A trifluoromethyl-containing benzofuran derivative and a method for preparing the same
The one-pot reaction method for preparing trifluoromethylbenzofuran derivatives using trifluoromethane and borate-containing benzofuran derivatives solves the problems of harsh reaction conditions and high costs in existing technologies, enabling the inexpensive synthesis of target compounds with good properties, suitable for pharmaceuticals and functional materials.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-10-30
- Publication Date
- 2026-03-27
AI Technical Summary
Existing synthetic methods for trifluoromethylbenzofuran derivatives require harsh reaction conditions and use expensive fluorinated building blocks, resulting in high costs.
Trifluoromethylbenzofuran derivatives were prepared by a one-pot reaction using trifluoromethane and borate-containing benzofuran derivatives as starting materials. Cuprous thiocyanate, potassium tert-butoxide, and triethylamine hydrochloride were used as catalysts, and the reaction was carried out under mild conditions.
A synthetic route with mild reaction conditions and inexpensive raw materials is provided to prepare trifluoromethylbenzofuran derivatives with good metabolic stability, solubility and lipophilicity, which are suitable for the fields of medicine, pesticides and functional materials.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application belongs to the technical field of medical intermediates, and particularly relates to a trifluoromethyl-containing benzofuran derivative and a preparation method thereof. BACKGROUND
[0002] Trifluoromethyl-containing benzofuran derivatives can play an important role in the fields of medicine, pesticides and surfactants, which has attracted great interest and attention.
[0003] The method for synthesizing trifluoromethyl-containing benzofuran compounds is mainly based on the trifluoromethylation reaction of compounds without benzofuran groups with trifluoromethyl reagents. In 2004, Konno synthesized trifluoromethyl-containing benzofuran derivatives by using phenol compounds and trifluoromethyl acetylenes as substrates under the catalysis of palladium [T. Konno, J. Chae, T. Ishihara, H. Yamanaka. Tetrahedron 2004, 60, 11695-11700]. In 2010, Qshima reported that phenol compounds reacted with trifluoromethyl-containing sulfides to generate trifluoromethyl-substituted benzofuran compounds under the action of sulfonic anhydride [T. Kobatake, D. Fujino, S. Yoshida, et al. J. Am. Chem. Soc. 2010, 132, 11838-11840]. In 2014, Zhang Xingguo's group synthesized 3-trifluoromethyl benzofuran derivatives by using trifluoromethyl-containing olefins as fluorine-containing building blocks and reacting with o-iodo or o-bromophenol [C. Wang, L. L. Chen, C. L. Deng, et al. Synthesis 2014, 46, 313-319]. However, this route has harsh reaction conditions, and the trifluoromethyl reagent used is relatively expensive. Therefore, it is of great significance to develop a new route for the synthesis of trifluoromethyl-containing benzofuran derivatives. SUMMARY
[0004] In order to overcome the shortcomings of the prior art, the purpose of the present application is to provide a trifluoromethyl-containing benzofuran derivative and a preparation method thereof, which solves the technical problems of the existing preparation method requiring high reaction conditions and using expensive fluorine-containing building blocks.
[0005] In order to achieve the above purpose, the technical scheme adopted by the present application is as follows:
[0006] The present application discloses a preparation method of a trifluoromethyl-containing benzofuran derivative, comprising the following steps:
[0007] S1: after mixing cuprous thiocyanate, potassium tert-butoxide and DMF in a reaction device, then introducing trifluoromethane into the reaction device, mixing after stirring, discharging trifluoromethane, obtaining mixed solution A;
[0008] S2: after mixing mixed solution A and triethylamine hydrochloride, then mixing with boronic acid group containing benzofuran derivative, then introducing trifluoromethane into the reaction device, mixing after stirring, obtaining reaction product B;
[0009] S3: after post-treatment of reaction product B, obtaining trifluoromethyl containing benzofuran derivative.
[0010] Further, in S1, the molar ratio of cuprous thiocyanate and potassium tert-butoxide is 1: (1-4); DMF is 3.5 mL.
[0011] Further, in S1, the stirring is stirring at room temperature (5-30) min.
