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Synthesis of 6,7-dimethoxy-3,4-diphenyl-2(1H)-quinazolinone from 1-(3,4-dimethoxyphenyl)-urea and benzoic acid in polyphosphoric acid

Department of Organic Chemistry, Faculty of Chemistry, Plovdiv University, 24 Tsar Assen str., Plovdiv, BG-4000, Bulgaria
Molbank 2006, 2006(5), M492; https://doi.org/10.3390/M492
Submission received: 21 April 2006 / Accepted: 1 May 2006 / Published: 1 September 2006
The quinazoline skeleton, when selectively functionalized, is a building block for the preparation of numerous alkaloids and substances capable of exhibiting a wide variety of biological activity [1]. The quinazolinones were investigated in several research laboratories, as potent antagonists of platelet activating factor [2]. They were also used as alpha-1-adrenergic receptor antagonists [3] and as agonists on human ORL1 (nociceptin) receptor [4]. There have been few reports about the synthesis of quinazolinones. R. Conley et al. [5] were used direct metalation starting with 3,4-dimethoxyanilin with n-butillithium, then treating with potassium cyanate and followed cyclization in PPA [5,6]. Recently, J. Vicente et al. reports the first ortho-palladated arylurea complexes, obtained by oxidative addition reactions, and has studied their reactivity toward different reagents to prepare quinazolinone derivatives [7]. The Friedel-Crafts acylation of activated benzene rings in the presence of polyphosphoric acid is a very convenient method for direct synthesis of aromatic ketones [8]. The newly synthesized compound 6,7-dimethoxy-3,4-diphenyl-2(1H)-quinazolinone was obtained from 1-(3,4-dimethoxy-phenyl)-3-phenyl-urea.
Molbank 2006 m492 i001
1-(3,4-dimethoxyphenyl)-3-phenylurea (1) (0.544 g, 2 mmol) and benzoic acid (2) (0.366 g, 3 mmol) were dissolved in CH2Cl2 (3-5 mL) in an open flask and polyphosphoric acid (10 g) was added. The mixture was stirred at 80°C for 6 h, then poured on crushed ice. The solution was alkalized with 25% ammonia, then extracted with CH2Cl2 (3 x 20 mL) and the combined extracts were dried (Na2SO4) and concentrated. To crude product 6,7-dimethoxy-3,4-diphenyl-3H-quinazolinone 3 in 15 mL methanol, NaBH4 (4 mmol, 0,18 g) was added portionwise. The solution was stirred 30 min at room temperature, than the solvent was removed under vacuum. Water (30 mL) was added to the residue and the solution was extracted with CH2Cl2 (3 x 20 mL), then the combined extracts were dried (Na2SO4) and filtered. The products were filtered through a short column with neutral Al2O3 and then were purified by recrystallization from ether or n-hexane/ether=1:1 (yield 59%).
Melting Point: 210-211°C
IR (KBr, cm-1): n 3334(NH); n 1674(CO).
1H-NMR (CDCl3, 250 MHz): δ= 3.73 (3H, s, OCH3), 3.75 (3H, s, OCH3), 5.71 (1H, s, C-4), 6.38-7.28 (12H, m, Ar), 8.87 (1H, s, NH).
13C-NMR (CDCl3, 67.5 MHz): δ= 55.9, 56.4, 66.9, 98.8, 109.6, 113.1, 126.6, 126.7, 127.4, 127.9, 128.8, 129.5, 141.5, 142.2, 144.5, 149.3, 154.0.
Elemental Analysis: Calculated for C22H20N2O3: C 73.32, H 5.59, N 7.77. Found: C 73.45, H 5.71, N 7.90.

Supplementary materials

Supplementary File 1Supplementary File 2Supplementary File 3

Acknowledgment

The author acknowledges financial support from the Fund for scientific research of the Plovdiv University.

References

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  2. Walser, A.; Flynn, T.; Mason, C.; Crowley, H.; Maresca, C.; Yaremko, B.; O’Donnell, M. J. Med. Chem. 1991, 34, 1209–1221. [CrossRef] [PubMed]
  3. Chin, E.; Cournoyer, R.; Keitz, P.; Lee, E.; Lopez-Tapia, F.; Melville, C.; Padilla, F.; Weinhardt, K. Patent 2005. Connolly, T.; Keitz, P.; Lee, E.; Li, J.; Lopez-Tapia, F.; McGrarry, P.; Melville, C.; Nitzan, D.; O'Yang, C.; Padilla, F.; Weinhardt, K. Patent 2005.
  4. Den Hartog, J.; David, S.; Jasserand, D.; Van Scharrenburg, G.; Van Stuivenberg, H.; Tuinstra, T. Patent 2005.
  5. Conley, R.; Barton, D.; Stefanick, S.; Lam, M.; Lindabery, G.; Kasulanis, C.; Cesco-Cancian, S.; Currey, S.; Fabian, A.; Levine, S. J. Heterocycl.Chem. 1995, 32, 761–770. [CrossRef]
  6. Bandurco, V.; Schwender, C.; Bell, S.; Combs, D.; Kanojia, R.; Levine, S.; Mulvey, D.; Appollina, M.; Reed, M.; Malloy, E.; Falotico, R.; Moore, J.; Tobia, A. J. Med. Chem. 1987, 30, 1421–1426. [CrossRef] [PubMed]
  7. Vicente, J.; Abad, J.A.; López-Serrano, J.; Jones, P.; Nájera, C.; Botella-Segura, L. Organometallics 2005, 24, 5044–5057. [CrossRef]
  8. Schellhammer, W. ‘Methoden der Organischen Chemie’; Vol. 7/2a, ed.; Műller, E., Ed.; Houben-Weyl Thieme: Stuttgar, 1973; p. 281. [Google Scholar] Staskun, B. J. Org.Chem. 1964, 29, 2856–2860. Venkov, A.; Ivanov, I. Tetrahedron 1996, 52, 12299–12308. Laudien, R.; Mitzner, R. J. Chem. Soc.; Perkin Trans. 2 2001, 2226–2229.

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MDPI and ACS Style

Ivanov, I. Synthesis of 6,7-dimethoxy-3,4-diphenyl-2(1H)-quinazolinone from 1-(3,4-dimethoxyphenyl)-urea and benzoic acid in polyphosphoric acid. Molbank 2006, 2006, M492. https://doi.org/10.3390/M492

AMA Style

Ivanov I. Synthesis of 6,7-dimethoxy-3,4-diphenyl-2(1H)-quinazolinone from 1-(3,4-dimethoxyphenyl)-urea and benzoic acid in polyphosphoric acid. Molbank. 2006; 2006(5):M492. https://doi.org/10.3390/M492

Chicago/Turabian Style

Ivanov, Iliyan. 2006. "Synthesis of 6,7-dimethoxy-3,4-diphenyl-2(1H)-quinazolinone from 1-(3,4-dimethoxyphenyl)-urea and benzoic acid in polyphosphoric acid" Molbank 2006, no. 5: M492. https://doi.org/10.3390/M492

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