CC BY-NC-ND 4.0 · SynOpen 2020; 04(03): 62-65
DOI: 10.1055/s-0040-1707267
paper

Expedient Approach to the Synthesis of Betrixaban

a  Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, India
b  Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India
,
Sudam N. Sinare
b  Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India
› Author Affiliations
C.R.R. is grateful to the Council of Scientific and Industrial Research (CSIR), New Delhi for financial support as part of mission mode project (INPROTICS; HCP 011).


Abstract

A new scalable route to synthesize the factor Xa (FXa) inhibitor betrixaban is disclosed. The product is obtained in a seven-step reaction sequence (in five stages using two one-pot reactions) starting from easily accessible 4-(N,N-dimethylcarbamimidoyl)benzoate. Effective isolation of intermediates, use of cost-effective amide formation and 2-methyltetrahydrofuran as an effective reaction solvent as well as for extraction in three of the stages, are key features. The strategy provides the desired product in 38% overall yield with high purity (>98%).

Supporting Information



Publication History

Received: 29 July 2020

Accepted after revision: 17 August 2020

Publication Date:
04 September 2020 (online)

© 2020. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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  • References

  • 1 Eriksson BI, Quinlan DJ, Weitz JI. Clin. Pharmacokinet. 2009; 48: 1
  • 2 Turpie AG. G, Bauce KA, Davidson BL, Fisher WD, Gent M, Huo MH, Sinha U, Gretler DD. Thromb. Haemost. 2009; 101: 68
  • 3 Palladino M, Merli G, Thomson L. Expert Opin. Invest. Drugs 2013; 22: 1465
  • 4 Zhang P, Huang W, Wang L, Bao L, Jia ZJ, Bauer SM, Goldman EA, Probst GD, Song Y, Su T, Fan J, Wu Y, Li W, Woolfrey J, Sinha U, Wong PW, Edwards ST, Arfsten AE, Clizbe LA, Kanter J, Pandey A, Park G, Hutchaleelaha A, Lambing JL, Hollenbach SJ, Scarborough RM, Zhu B.-Y. Bioorg. Med. Chem. Lett. 2009; 19: 2179
  • 5 Huisman MV, Klok FA. Eur. Heart J. Suppl. 2018; 20: E12
  • 6 Kanter JP, Suizno K, Zuberi SS. PCT Int. Appl. WO2008057972, 2008
  • 7 Pandey A, Leitao EP. T, Rato J, Song ZJ. PCT application WO 2011084519, 2011
  • 8 Li J, Chen L, Yan X, Li Y, Wei D, Wang D. J. Chem. Res. 2015; 39: 524
  • 9 Pinto DJ, Qiao JX, Gangor T, Lam PY. S, Li Y.-L. PCT Int. Appl. WO2004083174, 2004 ; A2 20040930, 2004
  • 10 Bailey C, Baker E, Hayler J, Kane P. Tetrahedron Lett. 1999; 40: 4847
  • 11 Chen H, Xu X, Liu L, Tang G, Zhao Y. RSC Adv. 2013; 3: 16247
  • 12 Errede LA, McBrady JJ. J. Org. Chem. 1977; 42: 3863
    • 13a Li J, Mi Y, He J, Luo X, Fan E. J. Heterocycl. Chem. 2013; 50: 304
    • 13b Javorskis T, Orentas E. J. Org. Chem. 2017; 82: 13423