Synthesis method of benzofuran compound

Abstract

The invention belongs to the technical field of chemical synthesis, and particularly discloses synthesis of benzofuran compounds, which is characterized in that p-benzoquinone-2-methyl formate and 1-benzoylmethylpyridine bromide compounds are used as raw materials and react for 8-16 hours at the temperature of 80 DEG C in a proper amount of reaction solvent under the alkaline condition and under the protection of nitrogen to obtain target compounds. The method has the advantages of simple operation, easily available raw materials and high yield.

Description

Technical Field

[0001] This invention relates to the field of synthesis technology of benzofuran compounds, and more specifically to a method for synthesizing benzofuran compounds. Background Technology

[0002] Benzofurans are a class of naturally occurring compounds widely found in nature. As an important class of heterocyclic compounds, they are prevalent in higher plants, and their diverse biological activities have always been a focus of research. Many of these compounds possess a wide range of biological activities, including anticancer, antibacterial, and insecticidal effects. Since the structure of benzofurans was first determined in 1909, at least 30 compounds containing benzofuran structures have been used clinically. To date, there are at least 40 therapeutic drugs derived from benzofurans, such as ramelteamide for treating sleep disorders, 6-APB for treating psychotropic diseases, psoralen for treating psoriasis, vitiligo, and cutaneous lymphoma, dafinacin for treating urinary incontinence, and sapridesartan for treating arrhythmias. Due to the excellent physiological activity of benzofurans, their synthesis has been a hot topic in organic synthesis research.

[0003] Currently, the literature reports on the synthesis of benzofuran mainly includes the following methods: (1) Traditional methods for synthesizing benzofuran, such as the dehydration reaction of phenoxyalkylones under acidic conditions, the dehydration reaction of o-hydroxybenzophenones under acidic conditions, the decarboxylation reaction of o-acetylphenoxyacetic acid or its esters under alkaline conditions, and the cyclization of o-hydroxybenzophenones to construct benzofuran rings; (2) Transition metal-catalyzed synthesis of benzofuran; among which, transition metal-catalyzed synthesis of benzofuran generally uses palladium, copper, and other noble metals for catalysis. However, since the synthesis of such compounds still has problems such as excessively long routes and harsh reaction conditions, developing new methods for synthesizing benzofuran compounds will be of certain significance.

[0004] In view of this, the present invention is proposed. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide a method for synthesizing a class of benzofuran compounds. This method features mild and simple reaction conditions, broad substrate applicability, and readily available and inexpensive raw materials. The structural formula of these compounds is shown in formula (I):

[0006]

[0007] The synthesis method of compound (I) is as follows: using methyl p-benzoquinone 2-carboxylate and 1-benzoylmethylpyridine bromide as raw materials, under alkaline conditions and nitrogen protection, the mixture is heated under reflux for 8-16 hours in an appropriate amount of reaction solvent to obtain the target product (I).

[0008] The structural formula of the p-benzoquinone 2-formate methyl ester is:

[0009] The structural formula of the 1-benzoylmethylpyridine bromide compound is:

[0010] Wherein, R is selected from one of the following: benzene ring, 4-methylphenyl, 4-ethylphenyl, 4-phenylphenyl, 4-esterylphenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 3-fluorophenyl, 3-trifluoromethylphenyl, 3-chlorophenyl, 3-bromophenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, and furan ring.

[0011] Preferably, the method for synthesizing the compound of formula (I) includes the following steps:

[0012] Under nitrogen protection, methyl p-benzoquinone 2-carboxylate and 1-benzoylmethylpyridine bromide, a base, and an appropriate amount of reaction solvent were added sequentially to a dry container. The mixture was heated under reflux for 8–16 hours to induce Michael addition. After the reaction was complete, the reaction solution was adjusted to a weakly acidic state and extracted with ethyl acetate. The organic phase was collected, washed, and dried (preferably washed with saturated brine and dried with anhydrous magnesium sulfate). After concentration under reduced pressure and rotary evaporation, isocratic elution was performed by silica gel column chromatography using petroleum ether and ethyl acetate in a volume ratio of 15:1 as eluents. TLC was performed using petroleum ether and ethyl acetate in a volume ratio of 5:1 as developing solvents. The eluent with an Rf value of 0.5 was collected, and the solvent was removed by rotary evaporation under reduced pressure to obtain the compound shown in formula (Ⅰ).

[0013] Preferably, the reaction solvent is acetonitrile, dichloromethane, toluene, 1,4-dioxane, N,N-dimethylformamide, or tetrahydrofuran, more preferably acetonitrile, and the reflux conditions are: reflux at 80±5℃ for 12h.

[0014] Preferably, the alkali used is potassium carbonate, cesium carbonate, potassium phosphate, sodium acetate, triethylamine, or N,N-diisopropylethylamine.

[0015] Preferably, the molar ratio of the raw material methyl 2-benzoquinone carboxylate and 1-benzoylmethylpyridine bromide is 1:2.5.

[0016] Preferably, the molar ratio of the base to methyl p-benzoquinone 2-carboxylate is 2.5:1.

[0017] The present invention also provides the application of the benzofuran compound obtained by the above synthesis method in the preparation of drugs that inhibit the PIM-1 proto-oncogene.

