Synthesis, recyclization under the action of methanol and analgetic activity of N'-(5-aryl-2-oxofuran-3(2H)-ylidene)furan-2-carbohydrazides published by Ural Federal University eISSN 2411-1414 chimicatechnoacta.ru ARTICLE 2023, vol. 10(1), No. 202310101 DOI: 10.15826/chimtech.2023.10.1.01 1 of 8 Synthesis, recyclization under the action of methanol and analgetic activity of N'-(5-aryl-2-oxofuran-3(2H)- ylidene)furan-2-carbohydrazides Sergei N. Igidov ab , Irina A. Gorbunova с * , Aleksey Yu. Turyshev a , Daria A. Shipilovskikh d * , Danil A. Kozlov с, Anna S. Rogova e, Ramiz R. Makhmudov c, Pavel S. Silaichev c , Nazim M. Igidov a a: Perm State Pharmaceutical Academy, Ministry of Health of the Russian Federation, Perm 614990, Russia b: Merck LLC, Moscow 115054, Russia c: Perm State National Research University, Perm 614990, Russia d: Perm National Research Polytechnic University, Perm 614990, Russia e: Peter the Great St. Petersburg Polytechnic University, St. Petersburg 195251, Russia * Corresponding author: gorbunova@psu.ru (I.A. Gorbunova), shipilovskikh@psu.ru (Daria A. Shipilovskikh). This paper belongs to the MOSM2022 Special Issue. Abstract New methyl 5-aryl-1-(furan-2-carbonyl)-1H-pyrazole-3-carboxylates were obtained via decyclization reaction of N'-(5-aryl-2-oxofuran-3(2H)- ylidene)furan-2-carbohydrazides under the action of methanol. Starting N'- (5-aryl-2-oxofuran-3(2H)-ylidene)furan-2-carbohydrazides were obtained by intramolecular cyclization of substituted 4-aryl-2-[2-(furan-2- ylcarbonyl)hydrazinylidene]-4-oxobutanoic acids in propionic anhydride. The structure of the compounds obtained was confirmed by the 1H NMR spectroscopy, IR spectrometry and elemental analysis methods. Analgesic activity of some obtained compounds was studied by the “hot plate” meth- od on outbred white mice of both sexes with intraperitoneal injection. Keywords 2,4-dioxobutanoic acid 2-hydrazono-4-oxobutanoic acids 3-hydrazonofuran-2(3H)-one analgesic activity drugs Received: 14.11.22 Revised: 21.11.22 Accepted: 21.11.22 Available online: 01.12.22 Key findings ● The synthesis method for obtaining methyl 5-aryl-1-(furan-2-carbonyl)-1H-pyrazole-3-carboxylates developed. ● Five new compounds not previously described in the literature were obtained. ● Some of the compounds obtained have been found to have significant analgetic effects. © 2022, the Authors. This article is published in open access under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). 1. Introduction The development and creation of new drug forms with lower toxicity is one of the most important tasks of mod- ern pharmaceutical and medicinal chemistry [1–7], since modern medicine is always in need of new drugs. It is necessary to create a universal basic structure that will allow obtaining a wide diversity of different structures possessing biological activity. Such a universal structural fragment can be found among the 3-imino- (hydrazinylidene)-furan-2(3H)-one derivatives, which results from their chemical availability due to the scala- bility of the synthetic methods [8] and the reactivity [9– 15]. For example, the reactions of 3-imino- (hydrazinylidene)-furan-2(3H)-ones derivatives with various nucleophilic reagents lead to the attack on