[0012] Further, in S2, the amount of triethylamine hydrochloride is equal to the molar amount of cuprous thiocyanate; the molar amount of boronic acid group containing benzofuran derivative is (0.02-0.2) mmol.
[0013] Further, in S2, the amount of trifluoromethane introduced is (0.25-2) MPa.
[0014] Further, in S2, the reaction temperature is (25-110) DEG C, and the time is (5-60) min.
[0015] Further, in S3, the post-treatment includes ice bath, liquid separation, extraction, washing, drying and water removal, filtration, evaporation, desolvation treatment, column separation and rotary drying of reaction product B in sequence.
[0016] Further, the drying and water removal is carried out by using magnesium sulfate; the column separation is carried out by using eluent.
[0017] The application further discloses a trifluoromethyl containing benzofuran derivative prepared by the preparation method.
[0018] Compared with the prior art, the application has the following beneficial effects:
[0019] The application discloses a preparation method of a trifluoromethyl containing benzofuran derivative.
[0020] The application also discloses the trifluoromethyl-containing benzofuran derivative prepared by the preparation method. BRIEF DESCRIPTION OF DRAWINGS
[0021] Figure 1 Synthetic route of the trifluoromethyl-containing benzofuran derivative of the application;
[0022] Figure 2 NMR spectra of the trifluoromethyl-containing benzofuran derivatives prepared in Examples 1-5;
[0023] Wherein: a - the nuclear magnetic resonance hydrogen spectrum of the trifluoromethyl-containing benzofuran derivative prepared in Examples 1-5; b - the nuclear magnetic resonance carbon spectrum of the trifluoromethyl-containing benzofuran derivative prepared in Examples 1-5; c - the nuclear magnetic resonance fluorine spectrum of the trifluoromethyl-containing benzofuran derivative prepared in Examples 1-5. DETAILED DESCRIPTION
[0024] To enable those skilled in the art to understand the features and effects of the present application, the following is a general description and definition of the terms and phrases mentioned in the specification and claims. Unless otherwise specified, all technical and scientific words used herein have their usual meanings understood by those skilled in the art of the present application, and in the event of a conflict, the definitions in the specification shall prevail.
[0025] Theories or mechanisms described and disclosed herein, whether correct or not, should not be considered limiting the scope of the present application, i.e., the present application can be practiced without relying on any particular theory or mechanism.
[0026] Herein, all features defined in the form of numerical ranges or percentage ranges, such as values, quantities, contents and concentrations, are for the sake of brevity and convenience. Therefore, the description of numerical ranges or percentage ranges should be considered to have encompassed and specifically disclosed all possible sub-ranges and individual values within the range (including integers and fractions).
[0027] Herein, unless otherwise specified, "comprise", "include", "contain", "have" or similar words encompass the meaning of "consist of" and "consist essentially of", for example, "A comprises a" encompasses the meaning of "A comprises a and other" and "A only comprises a".
[0028] Herein, all possible combinations of the various technical features in the various embodiments or examples are not described in order to simplify the description. Therefore, the various technical features in the various embodiments or examples can be combined with each other as long as there is no contradiction, and all possible combinations should be considered as falling within the scope of the present specification.
[0029] The present application provides a preparation method of trifluoromethyl-containing benzofuran derivatives. The target product is obtained through one-pot reaction with trifluoromethane and a boronic acid group-containing benzofuran derivative as starting materials. The synthesis route is shown in Figure 1
[0030] The specific preparation method comprises the following steps:
[0031] (1) Mix cuprous thiocyanate and potassium tert-butoxide in a molar ratio of 1:3 in a reaction device;
[0032] (2) Add 3.5 mL of DMF to the reaction device and charge 0.25 MPa of trifluoromethane, and stir at room temperature for 20 min;
[0033] (3) Discharge the trifluoromethane, and add an equimolar amount of triethylamine hydrochloride to the reaction device;
[0034] (4) Add the boronic acid group-containing benzofuran derivative dissolved in DMF and charge 0.25 MPa of trifluoromethane, and react at 70°C for 15 min;
[0035] (5) Take out the reaction device, and after ice bath for 15 min, separate the liquid, extract with diethyl ether, wash with water, and dry with magnesium sulfate to remove water, filter, and evaporate;
[0036] Remove the solvent with a rotary evaporator to obtain a solid powder, then separate it by column chromatography with an eluent, and obtain the trifluoromethyl-containing benzofuran derivative after rotary evaporation.
