Methyl α-[(4-oxoquinazolin-2-yl)thio]acetate as Precursor to New Heterocyclic Compounds

The Eurasia Proceedings of Science, Technology, Engineering & Mathematics (EPSTEM) ISSN: 2602-3199 The Eurasia Proceedings of Science, Technology, Engineering & Mathematics (EPSTEM), 2019 Volume 7, Pages 63-67 IConTES 2019: International Conference on Technology, Engineering and Science Methyl α-[(4-oxoquinazolin-2-yl)thio]acetate as Precursor to New Heterocyclic Compounds Hiba Amin AL-ALAAF University of Mosul Mohammed Ahmed AL-IRAQI University of Mosul Abstract: Methyl α-[(4-oxoquinazolin-2-yl)thio]acetate (3) is one of the important heterocyclic compounds. It is used as a precursor to synthesize new derivatives of quinazolin-4-one moiety. The compound (4) was synthesized via a series of steps from anthranilic acid. Firstly, the anthranilic acid was converted to its methyl ester (1) by esterification with methanol under acidic condition. The ester (1) was reacted with chloroacetyl chloride to produce methyl α-chloroacetamido benzoate (2). The chloro compound (2) was converted to the to the target precursor (3) by boiling of the chloro compound (2) with ammonium thiocyanate for 12 h. The compound (3) was used as synthon to synthesize new series of five membered ring heterocyclic derivatives, via its conversion to the corresponding acid hydrazide (4). The acid hydrazide (4) was reacted with carbon disulfide under boiling condition to produce 1,3,4-oxadiazole-5-thione derivative (5). The oxadiazole compound (5) was reacted with alkyl halides to afforded the corresponding alkylthio compounds (6-11), and with aromatic aldehydes to afforded the carbinol derivatives (12-18). The synthesized compounds were identified via the physical and spectral data. Keyword: 2-Mercaptoquinazolin-4-one, Methyl 2-chloroacetaminobenzoate, Methyl anthranilate, 1,3,4 Oxadiazol, Alkylthio derivatives, Acetohydrazide compounds Introduction Quinazolin-4(3)-one is one of most important nucleus in heterocyclic chemistry owing to its participation in building block enormous number of biologically active compounds, by incorporation of the quinazolin-4(3)-one nucleus with deffirent heterocyclic moieties, such as triazole, thiadiazole and oxadiazole moieties. These compounds have been entice the medicinal chemists to find and design novel structures having pharmacological activity (Vijai Anand etal., 2009)1. Quinazolin-4(3H)-one derivatives showed diversity of biological activity such as analgesic, anti-inflammatory (Bhalla et al ;1993),2 anti-hypertensive (Kotto et al; 1985),3 antihistaminic, anti-cancer (Brana et al; 1994),4 (Boyle et al; 1993),5 (Parasharya and Parkh, 1994),6 anti-tumor (AlOmary et al; 2012),7 sedative, hypnotic and anti-microbial activity (Khalil; 1989)8 (Vogel’s; 1994),9 antileishmanial activity (Agarwal et al; 2009)10 and as anti-oxidant (Decker; 2008)..11 So, the previous views encouraged us to synthesize novel compounds containing quinazolin-4(3H)-one nucleus incorporated with oxadiazole moiety starting from methyl α-[(4-oxoquinazolin-2-yl)thio]acetate. Experimental Melting points were recorded on a Stuart melting point SMP30 apparatus and were uncorrected. IR spectra were recorded as neat using Bruker system 2000 FT.IR spectrophotometer. 