Synthesis method and application of 2, 3-disubstituted benzofuran compound

Abstract

The invention provides a synthesis method of a 2, 3-disubstituted benzofuran compound and application of the 2, 3-disubstituted benzofuran compound. According to the invention, o-hydroxychalcone and gamma-bromo-crotonate are used as reaction raw materials, and under the promotion of alkali, a series of 2, 3-disubstituted benzofuran compounds are obtained through a one-pot multi-step cascade reaction. The method has the advantages that reaction reagents are cheap and easy to obtain, reaction is efficient, reaction steps are short, and the method is economical, practical and environment-friendly; and the reaction is easy to amplify. The compounds have certain inhibitory activity on alpha-glucosidase, or can be used for treating diabetes mellitus.

Description

Technical Field

[0001] The present invention mainly relates to a synthesis method of 2,3-disubstituted benzofuran compounds and application of the same in pharmaceutical preparation. Background Art

[0002] Compounds with benzofuran as the core skeleton are widely present in natural products and drugs in nature. At the same time, many compounds containing this skeleton show potential biological activity, and some compounds have become marketed drugs. One of the traditional methods for obtaining benzofuran is based on the Rap−Stoermer reaction, which is essentially a base-induced reaction of salicylaldehyde / o-hydroxyphenyl ketone and α-haloketone. Among them, 2,3-disubstituted benzofuran is one of the important benzofuran derivatives, which show excellent biological and therapeutic activities.

[0003]

[0004] Drugs and active molecules containing 2,3-disubstituted benzofuran skeletons The development of synthetic strategies for 2,3-disubstituted benzofuran structures has always been a topic of great concern in the organic synthesis community. However, apart from transition metal catalysis, few organic catalytic strategies for the synthesis of this skeleton have been reported. In 2018, Suresh et al. reported the synthesis of 2,3-disubstituted benzofuran compounds by the base-promoted reaction of o-hydroxycinnamate or o-hydroxychalcone with γ-bromocrotonate (Org. Lett. 2019, 21, 6, 1823–1827). However, this strategy needs to be carried out at a high temperature of 120 °C, which has very high requirements for equipment, so it is urgent to develop a mild method.

[0005] The goal of the present invention is to design a simple and practical catalytic method to prepare the framework. Therefore, the present invention uses base to promote the construction of 2,3-disubstituted benzofuran compounds from cheap and readily available raw materials under mild conditions. Summary of the invention

[0006] The present invention innovatively realizes a method for efficiently constructing a 2,3-disubstituted benzofuran skeleton. The inventors have found through research that o-hydroxychalcone is a unique class of compounds with hydroxyl-substituted benzene rings, which has the characteristics of stability and easy preparation. In view of this, the present invention designs a reaction method for preparing 2,3-disubstituted benzofuran compounds by reacting o-hydroxychalcone with γ-bromocrotonate.

[0007] The present invention proposes a method for synthesizing a 2,3-disubstituted benzofuran compound, wherein o-hydroxychalcone and γ-bromocrotonate are used as reaction raw materials under base mediation, and react in a reaction solvent to effectively achieve the corresponding transformation, thereby preparing a 2,3-disubstituted benzofuran compound as shown in formula (III). The reaction process is shown in the following reaction formula (a): ; Among them, R 1 is an alkyl or aryl group; R 2 is an alkyl or aryl group; R 3 is an alkyl group or an aryl group.

[0008] Preferably, R 1 is methyl, ethyl, benzyl; R 2 is methyl, phenyl, thienyl, naphthyl; R 3 It is either hydrogen or methoxy.

[0009] As shown in the above reaction formula (a), the present invention utilizes o-hydroxychalcone represented by formula (I) and γ-bromocrotonate represented by formula (II) as reaction raw materials, and reacts in a reaction solvent under the mediation of a base to obtain a 2,3-disubstituted benzofuran compound represented by formula (III).

[0010] In the present invention, the base is KOH, NaOH, Cs2CO3, DIPEA, DBU. Preferably, the base is DBU.

[0011] In the present invention, the solvent is MeCN, DMSO, THF, EtOH, Acetone, DMF, Toluene. Preferably, the solvent is MeCN.

[0012] In the present invention, the ratio of the starting material, such as the o-hydroxychalcone raw material shown in formula (I) and the γ-bromocrotonate shown in formula (II) is 1:1-1:2. Preferably, the ratio of the two is 1:1.5.

[0013] In the present invention, the reaction temperature is 20-30°C; preferably, the temperature is 25°C.