the carbonyl group of the lactone fragment and to the for- mation of acyclic or heterocyclic structures [16–21] that retain the pharmacophore fragment of 2,4-dioxobutanoic acid [22–32]. This fragment was found in the structure of various biologically active and natural compounds [33, 34], which indicates that this idea is worth developing. Previously, we proposed a simple method for the prepa- ration of 3-hydrazinylidenefuran-2(3H)-one derivatives by intramolecular cyclization of substituted 2-[2-(4-R- benzoyl)hydrazinylidene]-4-oxobutanoic acids in the presence of acetic or propionic anhydride [35, 36]. Fur- thermore, this method was applied to 3-imino(thiophen- 2-yl)furan-2(3H)-ones derivatives, which include the pharmacophore fragment, Gewald aminothiophene [37– 41]. Compounds that contain this pharmacophore frag- ment exhibit analgesic [42–44], anti-inflammatory [45, 46], antimicrobial [47–49] and photoluminescent proper- ties [50, 51] and other biological activities [52–54]. Also, http://chimicatechnoacta.ru/ https://doi.org/10.15826/chimtech.2023.10.1.01 mailto:gorbunova@psu.ru mailto:shipilovskikh@psu.ru http://creativecommons.org/licenses/by/4.0/ https://orcid.org/0000-0001-6006-168X http://orcid.org/0000-0003-3028-7914 https://orcid.org/0000-0003-3867-5305 https://orcid.org/0000-0001-6086-4300 https://orcid.org/0000-0002-2840-6809 https://orcid.org/0000-0003-0976-9951 https://crossmark.crossref.org/dialog/?doi=https://doi.org/10.15826/chimtech.2023.10.1.01&domain=pdf&date_stamp=2022-12-1 Chimica Techno Acta 2023, vol. 10(1), No. 202310101 ARTICLE 2 of 8 DOI: 10.15826/chimtech.2023.10.1.01 we showed that N′-[5-aryl-2-oxofuran-3(2Н)- ylidene]furan-2-carbohydrazides and its precursor 4- aryl-2-[2-(furan -2-ylcarbonyl)hydrazinylidene] -4- oxobutanoic acids have analgesic activity in the previous studies [55]. The interaction of 3-hydrazinylidenefuran- 2(3H)-one with alcohols in the presence of triethylamine, which leading to the formation of a mixture of alkyl 2- hydrazinylidene-4-oxobutanoates and alkyl 5-hydroxy-4,5- dihydro-1H-pyrazole-3-carboxylates, was described earlier [56] (Scheme 1). In the this study, the research into the re- activity of 3-hydrazinylidenefuran-2(3H)-one towards alco- hols was continued. Namely, we considered the interaction of N′-[5-aryl-2-oxofuran-3(2Н)-ylidene]furan-2- carbohydrazides with methanol in the presence of p- toluenesulfonic acid, which leads to the formation of methyl 1-(furan-2-carbonyl)-1H-pyrazole-3-carboxylates as sole products (Scheme 1). In addition, the analgesic activity of the original N′-[5-aryl-2-oxofuran-3(2Н)-ylidene]furan-2- carbohydrazides and the resulting methyl 5-aryl-1-(furan-2- carbonyl)-1H-pyrazole-3-carboxylates was studied. 2. Experimental IR spectra were recorded on an FSM-1202 instrument in vaseline oil. The 1H NMR spectra were recorded at 400 MHz at the temperature of 313 K; the chemical shifts (δ) were measured in ppm with respect to the solvent ([D6] DMSO, 1H: δ= 2.50 ppm). The coupling constants (JHH) are given in Hertz. The splitting pat- terns of apparent multiplets associated with an aver- aged coupling constants were designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets) and br (broadened). Elemental analysis was performed on a LECO CHNS-932 instru- ment. The chemical purity of the compounds and the reactions progress were monitored by TLC on Sorbfil plates in the diethyl ether–benzene–acetone (10:9:1) system, detection in UV light and iodine vapor. Melting points were determined on an SMP40 apparatus. Furan-2-carbohydrazide 1 [57] and 4-aryl-2,4- dioxobutanoic acids 2a–e [58, 59] were prepared ac- cording to the literature methods. 