1H NMR spectra were measured on a Bruker DPX(400) super conducting NMR Spectrometer (400 MHz) using DMSO-d6 as a solvent and TMS as an internal standard. - This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 Unported License, permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. - Selection and peer-review under responsibility of the Organizing Committee of the Conference © 2019 Published by ISRES Publishing: www.isres.org International Conference on Technology, Engineering and Science (IConTES), October 26-29, 2019, Antalya/Turkey Synthesis of methyl anthranilate (1) (Bhasker et al.1996) 12 A solution of anthranilic acid (0.1mol, 14.7 g) in absolute methanol (250 ml) was cooled to 0-5 oC, then a concentrated sulfuric acid (20 ml) was added dropwise with stirring. After the addition was completed, the mixture was refluxed for 72 h. The volatile components were evaporated under reduced pressure. A cold water (100 ml) was added to the residue. The mixture was basified by dropwise addition of (5 % ) sodium bicarbonate solution, then the resulted mixture extracted with (20 * 30 ml) dichloromethane. The organic layers were collected, dried over magnesium sulfate, then evaporated. The crude product was recrystallized from methanol to give red crystals in 85% yield: melting point 22-23 οC. IR spectrum (neat, ν Cm-1): 3369 (N-H), 1704 (C=O), 1604 (C=C), 1442 (CH3), 1245 (C-O). 1H NMR (DMSO-d6) (δ, ppm): 3.39 (s, 3H, CH3), 6.66 (s, 2H, NH2), 6.53 (t, 1H, H5), 6.79 (d, 1H, H3), 7.25 (t, 1H, H4), 7.71 (d, 1H, H6). Methyl N-(α-chloroacetyl)anthranilate (2) (Behbehani and Ibrahim, 2013) 13 To a solution of methyl anthranilate (0.01mol, 1.52 g) in chloroform (50 ml), chloroacetyl chloride (0.012 mol, 1.36 g) and potassium carbonate (0.015 mol, 2.1 g) were added. The reaction mixture was refluxed for 12 h. the volatile material was evaporated under reduced pressure. The residue was washed thoroughly with water then with 5% sodium bicarbonate solution and finally with water. The resulted product was dried then recrystallized from ethanol to give white crystals, in 98% yield, m.p. 90-91 oC, IR (neat, ν, cm -1): 3194 (N-H), 1682, 1676 (2C=O), 1441 (CH3),1226 (C-O). 1H NMR (DMSO-d6): δ, ppm: 3.89 (s, 3H, CH3), 4.45 (s, 2H, CH2), 7.27 (t, 1H, H5) , 7.66 (t, 1H, H4), 7.99 (d, 1H, H3), 8.40 (d, 1H, H6), 11.33 (s,1H, NH). Synthesis of methyl α-[(4'-oxoquinazolin-2'-yl)thio]acetate (3): To a solution of methyl 2-(α-chloroacetamino)benzoate (2) (0.01 mol, 2.27 g) in methanol (30 ml), ammonium thiocyanate (0.015 mol, 1.15 g) was added with stirring. The mixture was refluxed for 12h then cooled to room temperature. The resulted precipitate was filtered off, washed with water, dried then recrystallized from methanol to give pale yellow crystals in 98 % yield, m.p. 191-192 oC. IR (neat, ν,cm -1): 3170 (N-H), 1734, 1682 (2C=O), 1375 (CH3), 681 (C-S). 1H NMR (DMSO-d6): δ, ppm: 3.69 (s, 3H, CH3 ), 4.11 (s, 2H, CH2), 7.4 (t, 1H, H6) , 7.75 (t, 1H, H7), 7.98 (d, 1H, H5), 8.23 (d, 1H, H8), 11.14 (s,1H, NH). Synthesis of α-[4'-oxoquinazolin-2'-yl)thio]acetohydrazide (4): A solution of methyl α-(4'-oxoquinazolin-2'-yl)thio]acetate (3) (0.01 mol, 2.64 g), hydrazine hydrate (99.5 %) (0.015 mol, 0.75 g) in absolute ethanol (30 ml) was refluxed with stirring for 12 h. The solid product was separated by filtration, washed with cold water, dried, then recrystallized from ethanol to give green crystals in 90 % yield, m.p. 248 oC. IR (neat, ν, cm-1): 3289, 3128 (NH2, N-H), 1662 (2 C=O), 682 (C-S). 1H NMR (DMSO-d6): δ, ppm: 4.41 (s, 2H, CH2 ), 5.43 (s, 2H, NH2) (D2O exchangeable), 5.88 (s, 1H, NNH), 7.14 (t, 1H, H6), 7.31 (d,1H, H5), 7.70 (d, 1H, H8 (...truncated)