[0014] The synthesis reaction of the present invention comprises the following steps: The reaction of reaction formula (a) comprises the following steps: adding o-hydroxychalcone represented by formula (I), γ-bromocrotonate represented by formula (II), DBU and acetonitrile into a reaction vessel at 25 o C and stirred to obtain a 2,3-disubstituted benzofuran compound represented by formula (III).

[0015] In a specific example, as shown in reaction formula (a), the synthesis reaction of the present invention is to add o-hydroxychalcone (X mmol), γ-bromocrotonate (Y mmol), base (Z mmol), and solvent (V mL) into a reaction flask A, and the reaction system is heated at 25 o C for 12 hours; after the reaction is completed, the reaction system is concentrated, neutralized, and separated by column chromatography to obtain the target product.

[0016] The present invention also provides a pyrrolo-2,3-disubstituted benzofuran compound as shown in formula (III) prepared according to the above-mentioned synthesis method of the present invention,

[0017] Among them, R 1 is methyl, ethyl, benzyl, fluorenyl; R 2 is methyl, phenyl, thienyl, naphthyl; R 3 It is either hydrogen or methoxy.

[0018] The present invention has the following advantages: (1) the reaction reagents are cheap and readily available; (2) the reaction is highly efficient; (3) the reaction steps are short, economical, practical, and environmentally friendly; and (4) the reaction is easily scaled up and has practical value.

[0019] The present invention uses o-hydroxychalcone and γ-bromocrotonate as reaction raw materials, and obtains a series of 2,3-disubstituted benzofuran compounds through a one-pot multi-step cascade reaction mediated by DBU. The present invention has the following advantages: the reaction reagents are cheap and easy to obtain, the reaction is efficient, the reaction steps are short, the reaction is economical and practical, and it is environmentally friendly; the reaction is easy to scale up and has practical value. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 is the hydrogen spectrum of compound 1.

[0021] Figure 2 is the carbon spectrum of compound 1.

[0022] Figure 3 is the hydrogen spectrum of compound 2.

[0023] Figure 4 is the carbon spectrum of compound 2.

[0024] Figure 5 is the hydrogen spectrum of compound 3.

[0025] Figure 6 This is the carbon spectrum of compound 3.

[0026] Figure 7 is the hydrogen spectrum of compound 4.

[0027] Figure 8 This is the carbon spectrum of compound 4.

[0028] Fig. 9 is the hydrogen spectrum of compound 5.

[0029] Fig.10 This is the carbon spectrum of compound 5.

[0030] Fig.11 is the hydrogen spectrum of compound 6.

[0031] Fig.12 This is the carbon spectrum of compound 6.

[0032] Fig.13 is the hydrogen spectrum of compound 7.

[0033] Fig.14 This is the carbon spectrum of compound 7. DETAILED DESCRIPTION

[0034] The present invention is further described in detail in conjunction with the following specific examples, and the protection content of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, the changes and advantages that can be thought of by those skilled in the art are included in the present invention, and the attached claims are the scope of protection. The process, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the contents specifically mentioned below, are all common knowledge and common common sense in the art, and the present invention has no special restrictions. The data given in the following examples include specific operations and reaction conditions and products. The purity of the product is identified by nuclear magnetic resonance.

[0035] The synthesis reaction of the 2,3-disubstituted benzofuran compounds of the present invention comprises the following steps: As shown in formula a: o-hydroxychalcone, γ-bromocrotonate, DBU, and acetonitrile are added to a reaction vessel and stirred at 25°C to obtain a 2,3-disubstituted benzofuran compound of formula (III). The target product is then obtained by concentration, neutralization, and column chromatography separation. Condition screening was performed during this period, as shown in the following table:

[0036] Entry Base e Equiv of Base Solvent Yield[%] 1 KOH 2.0 MeCN 21 2 NaOH 2.0 MeCN 35 3 <![CDATA[Cs2CO3]]> 2.0 MeCN 24 4 DIPEA 2.0 MeCN 15 5 DBU 2.0 MeCN 68 6 DBU 2.0 EtOH 37 7 DBU 2.0 MeCN 52 8 DBU 2.0 THF 46 9 DBU 2.0 DMSO 57 10 DBU 2.0 DMF 62 11 DBU 2.0 Acetone 43 12 DBU 3.0 MeCN 90 13 DBU 4.0 MeCN 87 14 DBU 5.0 MeCN 58 The 2,3-disubstituted benzofuran compounds shown in Table 1 are all products synthesized by the method of the present invention.