2.1. General procedure for the synthesis of 4-aryl- 2-[2-(furan-2-carbonyl)hydrazinylidene]-4- oxobutanoic acids 3a–e To a solution of 0.01 mol of furan-2-carboxylic acid hydra- zide (1) in 30 mL of acetonitrile was added 0.01 mol of 4-aryl-2,4-dioxobutanoic acid 2a–e. The resulting mixture was heated to 50 °C and kept for 5 min at this temperature. The solution was cooled to 0 °C; the formed precipitate was filtered off and recrystallized from dioxane. 2.1.1. 2-[2-(Furan-2-carbonyl)hydrazinylidene]-4-oxo- 4-phenylbutanoic acid (3a) Yield 2.52 g (84%), yellow crystals, mp 165–166 °С (diox- ane). IR spectrum, ν, cm–1: 3379, 3299, 3137, 1735, 1645, 1600. 1H NMR spectrum (DMSO-d6), δ, ppm: form A (14%): 4.53 s (2Н, СН2), 6.71 dd (1Н, Harom, JHH 3.5, 1.6 Hz), 7.24–8.01 m (7Н, Harom), 11.32 br. s (1Н, NH); form B (79%): 3.21 d (1Н, С4Н2, JHH 20.0 Hz), 3.33 d (1Н, С4Н2, JHH 20.0 Hz), 6.68 dd (1Н, JHH 3.5, 1.8 Hz), 7.24– 8.01 m (7Н, Harom and ОН); form C (7%): 4.27 с (2Н, СН2), 6.71 dd (1Н, Harom, JHH 3.5, 1.6 Hz), 7.24–8.01 m (7Н, Harom) 13.72 br. s (1Н, NH). Found, %: C 60.02; H 4.01; N 9.36. C15H12N2О5. Calculated, %: C 60.00; H 4.03; N 9.33. 2.1.2. 2-[2-(Furan-2-carbonyl)hydrazinylidene]-4-(4- methylphenyl)-4-oxobutanoic acid (3b) Yield 2.29 g (73%), yellow crystals, mp 179–180 °С (diox- ane). 1Н NMR spectrum (DMSO-d6), δ, ppm: form A (30%): 2.41 s (3Н, CH3), 4.52 s (2Н, СН2), 6.73 dd (1Н, Harom, JHH 3.4, 1.7 Hz), 7.14–7.99 m (6Н, Harom), 11.38 br. s (1Н, NH); form B (58%): 2.30 с (3Н, CH3), 3.22 d (1Н, С4Н2, JHH 20.0 Hz), 3.32 d (1Н, С4Н2, JHH 20.0 Hz), 6.70 dd (1Н, JHH 3.5, 1.7 Hz), 7.14–7.98 m (6Н, Harom and ОН); form C (12%): 2.40 s (3Н, CH3), 4.29 s (2Н, СН2), 6.73 dd (1Н, Harom, JHH 3.4, 1.7 Hz), 7.14–7.99 m (6Н, Harom) 13.47 br. s (1Н, NH). Found, %: C 61.12; H 4.47; N 8.94. C16H14N2О5. Calculated, %: C 61.14; H 4.49; N 8.91. 2.1.3. 2-[2-(Furan-2-carbonyl)hydrazinylidene]-4-(4- methoxyphenyl)-4-oxobutanoic acid (3c) Yield 2.81 g (85%), yellow crystals, mp 159–160 °С (diox- ane). 1Н NMR spectrum (DMSO-d6), δ, ppm: form A (43%): 3.86 s (3Н, СН3О), 4.48 s (2Н, СН2), 6.71 dd (1Н, Harom, JHH 3.2, 1.7 Hz), 6.87–8.00 m (6Н, Harom), 11.29 br. s (1Н, NH); form B (37%): 3.21 d (1Н, С4Н2, JHH 20.0 Hz), 3.31 d (1Н, С4Н2, JHH 20.0 Hz), 6.68 dd (1Н, JHH 3.4, 1.6 Hz), 6.87–8.00 m (6Н, Harom and ОН); form C (20%): 3.81 s (3Н, СН3О), 4.24 s (2Н, СН2), 6.71 dd (1Н, Harom, JHH 3.2, 1.7 Hz), 6.87–8.00 m (6Н, Harom), 13.40 br. s (1Н, NH). Found, %: C 58.16; H 4.31; N 8.46. C16H14N2О6. Calculated, %: C 58.18; H 4.27; N 8.48. 2.1.4. 4-(4-Chlorophenyl)-2-[2-(furan-2- carbonyl)hydrazinylidene]-4-oxobutanoic acid (3d) Yield 2.58 g (77%), yellow crystals, mp 182–183 °С (diox- ane). IR spectrum, ν, cm–1: 3237, 3131, 1741, 1683, 1617, 1585. 