Improved synthesis of quinocetone and its two desoxymetabolites

J. Serb. Chem. Soc. 83 (3) 265–270 (2018) JSCS–5073 UDC 66.094.3:547.567.3+547.477.2+ 577.121:546.33’131 Short communication SHORT COMMUNICATION Improved synthesis of quinocetone and its two deoxy metabolites YUWEN LI, MEI QIU, YUBIN BAI, SHAOQI QU and ZHIHUI HAO* Agricultural Bio-pharmaceutical Laboratory, Qingdao Agricultural University, Qingdao 266109, China and National-Local Joint Engineering Laboratory of Agricultural Bio-pharmaceutical Technology, Qingdao 266109, China (Received 14 June, revised 9 November, accepted 13 November 2017) Abstract: Oxidation of o-nitroaniline with sodium hypochlorite afforded benzofurazan oxide in 96 % yield, and treatment of benzofurazan oxide with acetylacetone in the presence of triethylamine gave 2-acetyl-3-methyl-quinoxaline-1,4-dioxide in 94 % yield. Finally, condensation of 2-acetyl-3-methyl-quinoxaline-1,4-dioxide with benzaldehyde using 4-(dimethylamino)pyridinium acetate as a catalyst led to quinocetone in 95 % yield. Subsequently, reduction of the synthesized quinocetone with sodium dithionite resulted in two deoxy derivatives, 1-(3-methyl-4-oxido-2-quinoxalinyl)-3-phenyl-2-propen-1-one and 1-(3-methyl-2-quinoxalinyl)-3-phenyl-2-propen-1-one in 88.5 and 92 % yield, respectively. Furthermore, the synthesized quinocetone, and its deoxy derivatives were characterized by 1H-NMR, 13C-NMR and elemental analysis. Keywords: quinocetone; deoxy quinocetone; 4-(dimethylamino)pyridinum acetate; dideoxy quinocetone; synthesis. INTRODUCTION Chemically known as 1-(3-methyl-1,4-dioxide-2-quinoxalinyl)-3-phenyl-2-propen-1-one, quinocetone (QCT, Scheme 1) is a quinoxaline-1,4-N-dioxide, the family members of which are bioactive compounds displaying antibacterial, antiviral, and antifungal activities.1 QCT is widely used in veterinary medicine for swine, poultry, and aquatic animals due to its effectiveness and low toxicity. Two other family members, carbadox and olaquindox, were banned in 1999 due to their toxicity and food safety concerns.2 In addition, QCT is currently applied as an antibacterial feed additive and as a growth promoter.3 Thus, a facile and efficient synthesis of QCT would be agriculturally beneficial, particularly in livestock breeding and aquaculture industry. * Corresponding author. E-mail: https://doi.org/10.2298/JSC170614118L 265 Available on line at www.shd.org.rs/JSCS/ ________________________________________________________________________________________________________________________ (CC) 2018 SCS. 266 LI et al. Currently, there are several methods for the synthesis of QCT, but all are challenged by low yields, use of toxic reagents and unrecyclable catalysts, leading to environmental concerns.4,5 Previous studies revealed that QCT is metabolized in the liver and kidneys of pigs and at least 31 metabolites were identified in pig urine,6 including two deoxy metabolites 4 and 5 (Scheme 1). Research on the metabolites of a drug is beneficial to drug design and optimization, as well as guiding a reasonable clinical prescription, and hence, several syntheses of deoxy metabolites of quinocetone were developed.7,8 However, these methods are tedious due to the use of different starting materials, and other toxic and corrosive reagents. To obviate these drawbacks associated with the synthesis of quinocetone and its deoxy metabolites, an improved protocol for the chemical synthesis of quinocetone and its deoxy metabolites (Scheme 1) was developed in the present study. Scheme 1. Improved synthesis of quinocetone and its two deoxy metabolites. EXPERIMENTAL Chemicals 4-(Dimethylamino)pyridinium acetate was synthesized according to a published procedure.9 A sodium hypochlorite solution was freshly prepared prior to use according to a literature procedure.10 Other chemicals of analytical reagent grade were purchased from commercial sources and used without further purification. Apparatus Melting points were determined on a digital melting point apparatus (WRS-1B) without correction. 1H-NMR and 13C-NMR spectra were recorded in CDCl3 solvent on a Bruker Avance III400 spectrometer, operating at 400 and 500 MHz for protons and 100 and 125 MHz for carbons. The chemical shift values are expressed in δ values relative to the internal standard tetramethylsilane. Elemental analysis was realised using an Elementar Vario EL III analyzer (Hanau, Germany). Available on line at www.shd.org.rs/JSCS/ ________________________________________________________________________________________________________________________ (CC) 2018 SCS. SYNTHESIS OF QUINOCETONE AND DEOXY METABOLITES 267 Synthesis of benzofurazan oxide (1) A mixture of sodium hydroxide (25 g, 0.625 mol) and water 100 mL was stirred until the solid had dissolved. The solution was cooled to 0 °C, and 50 g of crushed ice was added. The flask was then placed in an ice bath, and chlorine gas from a tank was bubbled through the solution until 0.29 mol chlorine had been absorbed. The solution of sodium hypochlorite was stored in the dark at 0 °C prior to use. A mixture of potassium hydroxide (8.96 g, 0.160 mol) and 95 % ethanol (125 mL) was heated at 80 °C on an oil bath to obtain a clear alkali solution. To the warm alkali solution, o-nitroaniline (20.0 g, 0.145 mol) was added to obtain a deep red solution. The deep red solution was then cooled to 0 °C, and a freshly prepared sodium hypochlorite solution was added slowly under good stirring within 10 min. The flocculent yellow precipitate was collected by filtration on a Büchner funnel, and the cake was washed with 100 mL water and air-dried. Recrystallization of the crude product from 95 % ethanol gave benzofurazan oxide (1). Yield: 20.9 g (96 %); m.p.: 72.2–73.0 °C (lit:10 72–73 °C). Synthesis of 2-acetyl-3-methyl-quinoxaline 1,4-dioxide (2) A mixture of benzofurazan oxide 1 (10.2 g, 0.075 mol) and acetylacetone (12 g, 0.12 mol) in 25 mL ethanol was stirred at 45 °C, then triethylamine (4.55 g, 0.045 mol) was added to the solution and the mixture stirred for 2 h at 45 °C. On cooling, a yellow precipitate formed, which was collected by filtration, washed with 10 mL 95 % ethanol and air-dried. Recrystallization of the yellow precipitate from 95 % ethanol afforded compound 2. Yield: 15.38 g (94 %); m.p.: 154.2–154.8 °C (lit:4 153–154 °C). Synthesis of 1-(3-methyl-1,4-dioxide-2-quinoxalinyl)-3-phenyl-2-propen-1-one (3) A mixture of 2-acetyl-3-methyl-quinoxaline 1,4-dioxide (2) (8.09 g, 0.040 mol) and benzaldehyde (6.37 g, 0.060 mol) in 50 mL ethanol was heated at 70 °C for 30 min to obtain a clear solution, and then 4-(dimethylamino)pyridinium acetate (0.364 g, 2.0 mmol), readily prepared according to literature,9 was added to the solution. The solution was then stirred at 70 °C for 3 h. On cooling the solution to 0 °C, yellow crystals precipitated within 3 h. The yellow crystals were collected by filtration, washed with ethanol, and air-dried. The mother liquor was evaporated to recycle the catalyst 4-(dimethylamino)pyr (...truncated)