CN118221690A - Chromone pyridazine compound and synthetic method and application thereof - Google Patents

Chromone pyridazine compound and synthetic method and application thereof Download PDF

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CN118221690A
CN118221690A CN202410150414.6A CN202410150414A CN118221690A CN 118221690 A CN118221690 A CN 118221690A CN 202410150414 A CN202410150414 A CN 202410150414A CN 118221690 A CN118221690 A CN 118221690A
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arh
chromone
compound according
pyridazine
acid
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余富朝
宋思雨
张志来
彭孟林
董书维
夏雪山
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Kunming University of Science and Technology
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Kunming University of Science and Technology
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Abstract

The invention discloses a chromone pyridazine compound with a structural formula shown in the specification, which is prepared from o-hydroxyaryl enaminone and aryl diazonium salt serving as raw materials, and has the characteristics of simple preparation, mild reaction, low cost and high yield; the chromone pyridazine compound is applied to an anti-coronavirus experiment, and an experiment result shows that the chromone pyridazine compound has anti-coronavirus activity, has the effect equivalent to that of a positive control drug Abidol (ARB) and lower cytotoxicity, and has the potential of developing a drug for treating, preventing and relieving related diseases caused by coronaviruses;

Description

Chromone pyridazine compound and synthetic method and application thereof
Technical Field
The invention belongs to the technical field of organic synthesis technology and medical application, and particularly relates to a chromone pyridazine compound, a method for synthesizing the compound and application of the compound in resisting coronaviruses.
Background
Chromones are the most important class of natural heterocyclic compounds, which are widely found in nature, and their derivatives exhibit a variety of biological and pharmaceutical activities, such as antibacterial (chem. Rev.2014,114, 4960.), antioxidant (chem. Biol. Drug des.2012,79,981.), antifungal (Cell biochem. Function. 1991,9,79.) and anticancer properties (Cancer lett.1997,114, 153.), as well as excellent fluorescent properties (spectrochim. Acta Part a 2006,65,397.). In addition, combining two or more active backbone units into one compound, exerting its biological activity by combining multiple molecular cores, is one of the strategies for drug design. Therefore, the construction of chromones and chromone derivatives has received great attention from chemists.
To date, a number of synthetic methods have been developed to prepare chromones and their derivatives, including classical Claise condensation (eur.j. Chem.2012,3,57.), baker-VENKATAMARA rearrangement (j. Med. Chem.2011,54,7427.), kostanecki-Robinso reactions (j. Hetercycl. Chem.2002,39,627.). In addition, other reaction synthesis routes such as metal catalysis (j. Org. Chem.2010,75,948.), microwave assisted (Tetrahedron lett.2005,46,6315.), and the like have been utilized, for example, isoflavone was synthesized by reacting N, N-dimethyl-o-hydroxy enaminone with benzene derivatives under the action of iodine and 500w mercury lamp reported by Zhang group of subjects (chem. Commun.2016,52,12306.). However, most of the synthesis methods have the limitations of harsh reaction conditions, use of transition metal catalysts, difficulty in substrate preparation, limited structural diversity, low yield and the like. Therefore, the development of the chromone derivative with the multifunctional structure has the advantages of simple and easily obtained raw materials, mild reaction conditions, simple post-treatment and simplicity and high efficiency.
Coronaviruses, on the other hand, are single stranded RNA viruses that infect humans and a variety of spinal animals. Highly pathogenic coronaviruses spread and infect and pose a great hazard to public health, while less pathogenic coronaviruses are also emitted seasonally, affecting human health to some extent. Although vaccines against novel coronaviruses have been developed, there is a lack of specific drugs for coronaviruses that can infect humans, and clinical symptomatic and supportive care remains. In order to better cope with the harm to human caused by epidemic viruses and new infectious diseases, development of more medicines is needed. Therefore, finding candidate drugs that effectively inhibit coronaviruses is a technical problem to be solved.
Disclosure of Invention
In order to solve the defects in the prior art, the invention provides a chromone pyridazine compound, a simple and efficient synthesis method and an application of resisting coronaviruses.
In order to solve the technical problem of synthesis, the invention adopts the following technical scheme: adding o-hydroxyaryl enaminone 1, aryl diazonium salt 2 and a solvent into a reactor, reacting at 25-70 ℃ under the condition of oil bath, and monitoring the reaction progress by thin layer chromatography until the reaction is complete; then extracting for 3-4 times by using ethyl acetate and water, collecting and combining organic phases, washing the organic phases by using saturated saline, drying the organic phases by using anhydrous sodium sulfate, concentrating the organic phases under reduced pressure, and separating and purifying residues by using silica gel column chromatography or recrystallization to obtain the chromone pyridazine compound 3, wherein the synthetic route is as follows:
Wherein Ar 1 is selected from substituted or unsubstituted aryl, and the substituent is alkyl, alkoxy, halogen, aryl, heteroaryl; ar 2 is selected from substituted or unsubstituted aryl, and the substituent is alkyl, alkoxy, benzyloxy, halogen, cyano, benzoyl and amide.
The molar ratio of the o-hydroxyaryl enaminone 1 to the aryl diazonium salt 2 is 2-4:1.
When the chromone pyridazine compound is prepared, an additive can be added, wherein the additive is selected from difluoroacetic acid, trifluoroacetic acid, n-butyric acid, acetic acid, cyanoacetic acid, isobutyric acid, malonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, succinic anhydride, isobutyric anhydride, benzoic anhydride, acetic anhydride, trifluoroacetic anhydride, propionic anhydride and n-valeric anhydride; the molar ratio of the o-hydroxyaryl enaminone 1 to the additive is 2:1-3; the solvent is selected from 1, 4-dioxane, dimethyl sulfoxide, acetonitrile, toluene, acetone, xylene, and dichloromethane.
The above synthesis reaction is carried out under an inert atmosphere, an air atmosphere or an oxygen atmosphere.
The ortho-hydroxyarylaminones are prepared in conventional manner, for example, as described in the Eur.J. org.chem.2011,2011,399 literature; aryl diazonium salts are prepared in a conventional manner, for example as described in the literature Angew.chem.int.ed.2015,54, 7648-7652.