1Н NMR spectrum (DMSO-d6), δ, ppm: form A (9%), 4.49 s (2Н, СН2), 6.71 m (1Н, Harom), 7.22‒7.96 m (6Н, Harom), Scheme 1 Reaction of 3-hydrazinylidenefuran-2(3H)-one with alcohols in basic and acidic conditions. https://doi.org/10.15826/chimtech.2023.10.1.01 Chimica Techno Acta 2023, vol. 10(1), No. 202310101 ARTICLE 3 of 8 DOI: 10.15826/chimtech.2023.10.1.01 11.43 br. s (1Н, NH); form B (86%), 3.21 d (1Н, С4Н2, JHH 20.0 Hz), 3.30 d (1Н, С4Н2, JHH 20.0 Hz), 6.69 m (1Н, Harom), 7.22‒7.96 m (7Н, 6Нarom and ОН); form C (5%), 4.31 s (2Н, СН2), 6.84 m (1Н, Harom), 7.22‒7.96 m (6Н, Harom), 13.50 br. s (1Н, NH). Found, %: C 53.85; H 3.29; N 8.39. C15H11ClN2О5. Calculated, %: C 53.83; H 3.31; N 8.37. 2.1.5. (4-Bromophenyl)-2-[2-(furan-2- ylcarbonyl)hydrazinylidene]-4-oxobutanoic acid (3e) Yield 2.99 g (79%), yellow crystals, mp 179–180 °С (di- oxane). IR spectrum, ν, cm–1: 3242, 3148, 1734, 1666, 1614, 1583. 1Н NMR spectrum (DMSO-d6), δ, ppm: form A (8%), 4.51 s (2Н, СН2), 6.66 dd (1Н, Harom, JHH 3.5, 1.6 Hz), 7.37‒7.94 m (6Н, Harom), 11.29 br. s (1Н, NH); form B (87%), 3.25 d (1Н, С4Н2, JHH 20.0 Hz), 3.32 d (1Н, С4Н2, JHH 20.0 Hz), 6.68 dd (1НAr, JHH 3.6, 1.7 Hz), 7.37‒ 7.94 m (7Н, 6Нarom and ОН); form C (5%), 4.25 s (2Н, СН2), 6.71 dd (1H, Нarom, JHH 3.5, 1.8 Hz), 7.37‒7.94 m (6H, Нarom), 13.06 br. s (1Н, NH). Found, %: C 47.55; H 2.88; N 7.41. C15H11BrN2О5. Calculated, %: C 47.52; H 2.92; N 7.39. 2.2. General method of synthesis of N'-(5-aryl-2- oxofuran-3(2H)-ylidene)furan-2- carbohydrazides 4a–e Propionic anhydride (8 mL) was added to 0.01 mol of acid 3a–е. The resulting mixture was slowly heated with stirring to 150 °C and kept for 5 min. The precipitate formed after cooling was filtered off, washed with anhydrous diethyl ether, and recrystallized from anhydrous toluene or dioxane. 2.2.1. N'-(2-Oxo-5-phenylfuran-3(2Н)-ylidene)furan-2- carbohydrazide (4a) Yield 2.20 g (78%), yellow crystals, mp 246–248 °С (diox- ane). IR spectrum, ν, cm–1: 3188, 1801, 1698, 1667, 1617. 1Н NMR (DMSO-d6, 400 MHz) δ (ppm): form A (69%): 6.78 dd (1H, Harom, JHH 3.5, 1.8 Hz), 7.52 m (5H, Harom, 2H, 2CH), 8.04 d (1H, JHH 1.0 Hz), 11.90 br. s (1H, NH); form B (31%): 6.80 dd (1H, Harom, JHH 3.6, 1.7 Hz), 7.25 s (1H, CH), 7.65 m (5H, Harom, 1H, CH) 8.07 d (1H, Harom, JHH 1.0 Hz), 12.55 s (1Н, NH). Found, %: C 63.80; 3.55; N 9.91. C15H10N2O4. Calculated, %: C 63.83; H 3.57; N 9.93. 2.2.2. N'-[5-(4-Methylphenyl)-2-oxofuran-3(2H)- ylidene]furan-2-carbohydrazide (4b) Yield 1.57 g (53%), yellow crystals, mp 258–259 °С (di- oxane). IR spectrum, ν, cm–1: 3125, 1799, 1693, 1672, 1622. 1Н NMR (DMSO-d6, 400 MHz) δ (ppm): 2.41 s (3H, Me), 6.72 dd (1H, Harom, JHH 3.5, 1.8 Hz), 7.51 m (5H, Harom, 1H, CH), 7.98 d (1H, JHH 1.0 Hz), 11.89 br. s (1H, NH). Found, %: C 64.84; 4.11; N 9.48. C16H12N2O4. Calcu- lated, %: C 64.86; H 4.08; N 9.46. 2.2.3. N'-[5-(4-Methoxyphenyl)-2-oxofuran-3(2H)- ylidene]furan-2-carbohydrazide (4c) Yield 1.75 g, (56%), yellow crystals, mp 265–266 °С (diox- ane). IR spectrum, ν, cm–1: 3137, 1801, 1666, 1622, 1592. 