[0037]

[0038] Example 1

[0039] o-Hydroxychalcone (22.3 mg, 0.1 mmol), acetonitrile (1.0 mL), DBU (72.4 mg, 0.12 mmol, 3.0 equiv.) were added to the reaction tube, and then methyl γ-bromocrotonate (26.9 mg, 0.15 mmol, 1.5 equiv.) was added. o C reaction temperature and stirred for 12 hours. Then the reaction solution was neutralized, the solvent was removed under reduced pressure, and the product 1 was obtained after column chromatography separation (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 90%; 1 H NMR (400 MHz, CDCl3) δ 8.13 – 8.02 (m, 2H), 7.64 – 7.56 (m, 1H), 7.53 – 7.46(m, 2H), 7.44 – 7.35 (m, 2H), 7.25 – 7.14 (m, 2H), 4.34 (s, 2H), 3.66 (s,3H), 3.09 (t, J = 7.4 Hz, 2H), 2.78 (d, J = 7.4 Hz, 2H). 13 C{ 1 H} NMR (100 MHz,CDCl3) δ 196.3, 172.9, 154.1, 153.8, 136.5, 133.3, 129.2, 128.7, 128.3, 123.7,122.5, 119.2, 110.9, 108.7, 51.8, 33.7, 32.1, 22.0. Example 2

[0040] After adding trans-4-(2-hydroxyphenyl)-1-(2-(4-methoxy)phenyl)-2-propen-1-one (22.3 mg, 0.1 mmol), acetonitrile (1.0 mL), and DBU (72.4 mg, 0.12 mmol, 3.0 equiv.) into a reaction tube, methyl γ-bromocrotonate (26.9 mg, 0.15 mmol, 1.5 equiv.) was added and the mixture was stirred at 20 ℃ for 1 h. o C reaction temperature and stirred for 12 hours. Then the reaction solution was neutralized, the solvent was removed under reduced pressure, and the product 2 was obtained after column chromatography separation (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 84%; 1H NMR (400 MHz, Chloroform- d ) δ 8.05 (d, J =8.8 Hz, 2H), 7.39 (dd, J = 7.6, 1.4 Hz, 2H), 7.24 – 7.14 (m, 2H), 7.01 – 6.94(m, 2H), 4.28 (s, 2H), 3.87 (s, 3H), 3.66 (s, 3H), 3.09 (t, J = 7.4 Hz, 2H),2.77 (t, J = 7.4 Hz, 2H). 13 C{ 1 H} NMR (100 MHz, Chloroform- d ) δ 194.8, 172.9,163.6, 154.0, 153.7, 130.6, 129.6, 129.2, 123.6, 122.4, 119.3, 113.8, 110.8,109.0, 55.5, 51.7, 33.4, 32.1, 22.0. Example 3

[0041] After adding trans-4-(2-hydroxyphenyl)-1-(2-naphthyl)-2-propen-1-one (27.4 mg, 0.1 mmol), acetonitrile (1.0 mL), and DBU (72.4 mg, 0.12 mmol, 3.0 equiv.) into a reaction tube, methyl γ-bromocrotonate (26.9 mg, 0.15 mmol, 1.5 equiv.) was added and the mixture was stirred at 20 ℃ for 1 h. o C reaction temperature and stirred for 12 hours. Then the reaction solution was neutralized, the solvent was removed under reduced pressure, and the product 3 was obtained after column chromatography separation (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 69% 1 H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 8.10 (dd, J = 8.6,1.8 Hz, 1H), 8.00 (dd, J= 8.1, 1.4 Hz, 1H), 7.96 – 7.87 (m, 2H), 7.68 – 7.54(m, 2H), 7.50 – 7.37 (m, 2H), 7.26 – 7.14 (m, 2H), 4.48 (s, 2H), 3.67 (s,3H), 3.14 (t, J = 7.4 Hz, 2H), 2.80 (t, J = 7.4 Hz, 2H). 13 C{ 1 H} NMR (100 MHz,CDCl3) δ 196.2, 172.9, 154.1, 153.9, 135.6, 133.8, 132.5, 130.0, 129.6, 129.2,128.6, 127.8, 126.9, 124.0, 123.7, 122.5, 119.3, 110.9, 108.9, 51.8, 33.8,32.1, 22.0. Example 4