[0018] Preferably, the gene targets of the drug are uronorductase, protoporphyrinogen oxidase, heat shock protein 90-β and / or serine / threonine kinase.

[0019] Compared with the prior art, the advantages and beneficial effects of the present invention are as follows:

[0020] This invention synthesizes benzofuran compounds under alkaline conditions using methyl p-benzoquinone 2-carboxylate (1) and 1-benzoylmethylpyridine bromide (II) as raw materials. This method establishes a novel transformation of methyl p-benzoquinone 2-carboxylate and 1-benzoylmethylpyridine bromide, providing an effective method for assembling the benzofuran ring. This method is novel and has the advantages of simple operation and good yield. The synthesized compounds possess multiple furan and aromatic ring structures, allowing them to penetrate the active pockets of various proteins. They also possess hydroxyl and ester groups, enabling them to form stable hydrogen bonds with many amino acids in the active pockets. Attached Figure Description

[0021] Figure 1 The image shows the proton NMR spectrum of compound 3a provided in the specific implementation.

[0022] Figure 2 The image shows the carbon NMR spectrum of compound 3a provided in the specific implementation.

[0023] Figure 3 The image shows the hydrogen nuclear magnetic resonance spectrum of compound 3b provided in the specific implementation embodiment.

[0024] Figure 4 The image shows the carbon NMR spectrum of compound 3b provided in the specific implementation.

[0025] Figure 5 The image shows the hydrogen nuclear magnetic resonance spectrum of compound 3c provided in the specific embodiment.

[0026] Figure 6 The image shows the carbon NMR spectrum of compound 3c provided in the specific implementation.

[0027] Figure 7 The image shows the hydrogen nuclear magnetic resonance spectrum of compound 3f provided in the specific implementation.

[0028] Figure 8 The image shows the carbon NMR spectrum of compound 3f provided in the specific implementation.

[0029] Figure 9 The image shows the hydrogen nuclear magnetic resonance spectrum of compound 3n provided in the specific implementation.

[0030] Figure 10 The image shows the carbon NMR spectrum of compound 3n provided in the specific implementation.

[0031] Figure 11 The image shows the hydrogen nuclear magnetic resonance spectrum of compound 3m provided in the specific implementation embodiment.

[0032] Figure 12 The image shows the carbon NMR spectrum of compound 3m provided in the specific implementation method.

[0033] Figure 13 This is a three-dimensional diagram illustrating the docking of compound 3l with PIM-1 kinase in a specific embodiment.

[0034] Figure 14 This is a three-dimensional diagram illustrating the docking of compound 3d with heat shock protein 90-β in a specific embodiment.

[0035] Figure 15 This is a three-dimensional rendering of the docking of compound 3e' with protoporphyrinogen oxidase in a specific embodiment.

[0036] Figure 16 This is a three-dimensional rendering of the docking of compound 3o' with uronic acid reductase in a specific embodiment. Detailed Implementation

[0037] The following specific embodiments are only used to illustrate the specific implementation of the present invention and do not limit the scope of protection claimed in the claims. Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods; the materials and reagents used are commercially available unless otherwise specified.

[0038] The starting material, methyl p-benzoquinone 2-carboxylate, is a known compound and was synthesized according to the method described in reference [1]. The starting material, 1-benzoylmethylpyridine bromide, is a known compound and was synthesized according to the general method described in reference [2].

[0039] [1]Ze-Ran Jing,Dong-Dong Liang,Jin-Miao Tian,Fu-Min Zhang,and Yong-Qiang Tu.Enantioselective Construction of 2-Aryl-2,3-dihydrobenzofuranScaffolds Using Cu / SPDO-Catalyzed[3+2]Cycloaddition[J].Organic Letters 202123(4),1258-1262;

[0040] [2] Dominik S. Peter Mayer,and Herbert Mayr.NucleophilicityParameters of Pyridinium Ylides and Their Use in Mechanistic Analyses[J].Journal of the American Chemical Society 2013 135(40),15216-15224.

[0041] Example 1: Preparation method of compound 3a

[0042]

[0043] Under nitrogen protection at room temperature (25°C in this invention), methyl p-benzoquinone 2-carboxylate (0.2 mmol), raw material 2 (0.5 mmol), and potassium carbonate (0.5 mmol) were added sequentially to a dried round-bottom flask, followed by acetonitrile (4 mL). The reaction was carried out at 80°C for 12 h. After the reaction was completed, 17 wt% dilute hydrochloric acid was added to adjust the pH to weakly acidic (pH≈5). The mixture was extracted three times with ethyl acetate (5 mL each time), and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. Using petroleum ether:ethyl acetate = 15:1 (v:v) as the eluent, isocratic elution was performed by silica gel (200-300 mesh) column chromatography at a flow rate of 20 mL / min and an eluent volume of 400 mL. TLC was performed using petroleum ether and ethyl acetate in a volume ratio of 5:1 as the developing solvent. The eluent with an Rf value of 0.5 was collected, and the solvent was removed by rotary evaporation under reduced pressure to obtain 44 mg of yellow liquid, which was the target compound 3a, with a yield of 55%. 1 H NMR(500MHz,Chloroform-d)δ11.40(s,1H),8.11(dd,J=8.4,1.2Hz,2H),7.95(d,J=7.4Hz,2H),7.80(d,J =9.2Hz,1H),7.63-7.59(m,1H),7.59-7.54(m,1H),7.52-7.43(m,4H),7.26(d,J=9.2Hz,1H),3.35(s,3H). 13C NMR(126MHz,Chloroform-d)δ191.1,182.9,169.4,161.5,151.6,149.1,137.8,135.8,133.7 ,133.4,130.2,128.8,128.8,128.6,128.6,124.1,120.6,120.4,104.4,50.8.HRMS(ESI)m / z calcd for C 24 H 17 O6 + [M+H] + =401.1020,found=401.1020.