1Н NMR (DMSO-d6, 400 MHz) δ (ppm): form A (76%): 3.86 s (3H, MeO), 6.74 dd (1H, Harom, JHH 3.6, 1.7 Hz), 7.14 d (2H, Harom, JHH 8.0 Hz), 7.38 s (1H, CH ), 7.56 dd (1H, Harom, JHH 3.6, 0.8 Hz), 7.72 d (2H, Harom, JHH 8.0 Hz), 7.99 dd (1H, JHH 1.6, 0.8 Hz), 11.66 br. s (1H, NH); form B (24%): 3.85 s (3H, MeO), 6.76 dd (1H, Harom, JHH 3.6, 1.7 Hz), 7.03 s (1H, CH), 7.11 d (2H, Harom, JHH 9.0 Hz) , 7.40 d (1H, Harom, JHH 1.0 Hz), 7.80 d (2H, Harom, JHH 9.0 Hz), 8.02 d (1H, Harom, JHH 1.0 Hz), 12.44 s (1H, NH). Found, %: C 61.53; 3.85; N 8.99. C16H12N2O5. Calculated, %: C 61.54; H 3.87; N 8.97. 2.2.4. N′-[5-(4-Chlorophenyl)-2-oxofuran-3(2Н)- ylidene]furan-2-carbohydrazide (4d) Yield 2.35 g, (74%), yellow crystals, mp 268–269 °С (di- oxane). IR spectrum, ν, cm–1: 3137, 1776, 1694, 1619. 1Н NMR (DMSO-d6, 400 MHz) δ (ppm): form A (16%), 6.78 dd (1Н, Нarom, JHH 3.6, 1.7 Hz), 7.50 s (1Н, СН), 7.59 m (1Н, Нarom), 7.63 m (2Н, Нarom), 7.88 m (2Н, Нarom), 8.04 m (1Н, Нarom), 11.75 br. s (1Н, NH); form B (84%), 6.80 dd (1Н, Нarom, JHH 3.6, 1.7 Hz), 7.17 s (1Н, СН), 7.38 m (2Н, Нarom), 7.43 dd (1Н, Нarom, JHH 3.5, 0.6 Hz), 7.76 m (2Н, Нarom), 8.07 dd (1Н, Нarom, JHH 1.6, 0.6 Hz), 12.54 s (1Н, NH). Found, %: C 56.87; H 2.88; N 8.87. С15H9ClN2O4. Cal- culated, %: C 56.89; H 2.86; N 8.85. 2.2.5. N′-[5-(4-Bromophenyl)-2-oxofuran-3(2Н)- ylidene]-furan-2-carbohydrazide (4e) Yield 2.35 g, (65%), yellow crystals, mp 267–268 °С (di- oxane). IR spectrum, ν, cm–1: 3181, 1803, 1683, 1614. 1Н NMR (DMSO-d6, 400 MHz) δ (ppm): 6.78 dd (1Н, Нarom, JHH 3.6, 1.7 Hz), 7.27 s (1Н, СН), 7.42 dd (1Н, Нarom, JHH 3.6, 0.6 Hz), 7.74 m (4Н, Нarom), 8.04 m (1Н, Нarom), 12.37 br. s (1Н, NH). Found, %: C 49.87; H 2.53; N 7.73. С15H9BrN2O4. Calculated, %: C 49.89; H 2.51; N 7.76 2.3. General method of synthesis of methyl 5-aryl- 1-(furan-2-carbonyl)-1H-pyrazole-3- carboxylates 5a–e. To a suspension of 0.0025 mol N'-[5-aryl-2-oxofuran- 3(2H)-ylidene]furan-2-carbohydrazide 4a–e in 20 ml of methanol was added 1.16 mmol (0.2 g) of p-toluenesulfonic acid, stirred at 64 °C for 20–60 min and cooled to 0 °C. The formed precipitate was filtered off, washed with cold meth- anol and recrystallized from propan-2-ol. 2.3.1. Methyl 1-(furan-2-ylcarbonyl)-5-phenyl-1H- pyrazole-3-carboxylate (5a) Yield 0.43 g, (58%), colorless crystals, mp 122–123 °C (propan-2-ol). IR spectrum, ν, cm–1: 1746, 1706, 1557. 1Н NMR (DMSO-d6, 400 MHz) δ (ppm): 3.94 s (3H, MeO), 6.92 dd (1Н, Harom, JHH 3.7, 1.7 Hz), 7.18 s (1H, CH), 7.87 m (7Н, Harom). Found, %: s, 64.88; H 4.06; H 9.44; C16H12N2O4. Calculated, %: C, 64.86; H, 4.08; N, 9.46. 2.3.2. Methyl 1-(furan-2-ylcarbonyl)-5-(4- methylphenyl)-1H-pyrazole-3-carboxylate (5b) Yield (0.53 g, 68%), colorless crystals, mp 223–224 °C (propan-2-ol). IR spectrum, ν, cm–1: 1730, 1618, 1587. 1Н https://doi.org/10.15826/chimtech.2023.10.1.01 Chimica Techno Acta 2023, vol. 10(1), No. 202310101 ARTICLE 4 of 8 DOI: 10.15826/chimtech.2023.10.1.01 NMR (DMSO-d6, 400 MHz) δ (ppm): 2.34 s (3H, Me), 3.89 s (3H, MeO), 6.82 dd (1Н, Harom, JHH 3.7, 1.7 Hz), 7.02 s (1H, CH), 7.23 d (2Н, Harom, JHH 7.9 Hz), 7.35 d (2Н, Harom, JHH 7.9 Hz), 7.74 dd (1Н, Harom, JHH 3.7, 0.7 Hz), 8.14 dd (1Н, Harom, JHH 1.6, 0.6 Hz). Found, %: C, 65.83; H, 4.48; N, 9.05; C17H14N2O4. Calculated, %: C, 65.80; H, 4.55; N, 9.03. 2.3.3. Methyl 1-(furan-2-ylcarbonyl)-5-(4- methoxyphenyl)-1H-pyrazole-3-carboxylate (5c) Yield 0.56 g (69%), colorless crystals, mp 155–156 °C (propan-2-ol). IR spectrum, ν, cm–1: 1730, 1714, 1616, 1560. 