[0042] After adding trans-4-(2-hydroxyphenyl)-1-(2-thienyl)-2-propen-1-one (27.4 mg, 0.1 mmol), acetonitrile (1.0 mL), and DBU (72.4 mg, 0.12 mmol, 3.0 equiv.) into a reaction tube, methyl γ-bromocrotonate (26.9 mg, 0.15 mmol, 1.5 equiv.) was added and the mixture was stirred at 20 ℃ for 1 h. o C reaction temperature and stirred for 12 hours. Then the reaction solution was neutralized, the solvent was removed under reduced pressure, and the product 4 was obtained after column chromatography separation (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 90%; 1 H NMR (400 MHz, CDCl3) δ 7.92 – 7.84 (m, 1H), 7.70 –7.61 (m, 1H), 7.49 – 7.33 (m, 2H), 7.25 – 7.12 (m, 3H), 4.26 (s, 2H), 3.66(s, 3H), 3.13 (t, J = 7.4 Hz, 2H), 2.79 (t, J = 7.4 Hz, 2H). 13 C{ 1H} NMR (100 MHz,CDCl3) δ 189.18, 172.85, 154.00, 153.98, 143.45, 134.02, 132.32, 128.97,128.20, 123.72, 122.50, 119.27, 110.81, 108.58, 51.76, 34.48, 32.07, 22.00. Example 5

[0043] 4-(2-Hydroxyphenyl)but-3-en-2-one (16.2 mg, 0.1 mmol), acetonitrile (1.0 mL), and DBU (72.4 mg, 0.12 mmol, 3.0 equiv.) were added to a reaction tube, and then methyl γ-bromocrotonate (26.9 mg, 0.15 mmol, 1.5 equiv.) was added. o C reaction temperature and stirred for 12 hours. Then the reaction solution was neutralized, the solvent was removed under reduced pressure, and the product 5 was obtained after column chromatography separation (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 87%; 1 H NMR (400 MHz, CDCl3) δ 7.47 – 7.32 (m, 2H), 7.26 – 7.15 (m, 2H), 3.73 (s, 2H), 3.66 (s, 3H), 3.07 (t, J = 7.3 Hz, 2H), 2.78 (t, J = 7.3 Hz, 2H),2.19 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 205.47, 172.74, 154.01, 153.78,128.82, 123.84, 122.58, 118.98, 110.88, 108.64, 51.77, 38.82, 31.96, 29.08,21.74. Example 6

[0044] o-Hydroxychalcone (22.3 mg, 0.1 mmol), acetonitrile (1.0 mL), and DBU (72.4 mg, 0.12 mmol, 3.0 equiv.) were added to a reaction tube, and then γ-bromocrotonic acid benzyl ester (38.1 mg, 0.15 mmol, 1.5 equiv.) was added. o C reaction temperature and stirred for 12 hours. Then the reaction solution was neutralized, the solvent was removed under reduced pressure, and the product 6 was obtained after column chromatography separation (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 67%; 1 H NMR (400 MHz, CDCl3) δ (dd, J = 8.4, 1.4 Hz, 2H), 7.64 – 7.57 (m, 1H), 7.54 – 7.46(m, 2H), 7.45 – 7.38 (m, 2H), 7.38 – 7.26 (m, 5H), 7.26 – 7.15 (m, 2H), 5.12(s, 2H), 4.31 (s, 2H), 3.13 (t, J = 7.3 Hz, 2H), 2.85 (t, J = 7.3 Hz, 2H). 13 C{ 1 H}NMR (100 MHz, CDCl3) δ 196.3, 172.2, 154.0, 153.7, 136.5, 135.7, 133.3, 129.1,128.6, 128.5, 128.3, 128.2, 128.1, 123.6, 122.4, 119.2, 110.8, 108.7, 66.4,33.7, 32.3, 22.0. Example 7

