Warfarin – its synthesis and properties in a twenty-year retrospective*

Česká verzia

Authors: Eva Milatová; Viktor Milata
Authors place of work: Slovenská technická univerzita ; Limbová 5, 833 05 Bratislava, Slovenská republika ; Oddelenie organickej chémie, Ústav organickej chémie, katalýzy a petrochémie, Fakulta chemickej a potravinárskej technológie ; I. Interná klinika SZÚ
Published in the journal: Čes. slov. Farm., 2013; 62, 111-119
Category: Přehledy a odborná sdělení

*Táto práca je venovaná prof. RNDr. Jozefovi Čižmárikovi, PhD. pri príležitosti jeho životného jubilea.

Summary

The review paper deals with some aspects of warfarin history and its use, at the beginning as a rodenticide and later as an anticoagulant. It describes its principal physical-chemical properties and it analyzes schematically the possibilities of its preparation by both selective and non-selective synthesis from coumarin derivatives. A survey of syntheses and its results are tabulated, including the literary references, and the paper is concluded with an evaluation of the prospects of this agent in comparison with alternative anticoagulants and its advantages, disadvantages and prospects.

Keywords:
warfarin • anticoagulants • coumarins • review of syntheses

Zdroje

1. Mazúch J., Čalkovská A., Dobrotová M., Kubisz P., Lindner J., Mištuna D., Mayzlík J., Musil D., Pullmann R., Radoňák J., Staško J., Tatár M. Tromboembolická choroba venózneho pôvodu. Martin: Osveta 2008.

2. Bátorová A. Nové antikoagulanciá- súčasnosť a perspektívy ďalšieho rozvoja. Kardiol prax 2008; 6, 45–50.

3. Bátorová A. Profylaxia a liečba venózneho tromboembolizmu. Abstrakty. Satelitné sympózium. Ortopedický kongres s medzinárodnou účasťou. Bratislava 2009; 1.

4. Guyatt G. H., Akl E. A., Crowther M., Gutterman H. J. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: american college of chest physicians evidence-based clinical practice guidelines. Chest 2012; 141, 7S–47S.

5. Tomek A., Maťoška V., Kumstýřová T., Táborský L. Využití farmakogenetiky při léčbě warfarinem. Vnitř Lék 2009; 55, 565–569.

6. Lukl J., Bulava A., Benešová M., Neužil P., Černý Š. Fibrilace síní. Praha: Grada Publishing 2009.

7. Stahmann M. A., Ikawa M., Link K. P. 3-substituted 4-hydroxycoumarin and process of making it. U.S. 2427578, 1947 pre Wisconsin Alumni Research Found.

8. Wardrop D., Keeling D. The Story of the discovery of heparin and warfarin. British J. Haematology 2008; 141, 757-776, DOI:10.1111/j.1365-2141.2008.07119.x3.

9. Bravic G., Gaultier J., Hauw C. Structure cristalline d´une antivitamine K: la warfarine. Comptes Rendus des Seances de l’Academie des Sciences, Serie C: Sciences Chimiques, 1973; 277, 1215–1218.

10. Dentali F., Donadini M. P., Nathan C., Clark N., Crowther M. A., Garcia D., Hylek E., Witt D. M., Ageno W. Warfarin Associated Research Projects and Other Endeavors (WARPED) Consortium. Brand name versus generic warfarin: a systematic review of the literature. Pharmacotherapy 2011; 31, 386–393.

11. West B. D., Preis S., Schroeder C. H., Link K. P. Studies on the 4-Hydroxycoumarins. XVII. The resolution and absolute configuration of warfarin. J. Am. Chem. Soc. 1961; 83, 2676–2679.

12. Valente E. J., Lingafelter E. C., Porter W. R., Trager W. F. Structure of warfarin in solution. J. Med. Chem. 1977; 20, 1489–1493.

13. Ring P. R., Bostick J. M. Validation of a method for the determination of (R)-warfarin and (S)-warfarin in human plasma using LC with UV detection. J. Pharm. Biomed. Anal. 2000; 22, 573–581.

14. Sato Y., Suzuki Y. Optical resolution of drugs by cyclodextrin complexation. Chem. Pharm. Bull. 1985; 33, 4606–4609.

15. Varga G., Tarkanyi G., Nemeth K., Ivanyi R., Jicsinszky L., Toke O., Visy J., Szente L., Szeman J., Simoni M. Chiral separation by a monofunctionalized cyclodextrin derivative: From selector to permethyl-ββ-cyclodextrin bonded stationary phase. J. Pharm. Biomed. Anal. 2010; 51(1), 84–89.

