A Novel Synthetic Route of (Z)-Ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate:  A Key Intermediate of Apixaban

Leena N. Patil; Mubarak Ali R. Sayyed; Dilip R. Birari; Prashant A. Patil; Sandip Dhumal; Divyesh R. Joshi

doi:10.14233/ajchem.2025.32993

Issue

Vol. 37 No. 7 (2025): Vol 37 Issue 7, 2025

Issue Published : 30 June 2025

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

A Novel Synthetic Route of (Z)-Ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate: A Key Intermediate of Apixaban

https://doi.org/10.14233/ajchem.2025.32993

Leena N. Patil

Department of Chemistry, School of Science, Sandip University, Nashik-422213, India

https://orcid.org/0000-0003-3347-4897

Mubarak Ali R. Sayyed

Department of Chemistry, School of Science, Sandip University, Nashik-422213, India

https://orcid.org/0009-0002-3815-0111

Dilip R. Birari

Department of Process Research and Development, Megafine Pharma (P) Ltd., 201, Lakhmapure, Dindori, Nashik-422202, India

https://orcid.org/0009-0006-0152-7164

Prashant A. Patil

Department of Chemistry, School of Science, Sandip University, Nashik-422213, India; Department of Process Research and Development, Megafine Pharma (P) Ltd., 201, Lakhmapure, Dindori, Nashik-422202, India

https://orcid.org/0009-0001-2941-1941

Sandip Dhumal

Department of Chemistry, School of Science, Sandip University, Nashik-422213, India

https://orcid.org/0009-0004-7479-5886

Divyesh R. Joshi

Department of Process Research and Development, Megafine Pharma (P) Ltd., 201, Lakhmapure, Dindori, Nashik-422202, India

https://orcid.org/0009-0009-6769-7029

Corresponding Author(s) : Leena N. Patil

leena.patil@sandipuniversity.edu.in

Asian Journal of Chemistry, Vol. 37 No. 7 (2025): Vol 37 Issue 7, 2025
Article Published : 30 June 2025

Abstract

The objective of the present study to resolve the technical problem like long reaction time, low product yield for the synthetic method of Eliquis intermediate, (Z)-ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate and the inconsistency in the purity of product. Thus, a novel synthesis pathway for the Eliquis intermediate, (Z)-2-chloro-[(4-methoxyphenyl)hydrazono]ethyl acetate, which is a crucial precursor for apixaban is developed.

Keywords

Diazotization Japp-Klingemann Apixaban Hydrazono Anticoagulant Novel process

(1)

Patil, L. N.; Sayyed, M. A. R.; Birari, D. R.; Patil, P. A.; Dhumal, S.; Joshi, D. R. A Novel Synthetic Route of (Z)-Ethyl 2-Chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate: A Key Intermediate of Apixaban. ajc 2025, 37, 1707-1712.