[0045] o-Hydroxychalcone (22.3 mg, 0.1 mmol), acetonitrile (1.0 mL), and DBU (72.4 mg, 0.12 mmol, 3.0 equiv.) were added to a reaction tube, and then ethyl γ-bromocrotonate (29.0 mg, 0.15 mmol, 1.5 equiv.) was added. oC reaction temperature and stirred for 12 hours. Then the reaction solution was neutralized, the solvent was removed under reduced pressure, and the product 7 was obtained after column chromatography separation (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 74%; 1 H NMR (400 MHz, Chloroform- d ) δ 8.16 – 8.00 (m, 2H), 7.66 – 7.56 (m, 1H), 7.54 – 7.46(m, 2H), 7.43 – 7.33 (m, 2H), 7.25 – 7.12 (m, 2H), 4.34 (s, 2H), 4.12 (q, J =7.1 Hz, 2H), 3.09 (t, J = 7.4 Hz, 2H), 2.75 (t, J = 7.4 Hz, 2H), 1.23 (t, J = 7.1Hz, 3H). 13 C{ 1 H} NMR (100 MHz, Chloroform- d ) δ 196.3, 172.5, 154.1, 154.0, 136.5,133.3, 129.2, 128.7, 128.3, 123.7, 122.4, 119.2, 110.8, 108.6, 60.6, 33.8,32.4, 22.0, 14.1. Example 8 2,3-disubstituted benzofuran compounds α-glucosidase in vitro inhibitory activity experiment. The enzyme α-glucosidase used in the present invention has an in vitro inhibitory activity, and the inhibitory activity of multiple compounds on α-glucosidase is detected, and acarbose is a positive drug. Preparation of the reaction solution, the sample and the positive drug are dissolved in DMSO, and the compound concentrations are 90, 30, and 10 μM, respectively. α-glucosidase in vitro inhibitory activity, detecting the inhibitory activity of multiple compounds on α-glucosidase. The experiment is divided into an enzyme activity group (α-glucosidase solution and buffer solution), an enzyme blank group (buffer and sample), a positive group (α-glucosidase solution and positive drug solution), a positive blank group (buffer solution and positive drug solution), a sample group (α-glucosidase solution and sample) and a sample blank group (buffer solution and sample). For the above groupings, the present invention conducts corresponding research. First: accurately weigh 1-2 mg of sample and positive drug (acarbose), dissolve them in dimethyl sulfoxide (DMSO), and then dilute the sample solution to the corresponding concentration with PBS buffer solution (0.1 mol / mL, pH = 6.8); second: use a standard pipette to accurately measure 15μL of sample and 45μL of α-glucosidase solution (0.3μL / mL) and add them to a 96-well plate, shake and mix for 4 minutes to mix them completely. Then preheat at 37°C, add 20μl of substrate (PNPG) solution, shake and mix evenly, and react at 37°C for half an hour; third: add 100 μl of Na2CO3 solution to terminate the reaction. Finally, the inhibitory activity of the sample is obtained by measuring the absorbance OD at 405nm. By making a regression equation for different concentrations of inhibitors and the corresponding inhibition rates, the half inhibition concentration (IC 50 ). The cell viability was determined using the following formula: (1-Δ-like / Δ-enzyme) × 100%. Table 1 shows the determination results of the compounds.

[0046] Table 1: Test results of compounds .

Claims

1. A 2,3-disubstituted benzofuran compound, characterized in that: The compound structure is shown in formula (III): Among them, R 1 Any one selected from methyl, ethyl, benzyl, fluorenyl; R 2 Any one selected from methyl, phenyl, thienyl, naphthyl; R 3 Any one selected from hydrogen and methoxy.

2. The method for synthesizing benzofuran compounds according to claim 1, characterized in that: Taking o-hydroxychalcone and γ-γ-bromocrotonate as reaction raw materials, a reaction is carried out in a reaction solvent under the mediation of a base to obtain a benzofuran skeleton as shown in formula (III); the reaction process is shown in reaction formula (a); ； Among them, R 1 Any one selected from methyl, ethyl, benzyl, fluorenyl; R 2 Any one selected from methyl, phenyl, thienyl and naphthyl; R 3 Any one selected from hydrogen and methoxy.

3. The synthesis method according to claim 2, characterized in that The base is any one or more combinations of KOH, NaOH, Cs2CO3, DIPEA and DBU.

4. The synthesis method according to claim 2, characterized in that The solvent is selected from any one or more combinations of MeCN, DMSO, THF, EtOH, Acetone, DMF, and Toluene.

5. The synthesis method according to claim 2, characterized in that The ratio of the raw materials of the reaction, o-hydroxychalcone and gamma-bromocrotonate, is 1:1-1:1.

5.

6. The synthesis method according to claim 2, characterized in that The reaction temperature is 20-30°C.

7. An α-glucosidase inhibitor, characterized in that The invention comprises the 2,3-disubstituted benzofuran compound according to any one of claim 1 or the 2,3-disubstituted benzofuran compound prepared by the method according to any one of claims 2 to 7.

8. A drug for treating diabetes, characterized in that: The invention comprises the 2,3-disubstituted benzofuran compound according to any one of claim 1 or the 2,3-disubstituted benzofuran compound prepared by the method according to any one of claims 2 to 7.

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