Benzofuran pyran compound as well as synthesis method and application thereof

Abstract

The invention discloses a benzofuranopyran compound as well as a synthesis method and application thereof, and belongs to the field of organic chemical synthesis. The invention aims to provide a benzofuranopyran compound. The benzofuranopyran compound has certain cytotoxic activity on human cervical cancer Hela cells. Another purpose of the invention is to provide a synthesis method of the benzofuranopyran compound. The method has the advantages of mild reaction conditions, low cost and high yield. The method comprises the following steps: by taking # imgabs 1 # and malononitrile as reaction raw materials, ethyl acetate as a reaction solvent and N, N-diisopropylethylamine as an accelerant, carrying out stirring reaction, tracking the reaction by TLC until the reaction is complete, filtering, concentrating filtrate, and purifying to obtain the benzofuranopyran compound. The invention relates to an application of a benzofuranopyran compound in preparation of a medicine for inhibiting human cervical cancer Hela cells. According to the invention, the benzofuranopyran compound can be obtained.

Description

Technical Field

[0001] The invention belongs to the field of organic chemical synthesis, and specifically relates to a benzofuranopyran compound and a synthesis method and application thereof. Background Art

[0002] The benzofuranopyran skeleton is a special core structure in natural products and drugs with multiple biological activities. For example, the literature RSC Adv., 2015, 5, 96809 reported that this type of compound has strong α-glucosidase and anticholinesterase inhibitory effects; the literature Eur. J. Med. Chem., 2019, 162, 266 reported that this type of compound has potential inhibitory activity against intestinal cancer; the literature RSC Adv., 2019, 9, 27510 reported that this type of compound has anti-tumor activity.

[0003] Benzofuranopyran compounds have broad application prospects in the field of life sciences, so there is an urgent need to design and develop methods for efficiently constructing benzofuranopyran skeleton compounds and synthesizing benzofuranopyran compounds. Summary of the invention

[0004] The purpose of the present invention is to provide a benzofuranopyran compound, which has certain cytotoxic activity against human cervical cancer Hela cells;

[0005] Another object of the present invention is to provide a method for synthesizing the above-mentioned benzofuranopyran compound, which has mild reaction conditions, low cost and high yield.

[0006] A benzofuranopyran compound has a chemical structural formula of In the formula, R is selected from one of phenyl, o-methoxyphenyl, o-nitrophenyl, m-methylphenyl, m-chlorophenyl, m-nitrophenyl, p-methylphenyl, p-methoxyphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-nitrophenyl, 3,4-dichlorophenyl and 2-thienyl; R 1 One selected from the group consisting of hydrogen, 5-fluoro, 5-bromo, 6-methyl and 6-chloro.

[0007] A method for synthesizing a benzofuranopyran compound is specifically completed by the following steps:

[0008] Will and malononitrile as the reaction raw materials, ethyl acetate as the reaction solvent, N,N-diisopropylethylamine as the promoter, stirring the reaction, tracking the reaction to completion by TLC, filtering, concentrating the filtrate, and purifying to obtain a benzofuranopyran compound.

[0009] The reaction route is as follows:

[0010]

[0011] A benzofuranopyran compound is used in the preparation of a drug for inhibiting human cervical cancer Hela cells.

[0012] Advantages of the present invention:

[0013] 1. A benzofuranopyran compound of the present invention has certain cytotoxic activity against human cervical cancer Hela cells through biological activity tests, indicating that the benzofuranopyran compound synthesized by the present invention has application value in the research and development of new anti-tumor drugs. A method for synthesizing a benzofuranopyran compound of the present invention uses N,N-diisopropylethylamine as a promoter in the process of synthesizing the benzofuranopyran compound; the reaction conditions of the synthesis method are relatively conventional, the reaction process is mild, and it is suitable for industrial large-scale production, which broadens the scope of application of the method; a variety of substrates are used as reactants to obtain products with structural diversity and complexity, and the yield is high.

[0014] 2. The method of the present invention can not only realize the synthesis of benzofuranopyran compounds in one step, obtain excellent yield, high atom economy, environmental friendliness, and a wide range of applications, but also has readily available raw materials, simple and safe operation, mild reaction conditions, short reaction time, simple post-treatment, and diversified product structures, and thus has great implementation value and potential social and economic benefits. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 2-amino-4-phenyl-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 1 1 H NMR (400 MHz, CDCl3) graph;

[0016] Figure 2 2-amino-4-phenyl-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 1 13 C NMR (100 MHz, CDCl3) graph;

[0017] Figure 3 2-amino-4-(2-methoxyphenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 2 1 H NMR (400 MHz, CDCl3) graph;