The product structure is confirmed by nuclear magnetic resonance, high-resolution mass spectrum, single crystal diffraction test of representative products and the like.
The target product chromone pyridazine compound 3 has any one of the following structures:
the invention relates to an application of chromone pyridazine compounds or pharmaceutically acceptable salts thereof in preparation of a preparation for inhibiting coronavirus, wherein the coronavirus is HCoV-OC43 coronavirus.
The preparation for inhibiting coronavirus takes chromone and pyridazine compounds as active ingredients, and one or more pharmaceutically acceptable auxiliary materials can be added to improve the absorption effect of the medicine or facilitate the use, such as capsules or pills, powder, tablets, granules, oral liquid, injection and the like, namely, the preparation is prepared into proper dosage forms for treating, preventing and relieving related diseases caused by coronavirus.
The preparation comprises an effective amount of the chromone pyridazine compound or pharmaceutically acceptable salt, stereoisomer, active metabolite, prodrug, solvate or crystal form thereof and pharmaceutically acceptable excipients.
Compared with the prior art, the invention has the following advantages:
The invention discloses a chromone pyridazine compound with a brand new structure, and provides a high-universality synthesis method of the chromone pyridazine compound with a multifunctional structure and various structures, wherein the starting material of the synthesis method is obtained by simple synthesis with wide sources, various structures, low price and easy obtainment; the synthesis method is simple and efficient, mild in reaction condition, simple and convenient to operate, environment-friendly, high in yield and the like, is suitable for industrial amplification, and has good industrial application prospect;
The anti-coronavirus pharmacodynamic test proves that the chromone pyridazine compound has anti-coronavirus activity, the effect is equivalent to that of positive control Rede Wei Yaoa Bidol (ARB), the cytotoxicity is lower than that of ARB, and the chromone pyridazine compound has very good anti-coronavirus effect, and can be used for developing medicaments for treating, preventing and relieving related diseases caused by coronaviruses.
Drawings
FIG. 1 is a single crystal structure of Compound 3 s.
Detailed Description
The present invention will be described in further detail by way of examples, but the scope of the present invention is not limited to the above description, and the reagents in the examples are all conventional commercial reagents or reagents produced by conventional methods unless otherwise specified.
Example 1:
(E) -3- (dimethylamino) -1- (2-hydroxyphenyl) prop-2-en-1-one 1 (0.21 mmol), succinic anhydride (0.1 mmol), acetonitrile (2 mL) and p-methoxyphenyl diazonium tetrafluoroborate 2 (0.1 mmol) are sequentially added into a 15mL reaction tube, the reaction is monitored by TLC under nitrogen atmosphere at 25 ℃, after the raw material point is completely disappeared, the reaction product is extracted 3 times by ethyl acetate and water, the combined organic phases are collected and washed by saturated saline, the organic phase is dried by anhydrous Na 2SO4 after the collection, the dried liquid is concentrated by rotary evaporation at 45 ℃, then the concentrated evaporated matter is subjected to silica gel column chromatography separation and purification, the solvent adopted by column chromatography separation is a mixed solvent of petroleum ether-ethyl acetate, the eluent is collected, and the rotary evaporation is dried at 45 ℃ to obtain yellow solid 3a, the yield is 93 percent, the reaction is as follows:
the structure, morphology, melting point, nuclear magnetism, and high resolution mass spectrum data of product 3a are as follows:
V Petroleum ether /V Acetic acid ethyl ester ＝10:1,Rf = 0.25; yellow solid 40mg yield 93%; melting point ＝143-144℃;1H NMR(600MHz,CDCl3):δ＝11.82(s,1H,OH),8.20(s,1H,C＝CH),7.99(s,2H,ArH),7.57(t,J＝7.4Hz,1H,ArH),7.52(t,J＝7.3Hz,1H,ArH),7.37(d,J＝8.8Hz,2H,ArH),7.09(t,J＝8.9Hz,2H,ArH),6.99-6.93(m,4H,ArH),6.41(s,1H,C-CH),3.83(s,3H,ArOCH3);13C NMR(150MHz,CDCl3)δ＝193.2,181.2,163.8,158.3,157.6,140.3,137.1,136.6,136.0,133.2,129.0,127.3,123.4,122.3,120.3,120.3,118.9,118.5,118.5,118.4,114.7,114.7,109.5,64.2,55.6;HRMS(TOF ES+):m/z calcd for C25H19N2O5[(M+H)+],427.1288,found,427.1309.
The following examples were prepared in the same manner as in example 1;
example 2: the difference is that the compound 1 is (E) -3- (dimethylamino) -1- (2-hydroxy-5-methylphenyl) prop-2-en-1-one, and the structure, morphology, melting point, nuclear magnetism and high resolution mass spectrum data of the obtained product 3b are as follows;
V Petroleum ether /V Acetic acid ethyl ester ＝10:1,Rf = 0.25; yellow solid, 42mg yield 92%; melting point ＝178-179℃;1H NMR(600MHz,CDCl3):δ＝11.63(s,1H,OH),8.00(d,J＝9.4Hz,2H,ArH),7.78(s,1H,C＝CH),7.38(t,J＝9.0Hz,3H,ArH),7.32(d,J＝8.4Hz,1H,ArH),6.99(d,J＝8.5Hz,1H,ArH),6.95(d,J＝9.0Hz,2H,ArH),6.84(d,J＝8.4Hz,1H,ArH),6.35(s,1H,C-CH),3.83(s,3H,ArOCH3),2.34(s,3H,ArCH3),2.33(s,3H,ArCH3);13C NMR(150MHz,CDCl3):δ＝193.2,181.3,161.7,158.2,155.6,140.4,138.2,137.7,136.1,132.9,131.8,128.9,127.9,126.9,123.0,120.2,120.2,118.3,118.2,118.1,114.7,114.7,109.6,64.1,55.6,20.6,20.5;HRMS(TOF ES+):m/z calcd for C27H23N2O5[(M+H)+],455.1601,found,455.1603.