[0044] The preparation methods of compounds 3b to 3u are the same as those of 3a, both prepared from methyl p-benzoquinone 2-carboxylate (1) and 1-benzoylmethylpyridine bromide compound (II). The reaction formulas are as follows, and the feed ratios are the same as those of compound 3a. The differences are in the selection of feedstock 2 and the reaction time. The specific structural formulas of the feedstocks and the reaction yields are shown in Table 1. Table 1 shows the structural formulas of 1-benzoylmethylpyridine bromide compound (II) and the product R, along with the corresponding product yields.

[0045]

[0046] Table 1 Yields of compound 3a-3u

[0047]

[0048] The proton NMR spectra of compounds 3b to 3u are as follows:

[0049] Compound 3b: 1 H NMR(500MHz,Chloroform-d)δ11.39(s,1H),8.03(d,J=8.2Hz,2H),7.83(d,J=7.5Hz,2H),7.7 9(d,J=9.2Hz,1H),7.29(d,J=8.0Hz,2H),7.24(m,3H),3.37(s,3H),2.43(s,3H),2.40(s,3H). 13C NMR(126MHz,Chloroform-d)δ190.79,182.36,169.37,161.26,151.71,148.91,144.55,143.99,135.44,133.21,1 30.27,129.42,129.23,128.77,128.35,124.04,120.20,120.17,104.31,50.67,21.83,21.79.HRMS(ESI)m / zcalcd for C 26 H 21 O6 + [M+H] + =429.1333,found=429.1335 Compound 3c: 1 H NMR (500MHz, Chloroform-d) δ11.42(s,1H),8.08(d,J=8.3Hz,2H),7.88(d,J=7.6Hz,2H),7.82(d,J=9.2Hz,1H),7.34(d,J=8. 3Hz,2H),7.30–7.27(m,3H),3.39(s,3H),2.78–2.74(m,2H),2.74–2.70(m,2H),1.31(t,J=7.6Hz,3H),1.27(t,J=7.6Hz,3H). 13 C NMR(126MHz,Chloroform-d)δ190.78,182.43,169.39,161.26,151.72,150.65,150.07,148.92,135.62,133.46,130.3 7,128.86,128.36,128.20,128.04,124.06,120.18,120.15,104.33,50.65,29.08,29.01,15.15,15.08.HRMS(ESI)m / z calcd for C 28 H 25 O6 + [M+H] + =457.1646,found=457.1644

[0050] Compound 3d: 11H NMR (500 MHz, Chloroform-d) δ 11.43 (s, 1H), 8.25–8.21 (m, 2H), 8.03 (d, J = 7.6 Hz, 2H), 7.84 (d, J = 9.2 Hz, 1H), 7.75–7.71 (m, 2H), 7.69 (d, J = 8.7 Hz, 2H), 7.67–7.64 (m, 2H), 7.64–7.61 (m, 2H), 7.49 (t, J = 5.5 Hz, 2H), 7.48–7.44 (m, 2H), 7.44–7.37 (m, 2H), 7.29 (d, J = 9.2 Hz, 1H), 3.42 (s, 3H). 13 13C NMR (126 MHz, Chloroform-d) δ 189.60, 181.19, 168.28, 160.36, 150.65, 148.02, 145.21, 144.77, 138.82, 138.70, 135.55, 133.37, 129.72, 128.18, 127.98, 127.92, 127.46, 127.38, 127.22, 126.34, 126.29, 126.26, 126.12, 122.96, 119.43, 119.23, 103.27, 49.71. HRMS (ESI) m / z calcd for C 36 1 25 1 + [M + H] + = 553.1646, found = 553.1648

[0051] Compound 3e: 1 1H NMR (500 MHz, Chloroform-d) δ 11.41 (s, 1H), 8.16 (s, 3H), 8.14 (d, J = 8.7 Hz, 2H), 8.02 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 9.2 Hz, 1H), 7.31 (d, J = 9.2 Hz, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 3.35 (s, 3H). 1313C NMR (126 MHz, Chloroform-d) δ 189.15, 181.02, 167.96, 165.15, 165.09, 160.62, 150.03, 148.20, 139.75, 137.78, 133.17, 133.00, 128.97, 128.91, 128.63, 127.60, 127.47, 122.65, 120.14, 119.39, 103.04, 51.55, 51.50, 49.70. HRMS (ESI) m / z calcd for C 28 H 21 O 10 + [M+H] + =517.1129, found=517.1129

