Synthesis and Characterization of Key Stereoisomers Related to Eluxadoline

Dattatraya M. Chaudhari; Jaydeo T. Kilbile; Sanket P. Zanjad; Suchita S. Gadekar; Sarang V. Babar; Suryakant B. Sapkal

doi:10.14233/ajchem.2025.34745

Issue

Vol. 37 No. 12 (2025): Vol 37 Issue 12, 2025

Issue Published : 30 November 2025

This work is licensed under a Creative Commons Attribution 4.0 International License.

Synthesis and Characterization of Key Stereoisomers Related to Eluxadoline

https://doi.org/10.14233/ajchem.2025.34745

Dattatraya M. Chaudhari

Department of Chemistry, School of Basic and Applied Sciences, M.G.M. University, Chhatrapati Sambhajinagar-431003, India

https://orcid.org/0009-0006-1733-456X

Jaydeo T. Kilbile

Department of Chemistry, School of Basic and Applied Sciences, M.G.M. University, Chhatrapati Sambhajinagar-431003, India

https://orcid.org/0000-0003-3716-4677

Sanket P. Zanjad

Department of Chemistry and Research Centre, Padmashri Vikhe Patil College of Arts, Science and Commerce, Pravaranagar-413713, India

https://orcid.org/0009-0006-6150-6285

Suchita S. Gadekar

Department of Chemistry, School of Basic and Applied Sciences, M.G.M. University, Chhatrapati Sambhajinagar-431003, India

https://orcid.org/0009-0002-2357-4608

Sarang V. Babar

Department of Chemistry, Maharaja Jivajirao Shinde Arts, Science, Commerce College, Shrigonda-413701, India

https://orcid.org/0009-0005-3618-1944

Suryakant B. Sapkal

Department of Chemistry, School of Basic and Applied Sciences, M.G.M. University, Chhatrapati Sambhajinagar-431003, India

https://orcid.org/0000-0001-5955-1585

Corresponding Author(s) : Dattatraya M. Chaudhari

dr.datta2007@rediffmail.com

Asian Journal of Chemistry, Vol. 37 No. 12 (2025): Vol 37 Issue 12, 2025
Article Published : 30 November 2025

Abstract

Eluxadoline is a novel active pharmaceutical ingredient (API) employed in the treatment of diarrhea and abdominal discomfort associated with diarrhea-predominant irritable bowel syndrome (IBS-D). Throughout the laboratory optimization and late-phase manufacturing studies of eluxadoline, the emergence of several stereoisomers was observed. To elucidate the comprehensive stereoisomer profile of eluxadoline, we have synthesized and meticulously characterized the (R,R)-eluxadoline enantiomer impurity, (S,R)-eluxadoline diastereomer impurity and (R,S)-eluxadoline stereoisomers of eluxadoline for the first time. These impurities were identified, synthesized and characterized with IR, ¹H NMR, ¹³C NMR and mass spectra. This investigation will facilitate access to reference standards of these stereoisomers and may bear significant implications for the advancement of new medicinal therapies.

Keywords

Eluxadoline Synthesis Characterization Stereoisomeric impurities

(1)

Chaudhari, D. M.; Kilbile, J. T.; Zanjad, S. P.; Gadekar, S. S.; Babar, S. V.; Sapkal, S. B. Synthesis and Characterization of Key Stereoisomers Related to Eluxadoline. ajc 2025, 37, 3093-3101.