Example 3: the difference is that the compound 1 is (E) -1- (5-chloro-2-hydroxyphenyl) -3- (dimethylamino) prop-2-en-1-one, and the structure, morphology, melting point, nuclear magnetism and high resolution mass spectrum data of the obtained product 3c are as follows;
V Petroleum ether /V Acetic acid ethyl ester ＝10:1,Rf = 0.25; yellow solid 33mg yield 67%; melting point ＝140-141℃;1H NMR(600MHz,CDCl3):δ＝11.68(s,1H,OH),8.28(d,J＝2.4Hz,1H,ArH),7.99(s,1H,C＝CH),7.95(d,J＝2.4Hz,1H,ArH),7.53-7.50(m,1H,ArH),7.48-7.46(m,1H,ArH),7.38(d,J＝8.9Hz,2H,ArH),7.04(d,J＝8.9Hz,1H,ArH),6.98(d,J＝8.9Hz,2H,ArH),6.92(d,J＝8.8Hz,1H,ArH),6.39(s,1H,C-CH),3.85(s,3H,ArOCH3);13C NMR(150MHz,CDCl3):δ＝191.7,180.0,162.2,158.6,155.9,139.8,136.8,136.5,135.8,132.4,129.6,127.9,126.8,124.1,123.7,120.6,120.6,120.3,120.1,118.8,114.9,114.9,109.4,64.1,55.7;HRMS(TOF ES+):m/z calcd for C25H17Cl2N2O5[(M+H)+],495.0509,found,495.0507.
Example 4: the difference is that the compound 1 is (E) -1- (5-bromo-2-hydroxyphenyl) -3- (dimethylamino) prop-2-en-1-one, and the structure, morphology, melting point, nuclear magnetism and high resolution mass spectrum data of the obtained product 3d are as follows;
V Petroleum ether /V Acetic acid ethyl ester ＝10:1,Rf = 0.25; yellow solid, 24mgg yield 41%; melting point ＝201-202℃;1H NMR(600MHz,CDCl3):δ＝11.68(s,1H,OH),8.45(s,1H,C＝CH),8.04(d,J＝73.8Hz,2H,ArH),7.59(s,2H,ArH),7.38(s,2H,ArH),6.98(s,3H,ArH),6.85(s,1H,ArH),6.38(s,1H,C-CH),3.84(s,3H,ArOCH3);13C NMR(150MHz,CDCl3):δ＝189.8,178.2,160.9,156.9,154.6,137.9,137.7,137.5,134.0,133.7,128.1,127.8,122.8,118.8,118.8,118.8,118.7,117.7,113.4,113.1,113.1,108.8,107.7,62.3,53.9;HRMS(TOF ES+):m/z calcd for C25H17Br2N2O5[(M+H)+],582.9499,found,582.9494.
Example 5: the difference is that the compound 1 is (E) -3- (dimethylamino) -1- (4-hydroxy- [1,1' -biphenyl ] -3-yl) prop-2-en-1-one, and the structure, morphology, melting point, nuclear magnetism and high resolution mass spectrum data of the obtained product 3E are as follows;
V Petroleum ether /V Acetic acid ethyl ester ＝8:1,Rf = 0.25; yellow solid 45mg yield 77%; melting point ＝195-196℃;1H NMR(600MHz,CDCl3):δ＝11.91(s,1H,OH),8.58(s,1H,ArH),8.23(s,1H,ArH),8.00(s,1H,C＝CH),7.83-7.77(m,2H,ArH),7.61(d,J＝7.3Hz,2H,ArH),7.52(d,J＝7.3Hz,2H,ArH),7.44(t,J＝7.4Hz,2H,ArH),7.41-7.33(m,6H,ArH),7.17(d,J＝8.6Hz,1H,ArH),7.04(d,J＝8.5Hz,1H,ArH),6.89(d,J＝8.6Hz,2H,ArH),6.46(s,1H,C-CH),3.82(s,3H,ArOCH3);13C NMR(150MHz,CDCl3):δ＝192.7,181.3,163.3,158.4,157.0,140.3,139.9,139.5,136.1,135.8,135.3,135.3,132.2,131.8,129.2,128.9,128.9,128.9,128.9,127.5,127.2,126.8,126.8,126.7,126.7,125.4,123.5,120.7,120.7,119.1,118.9,118.5,114.7,114.7,110.1,64.2,55.7;HRMS(TOF ES+):m/zcalcd for C37H27N2O5[(M+H)+],579.1914,found,579.1917.
Example 6: the difference is that the compound 1 is (E) -3- (dimethylamino) -1- (2-hydroxy-6-methoxyphenyl) prop-2-en-1-one, and the structure, morphology, melting point, nuclear magnetism and high resolution mass spectrum data of the obtained product 3f are as follows;
V Petroleum ether /V Acetic acid ethyl ester ＝10:1,Rf = 0.25; yellow solid, 35mg yield 72%; melting point ＝165-166℃;1H NMR(600MHz,CDCl3):δ＝11.26(s,1H,OH),8.79(s,1H,C＝CH),7.75(s,1H,ArH),7.71(s,1H,ArH),7.46(t,J＝8.3Hz,1H,ArH),7.36(t,J＝8.3Hz,1H,ArH),6.90(d,J＝8.4Hz,1H,ArH),6.85(d,J＝8.9Hz,1H,ArH),6.70(d,J＝8.2Hz,1H,ArH),6.61(s,1H,ArH),6.49(d,J＝8.3Hz,1H,ArH),6.35(d,J＝8.2Hz,1H,ArH),5.61(s,1H,C-CH),3.84(s,3H,ArOCH3),3.77(s,3H,ArOCH3),3.59(s,3H,ArOCH3);13C NMR(150MHz,CDCl3):δ＝195.3,192.9,176.3,160.8,159.9,158.4,157.8,157.5,152.9,138.8,137.1,136.5,133.6,123.4,119.8,119.8,114.5,114.5,110.6,109.9,106.4,102.8,101.8,56.3,55.9,55.6,29.9;HRMS(TOF ES+):m/z calcd for C27H23N2O7[(M+H)+],487.1500,found,487.1500.