[0052] Compound 3f: 1 1H NMR (500 MHz, Chloroform-d) δ 11.41 (s, 1H), 8.22 (d, J = 8.2 Hz, 2H), 8.07 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 9.2 Hz, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 9.3 Hz, 1H), 3.37 (s, 3H). 13 13C NMR (126 MHz, Chloroform-d) δ 189.70, 181.64, 168.90, 161.76, 150.87, 149.29, 140.23, 138.18, 134.67 (dd, J = 36.9, 32.8 Hz), 130.37, 128.88, 128.60, 125.91 (q, J = 3.6 Hz), 125.61 (q, J = 3.7 Hz), 123.58, 123.52 (dd, J = 272.8, 7.6 Hz), 121.46, 120.64–120.32 (m), 104.01, 50.78. 19 19F NMR (471 MHz, Chloroform-d) δ -103.41–-103.48 (m), -104.60–-104.69 (m). HRMS (ESI) m / z calcd for C 24 H 15 F2O6 + [M+H] + =437.0831, found=437.0831

[0053] Compound 3g: 11H NMR (500 MHz, Chloroform-d) δ 11.41 (s, 1H), 8.22 (d, J = 8.2 Hz, 2H), 8.07 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 9.2 Hz, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 9.3 Hz, 1H), 3.37 (s, 3H). 13 13C NMR (126 MHz, Chloroform-d) δ 189.44, 181.02, 169.14, 167.20–164.47 (m), 161.51, 151.23, 149.02, 134.32 (d, J = 2.9 Hz), 132.92 (d, J = 9.5 Hz), 131.90 (d, J = 3.0 Hz), 131.16 (d, J = 9.3 Hz), 128.38, 123.72, 120.77, 120.29, 115.92 (dd, J = 22.0, 15.1 Hz), 104.16, 50.69. 19 19F NMR (471 MHz, Chloroform-d) δ -63.03, -63.23. HRMS (ESI) m / z calcd for C 26 H 15 F6O6 + [M + H] + = 537.0767, found = 537.0766

[0054] Compound 3h: 1 1H NMR (500 MHz, Chloroform-d) δ 11.33 (s, 1H), 8.01 (d, J = 8.5 Hz, 2H), 7.81 (d, J = 7.8 Hz, 2H), 7.74 (d, J = 9.2 Hz, 1H), 7.41 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 5.7 Hz, 1H), 3.31 (s, 3H). 13 13C NMR (126 MHz, Chloroform-d) δ 189.72, 181.31, 169.07, 161.57, 151.17, 149.07, 140.32, 139.68, 136.17, 133.79, 131.52, 129.94, 129.15, 128.97, 128.38, 123.69, 120.94, 120.33, 104.10, 50.76. HRMS (ESI) m / z calcd for C 24 H 15Cl2O6 + [M+H] + =469.0240, found=469.0240

[0055] Compound 3i: 1 H NMR(500MHz, Chloroform-d)δ11.40(s, 1H), 8.00(d, J=8.6Hz, 2H), 7.80(d, J=9.1Hz, 3H), 7.65(d, J=8.5Hz, 2H), 7.61(d, J=8.7Hz, 2H), 7.28(dd, J=9.2, 1.2Hz, 1H), 3.39(s, 3H). 13 C NMR(126MHz, Chloroform-d)δ189.91, 181.50, 169.06, 161.58, 151.15, 149.08, 136.55, 134.20, 132.13, 131.96, 131.57, 130.04, 129.14, 128.47, 128.36, 123.68, 120.98, 120.34, 104.09, 50.78. HRMS(ESI)m / z calcd for C 24 H 15 Br2O6 + [M+H] + =556.9230, found=556.9232

[0056] Compound 3j: 1 H NMR(500MHz, Chloroform-d)δ11.40(s, 1H), 7.90–7.86(m, 2H), 7.83(d, J=8.7Hz, 4H), 7.80(d, J=9.2Hz, 1H), 7.65(d, J=8.0Hz, 2H), 7.28(d, J=9.2Hz, 1H), 3.39(s, 3H). 13 C NMR(126MHz, Chloroform-d)δ189.19, 180.78, 168.01, 160.52, 150.11, 148.03, 137.05, 136.89, 136.03, 133.70, 130.31, 128.87, 127.26, 122.65, 119.92, 119.28, 103.05, 101.04, 100.34, 49.74. HRMS(ESI)m / z calcd for C 24 H 15 I2O6 + [M+H] += 652.8953, found = 652.8951

[0057] Compound 3k: 1 H NMR (500 MHz, Chloroform-d) δ 11.41 (s, 1H), 7.95 (dt, J = 7.8, 1.3 Hz, 1H), 7.83 (dd, J = 9.2, 2.7 Hz, 2H), 7.70 (d, J = 7.7 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.50 (td, J = 8.0, 5.5 Hz, 1H), 7.44 (td, J = 8.0, 5.4 Hz, 1H), 7.33 (tdd, J = 8.3, 2.7, 1.0 Hz, 1H), 7.29 (d, J = 9.2 Hz, 2H), 3.39 (s, 3H). 13 C NMR (126 MHz, Chloroform-d) δ 189.64, 181.26, 169.17, 162.83 (dd, J = 248.1, 48.2 Hz), 161.74, 151.17, 149.25, 138.66 (dd, J = 314.1, 6.5 Hz), 130.51 (dd, J = 25.9, 7.7 Hz), 128.61, 126.03 (d, J = 3.1 Hz), 124.55, 123.75, 121.19, 120.67 (dd, J = 46.8, 21.4 Hz), 120.52, 117.03 (d, J = 23.2 Hz), 115.22 (d, J = 22.4 Hz), 104.19, 50.86. 19 F NMR (471 MHz, Chloroform-d) δ -111.46 – -111.57 (m). HRMS (ESI) m / z calcd for C 24 H 15 F2O6 + [M + H] + = 437.0831, found = 437.0832

