Synthesis method of 2,3-disubstituted benzofuran compounds and application thereof

Abstract

The application provides a synthesis method of 2,3-disubstituted benzofuran compounds and application thereof. The application takes o-hydroxy chalcone and gamma-bromobutyric acid ester as reaction raw materials, and obtains a series of 2,3-disubstituted benzofuran compounds through one-pot multi-step tandem reaction under the promotion of alkali. Advantages of the application include: the reaction reagent is cheap and easy to obtain, the reaction is efficient, the reaction step is short, the application is economical and practical, and the application is environment-friendly; the reaction is easy to enlarge, and has practical value. The compounds have certain inhibitory activity on alpha-glucosidase, and can be used for treating diabetes.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for synthesizing 2,3-disubstituted benzofuran compounds and its application in pharmacy. BACKGROUND

[0002] Benzofuran as a core skeleton compound widely exists in natural products and drugs in nature, and many compounds containing this skeleton show potential biological activity, and some compounds have become listed drugs. One of the traditional methods to obtain benzofuran is based on Rap-Stoermer reaction, which is essentially an alkaline-induced reaction of salicylaldehyde / ortho-hydroxy phenyl ketone and α-halo ketone. 2,3-disubstituted benzofuran is one of the important benzofuran derivatives, which shows excellent biological and therapeutic activity.

[0003]

[0004] Drugs and active molecules containing 2,3-disubstituted benzofuran skeleton

[0005] Developing a synthetic strategy for 2,3-disubstituted benzofuran structure has been a very concerned topic in the field of organic synthesis, however, in addition to excess metal catalysis, there are few reports on organic catalytic strategies for synthesizing this skeleton. In 2018, Suresh et al. reported the synthesis of 2,3-disubstituted benzofuran compounds by the reaction of ortho-hydroxycinnamate or ortho-hydroxychalcone with γ-bromocrotonate under the promotion of base (Org. Lett. 2019, 21, 6, 1823-1827), but this strategy needs to be carried out at high temperature of 120 °C, which requires very high equipment, so it is urgent to develop a mild method.

[0006] The object of the present application is to design a simple and practical catalytic method to prepare the skeleton. Therefore, the present application constructs 2,3-disubstituted benzofuran compounds by mild conditions starting from cheap and readily available raw materials under the promotion of base. SUMMARY

[0007] The present application innovatively realizes a method for efficiently constructing 2,3-disubstituted benzofuran skeleton. The present inventors found that ortho-hydroxychalcone is a unique compound with a hydroxyl-substituted benzene ring, which has the characteristics of stability and easy preparation. In view of this, the present application designs a reaction method for preparing 2,3-disubstituted benzofuran compounds by the reaction of ortho-hydroxychalcone with γ-bromocrotonate.

[0008] The application provides a synthesis method of a 2,3-disubstituted benzofuran compound, which is prepared by using o-hydroxy chalcone and gamma-bromine butyric acid ester as raw materials, and reacting in a reaction solvent under the mediation of an alkali, so that corresponding conversion is effectively realized, and a 2,3-disubstituted benzofuran compound shown in formula (III) is prepared. The reaction process is shown in the following reaction formula (a).

[0009] ;

[0010] wherein, R 1 is an alkyl or aryl group; R 2 is an alkyl or aryl group; and R 3 is an alkyl or aryl group.

[0011] Preferably, R 1 is a methyl group, an ethyl group or a benzyl group; R 2 is a methyl group, a phenyl group, a thiophene group or a naphthyl group; and R 3 is any one of hydrogen or a methoxy group.

[0012] As shown in the above reaction formula (a), the application uses o-hydroxy chalcone shown in formula (I) and gamma-bromine butyric acid ester shown in formula (II) as raw materials, and reacts in a reaction solvent under the mediation of an alkali, so as to obtain a 2,3-disubstituted benzofuran compound shown in formula (III).

[0013] In the application, the alkali is KOH, NaOH, Cs2CO3, DIPEA or DBU. Preferably, the alkali is DBU.