1Н NMR (DMSO-d6, 400 MHz) δ (ppm): 3.80 s (3H, MeO), 3.89 s (3H, MeO), 6.87 dd (1Н, Harom, JHH 3.6, 1.8 Hz), 6.99 d (2Н, Harom, JHH 8.0 Hz) 7.07 s (1H, CH), 7.43 d (2Н, Harom, JHH 8.0 Hz), 7.77 dd (1Н, Harom, JHH 3.7, 0.6 Hz), 8.21 m (1Н, Harom). Found, %: C, 62.54; H, 4.34; N, 8.62. C17H14N2O5. Calculated, %: C, 62.57; H, 4.32; N, 8.59. 2.3.4. Methyl 5-(4-chlorophenyl)-1-(furan-2- ylcarbonyl)-1H-pyrazole-3-carboxylate (5d) Yield 0.54 g (65%), colorless crystals, mp 85–86 °C (pro- pan-2-ol). IR spectrum, ν, cm–1: 1751, 1724, 1600. 1Н NMR (DMSO-d6, 400 MHz) δ (ppm): 3.91 s (3H, MeO), 6.89 dd (1Н, Harom, JHH 3.7, 1.7 Hz), 7.17 s (1Н, CH), 7.77 m (6Н, Harom). Found, %: C, 58.09; H, 3.37; N, 8.51. C16H11ClN2O4. Calculated, %: C, 58.11; H, 3.35; N, 8.47. 2.3.5. Methyl 5-(4-bromophenyl)-1-(furan-2- ylcarbonyl)-1H-pyrazole-3-carboxylate (5e) Yield 0.58 g (62%), colorless crystals mp 183–184 °C (propan-2-ol). IR spectrum, ν, cm–1: 1743, 1685, 1616, 1584. 1Н NMR (DMSO-d6, 400 MHz) δ (ppm): 3.91 s (3H, MeO), 6.89 dd (1Н, Harom, JHH 3.7, 1.7 Hz), 7.15 s (1Н, CH), 7.48 d (2Н, Harom, JHH 8.0 Hz) 7.65 d (2Н, Harom, JHH 8.0 Hz), 7.83 dd (1Н, Harom, JHH 3.7, 0.7 Hz), 8.23 dd (1Н, Harom, JHH 3.7, 0.7 Hz, JHH 1.7, 0.8 Hz). Found, %: C, 51.24; H, 2.93; N, 7.50. C16H11BrN2O4. Calculated, %: C, 51.22; H, 2.96; N, 7.47. 2.4. Evaluation of biological activity of target compounds Evaluation of analgesic activity was carried out in the Perm State National Research University, the Research Laboratory of Biologically Active Substances. Analgesic activity was determined on outbred white mice of both sexes weighing 18–22 g using the “hot plate” method [60]. The studied compounds were administered intraperitone- ally in the form of a suspension in a 2% starch solution at a dose of 50 mg/kg 30 min before the animals were placed on a metal plate heated to 53.5 °C [61]. Studies were per- formed 30, 60, 90, 120 min after administration of the compound. The indicator of the change in pain sensitivity was the length of time the animals stay on the hot plate until adefensive pain reflex occurs – licking the hind legs or trying to tear off all four paws from the surface of the plate. The time of onset of this reflex from the beginning of the placement of the animal on the plate was meas- ured in seconds (latent period). The maximum duration of the latent period is the interval of 40 s. In the experi- ment we used animals with the initial time of the onset of the defensive reflex of no more than 15 s. Each com- pound was tested on 6 animals. The results were evalu- ated by increasing the time of the onset of the defensive reflex compared with the initial data. The control group of animals was injected with 2% starch mucus. Met- amizole sodium (Farmkhimkomplekt LLC) at a dose of 93 mg/kg (ED50) was used as a comparison compound. Statistical processing of experimental data was carried out using Student's confidence criteria. The effect was considered significant at p<0.05 [62]. The studies were carried out in accordance with all applicable international, national and institutional guidelines for the care and use of animals. 