Example 7: the difference is that the compound 1 is (E) -3- (dimethylamino) -1- (4-fluoro-2-hydroxyphenyl) prop-2-en-1-one, and the structure, morphology, melting point, nuclear magnetism and high resolution mass spectrum data of 3g of the obtained product are as follows;
V Petroleum ether /V Acetic acid ethyl ester ＝10:1,Rf = 0.25; red solid 40mg yield 86%; melting point ＝196-197℃;1H NMR(600MHz,CDCl3):δ＝12.15(s,1H,OH),8.27-8.23(m,1H,ArH),8.03-8.00(m,1H,ArH),7.98(s,1H,C＝CH),7.35(d,J＝8.9Hz,2H,ArH),6.96(d,J＝8.9Hz,2H,ArH),6.81(t,J＝7.3Hz,1H,ArH),6.76(d,J＝10.2Hz,1H,ArH),6.69(t,J＝8.5Hz,1H,ArH),6.65(d,J＝9.6Hz,1H,ArH),6.43(s,1H,C-CH),3.83(s,3H,ArOCH3);13C NMR(150MHz,CDCl3):δ＝191.7,179.9,167.9(C-F,J＝258.2Hz),167.9(C-F,J＝256.7Hz),166.5(C-F,J＝15.1Hz),159.3(C-F,J＝13.6Hz),158.4,139.9,135.9,135.7(C-F,J＝11.7Hz),129.9(C-F,J＝11.4Hz),129.2,120.4,120.4,120.2(C-F,J＝2.5Hz),115.5(C-F,J＝1.5Hz),114.8,114.8,110.7(C-F,J＝22.7Hz),109.1,107.5(C-F,J＝22.6Hz),105.4(C-F,J＝24.5Hz),105.1(d,J＝23.6Hz),64.7,55.6;HRMS(TOF ES+):m/z calcd for C25H17F2N2O5[(M+H)+],463.1100,found,436.1104.
Example 8: the difference is that the compound 1 is (E) -3- (dimethylamino) -1- (4-bromo-2-hydroxyphenyl) prop-2-en-1-one, and the obtained product 3h has the following structure, morphology, melting point, nuclear magnetism and high resolution mass spectrum data;
V Petroleum ether /V Acetic acid ethyl ester ＝10:1,Rf = 0.25; yellow solid 27mg yield 47%; melting point ＝210-211℃;1H NMR(600MHz,CDCl3):δ＝11.87(s,1H,OH),8.07(d,J＝8.7Hz,1H,ArH),7.97(s,1H,C＝CH),7.84(d,J＝8.4Hz,1H,ArH),7.34(d,J＝8.9Hz,2H,ArH),7.28(s,1H,ArH),7.23(d,J＝8.5Hz,1H,ArH),7.17(s,1H,ArH),7.11(d,J＝8.6Hz,1H,ArH),6.96(d,J＝8.9Hz,2H,ArH),6.40(s,1H,C-CH),3.84(s,3H,ArOCH3);13C NMR(150MHz,CDCl3):δ＝192.3,180.4,164.2,158.5,157.7,139.9,135.8,134.0,131.9,131.1,129.3,128.6,125.9,122.7,122.3,121.7,121.7,120.4,120.4,117.3,114.9,114.9,109.3,64.5,55.7;HRMS(TOF ES+):m/z calcd for C25H17Br2N2O5[(M+H)+],582.9499,found,582.9493.
Example 9: the difference is that the compound 1 is (E) -3- (dimethylamino) -1- (2-hydroxy-4- (thiophene-2-yl) phenyl) prop-2-en-1-one, and the structure, morphology, melting point, nuclear magnetism and high resolution mass spectrum data of the obtained product 3i are as follows;
V Petroleum ether /V Acetic acid ethyl ester ＝7:1,Rf = 0.25; yellow solid 22mg yield 37%; melting point ＝194-195℃;1H NMR(600MHz,CDCl3):δ＝12.03(s,1H,OH),8.23(d,J＝9.7Hz,1H,C＝CH),8.01(s,1H,C＝CH),8.00(d,J＝8.5Hz,1H,C＝CH),7.52(d,J＝2.8Hz,1H,C＝CH),7.43(s,2H,ArH),7.39(d,J＝8.9Hz,2H,ArH),7.37(s,1H,ArH),7.34(d,J＝8.2Hz,2H,ArH),7.24(d,J＝6.7Hz,1H,C＝CH),7.21(s,1H,ArH),7.15(t,J＝3.0Hz,1H,C＝CH),7.11(t,J＝4.5Hz,1H,C＝CH),6.97(d,J＝9.1Hz,2H,ArH),6.45(s,1H,C-CH),3.84(s,3H,ArOCH3);13C NMR(150MHz,CDCl3):δ＝192.2,180.5,164.4,158.3,157.9,142.5,142.5,142.5,142.3,140.3,136.1,133.9,128.9,128.5,128.4,128.1,127.5,127.1,125.7,125.3,122.1,120.3,120.3,119.8,117.4,116.6,114.8,114.8,114.7,114.5,109.5,64.4,55.7;HRMS(TOF ES+):m/z calcd for C33H23N2O5S2[(M+H)+],591.1043,found,591.1049.
Example 10: the difference is that the compound 1 is (E) -3- (dimethylamino) -1- (5-chloro-2-hydroxy-4-methylphenyl) prop-2-en-1-one, and the structure, morphology, melting point, nuclear magnetism and high resolution mass spectrum data of the obtained product 3j are as follows;
v Petroleum ether /V Acetic acid ethyl ester ＝10:1,Rf = 0.25; yellow solid 44mg yield 84%; melting point ＝200-201℃;1H NMR(600MHz,CDCl3):δ＝11.69(s,1H,OH),8.28(s,1H,C＝CH),7.95(d,J＝19.8Hz,2H,ArH),7.38(d,J＝9.2Hz,2H,ArH),6.97(d,J＝9.8Hz,3H,ArH),6.86(s,1H,ArH),6.34(s,1H,C-CH),3.84(s,3H,ArOCH3),2.42(s,3H,ArCH3),2.37(s,3H,ArCH3);13C NMR(150MHz,CDCl3):δ＝191.3,179.9,162.2,158.5,155.7,146.4,145.9,139.9,135.9,132.7,129.3,128.5,127.0,124.4,122.3,120.5,120.4,120.4,120.4,117.1,114.8,114.8,109.5,64.1,55.6,20.9,20.9;HRMS(TOF ES+):m/z calcd for C27H21Cl2N2O5[(M+H)+],523.0822,found,523.0829.