[0014] In the application, the solvent is MeCN, DMSO, THF, EtOH, Acetone, DMF or Toluene. Preferably, the solvent is MeCN.

[0015] In the application, the use ratio of the starting raw material, i.e., o-hydroxy chalcone shown in formula (I) and gamma-bromine butyric acid ester shown in formula (II), is 1:1-1:2. Preferably, the use ratio is 1:1.5.

[0016] In the application, the reaction temperature is 20-30 DEG C. Preferably, the temperature is 25 DEG C.

[0017] The synthesis reaction of the application comprises the following steps:

[0018] The reaction shown in reaction formula (a) comprises the following steps: adding o-hydroxy chalcone shown in formula (I), gamma-bromine butyric acid ester shown in formula (II), DBU and acetonitrile into a reaction container, and stirring and reacting under the condition of 25 DEG C to obtain a 2,3-disubstituted benzofuran compound shown in formula (III). o ​

[0019] In one embodiment, as shown in reaction (a), the synthetic reaction of the present application is carried out in reaction flask A by adding o-hydroxychalcone (X mmol), γ-bromocrotonic acid ester (Y mmol), base (Z mmol), solvent (V mL), and the reaction system is stirred 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.

[0020] The present application also provides a pyrrolo 2,3-disubstituted benzofuran compound as shown in formula (III) prepared by the above-mentioned synthetic method of the present application,

[0021]

[0022] wherein, R 1 is methyl, ethyl, benzyl, fluorenyl; R 2 is methyl, phenyl, thienyl, naphthyl; R 3 is any one of hydrogen, methoxy.

[0023] The present application has the following advantages: (1) the reaction reagents are cheap and easy to obtain; (2) the reaction is efficient; (3) the reaction steps are short, economical and practical, and friendly to the environment; (4) the reaction is easy to scale up and has practical value.

[0024] The present application uses o-hydroxychalcone and γ-bromocrotonic acid ester as reaction raw materials, and obtains a series of 2,3-disubstituted benzofuran compounds through one-pot multi-step tandem reaction under the mediation of DBU. The present application has the following advantages: the reaction reagents are cheap and easy to obtain, the reaction is efficient, the reaction steps are short, economical and practical, and friendly to the environment; the reaction is easy to scale up and has practical value. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 is the hydrogen spectrum of compound 1.

[0026] Figure 2 is the carbon spectrum of compound 1.

[0027] Figure 3 is the hydrogen spectrum of compound 2.

[0028] Figure 4 is the carbon spectrum of compound 2.

[0029] Figure 5 is the hydrogen spectrum of compound 3.

[0030] Figure 6 is the carbon spectrum of compound 3.

[0031] Figure 7 is the hydrogen spectrum of compound 4.

[0032] Figure 8 The carbon spectrum of compound 4.

[0033] Figure 9 The hydrogen spectrum of compound 5.

[0034] Figure 10 The carbon spectrum of compound 5.

[0035] Figure 11 The hydrogen spectrum of compound 6.

[0036] Figure 12 The carbon spectrum of compound 6.

[0037] Figure 13 The hydrogen spectrum of compound 7.

[0038] Figure 14 The carbon spectrum of compound 7. DETAILED DESCRIPTION

[0039] The present application will be further described in conjunction with the following specific examples, and the protection scope of the present application is not limited to the following examples. Changes and advantages that can be thought of by those skilled in the art without departing from the spirit and scope of the present application are included in the present application, and are protected by the appended claims. The process, conditions, reagents, experimental methods, etc. for implementing the present application, except for the following specifically mentioned contents, are the general knowledge and common sense in the art, and the present application has no special limitation. The data given in the following examples include specific operations and reaction conditions and products. The product purity is identified by nuclear magnetic resonance.

