(2S)-2-[(S)-(2-ethoxyphenoxy)(phenyl)methyl]morpholine butanedioate (1:1)
(2S)-2-[(S)-(2-Ethoxyphenoxy)(phenyl)methyl]morpholine succinate (1:1)
Morpholine, 2-[(S)-(2-ethoxyphenoxy)phenylmethyl]-, (2S)-, butanedioate (1:1)
Succinic acid – (2S)-2-[(S)-(2-ethoxyphenoxy)(phenyl)methyl]morpholine (1:1)
Reboxetine mesylate (1) and succinate (2).
||Scheme 2 The conversion of (±)-reboxetine mesylate to (S,S)-reboxetine succinate.
||Scheme 3 The Pfizer early resolution route to (S,S)-reboxetine succinate.
||Scheme 4 The Pfizer asymmetric synthesis for (S,S)-reboxetine intended for commercialisation.
(S,S)-Reboxetine succinate (3) (Figure 1) has been under late-stage development at Pfizer for the medication of neuropathic and fibromyalgia pain.(16)
16.(a) Hughes, B.; McKenzie, I.; Stoker, M. J. WO2006/000903, May 1, 2006.
(b) Allen, A. J.; Hemrick-Luecke, S.; Sumner, C. R.; Wallace, O. B. WO2005/060949, July 7, 2005.
(c) Kelsey, D. K. WO2005/021095, Oct 3, 2005.
(d) Allen, A. J.; Kelsey, D. K. WO 2005/020976, Oct 3, 2005.
(e) Sumner, C. R. WO2005/020975, Oct 3, 2005.
(f) Hassan, F. WO2004/016272, Feb 26, 2004.
(g) Wong, E. H. F. WO2004/002463, Jan 8, 2004.
Process Development for (S,S)-Reboxetine Succinate via a Sharpless Asymmetric Epoxidation
Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, U.S.A.
Org. Process Res. Dev., 2007, 11 (3), pp 354–358
Publication Date (Web): March 23, 2007
Copyright © 2007 American Chemical Society
Reboxetine mesylate is a selective norepinephrine uptake inhibitor (NRI) currently marketed as the racemate. The (S,S)-enantiomer of reboxetine is being evaluated for the treatment of neuropathic pain and a variety of other indications. (S,S)-Reboxetine has usually been prepared by resolution of the racemate as the (−)-mandelate salt, an inherently inefficient process. A chiral synthesis starting with a Sharpless asymmetric epoxidation of cinnamyl alcohol to yield (R,R)-phenylglycidol was developed. (R,R)-Phenylglycidol was reacted without isolation with 2-ethoxyphenol to give 4, which was isolated by direct crystallization. Key process variables for the asymmetric epoxidation were investigated. Conversion of (R,S)-4 to reboxetine parallels the racemic synthesis with streamlined and optimized processing conditions. (S,S)-Reboxetine free base was converted directly to the succinate salt without isolation as the mesylate salt.
(2S,3S)-Reboxetine Succinate (9).
mp 145.2−147.1 °C (lit. mp 148 °C).8 1H NMR (400.13 MHz, CDCl3) δ 1.41 (t, J = 7.0 Hz, 3H), 2.4 (s, 4H), 2.9−3.06 (m, 2H), 3.15−3.22 (m, 2H), 3.81−3.86 (m, 1H), 4.02−4.09 (m, 3H), 4.17−4.24 (m, 1H), 5.13 (d, J = 4.3 Hz), 6.66−6.90 (m, 4H), 7.26−7.39 (m, 5H). 13C NMR (100.62 MHz, CDCl3) δ 15.08, 31.89, 43.24, 44.84, 64.72, 76.91, 82.91, 113.94, 118.27, 121.1, 127.38, 128.66, 136.94, 149.8, 178.73. LRMS-APCI m/z calcd for C19H23NO3 (M + H)+: 314. Found: m/z = 314 [M + 1]+. Anal. Calcd for C19H23NO3−C4H6O4: C, 64.02; H, 6.77; N, 3.25. Found: C, 63.99; H, 6.77; N, 3.16. [α]32.4D +17.24° (c 0.5, EtOH).
8) Zampieri, M.; Airoldi, A.; Martini, A. WO2003/106441, 12/24/03.
Commercial Synthesis of (S,S)-Reboxetine Succinate: A Journey To Find the Cheapest Commercial Chemistry for Manufacture
Chemical Research and Development, Pfizer Inc., Sandwich Laboratories, Sandwich, Kent, CT13 9NJ, United Kingdom
Org. Process Res. Dev., 2011, 15 (6), pp 1305–1314
Publication Date (Web): August 18, 2011
Copyright © 2011 American Chemical Society
The development of a synthetic process for (S,S)-reboxetine succinate, a candidate for the treatment of fibromylagia, is disclosed from initial scale-up to deliver material for registrational stability testing through to commercial route evaluation and subsequent nomination. This entailed evaluation of several alternative routes to result in what would have been a commercially attractive process for launch of the compound.
