Reilly JG, Ayis SA, Ferrier IN, Jones SJ, Thomas SH. L. Lancet 2000; 355: 1048
• 14 Thanacoody RH. K. Recent Pat. Anti-Infect. Drug Discovery 2011; 6: 92
• 15 Abbate E, Vescovo M, Natiello M, Cufre M, Garcia A, Gonzalez Montaner P, Ambroggi M, Ritacco V, van Soolingen D. J. Antimicrob. Chemother. 2012; 67: 473
• 16 Dastidar SG, Kristiansen JE, Molnar J, Amaral L. Antibiotics 2013; 2: 58
• 17 Amaral L, Viveiros M. Int. J. Antimicrob. Agents 2012; 39: 376
• 18 Ordway D, Viveiros M, Leandro C, Bettencourt R, Almeida J, Martins M, Kristiansen JE, Molnar J, Amaral L. Antimicrob. Agents Chemother. 2003; 47: 917
• 19 Martins M, Bleiss W, Marko A, Ordway D, Viveiros M, Leandro C, Pacheco T, Molnar J, Kristiansen JE, Amaral L. In Vivo 2004; 18: 787
• 20 Stenger M, Behr-Rasmussen C, Klein K, Groennemose RB, Andersen TE, Klitgaard JK, Kolmos HJ, Lindholt JS. PLoS One 2017; e0173362
• 21 Daniel WA, Wojcikowski J. Toxicol. Appl. Pharmacol. 1999; 158: 115
• 22 Zhang C, Gong P, Liu P, Zhou N, Zhou Y, Wang Y. Oncol. Rep. 2017; 37: 1168
• 23 Sachlos E, Risueno RM, Laronde S, Shapovalova Z, Lee J.-H, Russell J, Malig M, McNicol JD, Fiebig-Comyn A, Graham M, Levadoux-Martin M, Lee JB, Giacomelli AO, Hassell JA, Fischer-Russell D, Trus MR, Foley R, Leber B, Xenocostas A, Brown ED, Collins TJ, Bhatia M. Cell 2012; 149: 1284
• 24 Cheng HW, Liang YH, Kuo YL, Chuu CP, Lin CY, Lee MH, Wu AT. H, Yeh CT, Chen EI. T, Whang-Peng J, Su CL, Huang CY. F. Cell Death Dis. 2015; 6: e1753
• 25 Yue H, Huang D, Qin L, Zheng Z, Hua L, Wang G, Huang J, Huang H. BioMed Res. Int. 2016; 6709828
• 26 Spengler G, Csonka A, Molnar J, Amaral L. Anticancer Res. 2016; 36: 5701
• 27 Svendsen CN, Froimowitz M, Hrbek C, Campbell A, Kula N, Baldessarini RJ, Cohen BM, Babb S, Teicher MH, Bird ED. Neuropharmacology 1988; 27: 1117
• 28 Jortani SA, Poklis A. J. Anal. Toxicol. 1993; 17: 374
• 29 Jensen AS, Pennisi CP, Sevcencu C, Christensen JB, Kristiansen JE, Struijk JJ. Eur. J. Pharmacol. 2015; 747: 7
• 30 Bourquin JP, Schwarb G, Gamboni G, Fischer R, Ruesch L, Guldimann S, Theus V, Schenker E, Renz J. Helv. Chim. Acta 1958; 41: 1072
• 31 Choi S, Haggart D, Toll L, Cuny GD. Bioorg. Med. Chem. Lett. 2004; 14: 4379
• 32 Bosque I, González-Gómez JC, Foubelo F, Yus M. J. Org. Chem. 2012; 77: 780
• 33 Patrick KS, Singletary JL. Chirality 1991; 3: 208
• 34 Mohammad T, Hawes EM, McKay G, Midha KK. J. Labelled Compd. Radiopharm. 1990; 28: 1087
• 35 Mohammad T, Midha KK, Hawes EM. J. Labelled Compd. Radiopharm. 1988; 25: 415
• 36 Flock S, Antonsen S, Gallantree-Smith H, Langseter AM, Skatteboel L, Stenstroem Y. Tetrahedron Lett. 2016; 72: 4518
• 37 Sun X.-W, Liu M, Xu M.-H, Lin G.-Q. Org. Lett. 2008; 10: 1259