[0018] Figure 4 2-amino-4-(2-methoxyphenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 2 13 C NMR (100 MHz, CDCl3) graph;

[0019] Figure 5 2-amino-4-(2-nitrophenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 3 1 H NMR (400 MHz, DMSO-d6) pattern;

[0020] Figure 6 2-amino-4-(2-nitrophenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 3 13 C NMR (100 MHz, DMSO-d6) pattern;

[0021] Figure 7 2-amino-4-(m-tolyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 4 1 H NMR (400 MHz, CDCl3) graph;

[0022] Figure 8 2-amino-4-(m-tolyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 4 13 C NMR (100 MHz, CDCl3) graph;

[0023] Fig. 9 2-amino-4-(3-chlorophenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 5 1 HNMR (400MHz, CDCl3) graph;

[0024] Fig.10 2-amino-4-(3-chlorophenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 5 13 C NMR (100 MHz, CDCl3) graph;

[0025] Fig.11 2-amino-4-(3-nitrophenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 6 1 H NMR (400 MHz, DMSO-d6) pattern;

[0026] Fig.12 2-amino-4-(3-nitrophenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 6 13 C NMR (100 MHz, DMSO-d6) pattern;

[0027] Fig.132-amino-4-(p-tolyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 7 1 H NMR (400 MHz, CDCl3) graph;

[0028] Fig.14 2-amino-4-(p-tolyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 7 13 C NMR (100 MHz, CDCl3) graph;

[0029] Fig.15 2-amino-4-(4-methoxyphenyl)-4H-pyrano[3,2-b]benzofuran-3-carbon prepared in Example 8 1 H NMR (400 MHz, CDCl3) graph;

[0030] Fig.16 2-amino-4-(4-methoxyphenyl)-4H-pyrano[3,2-b]benzofuran-3-carbon prepared in Example 8 13 C NMR (100 MHz, CDCl3) graph;

[0031] Fig.17 2-amino-4-(4-chlorophenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 9 1 H NMR (400 MHz, CDCl3) graph;

[0032] Fig.18 2-amino-4-(4-chlorophenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 9 13 C NMR (100 MHz, CDCl3) graph;

[0033] Fig.19 2-amino-4-(4-bromophenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 10 1 H NMR (400 MHz, CDCl3) graph;

[0034] Fig. 20 2-amino-4-(4-bromophenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 10 13 C NMR (100 MHz, CDCl3) graph;

[0035] Fig.21 2-amino-4-(4-fluorophenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 111 H NMR (400 MHz, CDCl3) graph;

[0036] Fig. 22 2-amino-4-(4-fluorophenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 11 13 C NMR (100 MHz, CDCl3) graph;

[0037] Fig.23 2-amino-4-(4-nitrophenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 12 1 H NMR (400 MHz, DMSO-d6) pattern;

[0038] Fig.24 2-amino-4-(4-nitrophenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 12 13 C NMR (100 MHz, DMSO-d6) pattern;

[0039] Fig.25 2-amino-4-(3,4-dichlorophenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 13 1 H NMR (400 MHz, CDCl3) graph;

[0040] Fig.26 2-amino-4-(3,4-dichlorophenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 13 13 C NMR (100 MHz, CDCl3) graph;

[0041] Fig. 27 2-amino-4-(thiophene-2-yl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 14 1 H NMR (400 MHz, CDCl3) graph;

[0042] Fig.28 2-amino-4-(thiophene-2-yl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 14 13 C NMR (100 MHz, CDCl3) graph;

[0043] Fig.29 2-amino-8-bromo-4-phenyl-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 15 1H NMR (400 MHz, DMSO-d6) pattern;

[0044] Fig.30 2-amino-8-bromo-4-phenyl-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 15 13 C NMR (100 MHz, DMSO-d6) pattern;

[0045] Fig.31 2-amino-8-fluoro-4-phenyl-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 16 1 H NMR (400 MHz, DMSO-d6) pattern;

[0046] Fig.32 2-amino-8-fluoro-4-phenyl-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 16 13 C NMR (100 MHz, DMSO-d 60 )picture;

[0047] Fig.33 2-amino-7-methyl-4-phenyl-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 17 1 H NMR (400 MHz, CDCl3) graph;

[0048] Fig.34 2-amino-7-methyl-4-phenyl-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 17 13 C NMR (100 MHz, CDCl3) graph;

[0049] Fig.35 2-amino-7-chloro-4-phenyl-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 18 1 H NMR (400 MHz, CDCl3) chart.