(2S,3S)-2-[α-(2-Ethoxyphenoxy)benzyl]morpholine Succinate Salt (S,S)-Reboxetine Succinate
(S,S)-reboxetine succinate (897 g, 82%) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 7.22–7.54 (m, 5H), 6.66–6.96 (m, 4H), 5.27 (d, J = 6.0 Hz, 1H), 4.01 (q, J = 7.1 Hz, 2H), 3.83 (m, 2H), 3.50 (m, 2H), 2.61–2.82 (m, 3H), 2.34 (br s, 4H), 1.33 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, d6-DMSO) δ 174.4, 149.0, 147.3, 137.8, 128.2, 127.3, 120.7, 116.7, 114.4, 80.8, 77.5, 65.9, 64.1, 45.8, 44.1, 39.7, 39.
- ^ Jump up to:a b Matilda Bingham; Napier, Susan Jolliffe (2009). Transporters as Targets for Drugs (Topics in Medicinal Chemistry). Berlin: Springer. ISBN 3-540-87911-0.
- Jump up^ Rao SG (October 2009). “Current progress in the pharmacological therapy of fibromyalgia”. Expert Opinion on Investigational Drugs. 18 (10): 1479–93. PMID 19732029. doi:10.1517/13543780903203771.
- Jump up^ “Search of: esreboxetine – List Results – ClinicalTrials.gov”.
- Jump up^ “Musculoskeletal Report: Pfizer Stops Work on Esreboxetine for FM”.
- Jump up^ Fish, P. V.; MacKenny, M.; Bish, G.; Buxton, T.; Cave, R.; Drouard, D.; Hoople, D.; Jessiman, A.; Miller, D.; Pasquinet, C.; Patel, B.; Reeves, K.; Ryckmans, T.; Skerten, M.; Wakenhut, F. (2009). “Enantioselective synthesis of (R)- and (S)-N-Boc-morpholine-2-carboxylic acids by enzyme-catalyzed kinetic resolution: application to the synthesis of reboxetine analogs”. Tetrahedron Letters. 50 (4): 389. doi:10.1016/j.tetlet.2008.11.025.
- Jump up^ Arnold, L. M., Hirsch, I., Sanders, P., Ellis, A. and Hughes, B. (2012), Safety and efficacy of esreboxetine in patients with fibromyalgia: A fourteen-week, randomized,
1: Fujimori I, Yukawa T, Kamei T, Nakada Y, Sakauchi N, Yamada M, Ohba Y, Takiguchi M, Kuno M, Kamo I, Nakagawa H, Hamada T, Igari T, Okuda T, Yamamoto S, Tsukamoto T, Ishichi Y, Ueno H. Design, synthesis and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitor. Bioorg Med Chem. 2015 Aug 1;23(15):5000-14. doi: 10.1016/j.bmc.2015.05.017. Epub 2015 May 15. PubMed PMID: 26051602.
2: Shen F, Tsuruda PR, Smith JA, Obedencio GP, Martin WJ. Relative contributions of norepinephrine and serotonin transporters to antinociceptive synergy between monoamine reuptake inhibitors and morphine in the rat formalin model. PLoS One. 2013 Sep 30;8(9):e74891. doi: 10.1371/journal.pone.0074891. eCollection 2013. PubMed PMID: 24098676; PubMed Central PMCID: PMC3787017.
3: Arnold LM, Hirsch I, Sanders P, Ellis A, Hughes B. Safety and efficacy of esreboxetine in patients with fibromyalgia: a fourteen-week, randomized, double-blind, placebo-controlled, multicenter clinical trial. Arthritis Rheum. 2012 Jul;64(7):2387-97. doi: 10.1002/art.34390. PubMed PMID: 22275142.
4: Arnold LM, Chatamra K, Hirsch I, Stoker M. Safety and efficacy of esreboxetine in patients with fibromyalgia: An 8-week, multicenter, randomized, double-blind, placebo-controlled study. Clin Ther. 2010 Aug;32(9):1618-32. doi: 10.1016/j.clinthera.2010.08.003. PubMed PMID: 20974319.
5: Klarskov N, Scholfield D, Soma K, Darekar A, Mills I, Lose G. Measurement of urethral closure function in women with stress urinary incontinence. J Urol. 2009 Jun;181(6):2628-33; discussion 2633. doi: 10.1016/j.juro.2009.01.114. Epub 2009 Apr 16. PubMed PMID: 19375093.
////////////(+)-(S,S)-Reboxetine, (S,S)-Reboxetine, Reboxetine, Esreboxetine succinate