[0040] The synthesis reaction of the 2,3-disubstituted benzofuran compound of the present application includes the following steps:

[0041] As shown in equation a: add o-hydroxychalcone, γ-bromocrotonate, DBU, acetonitrile in a reaction vessel, stir the reaction at 25°C, to obtain the 2,3-disubstituted benzofuran compound shown in formula (III). Then concentrate, neutralize, and separate by column chromatography to obtain the target product. During the process, condition screening is carried out, as shown in the following table:

[0042]

[0043]

[0044] The 2,3-disubstituted benzofuran compounds shown in Table 1 are all products synthesized by the method of the present application.

[0045]

[0046] Example 1

[0047]

[0048] 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), DBU (72.4 mg, 0.12 mmol, 3.0 equiv.) to a reaction tube, γ-methyl bromocrotonate (26.9 mg, 0.15 mmol, 1.5 equiv.) was added and stirred at 20 °C for 12 hours. After neutralizing the reaction solution, the solvent was removed under reduced pressure and the product 1 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / methylene chloride 20:1:1). Yield: 90%; o Creacted at room temperature for 12 hours. After neutralizing the reaction solution, the solvent was removed under reduced pressure and the product 1 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / methylene chloride 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.

[0049] Example 2

[0050]

[0051] 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), DBU (72.4 mg, 0.12 mmol, 3.0 equiv.) to a reaction tube, γ-methyl bromocrotonate (26.9 mg, 0.15 mmol, 1.5 equiv.) was added and stirred at 20 °C for 12 hours. After neutralizing the reaction solution, the solvent was removed under reduced pressure and the product 1 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / methylene chloride 20:1:1). Yield: 90%; oC at reaction temperature for 12 hours. After neutralization of the reaction solution, 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% 1 H 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.

[0052] Example 3

[0053]

[0054] After trans-4-(2-hydroxyphenyl)-1-(2-naphthalenyl)-2-propen-1-one (27.4 mg, 0.1 mmol), acetonitrile (1.0 mL), DBU (72.4 mg, 0.12 mmol, 3.0 equiv.) were added to the reaction tube, methyl γ-bromocrotonate (26.9 mg, 0.15 mmol, 1.5 equiv.) was added, and the mixture was stirred at 20 o C at reaction temperature for 12 hours. After neutralization of the reaction solution, 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% 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.

[0055] Example 4

[0056]

[0057] After trans 4-(2-hydroxyphenyl)-1-(2-thienyl)-2-propen-1-one (27.4 mg, 0.1 mmol), acetonitrile (1.0 mL), DBU (72.4 mg, 0.12 mmol, 3.0 equiv.) were added to the reaction tube, methyl γ-bromocrotonate (26.9 mg, 0.15 mmol, 1.5 equiv.) was added and stirred at 20 o Cfor 12 hours. After neutralization of the reaction, the solvent was removed under reduced pressure and the product 4 was obtained after column chromatography (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{ 1 H} 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.

[0058] Example 5

[0059]

[0060] After 4-(2-hydroxyphenyl)but-3-en-2-one (16.2 mg, 0.1 mmol), acetonitrile (1.0 mL), DBU (72.4 mg, 0.12 mmol, 3.0 equiv.) were added to the reaction tube, methyl γ-bromocrotonate (26.9 mg, 0.15 mmol, 1.5 equiv.) was added and stirred at 20 o Cfor 12 hours. After neutralization of the reaction, the solvent was removed under reduced pressure and the product 5 was isolated by column chromatography (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.

[0061] Example 6

[0062]

[0063] After 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, γ-bromocrotonic acid ethyl ester (29.0 mg, 0.15 mmol, 1.5 equiv.) was added and stirred at 20 o Cfor 12 hours. After neutralization of the reaction, the solvent was removed under reduced pressure and the product 6 was isolated by column chromatography (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.

[0064] Example 7

[0065]

[0066] After 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, γ-bromocrotonic acid ethyl ester (29.0 mg, 0.15 mmol, 1.5 equiv.) was added and stirred at 20o The reaction mixture was stirred at the C reaction temperature for 12 hours. Then, after neutralization of the reaction mixture, the solvent was removed under reduced pressure and the product 7 was isolated by column chromatography (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 = 7.1 Hz, 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.