Example 11: the difference is that the compound 1 is (E) -3- (dimethylamino) -1- (2-hydroxy-4, 5-dimethylphenyl) prop-2-en-1-one, and the structure, morphology, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 3k are as follows;
V Petroleum ether /V Acetic acid ethyl ester ＝10:1,Rf = 0.25; yellow solid, 42mg yield 87%; melting point ＝186-187℃;1H NMR(600MHz,CDCl3):δ＝11.95(s,1H,OH),7.98(s,1H,C＝CH),7.87(s,1H,ArH),7.62(s,1H,ArH),7.37(d,J＝9.0Hz,2H,ArH),7.27(s,1H,ArH),7.19(s,1H,ArH),6.96-6.92(m,2H,ArH),6.29(s,1H,C-CH),3.83(s,3H,ArOCH3),2.32(s,3H,ArCH3),2.30(s,6H,ArCH3),2.07(s,3H,ArCH3);13C NMR(150MHz,CDCl3):δ＝193.4,181.7,160.1,158.1,153.9,140.6,139.1,138.6,136.2,131.1,130.5,128.8,127.7,127.2,127.1,124.4,122.9,120.1,120.1,117.6,114.7,114.7,109.6,64.2,55.6,20.7,20.6,15.6,15.5;HRMS(TOF ES+):m/z calcd for C29H27N2O5[(M+H)+],483.1914,found,483.1911.
Example 12: the difference is that the compound 1 is (E) -3- (dimethylamino) -1- (1-hydroxynaphthalene-2-yl) prop-2-en-1-one, and the structure, morphology, melting point, nuclear magnetism and high resolution mass spectrum data of the obtained 3l product are as follows;
V Petroleum ether /V Acetic acid ethyl ester ＝10:1,Rf = 0.25; yellow solid 48mg yield 91%; melting point ＝180-181℃;1H NMR(600MHz,CDCl3):δ＝8.57(d,J＝8.3Hz,1H,ArH),8.26(d,J＝8.9Hz,1H,ArH),8.18(s,1H,C＝CH),8.09(d,J＝8.3Hz,1H,ArH),7.99(d,J＝8.8Hz,1H,ArH),7.83-7.78(m,2H,ArH),7.70(t,J＝7.7Hz,1H,ArH),7.60(s,2H,ArH),7.49(d,J＝8.7Hz,1H,ArH),7.45(t,J＝7.7Hz,1H,ArH),7.35(d,J＝8.4Hz,2H,ArH),7.10(s,2H,ArH),6.83(d,J＝8.4Hz,1H,ArH),6.57(s,1H,C-CH),3.84(s,3H,ArOCH3);13C NMR(150MHz,CDCl3):δ＝192.5,180.8,164.9,160.7,155.7,143.6,140.1,137.8,137.6,130.8,130.5,129.9,128.1,127.8,127.5,126.7,126.5,126.1,125.2,124.9,124.6,123.8,122.0,121.9,118.3,117.9,112.4,112.1,110.1,109.6,104.2,65.1,55.5;HRMS(TOF ES+):m/z calcd for C33H23N2O5[(M+H)+],527.1601,found,527.1597.
Example 13: the difference is that the compound 1 is (E) -3- (dimethylamino) -1- (2-hydroxyphenyl) prop-2-en-1-one, and the structure, morphology, melting point, nuclear magnetism and high resolution mass spectrum data of the obtained product 3m are as follows;
V Petroleum ether /V Acetic acid ethyl ester ＝10:1,Rf = 0.25; yellow solid 33mg yield 82%; melting point ＝163-164℃;1H NMR(600MHz,CDCl3):δ＝11.80(s,1H,OH),8.21(d,J＝8.1Hz,1H,ArH),8.10(s,1H,C＝CH),8.00(d,J＝7.9Hz,1H,ArH),7.58(t,J＝7.9Hz,1H,ArH),7.52(t,J＝7.8Hz,1H,ArH),7.45(d,J＝8.1Hz,4H,ArH),7.31-7.27(m,1H,ArH),7.10(d,J＝7.6Hz,2H,ArH),6.99(t,J＝7.2Hz,1H,ArH),6.95(d,J＝8.1Hz,1H,ArH),6.40(s,1H,C-CH);13C NMR(150MHz,CDCl3):δ＝193.3,181.1,163.9,157.7,142.4,140.7,137.2,136.7,133.3,129.8,129.8,128.5,127.4,126.6,123.4,122.4,119.1,118.6,118.5,118.5,118.3,118.3,109.9,64.2;HRMS(TOF ES+):m/z calcd for C24H17N2O4[(M+H)+],397.1183,found,397.1188.
Example 14: the difference is that the compound 2 is 4-methylphenyl diazonium tetrafluoroborate, and the structure, morphology, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 3n are as follows;
v Petroleum ether /V Acetic acid ethyl ester ＝10:1,Rf = 0.25; yellow solid, 23mg yield 56%; melting point ＝175-176℃;1H NMR(600MHz,CDCl3):δ＝11.82(s,1H,OH),8.21(d,J＝7.8Hz,1H,ArH),8.06(s,1H,C＝CH),8.00(d,J＝7.5Hz,1H,ArH),7.58(t,J＝7.5Hz,1H,ArH),7.52(t,J＝7.1Hz,1H,ArH),7.34(d,J＝8.2Hz,2H,ArH),7.23(d,J＝8.1Hz,2H,ArH),7.09(d,J＝8.1Hz,2H,ArH),6.99-6.93(m,2H,ArH),6.41(s,1H,C-CH),2.37(s,3H,ArCH3);13C NMR(150MHz,CDCl3):δ＝193.2,181.2,163.8,157.6,140.4,140.2,137.1,136.6,136.6,133.3,130.2,130.2,128.6,127.4,123.4,122.3,118.9,118.5,118.5,118.4,118.4,118.4,109.7,64.2,20.9;HRMS(TOF ES+):m/z calcd for C25H19N2O4[(M+H)+],411.1339,found,411.1332.
