Molbank 2006

Molbank 2006, M492

http://www.mdpi.org/molbank/

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

Iliyan Ivanov

Department of Organic Chemistry, Faculty of Chemistry, Plovdiv University,

24 Tsar Assen str., Plovdiv, BG-4000, Bulgaria

Tel: +359 (32) 261 349, Fax: +359 (32) 628 392, e-mail: [email protected]

Received: 21 April 2006 / Accepted: 1 May 2006 / Published: 1 September 2006

Keywords: quinazolinone, polyphosphoric acid (PPA), urea.

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.

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.

Acknowledgment

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

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