16. Zhao M. G., Hao A. Y., Li J., Lin X.-L. ββ-cyclodextrin with low degree of 6-O-(Hydroxypropyltrimethylammonia)-substitution: convenient preparation and its application as a chiral selector in capillary electrophoresis. Chin. Chem. Lett. 2006; 17, 407–410.

17. Erlandsson P., Marle I., Hansson L., Isaksson R., Pettersson G., Pettersson C. immobilized cellulase (CBH I) as a chiral stationary phase for direct resolution direct resolution of enantiomers. J. Am. Chem. Soc. 1990; 112, 4573–4574.

18. Hagan E. C., Radomski J. L. The toxicity of 3-(acetonyl benzyl)-4-hydroxycoumarin (warfarin) to laboratory animals. J. Am. Pharm. Assoc. Sci. Ed. 1953; 42, 379–382.

19. Back N., Steger R., Glassman J. M. Comparative acute oral toxicity of sodium warfarin and microcrystalline warfarin in the Sprague-Dawley rat. Pharmacol. Res. Commun. 1978; 10, 445–452.

20. Bell R. G., Sadowski J. A., Matschiner J. T. Mechanism of action of warfarin. Warfarin and antimetabolite of vitamine K1. Biochemistry 1972; 11, 1959–1966.

21. Thijssen H. H. W. Warfarin-based rodenticides: mode of action and mechanism of resistance. Pestic. Sci. 1975; 43, 73–78.

22. Lewis R. J., Tragger W. F. The metabolic fate of warfarin: studies on the metabolites in plasma. Ann. N.Y. Acad. Sci. 1971; 179, 205–212.

23. Zacharski L. R., Henderson W. G., Rickles F. R., Forman W. B., Cornell C. J. Jr., Forcier R. J., Edwards R. L., Headley E., Kim S.-H., O’Donnell J. F., O’Dell R., Tornyos K., Kwaan H. C. Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate. Final report of VA Cooperative Study #75. Cancer 1984; 53, 2046-2052. DOI: 10.1002/1097-0142(19840515).

24. Neulauer B. L., Bemis K. G., Best K. L., Goode R. L., Hoover D. M., Smith G. F., Tanzer L. R., Merriman R. L. Inhibitory effect of warfarin on the metastasis of the PAIII prostatic adenocarcinoma in the rat. J. Urol. 1986; 135, 163–166.

25. Babhair S. A., Tariq M., Al-Badr A. A. Warfarin. In: Analytical profiles of drug substances. Ed. Florey K. New York: Academic Press 1985; 14, 423–452.

26. Hirsh J., Dalen J. E., Deykin D., Poller L. Oral anticoagulants. Mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 1992; 102(4 Suppl), 312–326.

27. Takahashi H., Echizen H. Pharmacogenetics of warfarin elimination and its clinical implications. Clin. Pharmacokinet. 2001; 40, 587–603.

28. Hurlen M., Abdelnoor M., Smith P., Erikssen J., Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N. Engl. J. Med. 2002; 347, 969–974.

29. Cook C. E., Ray Tallent C., Ballentine N. H., Taylor G. F., Kepler J. A. Synthesis of High Specific Activity R- and S-Warfarin – 3H. J. Label. Compd. Radiopharm. 1981; XVI, 623–631.

30. Savell Jr. V. H., Valente E. J., Eggleston D.S. Synthesis of 13C warfarin labelled at the hemiketal carbon, and its resolution. J. Label. Compd. Radiopharm. 1989; XXVII (6), 641–645.

31. Jung J.-C., Park O.-S. Synthetic approaches and biological activities of 4-hydroxycoumarin derivatives. Molecules 2009; 14, 4790-4803. DOI:10.3390/molecules14114790.

32. Peltier-Pain P., Timmons S. C., Grandemange A., Benoit E., Thorson J. S. Warfarin Glycosylation invokes a switch from anticoagulant to anticancer activity. ChemMedChem 2011; 6, 1347–1350. DOI: 10.1002/cmdc.201100178.

