Journal of the Korean Applied Science and Technology (한국응용과학기술학회지)

The Korean Society of Applied Science and Technology (한국응용과학기술학회)
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Synthesis of Azelastine.HCl from 4-Chlorophenyl Acetic Acid

4-염화페닐 아세트산을 이용한 염산 아젤라스틴의 합성

  • Ji, Hyun (Department of Engineering Chemistry, College of Engineering Chungbuk National University Chemistry) ;
  • Jeong, Noh-Hee (Department of Engineering Chemistry, College of Engineering Chungbuk National University Chemistry)
  • 지현 (충북대학교 공과대학 공업화학과) ;
  • 정노희 (충북대학교 공과대학 공업화학과)
  • Received : 2012.08.20
  • Accepted : 2012.09.25
  • Published : 2012.09.30
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Abstract

A kind of Antihistamines, Azelastine HCl which known as modern H1-blockers, was synthesized by four step process using phthalic anhydride, 4-chlorophenylacetic acid, hydrazine 2HCl. The first step was the reaction of removing carboxyl group and hydroxyl group and the second step was saponification of 3-(4-chlorobenzylidene)phthalide. The third step was the nucleophilic addition reactions of primary amines and the fourth step was addition reaction of N-methyl-1-aza-bicyclo[3,2,0]heptane to 4-(4-chlorobenzyl)-1-(2H)phthalazinone. As a result, product was analyzed by FT-IR and $^1H$-NMR and could be obtained with a yield of 80%.

본 연구에서는 H1-길항체로 알려진 항히스타민제의 일종인 염산 아젤라스틴을 합성하기 위하여 phthalic anhydride, 4-chlorophenylacetic acid, hydrazine 2HCl를 이용하여 4단계 반응을 거쳐 합성하였다. 첫 번째 반응은 카르복실기와 히드록실기가 제거되는 반응이고, 두 번째 반응은 3-(4-chlorobenzylidene)phthalide의 비누화 반응이다. 세 번째 반응은 일차아민의 친핵성 첨가반응이 일어나는 반응이며, 네 번째 반응은 N-methyl-1-aza-bicyclo[3,2,0]heptane에 세 번째 반응의 생성물을 첨가하여 반응시키면 4-(4-chlorobenzyl)-1-(2H)phthalazinone가 합성되는 반응이다. 합성한 생성물을 FT-IR, $^1H$-NMR을 이용하여 분석하였고, 80%의 수율로 합성물을 얻었다.

Keywords

References

  1. S. L. Spector, "Definition of Asthma", ATS News 8, 5 (1982).
  2. P. J. Barnes, "New Concepts in the Pathogenesis of Bronchial Asthma", J ournal of Allergy Clin Immunol, 83, 1013 (1989).
  3. A. K. Abbas, Lichtman AH and Pober JS, "Immunemediated Tissue Injury and Disease,Cellular and Molecular Immunology", 3rd ed. W.B. Saunder Company, Philadelphia, (1997).
  4. P. Rafferty, P. J. Harrison, R. Aurich and S. T. Holgate, "H1 Histamine Receptor Antagonist in Human Airways and Skin", Journal of Allergy Clin Immunol, 82, 1113 (1988).
  5. W. Diamantis, J. E. Harrison, J. Melton, J. L. Perhach and R. D. Sofia, "In Vivo and in Vitro H1 Antagonist Properties of Azelastine", Pharmacologist, 23, 149 (1981).
  6. W. Diamantis, N. Chand, J. E. Harrison, J. L. Pillar, J. L. Perhach and R. D. Sofia, "Inhibition of Release of SRS-A and Its Antagonism by Azelastine", Pharmacologist, 24, 200 (1982).
  7. D. G. Tinkelman, G. A. Bucholtz, J. P. Kemp , J. W. Koepke, L. W. Respher, S. L. Spector and W. W. Storms, "Evaluation of the Safety and Efficacy of Multiple Oses of Azelastine to Adult Patients with Bronchial Asthma Over Time", Am Rev Respir Dis 141, 569 (1990).
  8. John McMurry, Organic Chemistry, 7th ed., Cengage Learning (1997).
  9. American Psychiatric Association, "Diagnostic and Statistical Manual of Mental Disorders", 4th ed., Washington DC, American Psychiatric Association (1994).
  10. K. Tasaka, Epinastine, "An Update of Its Pharmacology, Metabolism, Clinical Efficacy and Tolerability in the Treatment of Allergic Diseases", Drugs Today, 36, 735 (2000).
  11. Pavia, L. Donald, "Introduction to Spectroscopy", 3rd ed., Brookscole, Stanford, U. S. A, (2007).
  12. Anton. Ter Laak, G. Donne-Op den kelder, A. Bast, H. Timmerman, "Is There a Difference in the Affinity of Histamine H1 Receptor Antagonists for CNS and Peripheral Receptors?", European Journal of Pharmacology, 232, 199 (1993).
  13. J. Weiler, E. Meltzer, P. Benson, K. Weiler, M.Widlitz, J. Freitag, "A Dose-ranging Study of the Efficacy and Safety of Azelastine Nasal Spray in Treatment of Seasonal Allergic Rhinitis with an Acute Model", Journal of Allergy and Clinical Immunology, 94, 972 (1994).
  14. H. Helpup, G. Scheffler, N. Brock, "Basically substituted Benzylphthalazone Derivatives", United States Patent Office, 218532, 3813384 (1974).
  15. I. Richards, L. Miller, D. Solomon, A. Kulkarni, S. Brooks, N. Sperelakis, "Azelastine and Desmethylazelastine Suppress Acetylcholine-induced Contraction and Depolarization in Human Airway Smooth Muscle", European Journal of Pharmacology, 186, 331 (1990).