[0058] Compound 3l: 11H NMR (500 MHz, Chloroform-d) δ 11.41 (s, 1H), 8.39 (s, 1H), 8.34 (d, J = 7.9 Hz, 1H), 8.27 (s, 1H), 8.07 (d, J = 7.5 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 9.2 Hz, 2H), 7.67 (t, J = 7.8 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.33 (d, J = 9.3 Hz, 1H), 3.35 (s, 3H). 13 13C NMR (126 MHz, Chloroform-d) δ 189.48, 181.22, 168.92, 161.77, 150.86, 149.32, 138.24, 135.92, 133.20, 131.92, 131.71–131.04 (m), 129.90 (dq, J = 42.2, 3.5 Hz), 129.53, 129.30, 128.48, 126.96 (q, J = 3.8 Hz), 125.02 (q, J = 3.6 Hz), 123.59 (dd, J = 272.6, 7.4 Hz), 123.55, 121.45, 120.52, 104.01, 50.72. 19 19F NMR (471 MHz, Chloroform-d) δ -62.66, -62.88. HRMS (ESI) m / z calcd for C 26 H 15 F6O6 + [M + H] + = 537.0767, found = 537.0769

[0059] Compound 3m: 1 1H NMR (500 MHz, Chloroform-d) δ 11.41 (s, 1H), 8.10 (t, J = 1.9 Hz, 1H), 8.03 (dt, J = 7.8, 1.3 Hz, 1H), 7.92 (s, 1H), 7.84 (d, J = 9.3 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.60 (ddd, J = 7.9, 2.1, 1.1 Hz, 1H), 7.55 (ddd, J = 7.9, 2.1, 1.1 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.30 (d, J = 9.2 Hz, 1H), 3.39 (s, 3H). 1313C NMR (126 MHz, Chloroform-d) δ 189.53, 181.20, 169.03, 161.65, 150.97, 149.19, 139.25, 136.95, 135.10, 134.83, 133.59, 133.27, 130.13, 130.04, 129.93, 128.44, 128.19, 126.75, 123.62, 121.14, 120.46, 104.07, 50.77. HRMS (ESI) m / z calcd for C 24 H 15 Cl2O6 + [M + H] + = 469.0240, found = 469.0242

[0060] Compound 3n: 1 1H NMR (500 MHz, Chloroform-d) δ 11.41 (s, 1H), 8.24 (t, J = 1.7 Hz, 1H), 8.07 (dt, J = 7.9, 1.3 Hz, 2H), 7.84 (d, J = 9.2 Hz, 2H), 7.75 (ddd, J = 8.0, 2.1, 1.1 Hz, 1H), 7.70 (ddd, J = 7.9, 2.1, 1.1 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.30 (d, J = 9.2 Hz, 1H), 3.39 (s, 3H). 13 13C NMR (126 MHz, Chloroform-d) δ 188.39, 180.06, 167.97, 160.60, 149.89, 148.16, 138.38, 136.11, 135.45, 135.14, 131.87, 130.28, 129.32, 129.11, 127.58, 127.35, 126.18, 122.57, 122.07, 121.74, 120.11, 119.42, 103.02, 49.74. HRMS (ESI) m / z calcd for C 24 H 15 Br2O6 + [M + H] + = 556.9230, found = 556.9231

[0061] Compound 3o: 11H NMR (500 MHz, Chloroform-d) δ 11.36 (s, 1H), 8.16 (td, J = 7.7, 1.9 Hz, 1H), 7.70 (d, J = 9.2 Hz, 1H), 7.61 (ddd, J = 7.7, 6.8, 1.8 Hz, 1H), 7.59–7.53 (m, 2H), 7.32 (td, J = 7.6, 1.1 Hz, 1H), 7.26 (s, 1H), 7.25–7.22 (m, 2H), 7.15 (ddd, J = 9.6, 8.4, 1.0 Hz, 1H), 7.07 (ddd, J = 11.2, 8.3, 1.1 Hz, 1H), 3.43 (s, 3H). 13 13C NMR (126 MHz, Chloroform-d) δ 185.98, 180.92, 168.27, 162.10–158.44 (m), 160.27, 148.93 (d, J = 2.0 Hz), 148.10, 133.71 (dd, J = 119.0, 8.8 Hz), 129.89, 129.69, 128.78, 124.82 (d, J = 8.7 Hz), 124.28 (d, J = 13.8 Hz), 123.39 (d, J = 3.6 Hz), 123.23 (d, J = 3.6 Hz), 122.40, 119.60, 119.28, 115.78 (d, J = 22.5 Hz), 115.35 (d, J = 21.5 Hz), 103.11, 49.72. 19 19F NMR (471 MHz, Chloroform-d) δ -110.13– -110.26 (m), -111.25 (dt, J = 11.0, 5.9 Hz). HRMS (ESI) m / z calcd for C 24 1 15 19 + [M + H] + = 437.0831, found = 437.0833