33. Shen D.-S., Liu X.-F., Yang G.-Z. Synthesis of coumarin anticoagulant and its analogues. Yingyong Huaxue 2005; 22, 1158–1160. DOI10.3969/j.issn.1000-0518.2005.10.027.

34. Cravotto G., Nano G. M., Palmisano G., Tagliapietra S. An asymmetric approach to coumarin anticoagulants via hetero-diels-alder cycloaddition. Tetrahedron Asymmetry 2001; 12, 707–709.

35. Peltier-Pain P., Timmons S. C., Grandemange A., Benoit E., Thorson J. S. Warfarin Glycosylation invokes a switch from anticoagulant to anticancer activity. ChemMedChem 2011; 6, 1347–1350. DOI: 10.1002/cmdc.201100178.

36. Bercovici S., Evron Y., Fuxman O., Jakoel M., Sasson S., Ulanenko K. Process for Synthesis of Pure Warfarin Acid, Warfarin Alkali Metal Salts and Corresponding Clathrates.U. S. Pat. Appl. 20020120155, 29. 8. 2002.

37. Lee D.-H., Kwon K.-H., Yi C. S. Dehydrative C−H alkylation and alkenylation of phenols with alcohols: expedient synthesis for substituted phenols and benzofurans. J. Am. Chem. Soc. 2012; 134, 7325–7328.

38. Reisch J. Die darstellung von antikoagulantien vom typ des warfarin® durch kondensation von alkinolen mit 4-hydroxycumarin. Arch. Pharm. Ber. Deutsch. Pharm. Ges. 1966; 299, 806–808.

39. Liu Y., Liu X., Wang M., He P., Lin L., Feng X. Enantioselective synthesis of 3,4-dihydropyran derivatives via organocatalytic michael reaction of αβ-unsaturated enones. J. Org. Chem. 2012; 77, 4136–4142.

40. Ma S., Wu L., Liu M., Wang Y. C2-symmetric proline-derived tetraamine as highly effective catalyst for direct asymmetric Michael addition of ketones to chalcones. Org. Biomol. Chem. 2012; 10, 3721–3729. DOI: 10.1039/c2ob06897d.

41. Lim Y. J., Kim D. Y. Enantioselective Conjugate Addition of 4-Hydroxycoumarin to Enones Catalyzed by Binaphthyl-Modified Primary Amine Organocatalyst. Bull. Korean Chem. Soc. 2012; 33, 1825–1826.

42. Rogozinska M., Adamkiewicz A., Mlynarski J. Efficient “on water” organocatalytic protocol for the synthesis of optically pure warfarin anticoagulant. Green Chem. 2011; 13, 1155–1157. DOI: 10.1039/c1gc15118e.

43. Xu L., Yang H., Jiang J., Lai G. Preparation method of chiral warfarin and chiral warfarin derivatives. Faming Zhuanli Shenqing, 102167689, 31. 8. 2011.

44. Xi Z., Lin A., Shi Y., Guo J., Zhu C., Cheng Y. Enantioselective synthesis of polycyclic coumarin derivatives catalyzed by an in situ formed primary amine-imine catalyst. Org. Lett. 2011; 13, 4382–4385.

45. Mei R.-Q., Xu X.-Y., Li Y.-C., Fu J.-Y., Huang Q.-C., Wang L.-X. Highly effective and enantioselective Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones promoted by simple chiral primary amine thiourea bifunctional catalysts. Tetrahedron Lett. 2011; 52, 1566–1568.

46. Yang H.-M., Li L., Jiang K.-Z., Jiang J.-X., Lai G.-Q., Xu L.-W. Highly enantioselective synthesis of warfarin and its analogs by means of cooperative LiClO4/DPEN-catalyzed Michael reaction: enantioselectivity enhancement and mechanism. Tetrahedron 2010; 66 (51), 9708–9713.

47. Yang H.-M., Gao Y.H., Li L., Jiang Z.-Y., Lai G.-Q., Xia C.-G., Xu L.-W. Iron-catalyzed Michael reactions revisited: a synthetically useful process for the preparation of tri-carbonyl compounds and chiral warfarin. Tetrahedron 2010; 51, 3836–3839.

48. Dong Z., Wang L., Chen X., Liu X., Lin L., Feng X. Organocatalytic enantioselective michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones: A simple synthesis of warfarin. Eur. J. Org. Chem. 2009; 30, 5192–5197. DOI: 10.1002/ejoc.200900831.