Example 15: the difference is that the compound 2 is 3, 5-dimethylphenyl diazonium tetrafluoroborate, and the structure, morphology, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 3o are as follows;
V Petroleum ether /V Acetic acid ethyl ester ＝10:1,Rf = 0.25; yellow solid 29mg yield 70%; melting point ＝166-167℃;1H NMR(600MHz,CDCl3):δ＝11.83(s,1H,OH),8.23(d,J＝7.8Hz,1H,ArH),8.05(s,1H,C＝CH),8.00(d,J＝7.5Hz,1H,ArH),7.57(t,J＝7.5Hz,1H,ArH),7.51(t,J＝7.3Hz,1H,ArH),7.23(s,1H,ArH),7.18(s,2H,ArH),7.10(t,J＝7.7Hz,2H,ArH),6.98(t,J＝7.6Hz,1H,ArH),6.94(d,J＝8.3Hz,1H,ArH),6.40(s,1H,C-CH),2.30(s,3H,ArCH3),2.27(s,3H,ArCH3);13C NMR(150MHz,CDCl3):δ＝193.3,181.2,163.8,157.6,140.4,140.3,138.2,137.1,136.6,135.3,133.4,130.6,128.8,127.3,123.39,122.3,119.6,118.9,118.5,118.5,118.4,115.9,109.6,64.3,20.1,19.3;HRMS(TOF ES+):m/z calcd for C26H21N2O4[(M+H)+],425.1496,found,425.1496.
Example 16: the difference is that the compound 2 is 3, 5-dimethoxy phenyl diazonium tetrafluoroborate, and the structure, morphology, melting point, nuclear magnetism and high resolution mass spectrum data of the obtained product 3p are as follows;
V Petroleum ether /V Acetic acid ethyl ester ＝10:1,Rf = 0.25; yellow solid, 33mg yield 72%; melting point ＝130-131℃;1H NMR(600MHz,CDCl3):δ＝11.84(s,1H,OH),8.27(d,J＝9.0Hz,1H,ArH),7.99(d,J＝7.7Hz,1H,ArH),7.85(s,1H,C＝CH),7.56-7.49(m,2H,ArH),7.10-7.05(m,2H,ArH),6.97-6.92(m,4H,ArH),6.89-6.86(m,1H,ArH),6.41(s,1H,C-CH),3.88(s,3H,ArOCH3),3.77(s,3H,ArOCH3);13C NMR(150MHz,CDCl3):δ＝193.4,181.3,163.8,157.7,153.7,146.5,140.4,137.0,136.5,133.5,132.8,132.0,127.4,123.6,122.2,118.8,118.6,118.5,118.4,114.3,113.2,111.0,108.1,63.9,56.4,55.9;HRMS(TOF ES+):m/z calcd for C26H21N2O6[(M+H)+],457.1394,found,457.1398.
Example 17: the difference is that the compound 2 is 2- (benzyloxy) phenyl diazonium tetrafluoroborate, and the structure, the morphology, the melting point, the nuclear magnetism and the high resolution mass spectrum data of the obtained product 3q are as follows;
V Petroleum ether /V Acetic acid ethyl ester ＝8:1,Rf = 0.25; yellow solid, 18mg yield 35%; melting point ＝200-201℃;1H NMR(600MHz,CDCl3):δ＝8.30(d,J＝7.5Hz,1H,ArH),8.09(s,1H,C＝CH),8.03(d,J＝7.3Hz,1H,ArH),7.70(t,J＝7.4Hz,1H,ArH),7.57(d,J＝7.4Hz,2H,ArH),7.49(d,J＝8.4Hz,2H,ArH),7.44(t,J＝7.6Hz,3H,ArH),7.37-7.32(m,2H,ArH),7.11(t,J＝7.5Hz,1H,ArH),7.00(d,J＝8.2Hz,1H,ArH),6.90(d,J＝6.9Hz,2H,ArH),6.84-6.80(m,1H,ArH),6.57(s,1H,C-CH),5.25(s,2H,CH2);13C NMR(150MHz,CDCl3):δ＝178.3,176.1,159.1,156.3,154.9,146.0,136.7,135.8,133.9,132.3,128.8,128.7,128.7,127.9,127.6,126.9,126.9,126.2,125.5,124.1,123.5,123.2,122.9,122.4,121.7,118.3,118.3,113.9,112.4,75.5,70.4;HRMS(TOF ES+):m/z calcd for C31H23N2O5[(M+H)+],503.1601,found,503.1604.
Example 18: the difference is that the compound 2 is 2-fluorophenyl diazonium tetrafluoroborate, and the structure, the morphology, the melting point, the nuclear magnetism and the high-resolution mass spectrum data of the obtained product 3r are as follows;
V Petroleum ether /V Acetic acid ethyl ester ＝10:1,Rf = 0.25; yellow solid 16mg yield 39%; melting point ＝202-203℃;1H NMR(600MHz,CDCl3):δ＝11.78(s,1H,OH),8.21(d,J＝7.3Hz,1H,ArH),7.99(d,J＝6.9Hz,1H,ArH),7.84(s,1H,C＝CH),7.56(t,J＝7.6Hz,1H,ArH),7.52(t,J＝7.7Hz,1H,ArH),7.44(t,J＝7.7Hz,1H,ArH),7.34(q,J＝7.2Hz,1H,ArH),7.26-7.20(m,2H,ArH),7.11-7.06(m,2H,ArH),6.98-6.93(m,2H,ArH),6.40(s,1H,C-CH);13C NMR(150MHz,CDCl3):δ＝193.2,180.92,163.9,157.7,155.0(C-F,J＝251.3Hz),141.1,137.3,136.6,133.3,131.5(C-F,J＝5.1Hz),130.9(C-F,J＝9.6Hz),129.3(C-F,J＝7.7Hz),127.4,125.1(C-F,J＝3.9Hz),124.9,123.4,122.4,119.1,118.5,118.4,118.4,117.3(C-F,J＝19.9Hz),109.1,63.8;HRMS(TOF ES+):m/z calcd for C24H16FN2O4[(M+H)+],415.1089,found,415.1090.