3. Results and Discussion Substituted 2-[2-(furan-2-ylcarbonyl)hydrazinilydene]-4- oxobutanoic acids 3a–e were obtained in 73–85% yields by reaction of furan-2-carbohydrazide 1 with correspond- ing 2,4-dioxobutanoic acids 2a–e in acetonitrile at 50 °C (Scheme 2). Compounds 3a–e are crystalline yellow substances, readily soluble in chloroform, DMSO, and, when heated, in toluene, dioxane, and ethanol, and insoluble in water and alkanes. The IR spectra of compounds 3a–e contains an absorption band at 1734–1741 cm–1, which is characteristic of the stretching vibrations of the carbonyl amide group, and absorption bands at 3131–3148 and 3237–3299 cm–1, which are characteristic of the stretching vibrations of the NH group. The 1H NMR spectra (DMSO-d6) of compounds 3a–e in the tautomeric form A are characterized by singlet signals of the NH protons (11.29–11.43 ppm) and CH2 (4.48–4.53 ppm) groups. Form B is characterized by the presence in the spec- trum of a doublet of protons of the CH2 group at 3.21‒3.25 and 3.30‒3.33 ppm, and for form C, singlets of the NH pro- tons (13.06‒13.72 ppm) and CH2 (4.24‒4.31 ppm). Scheme 2 Synthesis of 2-[2-(furan-2-ylcarbonyl)hydrazynilidene]-4- oxobutanoic acids 3a–e. https://doi.org/10.15826/chimtech.2023.10.1.01 Chimica Techno Acta 2023, vol. 10(1), No. 202310101 ARTICLE 5 of 8 DOI: 10.15826/chimtech.2023.10.1.01 Intramolecular cyclization of acids 3a–e occurs upon slow heating to 150 °С in propionic anhydride and leads to the formation of substituted N'-(2-oxofuran-3(2H)- ylidene)furan-2-carbohydrazides 4a–e (Scheme 3). Compounds 4a–е, obtained in 53–78% yields, are yel- low crystalline substances, readily soluble in DMSO, when heated – in toluene and ethanol, and insoluble in water and alkanes. The IR spectra of compounds 4a–е contain an absorption band in the region 1776–1803 cm–1, which is characteristic of the stretching vibrations of the lactone carbonyl of the furan ring, and an absorption band in the region 3125–3188 cm–1, which is characteristic of the stretching vibrations of the NH group. According to 1Н NMR data in DMSO-d6, compounds 4a, 4c, 4d are present as two geometric isomers A and B. The spectra of the isomers are characterized by the presence of signals of the NH groups [11.66‒11.90 (E-A) and 12.44‒ 12.55 ppm (Z-B)]. Compound 4b exists only as the E- isomer [δ(NH) 11.89 ppm], but compound 4e exists only as the Z-isomer [δ(NH) 12.37 ppm]. It was found that the reaction of N'-(2-oxofuran- 3(2Н)-ylidene)furan-2-carbohydrazides 4a–e with metha- nol in present of p-toluenesulfonic acid led to the for- mation of methyl 5-aryl-1-(furan-2-carbonyl)-1H- pyrazole-3-carboxylates 5a–e (Scheme 3). Compounds 5a–e are apparently formed due to the ad- dition of methanol to the lactone carbonyl group of furanones 4a–e, opening of the furanone ring at the O1–C2 bond, and subsequent closing of the pyrazole ring due to the addition NH group to carbonyl group of aroyl frag- ment followed by dehydration (Scheme 4). Compounds 5a–е, obtained in 58–69% yields, are col- orless crystalline substances. The IR spectra of com- pounds 5a–е are characterized by the absence of NH group signal, in contrast to the spectra of compounds 4a–e, and the presence of the absorption band of two car- bonyl groups in region 1685–1751 cm–1. Scheme 3 Synthesis of N'-(2-oxofuran-3(2Н)-ylidene)furan-2- carbohydrazides 4a–e. In 1Н NMR spectra, in addition to the signals of the protons of arylic and heterocyclic fragments, there are singlet signals of the methoxycarbonyl groups in the re- gion 3.89–3.94 ppm. Some of the compounds obtained were examined for analgesic activity. It is shown in Table 1 that all the studied compounds have a pronounced analgesic effect, surpassing the effect of the comparison drug metamizole. 