[0050] Fig.36 2-amino-7-chloro-4-phenyl-4H-pyrano[3,2-b]benzofuran-3-carbonitrile prepared in Example 18 13 C NMR (100 MHz, CDCl3) chart. DETAILED DESCRIPTION

[0051] Specific embodiment 1: This embodiment is a benzofuranopyran compound, whose chemical structure is wherein R is selected from the group consisting of phenyl, o-methoxyphenyl, o-nitrophenyl, m-methylphenyl, m-chlorophenyl, m-nitrophenyl, p-methylphenyl, p-methoxyphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-nitrophenyl, 3,4-dichlorophenyl and 2-thienyl; R 1 One selected from the group consisting of hydrogen, 5-fluoro, 5-bromo, 6-methyl and 6-chloro.

[0052] Specific embodiment 2: This embodiment differs from specific embodiment 1 in that the synthesis method is specifically completed according to the following steps:

[0053] Will and malononitrile as the reaction raw materials, ethyl acetate as the reaction solvent, N,N-diisopropylethylamine as the promoter, stirring the reaction, tracking the reaction by TLC until it is complete, filtering, concentrating the filtrate, and purifying to obtain a benzofuranopyran compound. The other steps are the same as those in the first embodiment.

[0054] Specific implementation method three: This implementation method is different from specific implementation method one or two in that: The preparation method is specifically completed according to the following steps:

[0055] At room temperature and under stirring, benzofuranone and aldehyde are added to dichloromethane, and activated alkaline alumina is added, and the reaction is stirred. The reaction is followed by TLC until it is complete, and the alumina is filtered, and the filter cake is washed with dichloromethane. The filtrate is concentrated to obtain a crude product, which is then chromatographed on a silica gel column, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1. Finally, a light yellow solid product is obtained by separation, which is

[0056] The structural formula of the benzofuranone is Where R 1 is selected from one of hydrogen, 5-fluoro, 5-bromo, 6-methyl and 6-chloro; the structural formula of the aldehyde is wherein R is selected from one of phenyl, o-methoxyphenyl, o-nitrophenyl, m-methylphenyl, m-chlorophenyl, m-nitrophenyl, p-methylphenyl, p-methoxyphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-nitrophenyl, 3,4-dichlorophenyl and 2-thienyl;

[0057] The molar volume ratio of the benzofuranone, aldehyde, activated basic alumina and dichloromethane is 1.0 mmol: 1.0 mmol: 5.0 mmol: 10 mL. The other steps are the same as those in the first or second embodiment.

[0058] Specific implementation method 4: This implementation method is different from specific implementation methods 1 to 3 in that: The molar ratio of the propylene glycol to malononitrile is 1:3. The other steps are the same as those in the first to third embodiments.

[0059] Specific embodiment 5: This embodiment differs from specific embodiments 1 to 4 in that the reaction temperature is 50° C. The other steps are the same as those of specific embodiments 1 to 4.

[0060] Specific embodiment 6: This embodiment differs from specific embodiments 1 to 5 in that the purification is performed by silica gel column chromatography, and the eluent is a mixture of petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate is 4:1. The other steps are the same as those of specific embodiments 1 to 5.

[0061] Specific embodiment 7: This embodiment differs from specific embodiments 1 to 6 in that: a benzofuranopyran compound is used in the preparation of a drug for inhibiting human cervical cancer Hela cells. The other steps are the same as those of specific embodiments 1 to 6.

[0062] The following examples are used to verify the beneficial effects of the present invention:

[0063] Embodiment 1: A method for synthesizing a benzofuranopyran compound is specifically completed by the following steps:

[0064] Add 0.1 mmol of (Formula 1a) and 0.3 mmol of malononitrile (Formula 2) as reactants, 0.2 mmol of DIPEA (N, N-diisopropylethylamine) as a promoter, react at 50°C for 8 hours, TLC tracking the reaction until completion, wash the filter cake with ethyl acetate, concentrate the obtained filtrate and separate it by silica gel column chromatography (eluent is a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 4:1), and obtain a benzofuranopyran compound as a yellow solid, and obtain 2-amino-4-phenyl-4H-pyrano[3,2-b]benzofuran-3-carbonitrile, that is, a benzofuranopyran compound (Formula 3), and the reaction equation is as follows:

[0065] Described in Example 1 Medium R 1 is H, R is Ph, the chemical name is (Z)-2-benzylidenebenzofuran-3(2H)-one, and the preparation method is specifically completed according to the following steps:

[0066] At room temperature and under stirring, benzofuranone and aldehyde are added to dichloromethane, and then activated alkaline alumina is added, and the reaction is stirred. TLC is used to track the reaction until it is complete, and the alumina is filtered, and the filter cake is washed with ethyl acetate. The filtrate is concentrated to obtain a crude product, and then the crude product is chromatographed on a silica gel column, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1. Finally, the product is separated to obtain a light yellow solid, which is The structural formula of the benzofuranone is Where R 1 is selected from hydrogen (H); the structural formula of the aldehyde is Wherein R is selected from phenyl (Ph);

[0067] The molar volume ratio of the benzofuranone, aldehyde, activated alkaline alumina and dichloromethane is 1.0 mmol: 1.0 mmol: 5.0 mmol: 10 mL.