Example 19: the difference is that the compound 2 is 3-chlorphenyl diazonium tetrafluoroborate, the structure, the morphology, the melting point, the nuclear magnetism and the high-resolution mass spectrum data of the obtained product 3s are as follows, and the single crystal structure diagram of the compound 3s is shown in figure 1;
V Petroleum ether /V Acetic acid ethyl ester ＝10:1,Rf = 0.25; yellow solid, 35mg yield 81%; melting point ＝215-216℃;1H NMR(600MHz,CDCl3):δ＝8.30(d,J＝7.6Hz,1H,ArH),8.13(s,1H,C＝CH),8.00(d,J＝7.5Hz,1H,ArH),7.72(t,J＝7.3Hz,1H,ArH),7.52(t,J＝8.0Hz,2H,ArH),7.46(t,J＝7.6Hz,1H,ArH),7.16-7.11(m,3H,ArH),7.03(d,J＝8.2Hz,1H,ArH),6.93(d,J＝7.0Hz,2H,ArH),6.48(s,1H,C-CH);13C NMR(150MHz,CDCl3):δ＝179.2,176.1,159.5,156.3,154.6,143.7,136.4,135.3,134.1,130.3,129.3,127.5,126.2,125.6,124.0,123.4,122.8,122.7,122.6,118.3,118.3,114.7,112.9,75.8;HRMS(TOF ES+):m/z calcd for C24H16ClN2O4[(M+H)+],431.0793,found,437.0787.
Example 20: the difference is that the compound 2 is 4-chlorophenyl diazotetrafluoroborate, and the structure, morphology, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 3t are as follows;
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V Petroleum ether /V Acetic acid ethyl ester ＝10:1,Rf = 0.25; yellow solid 34mg yield 78%; melting point ＝194-195℃;1H NMR(600MHz,CDCl3):δ＝11.75(s,1H,OH),8.15(d,J＝7.6Hz,1H,ArH),8.05(s,1H,C＝CH),7.99(d,J＝7.1Hz,1H,ArH),7.61-7.58(m,1H,ArH),7.53-7.50(m,1H,ArH),7.40(s,4H,ArH),7.13-7.09(m,2H,ArH),7.00-6.97(m,1H,ArH),6.94(d,J＝8.2Hz,1H,ArH),6.37(s,1H,C-CH);13C NMR(150MHz,CDCl3):δ＝193.1,180.9,163.9,157.7,140.9,137.3,136.7,133.1,131.9,129.8,129.8,127.9,127.4,123.2,122.4,119.3,119.3,119.1,118.6,118.5,118.4,115.8,110.0,64.1;HRMS(TOF ES+):m/z calcd for C24H16ClN2O4[(M+H)+],431.0793,found,431.0793.
Example 21: the difference is that the compound 2 is 3-bromophenyl diazonium tetrafluoroborate, and the structure, morphology, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 3u are as follows;
V Petroleum ether /V Acetic acid ethyl ester ＝10:1,Rf = 0.25; yellow solid, 42mg yield 88%; melting point ＝174-175℃;1H NMR(600MHz,CDCl3):δ＝11.75(s,1H,OH),8.15(d,J＝7.7Hz,1H,ArH),8.06(s,1H,C＝CH),8.00(d,J＝7.5Hz,1H,ArH),7.64(s,1H,ArH),7.62-7.58(m,1H,ArH),7.54-7.51(m,1H,ArH),7.40(d,J＝7.3Hz,2H,ArH),7.32-7.29(m,1H,ArH),7.11(d,J＝6.7Hz,2H,ArH),7.02-6.99(m,1H,ArH),6.95(d,J＝8.1Hz,1H,ArH),6.37(s,1H,C-CH);13C NMR(150MHz,CDCl3):δ＝193.0,180.9,163.9,157.7,143.3,141.1,137.4,136.7,133.1,130.9,129.4,127.8,127.4,123.4,123.2,122.5,121.3,119.1,118.5,118.5,118.4,116.5,110.2,64.1;HRMS(TOF ES+):m/z calcd for C24H16BrN2O4[(M+H)+],475.0288,found,475.0294.
Example 22: the difference is that the compound 2 is 3-cyano phenyl diazonium tetrafluoroborate, and the structure, morphology, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 3v are as follows;
V Petroleum ether /V Acetic acid ethyl ester ＝5:1,Rf = 0.25; yellow solid, 37mg yield 89%; melting point ＝186-187℃;1H NMR(600MHz,CDCl3):δ＝8.29(d,J＝7.8Hz,1H,ArH),8.16(s,1H,C＝CH),8.00(d,J＝7.7Hz,1H,ArH),7.73(t,J＝7.7Hz,1H,ArH),7.53(t,J＝8.3Hz,2H,ArH),7.48(t,J＝7.4Hz,1H,ArH),7.34(s,1H,ArH),7.30(t,J＝7.9Hz,1H,ArH),7.24-7.21(m,2H,ArH),7.14(t,J＝7.4Hz,1H,ArH),7.03(d,J＝8.2Hz,1H,ArH),6.43(s,1H,C-CH);13C NMR(150MHz,CDCl3):δ＝178.4,174.9,158.7,155.3,153.6,142.3,135.6,133.2,129.4,129.1,126.6,125.5,124.9,124.8,122.9,121.6,121.5,121.5,117.7,117.4,117.3,117.2,116.4,112.3,74.9;HRMS(TOF ES+):m/z calcd for C25H16N3O4[(M+H)+],422.1135,found,422.1129.