4. Limitations We have obtained new methyl 5-aryl-1-(furan-2- carbonyl)-1H-pyrazole-3-carboxylates with 58-69% yields, yields are significantly declining after recrystallisation of obtained compounds. Therefore, we are going to improve a method of purification for achievement higher product yields in our further studies. 5. Conclusions New methyl 5-aryl-1-(furan-2-carbonyl)-1H-pyrazole-3- carboxylates were obtained with 58-69% yields by the re- cyclization of N'-(5-aryl-2-oxofuran-3(2H)-ylidene)furan-2- carbohydrazides under the action methanol in the presence of p-toluenesulfonic acid. It was found that N'-(5-aryl-2- oxofuran-3(2H)-ylidene)furan-2-carbohydrazides and me- thyl 5-aryl-1-(furan-2-carbonyl)-1H-pyrazole-3-carboxylates exhibit significant analgesic activity, reliably exceeding the effect of a reference drug. Further study of biological activi- ty of the compounds obtained is planned. Scheme 4 Synthesis and proposed pathway of formation of me- thyl 5-aryl-1-(furan-2-carbonyl)-1H-pyrazole-3-carboxylates 5a–e. Figure 1 The structure of the 4a–e and 5b compounds. https://doi.org/10.15826/chimtech.2023.10.1.01 Chimica Techno Acta 2023, vol. 10(1), No. 202310101 ARTICLE 6 of 8 DOI: 10.15826/chimtech.2023.10.1.01 Table 1 Analgetic activity of substances 4a–e and 5b. Compound Dosage, mg/kg The latent period of the defensive reflex (120 min), s 4a 50 24.80±0.97 4b 50 26.60±1.36 4c 50 19.48±0.82 4d 50 21.66±0.46 4e 50 24.64±1.38 5b 50 22.18±0.34 Metamizole sodium 93 (ED50) 16.60±1.00 Control – 10.30±0.60 ● Supplementary materials No supplementary materials are available. ● Funding This study was performed under financial support of the “Rational Use of the Earth Interior” Perm Scientific Educa- tional Center 2023 and Ministry of Science and Higher education of Russian Federation FSEG-2022-0012. ● Acknowledgments None. ● Author contributions Conceptualization: D.A.S., N.M.I. Data curation: I.A.G., S.N.I., A.S.R., R.R.M., P.S.S. Formal Analysis: I.A.G., A.Yu.T., D.A.K, A.S.R., P.S.S. Funding acquisition: D.A.S., N.M.I Investigation: S.N.I., I.A.G., A.S.R., R.R.M. Methodology: S.N.I., I.A.G., D.A.K, A.S.R., R.R.M. Project administration: D.A.S., N.M.I. Resources: D.A.S., N.M.I. Supervision: D.A.S., N.M.I. Validation: D.A.S., P.S.S., N.M.I. Visualization: I.A.G., S.N.I., Writing – original draft: D.A.S., P.S.S., N.M.I. Writing – review & editing: D.A.S., N.M.I. ● Conflict of interest The authors declare no conflict of interest. ● Additional information Author IDs: Sergei N. Igidov, Scopus ID 57679291500; Irina A. Gorbunova, Scopus ID 57219990135; Aleksey Yu. Turyshev, Scopus ID 57431693900; Daria A. Shipilovskikh, Scopus ID 57193555475; Ramiz R. Makhmudov, Scopus ID 57366636900; Pavel S. Silaichev, Scopus ID 8521794900; Nazim M. Igidov, Scopus ID 6701786062. 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