[0068] 2-Amino-4-phenyl-4H-pyrano[3,2-b]benzofuran-3-carbonitrile (3a) prepared in Example 1:

[0069] Purified by flash column chromatography through silicagel (petroleum ether / EtOAc=4:1); 80% yield (23.1mg); yellow solid; mp203.7-204.5℃; 1 H NMR (400MHz, CDCl3): δ7.58–7.51(m,1H),7.35–7.39(m,3H),7.31–7.28(m,5H),5.00(s,1H),4.79(s,2H). 13 C NMR (100MHz, CDCl3): δ159.9,152.9,140.1,137.2,132.6,129.0,128.1,127.9,125.2,123.4,119.3, 118.8,117.4,112.2,61.9,39.4; IR(KBr):3334,3196,2920,2848,2195,1626,1300,1142,1007,747cm -1 ;ESI FTMS exact mass calcd for(C 18 H 12 N2O2+Na) + requires m / z 311.0797,found m / z 311.0795.

[0070] The difference between Example 2-18 and Example 1 is: R and R 1 Different, preparation Used when R and R 1 Different, the reaction raw materials in Example 2-18 R and R 1 As shown in Table 1, the products The yields are listed in Table 1;

[0071] Table 1 Reaction materials and yields of Examples 2-18

[0072]

[0073] As can be seen from Table 1, the method of the present invention can not only realize the synthesis of benzofuranopyran compounds in one step, obtain excellent yield, high atom economy, environmental friendliness, and a wide range of applications, but also has readily available raw materials, simple and safe operation, mild reaction conditions, short reaction time, simple post-treatment, and diversified product structures, and thus has great implementation value and potential social and economic benefits.

[0074] The X-ray single crystal data of 2-amino-4-phenyl-4H-pyrano[3,2-b]benzofuran-3-carbonitrile (3a) prepared in Example 1 are shown in Table 2;

[0075] Table 2

[0076]

[0077]

[0078] The benzofuranopyran compounds prepared by the present invention were tested for their cytotoxic activity against human cervical cancer Hela cells by the MTT method. The results are shown in Table 3. The results show that the compounds synthesized by the present invention have certain cytotoxic activity against human cervical cancer Hela cells. Among them, the most active one is compound 3f, which shows the strongest inhibitory effect (IC 50 =62.74 μg / mL), the solvent in the compound solutions in Table 3 was DMSO.

[0079] Table 3 Cytotoxic activity of the compounds of the present invention

[0080]

[0081] The chemical structural formulas and test data of the benzofuranopyran compounds prepared in Examples 2 to 18 are as follows:

[0082] 2-Amino-4-(2-methoxyphenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile (3b) prepared in Example 2: Purified by flash column chromatography through silica gel (petroleum ether / EtOAc=4:1); 76% yield (24.2mg); yellow solid; mp134.8-135.5℃; 1 H NMR (400MHz,CDCl3): 1 H NMR(400MHz,Chloroform-d)δ7.57–7.53(m,1H),7.39–7.36(m,1H),7.31–7.28(m,3 H),7.08(d,J=7.4Hz,1H),6.98–6.92(m,2H),5.56(s,1H),4.74(s,2H),3.92(s,3H). 13 C NMR (100MHz, CDCl3): δ160.3,157.3,152.7,137.5,133.0,129.1,128.4,124.9,123.2,121.0,119.6,119.0,11 7.2,112.2,111.3,61.7,55.9,32.2; IR(KBr):3340,3210,2921,2849,2194,1633,1402,1299,1142,1007,749cm -1 ;ESI FTMS exact masscalcd for(C 19 H 14 N2O3+Na) + requires m / z 341.0902,found m / z 341.0905.

[0083] 2-Amino-4-(2-nitrophenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile (3c) prepared in Example 3:

[0084] Purified by flash column chromatography through silicagel (petroleum ether / EtOAc=4:1); 50% yield (16.7mg); yellow solid; mp253.5-254.9℃; 1H NMR (400MHz, DMSO-d6): δ7.98(d,J=8.1Hz,1H),7.74–7.71(m,1H),7.60–7.51(m,4H),7.38–7.36(m,4H),5.68(s,1H). 13 C NMR (100MHz, DMSO-d6): δ161.6,152.6,149.7,136.4,134.9,134.3,132.9,131.6,129.7,126.0,124.9,124.2,12 0.0,118.7,117.8,112.7,56.0,55.4; IR(KBr):3200,2919,2849,2187,1651,1633,1403,1339,1262,1195,749cm -1 ;ESI FTMS exact mass calcd for(C 18 H 11 N3O4+Na) + requires m / z 356.0648,foundm / z 356.0647.