[0067] Example 8

[0068] 2,3-Disubstituted benzofuran compounds in vitro inhibitory activity of alpha-glucosidase. The enzyme alpha-glucosidase in vitro inhibitory activity of the present application, the detection of multiple compounds on the inhibitory activity of alpha-glucosidase, acarbose as a positive drug. The preparation of the reaction solution, the sample and the positive drug with DMSO dissolved, the concentration of the compound is 90, 30, 10 μM. Alpha-glucosidase in vitro inhibitory activity, detection of multiple compounds on the inhibitory activity of alpha-glucosidase. The experiment is divided into enzyme activity group (alpha-glucosidase solution and buffer solution), enzyme blank group (buffer and sample), positive group (alpha-glucosidase solution and positive drug solution), positive blank group (buffer solution and positive drug solution), sample group (alpha-glucosidase solution and sample) and sample blank group (buffer solution and sample). For the above grouping, the present application develops the corresponding research. First: accurately weigh 1-2 mg of the sample and the positive drug (acarbose), respectively, with dimethyl sulfoxide (DMSO) dissolved, and then dilute the sample solution to the corresponding concentration with PBS buffer solution (0.1 mol / mL, pH = 6.8); Second: accurately take 15 μL and 45 μL of the sample alpha-glucosidase solution (0.3 μL / mL) with a standard pipette and add it to the 96-well plate, shake and mix for 4 minutes to make it completely mixed. Then preheat at 37°C, add 20 μl of the 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 405 nm. By regression equation of different concentrations of inhibitors and the corresponding inhibition rate, the half inhibitory concentration (IC 50 ) can be obtained. Cell viability is determined using the following formula: (1-Δsample / Δenzyme) x 100%. Table 1 is the determination results of the compounds.

[0069] Table 1: Determination results of the compounds

[0070] .

Claims

1. A 2,3-disubstituted benzofuran compound, characterized by, The compound structure is shown as formula (III): wherein R is selected from the group consisting of methyl; R 1 is selected from the group consisting of hydrogen; R 2 is selected from the group consisting of hydrogen; R 3 is selected from the group consisting of hydrogen.

2. A 2,3-disubstituted benzofuran compound, characterized in that, The compound has a structural formula , or .

3. The method for synthesizing 2,3-disubstituted benzofuran compounds according to claim 1, characterized in that, The reaction is carried out in a reaction solvent under the mediation of a base, and a benzofuran skeleton shown as formula (III) is obtained, and the reaction formula is shown as follows: ； wherein R is selected from the group consisting of methyl; R 1 is selected from the group consisting of hydrogen, methyl; R 2 is selected from the group consisting of hydrogen, methyl; R 3 is selected from the group consisting of hydrogen.

4. The method of synthesis of claim 3, wherein, The base is any one or a combination of multiple of KOH, NaOH, Cs2CO3, DIPEA, and DBU.

5. The method of synthesis of claim 3, wherein, The solvent is any one or a combination of multiple of MeCN, DMSO, THF, EtOH, Acetone, DMF, and Toluene.

6. The method of synthesis of claim 3, wherein, The raw material o-hydroxy chalcone and γ-bromocrotonic acid ester is used in a proportion of 1:1-1:1.

5.

7. The method of synthesis of claim 3, wherein, The reaction temperature is 20-30℃.

8. An alpha-glucosidase inhibitor, characterized in that, The 2,3-disubstituted benzofuran compound of any one of claims 1-2 or the 2,3-disubstituted benzofuran compound prepared by the method of any one of claims 3-7.

9. A medicament for treating diabetes, characterized by comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof. The 2,3-disubstituted benzofuran compound of any one of claims 1-2 or the 2,3-disubstituted benzofuran compound prepared by the method of any one of claims 3-7.

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