Download Citation

References

N. Levy‑Cooperman, G. McIntyre, L. Bonifacio, M. McDonnell, J.M. Davenport, P.S. Covington, L.S. Dove and E.M. Sellers, J. Pharmacol. Exp. Ther., 359, 471 (2016); https://doi.org/10.1124/jpet.116.236547
F. Maltz and B. Fidler, P T., 42, 438 (2017).
K.C. Fragkos, Clin. Exp. Gastroenterol., 10, 229 (2017); https://doi.org/10.2147/CEG.S123621
K.P. Garnock-Jones, Drugs, 75, 1305 (2015); https://doi.org/10.1007/s40265-015-0436-4
A.E. Özdener and A. Rivkin, Drug Des. Devel. Ther., 11, 2827 (2017); https://doi.org/10.2147/DDDT.S127405
P. Wade, J. Palmer, S. McKenney, V. Kenigs, K. Chevalier, B. Moore, J. Mabus, P. Saunders, N. Wallace, C. Schneider, E. Kimball, H. Breslin, W. He and P. Hornby, Br. J. Pharmacol., 167, 1111 (2012); https://doi.org/10.1111/j.1476-5381.2012.02068.x
W. Fujita, I. Gomes, L.S. Dove, D. Prohaska, G. McIntyre and L.A. Devi, Biochem. Pharmacol., 92, 448 (2014); https://doi.org/10.1016/j.bcp.2014.09.015
B.E. Lacy, L.A. Harris, L. Chang, S. Lucak, C. Gutman, L.S. Dove, P.S. Covington and A. Lembo, Therap. Adv. Gastroenterol., 12, 1756284819841290 (2019); https://doi.org/10.1177/1756284819841290
A.E. Özdener and A. Rivkin, Drug Des. Devel. Ther., 11, 2827 (2017); https://doi.org/10.2147/DDDT.S127405
J.L. Abel, R.T. Carson and D.A. Andrae, Qual. Life Res., 28, 369 (2018); https://doi.org/10.1007/s11136-018-2008-z
R. Boinpally, D. McGeeney, E. Kaczynski and D. Weissman, Clin. Pharmacol. Drug Dev., 11, 1341 (2022); https://doi.org/10.1002/cpdd.1150
A. Teasdale, D. Elder, J. Harvey and S. Spanhaak, in eds.: A. Teasdale, D. Elder and R.W. Nims, Impurities in New Drug Substances and New Drug Products; In: ICH Quality Guidelines, Wiley (2017).
S. Görög, Trends Analyt. Chem., 25, 755 (2006); https://doi.org/10.1016/j.trac.2006.05.011
S. Gorog, The Nature and Origin of the Impurities in Drug Substances In: Progress in Pharmaceutical and Biomedical Analysis, Elsevier, vol. 4, pp. 9-22 (2000).
H.J. Breslin, C.-Z. Cai, W. He and R.W. Kavash, Compounds as Opioid Receptor Modulators, US Patent US 8,609,709 B2 (2007).
C-Z Cai and W. He, Process for the Preparation of Opioid Modulators US Patent WO2006099060A2 (2006).
S.T. Rajan, S. Eswaraiah, S.R. Reddy, M. Prabhakar and B. Rajesham Process for the preparation of 5-[[[(2s)-2-Amino-3-[4-(aminocarb-onyl)-2,6-dimethylphenyl]-1-oxopropyl][(1s)-1-(4-phenyl-1h-imidazol- 2-yl)ethyl]amino]methyl-2-methoxybenzoic acid and its polymorphs thereof, US Patents WO2017191650A1 (2016).
S. Pakalapati, C.S. Rumalla, A.R. Gudapati, R.B. Korupolu, S.B. Gajbhiye and M. Kaliyaperumal, SN Appl. Sci., 2, 1036 (2020); https://doi.org/10.1007/s42452-020-2834-9
K.P. Garnock-Jones, Drugs, 75, 1305 (2015); https://doi.org/10.1007/s40265-015-0436-4
J.M. Davenport, P. Covington, L. Bonifacio, G. McIntyre and J. Venitz, J. Clin. Pharmacol., 55, 534 (2015); https://doi.org/10.1002/jcph.442
A.J. Lembo, B.E. Lacy, M.J. Zuckerman, R. Schey, L.S. Dove, D.A. Andrae, J.M. Davenport, G. McIntyre, R. Lopez, L. Turner and P.S. Covington, N. Engl. J. Med., 374, 242 (2016); https://doi.org/10.1056/NEJMoa1505180
H.J. Breslin, C. Cai, W. He and R.W. Kavash Preparation of Imidazole Derivatives as Opioid Receptor Modulators, US Patent WO20050203143 A1 (2005).
R.R. Sagyam, E. Sajja, P. Macharla, R. Boge and T.R. Srinivasan Process for the Preparation of 5-[[[(2s)-2-amino-3-[4-(aminocarb-onyl)-2,6-dimethylphenyl]-1-oxopropyl][(1s)-1-(4-phenyl-1h-imidazol- 2-yl)ethyl]amino]methyl-2-methoxybenzoic Acid and Its Polymorphs Thereof, US Patent WO-2017191650-A1 (2017).
International Conference on Harmonization (ICH) Guidelines, Q3A (R) Impurities in New Drug Substances (2002).
International Conference on Harmonization (ICH) Guidelines, Q3B (R) Impurities in New Drug Substances (2002).