[0062] Compound 3p: 1 1H NMR (500 MHz, Chloroform-d) δ 11.35 (s, 1H), 8.03 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 9.2 Hz, 1H), 7.49–7.40 (m, 4H), 7.40–7.30 (m, 3H), 7.23 (d, J = 9.2 Hz, 1H), 3.44 (s, 3H). 13C NMR(126MHz,Chloroform-d)δ187.69,183.14,168.16,160.29,148.56,148.24,135.39,133.89,133.31,132.55,131.76, 131.31,131.09,130.60,129.00,128.72,128.32,125.77,125.74,123.20,119.80,119.30,103.35,49.79.HRMS(ESI)m / z calcd forC 24 H 15 Cl2O6 + [M+H] + =469.0240, found=469.0242

[0063] Compound 3q: 1 H NMR(500MHz,Chloroform-d)δ11.34(s,1H),7.97–7.93(m,1H),7.72–7.69(m,1H),7.68(d,J=9.2H z,1H),7.58–7.55(m,1H),7.37(dtt,J=10.5,7.4,3.5Hz,5H),7.23(d,J=9.2Hz,1H),3.44(s,3H). 13 C NMR(126MHz,Chloroform-d)δ177.48,168.28,167.85,160.29,152.62,149.57,149.25,147.87,147.35, 145.50,125.72,122.56,121.12,119.37,118.97,116.37,111.67,111.45,103.20,50.00.HRMS(ESI)m / z calcd forC 28 H 21 O 10 + [M+H] + =556.9230, found=556.9230 compound 3r: 11H NMR (500 MHz, Chloroform-d) δ 11.37 (s, 1H), 8.25 (td, J = 8.7, 6.5 Hz, 1H), 7.73 (d, J = 9.3 Hz, 1H), 7.71–7.66 (m, 1H), 7.29 (d, J = 6.9 Hz, 1H), 7.13–7.06 (m, 1H), 7.02 (tdd, J = 8.7, 2.4, 0.9 Hz, 1H), 6.94 (ddd, J = 10.0, 8.8, 2.4 Hz, 1H), 6.84 (ddd, J = 11.0, 8.6, 2.4 Hz, 1H), 3.49 (s, 3H). 13 13C NMR (126 MHz, Chloroform-d) δ 185.72, 180.76, 169.27, 166.01 (ddd, J = 256.7, 51.8, 12.1 Hz), 163.97–160.55 (m), 161.53, 149.90, 149.23, 132.85 (dd, J = 10.6, 2.2 Hz), 132.67 (dd, J = 10.6, 3.7 Hz), 129.81, 123.38 (d, J = 2.2 Hz), 122.97–121.72 (m), 121.01, 120.43, 112.42 (dd, J = 21.6, 3.4 Hz), 112.13 (dd, J = 21.7, 3.6 Hz), 105.08 (td, J = 25.6, 10.9 Hz), 104.15, 50.94. 19 19F NMR (471 MHz, Chloroform-d) δ -100.37, -101.39, -105.56, -106.20. HRMS (ESI) m / z calcd for C 24 1 13 19F4O6 + [M + H] + = 473.0643, found = 473.0645

[0064] Compound 3s: 1 1H NMR (500 MHz, Chloroform-d) δ 11.35 (s, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 9.2 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 1.8 Hz, 1H), 7.39 (dd, J = 8.4, 2.2 Hz, 2H), 7.35 (dd, J = 8.3, 1.9 Hz, 1H), 7.28 (s, 1H), 3.49 (s, 3H). 1313C NMR (126 MHz, Chloroform-d) δ 187.60, 183.12, 169.01, 161.49, 149.33, 139.48, 138.18, 135.09, 134.69, 133.54, 133.18, 131.40, 130.73, 130.10, 129.30, 127.36, 124.06, 121.26, 120.36, 104.27, 50.97. HRMS (ESI) m / z calcd for C 24 H 13 Cl4O6 + [M + H] + = 536.9461, found = 536.9464

[0065] Compound 3t: 1 1H NMR (500 MHz, Chloroform-d) δ 11.40 (s, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.01 (dd, J = 8.4, 2.0 Hz, 2H), 7.85 (d, J = 9.2 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 9.2 Hz, 1H), 3.43 (s, 3H). 13 13C NMR (126 MHz, Chloroform-d) δ 187.51, 179.00, 167.83, 160.74, 149.75, 148.20, 137.56, 136.88, 136.31, 133.73, 132.52, 132.33, 130.94, 129.97, 129.77, 129.19, 128.08, 127.30, 126.45, 122.40, 120.45, 119.45, 102.93, 49.85. HRMS (ESI) m / z calcd for C 24 H 13 Cl4O6 + [M + H] + = 536.9461, found = 536.9462