[0085] 2-Amino-4-(m-tolyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile (3d) prepared in Example 4: Purified by flash column chromatography through silica gel (petroleum ether / EtOAc=4:1); 72% yield (21.8mg); yellow solid; mp192.7-193.1℃; 1 H NMR (400MHz, CDCl3): δ7.60–7.54(m,1H),7.42–7.36(m,1H),7.33–7.28(m,3H),7.17–7.08(m,3H),4.97(s,1H),4.79(s,2H),2.37(s,3H). 13 C NMR (100MHz, CDCl3): δ159.9,152.8,140.0,138.7,137.3,132.5,131.0,128.9,128.8,128.6,125.1,123.3,119 .4,118.9,117.4,112.2,62.0,39.4,21.5; IR(KBr):3340,2921,2850,2360,1634,1463,1398,1265,1195,745cm-1 ;ESI FTMS exact mass calcd for(C19H14N2O2+Na) + requires m / z325.0953,found m / z 325.0959.

[0086] Example 5 Preparation of 2-amino-4-(3-chlorophenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile (3e): Purified by flash column chromatography through silica gel (petroleum ether / EtOAc=4:1); 70% yield (22.6mg); yellow solid; mp193.1-194.7℃; 1 H NMR (400MHz, CDCl3): δ7.58–7.51(m,1H),7.38–7.36(m,1H),7.33–7.29(m,2H),7 .29–7.26(m,2H),7.26-7.25(m,1H),7.22–7.20(m,1H),4.97(s,1H),4.85(s,2H). 13 C NMR (100MHz, CDCl3): δ160.2,152.9,142.1,136.4,134.9,132.7,130.2,128.4,128.1,126.3,125.4,123.5,119.1,118. 7,117.5,112.2,61.1,39.2; IR(KBr):3330,3196,2924,2853,2195,1627,1584,1401,1347,1273,1196,1142,1007,747cm -1 ;ESI FTMS exact mass calcdfor(C 18 H 11 ClN2O2+Na) + requires m / z 345.0407,found m / z 345.0413.

[0087] Example 6 Preparation of 2-amino-4-(3-nitrophenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile (3f): Purified by flash column chromatography through silicagel (petroleum ether / EtOAc=4:1); 84% yield (28.2mg); yellow solid; mp219.3-219.8℃; 1 H NMR (400MHz, DMSO-d6): δ8.20–8.18(m,2H),7.82–7.80(m,1H),7.72–7.68(m,1H),7.64–7.48(m,2H),7.37–7.33(m,4H),5.40(s,1H). 13 C NMR (100MHz, DMSO-d6): δ161.4,152.7,148.5,144.0,136.8,135.2,132.6,131.1,126.0,124.3,123.3,122.8,120. 2,118.8,117.9,112.7,56.4,55.4; IR(KBr):3330,3189,2920,2849,2191,1634,1403,1349,1271,1194,1143,748cm -1 ;ESI FTMS exact mass calcd for(C 18 H 11 N3O4+Na) + requires m / z356.0648,found m / z356.0648.

[0088] 2-Amino-4-(p-tolyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile (3 g) prepared in Example 7: Purified by flash column chromatography through silica gel (petroleum ether / EtOAc=4:1); 74% yield (22.3mg); yellow solid; mp152.6-153.4℃; 1 H NMR (400MHz, CDCl3): δ7.53(m,1H),7.37–7.32(m,1H),7.29–7.25(m,2H),7.20–7.15(m,4H),4.95(s,1H),4.77(s,2H),2.33(s,3H); 13C NMR (100MHz, CDCl3): δ159.9,152.8,137.8,137.4,137.1,132.5,130.0,129.8,129.7,129.6,127.8,125.1,123.3,119.5,1 18.9,117.4,112.2,62.0,39.0,21.2; IR(KBr):3334,3195,2924,2853,2195,1652,1450,1399,1301,1195,1142,1104,749cm -1 ;ESI FTMS exact mass calcd for(C 19 H 14 N2O2+Na) + requires m / z 325.0953,found m / z 325.0952.