References

N. Levy‑Cooperman, G. McIntyre, L. Bonifacio, M. McDonnell, J.M. Davenport, P.S. Covington, L.S. Dove and E.M. Sellers, J. Pharmacol. Exp. Ther., 359, 471 (2016); https://doi.org/10.1124/jpet.116.236547

F. Maltz and B. Fidler, P T., 42, 438 (2017).

K.C. Fragkos, Clin. Exp. Gastroenterol., 10, 229 (2017); https://doi.org/10.2147/CEG.S123621

K.P. Garnock-Jones, Drugs, 75, 1305 (2015); https://doi.org/10.1007/s40265-015-0436-4

A.E. Özdener and A. Rivkin, Drug Des. Devel. Ther., 11, 2827 (2017); https://doi.org/10.2147/DDDT.S127405

P. Wade, J. Palmer, S. McKenney, V. Kenigs, K. Chevalier, B. Moore, J. Mabus, P. Saunders, N. Wallace, C. Schneider, E. Kimball, H. Breslin, W. He and P. Hornby, Br. J. Pharmacol., 167, 1111 (2012); https://doi.org/10.1111/j.1476-5381.2012.02068.x

W. Fujita, I. Gomes, L.S. Dove, D. Prohaska, G. McIntyre and L.A. Devi, Biochem. Pharmacol., 92, 448 (2014); https://doi.org/10.1016/j.bcp.2014.09.015

B.E. Lacy, L.A. Harris, L. Chang, S. Lucak, C. Gutman, L.S. Dove, P.S. Covington and A. Lembo, Therap. Adv. Gastroenterol., 12, 1756284819841290 (2019); https://doi.org/10.1177/1756284819841290

A.E. Özdener and A. Rivkin, Drug Des. Devel. Ther., 11, 2827 (2017); https://doi.org/10.2147/DDDT.S127405

J.L. Abel, R.T. Carson and D.A. Andrae, Qual. Life Res., 28, 369 (2018); https://doi.org/10.1007/s11136-018-2008-z

R. Boinpally, D. McGeeney, E. Kaczynski and D. Weissman, Clin. Pharmacol. Drug Dev., 11, 1341 (2022); https://doi.org/10.1002/cpdd.1150

A. Teasdale, D. Elder, J. Harvey and S. Spanhaak, in eds.: A. Teasdale, D. Elder and R.W. Nims, Impurities in New Drug Substances and New Drug Products; In: ICH Quality Guidelines, Wiley (2017).

S. Görög, Trends Analyt. Chem., 25, 755 (2006); https://doi.org/10.1016/j.trac.2006.05.011

S. Gorog, The Nature and Origin of the Impurities in Drug Substances In: Progress in Pharmaceutical and Biomedical Analysis, Elsevier, vol. 4, pp. 9-22 (2000).

H.J. Breslin, C.-Z. Cai, W. He and R.W. Kavash, Compounds as Opioid Receptor Modulators, US Patent US 8,609,709 B2 (2007).

C-Z Cai and W. He, Process for the Preparation of Opioid Modulators US Patent WO2006099060A2 (2006).

S.T. Rajan, S. Eswaraiah, S.R. Reddy, M. Prabhakar and B. Rajesham Process for the preparation of 5-[[[(2s)-2-Amino-3-[4-(aminocarb-onyl)-2,6-dimethylphenyl]-1-oxopropyl][(1s)-1-(4-phenyl-1h-imidazol- 2-yl)ethyl]amino]methyl-2-methoxybenzoic acid and its polymorphs thereof, US Patents WO2017191650A1 (2016).

S. Pakalapati, C.S. Rumalla, A.R. Gudapati, R.B. Korupolu, S.B. Gajbhiye and M. Kaliyaperumal, SN Appl. Sci., 2, 1036 (2020); https://doi.org/10.1007/s42452-020-2834-9

K.P. Garnock-Jones, Drugs, 75, 1305 (2015); https://doi.org/10.1007/s40265-015-0436-4

J.M. Davenport, P. Covington, L. Bonifacio, G. McIntyre and J. Venitz, J. Clin. Pharmacol., 55, 534 (2015); https://doi.org/10.1002/jcph.442

A.J. Lembo, B.E. Lacy, M.J. Zuckerman, R. Schey, L.S. Dove, D.A. Andrae, J.M. Davenport, G. McIntyre, R. Lopez, L. Turner and P.S. Covington, N. Engl. J. Med., 374, 242 (2016); https://doi.org/10.1056/NEJMoa1505180

H.J. Breslin, C. Cai, W. He and R.W. Kavash Preparation of Imidazole Derivatives as Opioid Receptor Modulators, US Patent WO20050203143 A1 (2005).

R.R. Sagyam, E. Sajja, P. Macharla, R. Boge and T.R. Srinivasan Process for the Preparation of 5-[[[(2s)-2-amino-3-[4-(aminocarb-onyl)-2,6-dimethylphenyl]-1-oxopropyl][(1s)-1-(4-phenyl-1h-imidazol- 2-yl)ethyl]amino]methyl-2-methoxybenzoic Acid and Its Polymorphs Thereof, US Patent WO-2017191650-A1 (2017).

International Conference on Harmonization (ICH) Guidelines, Q3A (R) Impurities in New Drug Substances (2002).

International Conference on Harmonization (ICH) Guidelines, Q3B (R) Impurities in New Drug Substances (2002).

Author biographies is not available.