[0066] Compound 3u: 1H NMR(500MHz,Chloroform-d)δ11.38(s,1H),7.83(d,J=3.6Hz,1H),7.79(d,J=9.2Hz,1H),7.76–7.72(m,1H),7.56(s,1 H),7.25(d,J=9.2Hz,1H),7.13(d,J=3.3Hz,1H),6.66(dd,J=3.6,1.7Hz,1H),6.55(dd,J=3.6,1.7Hz,1H),3.60(s,3H). 13 C NMR(126MHz,Chloroform-d)δ177.48,168.28,167.85,160.29,152.62,149.57,149.25,147.87,147.35, 145.50,125.72,122.56,121.12,119.37,118.97,116.37,111.67,111.45,103.20,50.00.HRMS(ESI)m / z calcd for C 20 H 13 O8 + [M+H] + =381.0605,found=381.0604

[0067] Example 2

[0068] To identify potential targets of the synthesized compounds, reverse virtual screening was performed using the ePharmaLib database. The reverse virtual screening experiment was conducted according to the following reference [3]. Under the reverse virtual screening environment set at pH 7.4, compound 3a exhibited both molecular and ionic states. The reverse virtual screening results for the molecular form of compound 3a showed good compatibility with the PIM-1 proto-oncogene, serine / threonine kinase, and heat shock protein 90-β. The reverse virtual screening results for the ionic form of compound 3a showed good compatibility with protoporphyrinogen oxidase and uronic acid reductase.

[0069]

[0070] The molecular forms of compounds 3a-3u were molecularly docked with the PIM-1 proto-oncogene-serine / threonine kinase and heat shock protein 90-β, respectively. The ionic form 3a' of compound 3a, along with the corresponding ionic forms of other compounds, were molecularly docked with protoporphyrinogen oxidase and uronic acid reductase, respectively. The databases used in the experiments included the PDB database (http: / / www.rcsb.org / ), and the software used included SYBYL-X 1.10 (Tripos, USA), Discovery Studio 4.1 Client (DS, Accelrys, USA), and Pymol (USA). (Company). The molecular docking experimental procedure is as follows:

[0071] Step 1: In SYBYL-X 1.10 software, plot compound 3a-3u and its corresponding ionic compound 3a'-3u'. Use the Minimize module to optimize the structure of the compound, perform energy minimization calculations based on the Tripos force field, and load Gasteiger-Hückel charge. Save the optimized structure in mol2 format to build a ligand small molecule compound library in preparation for molecular docking.

[0072] Step 2: Download the crystal structures of PIM-1 proto-oncogene-serine / threonine kinase (PDB ID: 2OBJ), heat shock protein 90-β (PDB ID: 1YUM), protoporphyrinogen oxidase (PDB ID: 4IVM), and uronic acid reductase (PDB ID: 3V35) from the PDB database (http: / / www.rcsb.org). In SYBYL software, use the Define function of the Docking module in Applications to modify, hydrogenate, and load AMBER FF99 charges on the target proteins, and locate their active sites. Extract the ligand small molecules inherent in the crystal structures as positive control compounds, undergo the same energy optimization treatment as in Step 1, and add them to the ligand small molecule database.

[0073] Step 3: After processing, in the same Docking module, use the ligand small molecule compound library from Step 1 to dock with the target protein, and merge the small molecules in the small molecule compound library with the target protein in sequence, and save it as a PDF file.

[0074] Step 4: Analyze the molecular docking results using the Receptor-Ligand Interactions module in Discovery Studio software and create a 3D rendering. Use Pymol to draw a schematic diagram of the molecular surface cavities.

[0075] The docking results are as follows:

[0076] Table 2. Docking results of the compounds

[0077]

[0078]

[0079] In the docking results with PIM-1 kinase, 3l had the highest docking score of 6.4101; in the docking results with heat shock protein 90-β, 3d had the highest docking score of 7.9877; in the docking results with protoporphyrinogen oxidase, 3e' had the highest docking score of 7.0778; and in the docking results with uronic acid reductase, 3o' had the highest docking score of 6.7376. The above ligand molecules were docked with their respective targets, and the results were exported.

[0080] PIM-1 kinase is a serine / threonine kinase whose expression and activity are tightly regulated in normal tissues, but it is highly expressed in the development and progression of various malignant tumors, such as prostate cancer, mesothelioma, and osteosarcoma. PIM-1 regulates the growth, proliferation, apoptosis, and differentiation of tumor cells by phosphorylating downstream target proteins. PIM-1 kinase inhibitors have immunomodulatory potential and may be useful in cancer treatment.

[0081] 3l can fit well into the active pocket of PIM-1 kinase, such as Figure 13 As shown, its two dispersed trifluoromethylphenyl groups can penetrate deep into the hydrophobic pocket and bind tightly to the target site. At the same time, the oxygen on the carbonyl group of the small molecule forms a hydrogen bond with LYS67, and the four cyclic structures can form π-alkyl interactions with amino acids such as LEU44, ALA65, and ILE104.

[0082] In normal cells, the heat shock protein 90-β, with the participation of chaperone proteins, promotes the folding and maturation of various proteins through the ATP cycle, and then precisely regulates various biological processes such as gene expression, cell cycle and proliferation through the synergistic effect of multiple pathways.

[0083] Compound 3d can stably bind to heat shock protein 90-β, such as Figure 14 As shown. Due to its two biphenyl structures, the molecule can penetrate well into the hydrophobic active pocket composed of multiple β-helical structures. At the same time, the polycyclic feature of this structure allows the two benzene rings to form π-π conjugations with amino acids PHE22, LEU107, PHE138, and PHE170, respectively. In addition, the hydroxyl groups on the benzofuran structure can form hydrogen bonds with THR184 and other hydrophobic interactions with MET98.