[0089] 2-Amino-4-(4-methoxyphenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile (3h) prepared in Example 8: Purified by flash column chromatography through silicagel (petroleum ether / EtOAc=4:1); 57% yield (18.1mg); yellow solid; mp187.4-188.6℃; 1 H NMR (400MHz, CDCl3): δ7.56–7.51(m,1H),7.38–7.33(m,1H),7.30–7.25(m,2H),7. 21(d,J=8.4Hz,2H),6.89(d,J=8.0Hz,2H),4.95(s,1H),4.76(s,2H),3.79(s,3H); 13 CNMR (100MHz, CDCl3): δ159.8,159.3,152.8,137.4,132.4,132.3,132.1,129.0,125.1,123.3,119.4,118.9,117.4,114. 8,114.4,112.2,62.2,55.3,38.7; IR(KBr):3335,3197,2923,2851,2194,1511,1400,1302,1259,1176,1171,1031,750cm -1 ;ESI FTMS exact masscalcd for(C 19 H14 N2O3+Na) + requires m / z 341.0902,found m / z 341.0900.

[0090] 2-Amino-4-(4-chlorophenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile (3i) prepared in Example 9:

[0091] Purified by flash column chromatography through silicagel (petroleum ether / EtOAc=4:1); 70% yield (22.5mg); yellow solid; mp189.5-191.2℃; 1 H NMR (400MHz, CDCl3): δ7.60–7.55(m,1H),7.43–7.35(m,3H),7.34–7.32(m,2H),7.29–7.27(m,2H),5.02(s,1H),4.82(s,2H). 13 C NMR (100MHz, CDCl3): δ160.0,152.9,138.6,136.6,133.9,132.7,129.3,129.2,125.4,123.5,119.1,118.7 ,117.5,112.2,61.4,38.9; IR(KBr):2921,2850,2359,2195,1634,1399,1261,1195,1143,1089,1014,746cm -1 ;ESI FTMS exact mass calcd for(C 18 H 11 ClN2O2+Na) + requires m / z 345.0407,found m / z345.0408.

[0092] 2-Amino-4-(4-bromophenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile (3j) prepared in Example 10: Purified by flash column chromatography through silica gel (petroleum ether / EtOAc=4:1); 84% yield (31.0mg); yellow solid; mp193.2-194.7℃;1 H NMR (400MHz, CDCl3): δ7.57–7.52(m,1H),7.50(d,J=8.4Hz,2H),7.39–7.34 (m,1H),7.33–7.29(m,2H),7.18(d,J=8.0Hz,2H),4.97(s,1H),4.80(s,2H). 13 C NMR (100MHz, CDCl3): δ160.0,152.9,139.1,136.5,132.7,132.1,129.7,125.4,123.5,122.1,119.1,118 .7,117.5,112.2,61.3,39.0; IR(KBr):3378,3196,2922,2851,2198,1643,1401,1298,1195,1010,746cm -1 ;ESI FTMS exact mass calcd for(C 18 H 11 BrN2O2+Na) + requires m / z388.9902,found m / z388.9905.

[0093] 2-Amino-4-(4-fluorophenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile (3k) prepared in Example 11:

[0094] Purified by flash column chromatography through silicagel (petroleum ether / EtOAc=4:1); 83% yield (25.4mg); yellow solid; mp206.8-207.9℃; 1 H NMR (400MHz, CDCl3): δ7.57–7.51(m,1H),7.40–7.34(m,1H),7.33–7.30(m,1H),7.30–7.26(m,3H),7.08–7.03(m,2H),4.99(s,1H),4.79(s,2H). 13C NMR (100MHz, CDCl3): δ162.5(d,J=245.1Hz),160.0,152.9,136.9,135.9,135.8,132.6,129.6(d,J=8.3Hz),125.3,123.5,119.2,11 8.8,117.5,115.9(d,J=21.5Hz),112.2,61.6,38.7; IR(KBr):3324,3196,2920,2849,2195,1645,1507,1402,1265,1193,1156,745cm -1 ;ESI FTMS exactmass calcd for(C 18 H 11 FN2O2+Na) + requires m / z 329.0703,found m / z 329.0706.

[0095] Example 12 Preparation of 2-amino-4-(4-nitrophenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile (31):

[0096] Purified by flash column chromatography through silicagel (petroleum ether / EtOAc=4:1); 77% yield (25.8mg); yellow solid; mp243.6-244.4℃; 1 H NMR (400MHz, DMSO-d6): δ8.26–8.24(m,2H),7.62–7.57(m,3H),7.56–7.50(m,1H),7.42–7.29(m,4H),5.34(s,1H). 13 C NMR (100MHz, DMSO-d6): δ161.4,152.7,149.1,147.5,136.7,132.6,129.8,126.0,124.6,124.3,120.2 ,118.8,117.8,112.6,56.4,55.4; IR(KBr):3400,2920,2849,2194,1683,1520,1398,1347,1274,750cm -1 ;ESI FTMS exactmass calcd for(C 18 H 11 N3O4+Na) +requires m / z 356.0648,found m / z 356.0661.