• 38 Aggarwal VK, Barbero N, McGarrigle EM, Mickle G, Navas R, Suárez JR, Unthank MG, Yar M. Tetrahedron Lett. 2009; 50: 3482
• 39 Senter TJ, Schulte ML, Konkol LC, Wadzinski TE, Lindsley CW. Tetrahedron Lett. 2013; 54: 1645
• 40 Schlauderer F, Lammens K, Nagel D, Vincendeau M, Eitelhuber AC, Verhelst SH. L, Kling D, Chrusciel A, Ruland J, Krappmann D, Hopfner K.-P. Angew. Chem. Int. Ed. 2013; 52: 10384
• 41 Poulsen M. Ø, Klitgaard JK, Christensen JB, Kallipolitis BH, Kaatz GW, Plenge P, Fey SJ, Kristiansen JE. Am. J. Bioavailab. Bioequiv. 2018; 1: 1
• 42 N-Boc (S)-2-(1-methylpiperidin-2-yl)ethanal [(S)-13]: 2-Allyl piperidine (37 mg, 0.16 mmol) was dissolved in dioxane (9.5 mL) and the mixture stirred vigorously for 10 min. 2,6-Lutidine (0.038 mL, 2 equiv), OsO₄ in tert-butanol (2.5 wt%, 0.047 mL, 0.020 mol%), water (3.2 mL), and NaIO₄ (0.14 g, 0.65 mmol, 4 equiv) were added and the mixture was stirred for a further 5 h. The reaction was quenched by adding water (8 mL), CH₂Cl₂ (16 mL) was added and the phases were separated. The aqueous fraction was further extracted with CH₂Cl₂ (3 × 16 mL), and the combined organic phases were washed with brine (16 mL), dried over Na₂SO₄, filtered, concentrated under reduced pressure and purified by flash chromatography (SiO₂) to yield a colorless oil (36.3 mg, quantitative). [α] _d ²⁰ –51.7 (c = 1, CH₃Cl) {lit.⁴³ [α] _d ²⁰ –50.6 (c = 0.9, CH₃Cl)}; R_f = 0.31 (7:3 hex/EtOAc). ¹H NMR (400 MHz, CDCl₃): δ = 9.71 (dd, J = 3.3, 2.2 Hz, 1 H), 4.81 (d, J = 8.9 Hz, 1 H), 3.97 (d, J = 13.8 Hz, 1 H), 2.81–2.66 (m, 2 H), 2.51 (m, 1 H), 1.58 (m, 2 H), 1.42 (s, 10 H). ¹³C NMR (100 MHz, CDCl₃): δ = 200.80, 154.67, 79.90, 45.86, 44.64, 39.24, 28.88, 28.36, 25.21, 18.91. (S)-2-(1-Methylpiperidin-2-yl)ethan-1-ol [(S)-5]: To a solution of (S)-13 (0.95 g, 4.2 mmol) in tetrahydrofuran (10 mL) at 0 °C was added 2.0 M lithium aluminum hydride in tetrahydrofuran (0.28 mL, 0.56 mmol). The reaction was heated at 50 °C for 18 hours then cooled to 0 °C, when water (2.0 mL), 1 M aq. NaOH (2.0 mL) and water (2.0 mL) were added successively. The phases were separated, and the organic phase was filtered through a pad of Celite^®. The filtrate was concentrated under reduced pressure and distilled in vacuo to yield the product as a colorless oil of sufficient purity (0.53 g, 3.7 mmol, 88%). The hydrochloride salt was prepared for NMR comparison with the literature.³³ [α] _d ²⁰ –43.9 (c = 2.5, EtOH) {lit.