Download Citation

References

C.J. Murray and A.D. Lopez, Science, 274, 740 (1996); https://doi.org/10.1126/science.274.5288.740
Y. Ji, Q. Liu, X. Liuai, J. Jiang, Y. Wang, C. Wang and K. Yuyan, An Anti-thrombotic Drugs Apixaban Preparation, CN Patent 201010277358 (2012).
B.D. Maxwell, S.B. Tran, S.-Y. Chen, D. Zhang, B.-C. Chen, H. Zhang and S.J. Bonacorsi Jr., J. Labelled Comp. Radiopharm., 54, 418 (2011); https://doi.org/10.1002/jlcr.1890
J.P.P. Donald, T. McHardy, M.G. Rowlands, L.-J.K. Hunter, T.G. Davies, V. Berdini, R.G. Boyle, G.W. Aherne, M.D. Garrett and I. Collins, J. Med. Chem., 50, 2289 (2007); https://doi.org/10.1021/jm0700924
J. Zhou, O.M. Lynette, M. Philip and L. Hui, Synthesis of 4,5-Dihydro-pyrazolo[3,4-c]pyrid-2-ones, WO Patent 2003/049681 (2003).
S. Rafael, T.R. Lucius, M.M. Boguslaw, C. Nicolas, O. Matthew and Z. Huiping and C. Bang, Process for Preparing 4,5-Dihydropyrazolo[3, 4-c]pyrid-2-ones, US Patent 7,396,932 (2008).
J. Jiang and Y. Ji, Syn Commun., 43, 72 (2013); https://doi.org/10.1080/00397911.2011.591956
Y. Ji, Q. Liu, X. Liuai, J. Jiang, Y. Wang, C. Wang and K. Yuyan, Method for Preparing Antithrombotic Medicament Apixaban, CN Patent 201010277358 (2012).
S.W. Huo, K.Y. Guo and J. Zhong, Preparation Method of Apixaban Intermediates, CN Patent 201210305258 (2014).
F. Guo and X. Renli, A Method of Preparing Intermediates of Apixaban, CN Patent 201410113371 (2014).
S.D. Dwivedi, K.K. Singh, N. Tandon and D. Ware, An Improved Process for the Preparation of Apixaban and Intermediates thereof, WO Patent 2014/203275 (2014).
G. Thomas, G. Manouchehr and M. Shahbaz, US Patent 20100130543 (2009).
Y. Ji, J. Jiang, Q. Liu, Y. Yu, C. Wang, A. Liu and Y. Wang, Method for Preparing Antithrombotic Medicament Apixaban, CN 101967145 (2010).
S.S. Kumar, V. Sadasivan, S.S. Meena, R.S. Sreepriya and S. Biju, Inorg. Chim. Acta, 536, 120919 (2022); https://doi.org/10.1016/j.ica.2022.120919

References

C.J. Murray and A.D. Lopez, Science, 274, 740 (1996); https://doi.org/10.1126/science.274.5288.740

Y. Ji, Q. Liu, X. Liuai, J. Jiang, Y. Wang, C. Wang and K. Yuyan, An Anti-thrombotic Drugs Apixaban Preparation, CN Patent 201010277358 (2012).

B.D. Maxwell, S.B. Tran, S.-Y. Chen, D. Zhang, B.-C. Chen, H. Zhang and S.J. Bonacorsi Jr., J. Labelled Comp. Radiopharm., 54, 418 (2011); https://doi.org/10.1002/jlcr.1890

J.P.P. Donald, T. McHardy, M.G. Rowlands, L.-J.K. Hunter, T.G. Davies, V. Berdini, R.G. Boyle, G.W. Aherne, M.D. Garrett and I. Collins, J. Med. Chem., 50, 2289 (2007); https://doi.org/10.1021/jm0700924

J. Zhou, O.M. Lynette, M. Philip and L. Hui, Synthesis of 4,5-Dihydro-pyrazolo[3,4-c]pyrid-2-ones, WO Patent 2003/049681 (2003).

S. Rafael, T.R. Lucius, M.M. Boguslaw, C. Nicolas, O. Matthew and Z. Huiping and C. Bang, Process for Preparing 4,5-Dihydropyrazolo[3, 4-c]pyrid-2-ones, US Patent 7,396,932 (2008).

J. Jiang and Y. Ji, Syn Commun., 43, 72 (2013); https://doi.org/10.1080/00397911.2011.591956

Y. Ji, Q. Liu, X. Liuai, J. Jiang, Y. Wang, C. Wang and K. Yuyan, Method for Preparing Antithrombotic Medicament Apixaban, CN Patent 201010277358 (2012).

S.W. Huo, K.Y. Guo and J. Zhong, Preparation Method of Apixaban Intermediates, CN Patent 201210305258 (2014).

F. Guo and X. Renli, A Method of Preparing Intermediates of Apixaban, CN Patent 201410113371 (2014).

S.D. Dwivedi, K.K. Singh, N. Tandon and D. Ware, An Improved Process for the Preparation of Apixaban and Intermediates thereof, WO Patent 2014/203275 (2014).

G. Thomas, G. Manouchehr and M. Shahbaz, US Patent 20100130543 (2009).

Y. Ji, J. Jiang, Q. Liu, Y. Yu, C. Wang, A. Liu and Y. Wang, Method for Preparing Antithrombotic Medicament Apixaban, CN 101967145 (2010).

S.S. Kumar, V. Sadasivan, S.S. Meena, R.S. Sreepriya and S. Biju, Inorg. Chim. Acta, 536, 120919 (2022); https://doi.org/10.1016/j.ica.2022.120919

Author biographies is not available.