[0097] Example 13 Preparation of 2-amino-4-(3,4-dichlorophenyl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile (3m): Purified by flash column chromatography through silicagel (petroleum ether / EtOAc=4:1); 83% yield (29.6mg); yellow solid; mp234.2-234.9℃; 1 H NMR (400MHz,CDCl3): 1 H NMR(400MHz,Chloroform-d)δ7.60–7.52(m,1H),7.45(d,J=8.0Hz,1H),7.39 -7.34(m,2H),7.34–7.26(m,2H),7.19 -7.16(m,1H),4.97(s,1H),4.85(s,2H). 13 CNMR (100MHz, CDCl3): δ160.2,152.9,140.3,135.9,133.2,132.8,132.3,131.0,129.9,127.4,125.6,123.6,118.9,1 18.6,117.6,112.2,38.7; IR(KBr):3327,3196,2925,2853,2195,1679,1633,1449,1307,1273,1196,1031,1007,746cm -1 ;ESI FTMS exactmass calcd for(C 18 H 10 Cl2N2O2+Na) + requires m / z 379.0017,found m / z 379.0016.

[0098] Example 14 Preparation of 2-amino-4-(thiophene-2-yl)-4H-pyrano[3,2-b]benzofuran-3-carbonitrile (3n):

[0099] Purified by flash column chromatography through silicagel (petroleum ether / EtOAc=4:1); 54% yield (15.9mg); yellow solid; mp228.6-229.3℃; 1 H NMR (400MHz, CDCl3): δ7.54(d,J=7.2Hz,1H),7.41(d,J=8.0Hz,1H),7.34–7.27(m,3H),7.10–7.09(m,1H),6.70 -6.98(m,1H),5.33(s,1H),4.80(s,2H). 13 C NMR (100MHz, CDCl3): δ159.9,152.9,144.5,136.5,132.1,127.1,125.8,125.8,125.4,123.5,119.2,118 .8,117.6,112.3,62.1,34.7; IR(KBr):3325,3194,2920,2849,2195,1699,1646,1404,1275,1198,750cm -1 ;ESI FTMS exact mass calcd for(C 16 H 10 N2O2S+Na) + requires m / z 317.0361, found m / z317.0366.

[0100] Example 15 Preparation of 2-amino-8-bromo-4-phenyl-4H-pyrano[3,2-b]benzofuran-3-carbonitrile (3o):

[0101] Purified by flash column chromatography through silicagel (petroleum ether / EtOAc=4:1); 84% yield (30.8mg); yellow solid; mp256.3-258.2℃; 1 H NMR (400MHz, DMSO-d6) δ7.71(s,1H),7.58–7.51(m,2H),7.43–7.40(m,2H),7.36–7.31(m,3H),7.26(s,2H),5.13(s,1H). 13C NMR (100MHz, DMSO-d6) δ160.9,151.4,141.5,139.7,131.4,129.3,128.4,128.3,128.2,120.9,120.3,120. 0,116.3,114.7,57.4,55.4; IR(KBr):3319,3196,2920,2849,2194,1634,1587,1404,1276,1193,973,750cm -1 ;ESIFTMS exact mass calcd for(C 18 H 11 BrN2O2+Na) + requires m / z 388.9902,found m / z388.9907.

[0102] Example 16 Preparation of 2-amino-8-fluoro-4-phenyl-4H-pyrano[3,2-b]benzofuran-3-carbonitrile (3p): Purified by flash column chromatography through silica gel (petroleum ether / EtOAc=4:1); 85% yield (25.9mg); yellow solid; mp245.9-247.6℃; 1 H NMR (400MHz, DMSO-d6): δ7.613–7.59(m,1H),7.43–7.40(m,2H),7.38–7.30(m,4H),7.28–7.18(m,3H),5.13(s,1H). 13 C NMR (100MHz, DMSO-d6): δ160.9, 159.2 (d, J = 235.9Hz), 148.8, 141.5, 140.2 ,132.2(d,J=3.7Hz),129.3,128.3,128.1,120.3,119.6(d,J=11.1Hz),114 .1(d,J=9.6Hz),113.3(d,J=26.0Hz),103.6(d,J=26.5Hz),57.4,55.4; IR( KBr):3323,3197,2920,2849,2198,1634,1585,1405,1275,1123,984,748cm -1 ;ESI FTMSexact mass calcd for(C 18 H 11 FN2O2+Na)+ requires m / z 329.0703,found m / z 329.0698.