49. Kristensen T. E., Vestli K., Hansen F. K., Hansen T. New phenylglycine-derived primary amine organocatalysts for the preparation of optically active warfarin. Eur. J. Org. Chem. 2009; 30, 5185–5191. DOI: 10.1002/ejoc.200900664.

50. Jadhav M. R., Shinde D. B. Indian Pat. Appl. 2007MU00052, 19. 9. 2008.

51. Jadhav M. R., Shinde D. B. Synthesis and biological activity of 4-hydroxy-3-(1,5-diaryl-3-oxo-pent-4-enyl)chromen-2-ones. Chin. J. Chem. 2010; 28, 555–560. DOI: 10.1002/cjoc.201090111

52. Kischel J., Michalik D., Zapf A., Beller M. FeCl3-catalyzed addition of 1,3-dicarbonyl compounds to aromatic olefins. Chem. Asian J. 2007; 2, 909–914. DOI: 10.1002/asia.200700055.

53. Xie J.-W., Yue L., Chen W., Du W., Zhu J., Deng J.-G., Chen Y.-C. Highly enantioselective michael addition of cyclic 1,3-dicarbonyl compounds to α,β-unsaturated ketones. org. lett. 2007; 9, 413–415.

54. Kim H., Yen C., Preston P., Chin J. Substrate-directed stereoselectivity in vicinal diamine-catalyzed synthesis of warfarin. Org. Lett. 2006; 8, 5239–5242.

55. Tsuchiya Y., Hamashima Y., Sodeoka M. A New Entry to Pd-H Chemistry: catalytic asymmetric conjugate reduction of enones with EtOH and a highly enantioselective synthesis of warfarin. Org. Lett. 2006; 8, 4851–4854.

56. Halland N., Hansen T., Jorgensen K. A. Organocatalytic asymmetric michael reaction of cyclic 1,3-dicarbonyl compounds and α,β-unsaturated ketones – a highly atom-economic catalytic one-step formation of optically active warfarin anticoagulant. Angew. Chem. Int. Ed. Eng. 2003; 42, 4955–4957.

57. Mashraqui S. H., Karnik M. A. New application of 1,4-dihydropyridine system: Michael reactions mediated by 1,4-dihydropyridine-enolate adduct in micellar medium. Chem. Lett. 2003, 32(11), 1064–1065.

58. Li H.-Y., Robinson A. J. A novel asymmetric synthesis of R- and S-warfarin and its analogs. PCT Int. Appl. WO 9703062, 30. 1. 1997.

59. Manolov I., Karaivanova M. Synthesis and antimetastatic properties of 4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-1-benzopyran-2-one (Warfarin). Farmatsiya (Sofia, Bulgaria) 1990; 40, 1–6.

60. I., Manolov I., Alexandrova L. New Efficient Catalyst in the Synthesis of Warfarin and Acenocoumarol. Arch. Pharm. 1990; 323, 521–522.

61. Garcia D., Libby E., Crowther M. A. The New Oral Anticoagulants. Blood 2010; 115, 15–20.

62. Weitz J. I., Hirsch J., Samama M. M. New Antithrombotic Drugs: American College of Chest Physicians Evidence – Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133, 234S–256S.

63. Connolly S. J., Ezekowitz M. D., Salim Y., Eikelboom J., Oldgren J., Parekh A., Pogue J., Reilly P. A., Themeles E., Varrone J., Wang S., Alings M., Xavier D., Zhu J., Diaz R., Lewis B. S., Darius H., Diener H.-C., Joyner C. D., Wallentin L., the RE-LY Steering Committee and Investigators: Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl. J. Med. 2009; 361, 1139–1151.

64. Patel M. R., Mahaffey K. W., Garg J., Pan G., Singer D. E., Hacke W., Breithardt G., Halperin J. L., Hankey G. J., Piccini J. P., Becker R. C., Nessel C. C., Paolini J. F., Berkowitz S. D., Fox K. A. A., Califf R. M., the ROCKET AF Steering Committee, for the ROCKET AF Investigators: Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N. Engl. J. Med. 2011; 365, 883S–891S.

65. Garcia D., Libby E., Crowther M. A. The new oral anticoagulants. Blood 2010; 115, 15–20.

66. http://www.theheart.org/article/1484969.do#bib_1