A Novel Synthesis of Macitentan
263
Compound 7 (59.2 g, 0.27mol) was added to the mixture in portions. The temperature
was increased to 65ꢀC and stirred for 8 h. The reaction mixture was cooled to 20ꢀC, and
then water (2 L) was added. The pH was adjusted to 6.5 with 6 N HCl, then the resulting
precipitate was filtered and washed with water. The crude product was recrystallized
from methanol (700 ml) to provide macitentan (5) (120 g, 83%) as a white solid, mp
134ꢀC–135ꢀC. IR (KBr): 3285 (-NH stretching), 2360 (C D N stretching), 1571, 1385.
1H NMR (500 MHz, CDCl3): d 0.89–0.91 (t, JD7.4, Me), 1.50–1.58 (m, CH2), 2.90–2.94
(m, CH2), 4.58–4.59 (m, CH2), 4.67–4.69 (m, CH2), 5.67–5.69 (t, JD6.1, NH), 7.07 (s,
NH), 7.12–7.13 (d, 2 H, ArH), 7.49–7.51(d, 2 H, ArH), 8.41(s, 1 H, ArH), 8.43 (s, 2 H,
ArH). 13C NMR (125 MHz, CDCl3): d 11.65, 22.73, 46.09, 65.37, 66.03, 104.95, 112.55,
123.69, 128.42, 131.99, 133.05, 156.11, 156.79, 159.96, 163.80, 166.57.
Anal. Calcd. for C19H20Br2N6O4S: C, 38.79, H, 3.43; N, 14.29; Found: C, 38.60; H,
3.51; N, 14.31.
Acknowledgment
The authors wish to thank the financial support provided by Shahid Beheshti University
Research Council.
References
1. A. Khadka, D. B. Singh Brashier, A. Tejus and A. K. Sharma, J. Pharmacol. Pharmacother, 6,
53 (2015).
ꢀ
2. M. Humbert, R. Souza, N. Galie. V. McLaughlin, G. Simonneau and L. Rubin, Eur. Respir.
Rev., 21, 267 (2012).
3. J. Dupuis and M. M. Hoeper, Eur. Respir. J., 31, 407 (2008).
4. D. B. Badesch, H. C. Champion, M. A. Sanchez, M. M. Hoeper, J. E. Loyd, A. Manes, M. McGoon,
R. Naeije, H. Olschewski, R. J. Oudiz and A. Torbicki, J. Am. Coll. Cardiol., 54, 55 (2009).
5. O. Sitbon and N. Morrell, Eur. Respir. Rev., 21, 321 (2012).
6. R. J. Barst, M. McGoon, A. Torbicki, O. Sitbon, M. J. Krowka, H. Olschewski and S. Gaine, J.
Am. Coll. Cardiol., 43, 40 (2004).
7. T. D. Nauser and S. W. Stites, Am. Fam. Physician., 63, 1789 (2001).
8. L. J. Rubin, D. B. Badesch, R. J. Barst, N. Galie, C. M. Black, A. Keogh, T. Pulido, A. Frost, S.
Roux, I. Leconte, M. Landzberg and G. Simonneau, N. Engl. J. Med., 346, 896 (2002).
9. P. J. Harrington, H. N. Khatri, B. S. Dehoff, M. R. Guinn, M. A. Boehler and K. A. Glaser, Org.
Process Res. Dev., 6, 120 (2002).
10. E.-I. Lepist, H. Gillies, W. Smith, J. Hao, C. Hubert, R. L. St. Claire III, K. R. Brouwer and A.
S. Ray, PLoS One, 9, 87548 (2014).
ꢁ
11. N. Galie, D. Badesch, R. Oudiz, G. Simonneau, M. D. McGoon, A. M. Keogh, A. E. Frost, D.
Zwicke, R. Naeije, S.y Shapiro, H. Olschewski and L. J. Rubin, J. Am. Coll. Cardiol., 46, 529
(2005).
12. J. E. Frampton, Am. J. Cardiovasc. Drugs., 11, 215 (2011).
13. J. Xia, J. Song, L. Zhen, X. Zhang, X. Lei, L. Zheng, Q. Wang and H. Sun, Bioorg. Med. Chem.
Lett., 21, 3894 (2011).