[0103] Example 17 Preparation of 2-amino-7-methyl-4-phenyl-4H-pyrano[3,2-b]benzofuran-3-carbonitrile (3q):

[0104] Purified by flash column chromatography through silicagel (petroleum ether / EtOAc=4:1); 54% yield (16.0mg); yellow solid; mp274.1-274.6℃; 1 H NMR (400MHz, CDCl3): δ7.41 (d, J = 8.0Hz, 1H), 7.38–7.33 (m, 2H), 7.31–7.27 (m, 3H),7.16(s,1H),7.10(d,J=8.0Hz,1H),4.97(s,1H),4.73(s,2H),2.43(s,3H). 13 C NMR (100MHz, CDCl3): δ159.9,153.3,140.2,136.4,135.6,128.9,128.0,127.9,124.7,119.4,116.8, 116.4,112.4,62.0,39.4,21.8; IR(KBr):3320,3195,2920,2849,2198,1645,1402,1275,1153,750cm -1 ;ESI FTMS exact mass calcd for(C 19 H 14 N2O2+Na) + requires m / z325.0953,found m / z 325.0957.

[0105] 2-Amino-7-chloro-4-phenyl-4H-pyrano[3,2-b]benzofuran-3-carbonitrile (3r) prepared in Example 18:

[0106] Purified by flash column chromatography through silicagel(petroleum ether / EtOAc=4:1);62%yield(20.1mg);yellow solid;m.p.253.8-254.3℃; 1 H NMR(400MHz,CDCl3):δ7.45(d,J=8.4Hz,1H),7.41–7.34(m,3H),7.34–7.26(m,4H),4.98(s,1H),4.77(s,2H); 13 C NMR(100MHz,CDCl3):δ159.8,152.8,139.7,138.0,132.3,131.1,129.0,128.2,127.9,124.2,119.1,118.0,117.5,112.8,61.8,39.4.;IR(KBr):3320,3195,2919,2848,2197,1640,1589,1401,1275,1196,1148,1056,750cm -1 ;ESIFTMS exact mass calcd for(C 18 H 11 ClN2O2+Na) + requires m / z 345.0407,found m / z345.0409。

Claims

1. A benzofuranopyran compound, characterized in that Its chemical structure is: wherein R is selected from the group consisting of phenyl, o-methoxyphenyl, o-nitrophenyl, m-methylphenyl, m-chlorophenyl, m-nitrophenyl, p-methylphenyl, p-methoxyphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-nitrophenyl, 3,4-dichlorophenyl and 2-thienyl; R 1 One selected from the group consisting of hydrogen, 5-fluoro, 5-bromo, 6-methyl and 6-chloro.

2. The method for synthesizing a benzofuranopyran compound according to claim 1, characterized in that The synthetic method is specifically completed according to the following steps: Will and malononitrile as the reaction raw materials, ethyl acetate as the reaction solvent, N,N-diisopropylethylamine as the promoter, stirring the reaction, tracking the reaction to completion by TLC, filtering, concentrating the filtrate, and purifying to obtain a benzofuranopyran compound.

3. The method for synthesizing a benzofuranopyran compound according to claim 2, characterized in that The The preparation method is specifically completed according to the following steps: At room temperature and under stirring, benzofuranone and aldehyde are added to dichloromethane, and then activated alkaline alumina is added, and the reaction is stirred. TLC is used to track the reaction until it is complete, and the alumina is filtered, and the filter cake is washed with ethyl acetate. The filtrate is concentrated to obtain a crude product, and then the crude product is chromatographed on a silica gel column, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:

1. Finally, the product is separated to obtain a light yellow solid, which is The structural formula of the benzofuranone is Where R 1 One selected from the group consisting of hydrogen, 5-fluoro, 5-bromo, 6-methyl and 6-chloro; The structural formula of the aldehyde is wherein R is selected from one of phenyl, o-methoxyphenyl, o-nitrophenyl, m-methylphenyl, m-chlorophenyl, m-nitrophenyl, p-methylphenyl, p-methoxyphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-nitrophenyl, 3,4-dichlorophenyl and 2-thienyl; The molar volume ratio of the benzofuranone, aldehyde, activated alkaline alumina and dichloromethane is 1.0 mmol: 1.0 mmol: 5.0 mmol: 10 mL.

4. The method for synthesizing a benzofuranopyran compound according to claim 2, characterized in that The The molar ratio of 1:3 to malononitrile.

5. The method for synthesizing a benzofuranopyran compound according to claim 2, characterized in that The reaction temperature is 50°C.

6. The method for synthesizing a benzofuranopyran compound according to claim 2, characterized in that The purification is performed by silica gel column chromatography, and the eluent is a mixture of petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate is 4:

1.

7. The use of a benzofuranopyran compound as claimed in claim 1, characterized in that A benzofuranopyran compound is used in the preparation of a drug for inhibiting human cervical cancer Hela cells.

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