Example 23: the difference is that the compound 2 is 2- (4-fluorobenzoyl) phenyl diazonium tetrafluoroborate, and the structure, morphology, melting point, nuclear magnetism and high-resolution mass spectrum data of the obtained product 3w are as follows;
V Petroleum ether /V Acetic acid ethyl ester ＝7:1,Rf = 0.25; yellow solid 21mg yield 40%; melting point ＝203-204℃;1H NMR(600MHz,CDCl3):δ＝8.30(d,J＝7.6Hz,1H,ArH),8.13(d,J＝7.8Hz,1H,ArH),8.11(s,1H,C＝CH),7.80-7.77(m,2H,ArH),7.71(d,J＝7.3Hz,1H,ArH),7.65(d,J＝8.3Hz,1H,ArH),7.52-7.44(m,4H,ArH),7.37(t,J＝7.5Hz,1H,ArH),7.16-7.09(m,3H,ArH),7.01(d,J＝8.2Hz,1H,ArH),6.96(t,J＝7.3Hz,1H,ArH),6.56(s,1H,C-CH);13C NMR(150MHz,CDCl3):δ＝196.30,178.16,175.98,165.15(C-F,J＝253.8Hz),159.47,156.34,154.77,144.84,136.28,134.95(C-F,J＝3.0Hz),134.06(C-F,J＝14.6Hz),133.14,132.63(C-F,J＝9.1Hz),131.23,128.17,126.15,125.55,124.04,122.87(C-F,J＝26.9Hz),122.57,121.24,121.12,118.30,118.27,115.33(d,J＝21.8Hz),115.31,75.78;HRMS(TOF ES+):m/z calcd for C31H20FN2O5[(M+H)+],519.1351,found,519.1353.
Example 24: the difference is that the compound 2 is (-) -camphoric acid derived diazonium tetrafluoroborate, and the structure, morphology, melting point, nuclear magnetism and high resolution mass spectrum data of the obtained product 3x are as follows;
v Petroleum ether /V Acetic acid ethyl ester ＝5:1,Rf = 0.25; yellow solid, 20mg yield 33%; melting point ＝196-198℃;1H NMR(600MHz,CDCl3):δ＝13.97(s,1H,OH),8.28(d,J＝7.9Hz,1H,ArH),8.12(s,1H,NH),8.04(s,1H,C＝CH),7.99(d,J＝7.8Hz,1H,ArH),7.72(s,1H,ArH),7.53-7.42(m,4H,ArH),7.16-6.99(m,5H,ArH),6.50(s,1H,C-CH),2.58(d,J＝8.9Hz,1H,CH2),1.98(t,J＝11.6Hz,2H,CH2),1.74(d,J＝11.3Hz,1H,CH2),1.14(s,6H,CH3),0.95(s,3H,CH3);13C NMR(150MHz,CDCl3):δ＝178.8,177.9,175.9,164.9,159.3,156.3,154.7,139.4,136.1,133.9,132.6,128.4,127.4,126.1,125.5,123.9,122.9,122.7,122.5,121.0,121.0,118.2,118.2,115.2,115.2,92.4,75.5,55.4,54.4,30.4,29.0,16.7,16.6,9.7;HRMS(TOF ES+):m/z calcd for C34H30N3O7[(M+H)+],592.2078,found,592.2077.
Example 25: in vitro anti-coronavirus Activity assay
Abidol hydrochloride tablet (ARB, 0.1 g/tablet) (Europeanism pharmaceutical Co., ltd.) mainly for influenza caused by influenza A and B virus, and also has antiviral activity for other respiratory tract virus infection;
HCoV-OC43 cells (cultured by the Charpy molecular virology topic group of the university of Kunming university, ming and technology school);
the test drug prepared in the embodiment of the invention is used as an in vitro anti-coronavirus drug efficacy evaluation test, and the steps are shown in references Phytomedicine and 2021,93,153808; representative chromone pyridazines were selected for anti-coronavirus testing and the results are shown in Table 1;
TABLE 1 anti-coronavirus Activity test
As can be seen from Table 1, compounds 3b and 3g show higher anti-coronavirus activity, have similar antiviral activity to that of the anti-control drug Abidol on the market, and have lower cytotoxicity, and can be used for developing medicaments for treating, preventing and relieving related diseases caused by coronaviruses.

Claims (9)

1. Chromone pyridazine compounds with the structural formula shown in the specification:
Wherein Ar 1 is selected from substituted or unsubstituted aryl, and the substituent is alkyl, alkoxy, halogen, aryl and heteroaryl; ar 2 is selected from substituted or unsubstituted aryl, and the substituent is alkyl, alkoxy, benzyloxy, halogen, cyano, benzoyl and amide.
2. The chromopyridazine compound according to claim 1, wherein the compound has any one of the following structures:
3. the chromopyridazine compound according to claim 1, wherein: also comprises pharmaceutically acceptable salts and stereoisomers of the chromone pyridazine compounds.
4. The method for synthesizing the chromone pyridazine compound according to claim 1, which is characterized in that: in the presence of a solvent, the o-hydroxyaryl ketene and aryl diazonium salt react at 25-70 ℃, and the reaction progress is monitored by thin layer chromatography until the reaction is complete; extracting with ethyl acetate and water for 3-4 times, collecting and combining organic phases, washing with saturated saline water, collecting the organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying the concentrate by silica gel column chromatography or recrystallization to obtain chromone pyridazine compounds;
5. The method for synthesizing the chromone pyridazine compound according to claim 4, wherein the method comprises the following steps: during synthesis, additives are also added, wherein the additives are selected from difluoroacetic acid, trifluoroacetic acid, n-butyric acid, acetic acid, cyanoacetic acid, isobutyric acid, malonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, succinic anhydride, isobutyric anhydride, benzoic anhydride, acetic anhydride, trifluoroacetic anhydride, propionic anhydride and n-valeric anhydride, and the molar ratio of the o-hydroxyaryl enaminone to the additives is 2:1-3.
6. The method for synthesizing the chromone pyridazine compound according to claim 4, wherein the method comprises the following steps: the solvent is selected from 1, 4-dioxane, dimethyl sulfoxide, acetonitrile, toluene, acetone, xylene, and dichloromethane.
7. The method for synthesizing the chromone pyridazine compound according to claim 4, wherein the method comprises the following steps: the molar ratio of the o-hydroxyaryl enaminone to the aryl diazonium salt is 2-4:1.
8. The method for synthesizing the chromone pyridazine compound according to claim 4, wherein the method comprises the following steps: the reaction is carried out under an inert atmosphere, an air atmosphere or an oxygen atmosphere.
9. Use of a chromone pyridazine compound according to claim 1 for the preparation of a coronavirus inhibitor.
CN202410150414.6A 2024-02-02 Chromone pyridazine compound and synthetic method and application thereof Pending CN118221690A (en)

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