[0084] Animals, plants, bacteria, and fungi all contain protoporphyrinogen oxidase, which catalyzes the formation of protoporphyrinogen IX from protoporphyrin IX under molecular oxygen conditions. Protoporphyrinogen oxidase is the last common enzyme in tetrapyrrole biosynthesis, mainly synthesizing heme and chlorophyll, and is a key target for the treatment of porphyria in the human body.

[0085] Compound 3e' can stably bind to protoporphyrinogen oxidase, such as Figure 15 As shown, its polycyclic structure effectively occupies the hydrophobic active pocket. Simultaneously, the small molecule forms hydrogen bond interactions with ARG62, ARG-97, and VAL-456, and forms π-π conjugation with PHE331.

[0086] Aldose reductase is a small cytoplasmic monomeric enzyme belonging to the aldehyde-ketone reductase superfamily. Aldose reductase catalyzes the reduction of various aromatic and aliphatic carbonyl compounds dependent on nicotinamide adenine dinucleotide phosphate (NADPH). It is associated with the development of diabetic and galactosemia complications involving the lens, retina, nerves, and kidneys.

[0087] Compound 3o' can stably bind to uronic acid reductase, such as Figure 16 As shown. The hydrophobic pocket of this target is located on the surface, and a single benzene ring structure of the small molecule can penetrate deep into the non-surface portion of the hydrophobic active pocket. The ester group of the compound can form hydrogen bond interactions with SER302. The four ring structures can form π-π conjugations with TRP20, PHE122, and TRP219.

[0088] These hydrogen-bonded and hydrophobic interactions played a crucial role in the binding of these four compounds to the four targets mentioned above, based on docking scores and... Figures 13-16 The binding conformations and values ​​in the data indicate that these four compounds can bind stably to the four proteins mentioned above, and they may serve as potential inhibitors for these four targets in the future.

[0089] References:

[0090] [3]Aurélien FAMoumbock,Jianyu Li,Hoai TTTran,Rahel Hinkelmann,Evelyn Lamy,Henning J.Jessen,and Stefan Günther.ePharmaLib:A VersatileLibrary of e-Pharmacophores to Address Small-Molecule(Poly-)Pharmacology[J].Journal of Chemical Information and Modeling 2021 61(7),3659-3666.

Claims

1. A method for synthesizing a class of benzofuran compounds, wherein the structural formula of the compounds is shown in formula (Ⅰ): The synthesis method of compound (I) is as follows: using methyl p-benzoquinone 2-carboxylate and 1-benzoylmethylpyridine bromide as raw materials, under alkaline conditions and nitrogen protection, the mixture is heated under reflux for 8-16 hours in an appropriate amount of reaction solvent to obtain the target product (I). The structural formula of the p-benzoquinone 2-formate methyl ester is: The structural formula of the 1-benzoylmethylpyridine bromide compound is: in, The R is selected from one of the following: benzene ring, 4-methylphenyl, 4-ethylphenyl, 4-phenylphenyl, 4-esterylphenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 3-fluorophenyl, 3-trifluoromethylphenyl, 3-chlorophenyl, 3-bromophenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, and furan ring.

2. The synthesis method according to claim 1, characterized in that, The method for synthesizing the compound of formula (Ⅰ) includes the following steps: Under nitrogen protection, methyl p-benzoquinone 2-carboxylate, 1-benzoylmethylpyridine bromide, base, and appropriate amount of reaction solvent were added sequentially to a dry container. The mixture was heated under reflux for 8–16 hours to induce Michael addition. After the reaction was completed, the reaction solution was adjusted to weak acidity, extracted with ethyl acetate, and the organic phase was collected. The organic phase was washed, dried, concentrated under reduced pressure, and evaporated to dryness. The solution was then eluted isocratically using petroleum ether and ethyl acetate in a volume ratio of 15:1 as eluents, and analyzed by TLC using petroleum ether and ethyl acetate in a volume ratio of 5:1 as developing solvents. The eluent with an Rf value of 0.5 was collected, and the solvent was removed by rotary evaporation under reduced pressure to obtain the compound shown in formula (Ⅰ).

3. The synthesis method according to claim 2, characterized in that, The reaction solvent is acetonitrile, dichloromethane, toluene, 1,4-dioxane, N,N-dimethylformamide, or tetrahydrofuran.

4. The synthesis method according to claim 2, characterized in that, The bases used are potassium carbonate, cesium carbonate, potassium phosphate, sodium acetate, triethylamine, or N,N-diisopropylethylamine.

5. The synthesis method according to claim 2, characterized in that, The molar ratio of the raw materials methyl p-benzoquinone 2-carboxylate and 1-benzoylmethylpyridine bromide is 1:2.5; and / or The molar ratio of the base to methyl p-benzoquinone 2-carboxylate is 2.5:

1.

6. The use of the benzofuran compound obtained by the synthetic method according to any one of claims 1-5 in the preparation of a drug for inhibiting the PIM-1 proto-oncogene.

7. The application according to claim 6, characterized in that, The drug targets glucuronide reductase, protoporphyrinogen oxidase, heat shock protein 90-β, and / or serine / threonine kinase.

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