³³ [α] _d ²⁰ –44.2 (c = 2.5, EtOH)} ¹H NMR (400 MHz, CDCl₃): δ = 4.81 (br s, 1 H), 3.78 (m, 1 H), 3.59 (m, 1 H), 2.80 (m, 1 H), 2.26 (s, 3 H), 2.10 (m, 1 H), 2.00 (dd, J = 11.8, 3.5 Hz, 1 H), 1.81 (m, 1 H), 1.71–1.36 (m, 7 H), 1.28–1.15 (m, 1 H); ¹³C NMR (100 MHz, CDCl₃): δ = 61.99, 59.95, 56.61, 42.99, 33.43, 29.47, 25.08, 24.01.2-(2-Chloroethyl)-l-methylpiperidine [(S)-6]: Thionyl chloride (0.49 g, 0.30 mL, 4.1 mmol) was added dropwise to a stirred solution of the alcohol (0.25 g, 1.7 mmol) in anhydrous chloroform (15 mL) cooled in an ice bath. After addition was complete, the solution was heated to reflux on a steam bath for 3 hours. Volatiles were removed under reduced pressure and the residual solid was dissolved in 25% aq. HC1 (13 mL), treated with activated charcoal and filtered. The solution was evaporated to dryness on a rotary evaporator and the solid obtained was recrystallized from acetone, giving colorless crystals of the hydrochloride salt of (S)-6 (0.26 g, quantitative yield). [α] _d ²⁰ –44 (c = 1, H₂O) {lit.³³ [α] _d ²⁰ –44.9 (c = 2, H₂O)}; mp 132–133 °C [lit.³³ 131–132 °C]. ¹H NMR (400 MHz, CDCl₃): δ = 3.67–3.49 (m, 2 H), 2.81 (m, J = 11.7, 3.7, 1.4 Hz, 1 H), 2.25 (s, 3 H), 2.15–2.07 (m, 3 H), 1.86 (m, 1 H), 1.74–1.62 (m, 2 H), 1.61–1.46 (m, 2 H), 1.35–1.19 (m, 2 H); ¹³C NMR (100 MHz, CDCl₃): δ = 61.44, 56.90, 42.94, 41.71, 35.98, 30.47, 25.61, 24.07.Thioridazine [(S)-1]: A stirred mixture of phenothiazine 7 (0.25 g, 1 mmol), finely powdered NaOH (0.16 g, 4 mmol) and toluene (25 mL, dried over activated 4Å molecular sieves) was heated to reflux for 5 h under N₂ atmosphere. The hydrochloride of 6 (0.125 g, 0.51 mmol) was added portionwise over a period of 1 h. The mixture was then heated to reflux for 3 h, cooled to 0 °C and the phases were separated. The organic phase was extracted with 25% aq. HC1 (2 × 50 mL). The aqueous phase was then basified with NaOH and extracted with CH₂Cl₂ (3 × 50 mL). The combined organic extracts were washed with water (25 mL), dried over Na₂SO₄, filtered and evaporated on a rotary evaporator. The resulting residue was purified on silica to give (S)-thioridazine (0.15 g, 80% yield). All spectroscopic data correspond to the data of the racemate. The specific rotation corresponds to that previously published.^{9 1}H NMR (400 MHz, CDCl₃): δ = 7.24–6.75 (m, 7 H), 4.05–3.75 (m, 2 H), 2.95–2.70 (m, 1 H), 2.57–2.37 (m, 3 H), 2.23–2.18 (m, 3 H), 2.15–1.99 (m, 3 H), 1.93–1.79 (m, 1 H), 1.78–1.66 (m, 2 H), 1.58 (qd, J = 9.2, 7.4, 4.3 Hz, 2 H), 1.50–1.36 (m, 1 H), 1.36–1.24 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 145.75, 145.00, 137.54, 127.56, 127.47, 127.22, 125.32, 122.57, 122.26, 120.80, 115.71, 114.61, 62.15, 56.94, 43.97, 43.17, 30.92, 30.05, 25.74, 24.21, 16.50. [α] _d ²⁰ –21 (c = 1, EtOH) {lit.³⁰ [α] _d ²⁰ –21±2 (c = 1, EtOH)]; The racemic reference was purchased from Sigma–Aldrich chemicals.
• 43 Shaikh TM, Sudalai A. Eur. J. Org. Chem. 2010; 3437