[0037] Preferably, the reactions are all carried out under atmospheric pressure.
[0038] Preferably, the solvents, reagents or raw materials of the reactions are all chemically pure.
[0039] The present application will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not used to limit the scope of the present application. Furthermore, it should be understood that those skilled in the art can make various modifications or changes to the present application after reading the content taught by the present application, and these equivalent forms also fall within the scope of the appended claims.
[0040] The following examples use apparatus and equipment that are conventional in the art. The experimental methods in the following examples, unless otherwise specified, are generally conducted under conventional conditions, or under conditions recommended by the manufacturer. The following examples use various raw materials, unless otherwise specified, and use conventional commercially available products, which are of conventional specifications in the art. In the specification of the present application and in the following examples, unless otherwise specified, "%" means weight percent, "parts" means parts by weight, and ratios are weight ratios.
[0041] Example 1
[0042] A method for preparing a trifluoromethyl-containing benzofuran derivative, comprising the steps of:
[0043] Cuprous thiocyanate (0.0851 g, 0.7 mmol) and potassium tert-butoxide (0.2356 g, 2.1 mmol) were mixed in a reaction device in a molar ratio of 1:3; 3.5 mL of DMF was added to the reaction device and trifluoromethane was charged at 0.25 MPa, and stirred at room temperature for 20 min; the trifluoromethane was discharged to obtain a mixed solution A; an equimolar amount of triethylamine hydrochloride (0.0966 g, 0.7 mmol) with respect to cuprous thiocyanate was added to the reaction device and mixed with the obtained mixed solution A, and then benzofuran-2-boronic acid (0.0103 g, 0.05 mmol) dissolved in 1 mL of DMF was added and trifluoromethane was charged at 0.25 MPa, and reacted at 70°C for 15 min to obtain a reaction product B; the reaction device was ice-bathed for 15 min, and then separated into layers, extracted with diethyl ether, washed with water, and dried with magnesium sulfate to remove water, filtered, and evaporated; the solvent was removed with a rotary evaporator to obtain a solid powder, and then separated by column chromatography using an eluent, and dried to obtain a trifluoromethyl-containing benzofuran derivative (2-trifluoromethylbenzofuran).
[0044] Example 2
[0045] A method for preparing a trifluoromethyl-containing benzofuran derivative, comprising the steps of:
[0046] Cuprous thiocyanate (0.0851 g, 0.7 mmol) and potassium tert-butoxide (0.0785 g, 0.7 mmol) were mixed in a reaction device in a molar ratio of 1:1; 3.5 mL of DMF was added to the reaction device and 0.25 MPa of trifluoromethane was charged, and stirred at room temperature for 20 min; the trifluoromethane was discharged to obtain a mixed solution A; an equimolar amount of triethylamine hydrochloride (0.0966 g, 0.7 mmol) with cuprous thiocyanate was added to the reaction device, mixed with the obtained mixed solution A, and then benzofuran-2-boronic acid (0.0081 g, 0.05 mmol) dissolved in 1 mL of DMF was added and 0.25 MPa of trifluoromethane was charged, and reacted at 90°C for 40 min to obtain a reaction product B; the reaction device was ice-bathed for 15 min, and then separated, extracted with ether, washed with water, and dried with magnesium sulfate to remove water, filtered, and evaporated; the solvent was removed with a rotary evaporator to obtain a solid powder, which was then separated by column chromatography with an eluent to obtain a trifluoromethyl benzofuran derivative (2-trifluoromethyl benzofuran) after rotary evaporation.
[0047] Example 3
[0048] A method of preparing a trifluoromethyl benzofuran derivative, comprising the steps of:
[0049] Cuprous thiocyanate (0.0851 g, 0.7 mmol) and potassium tert-butoxide (0.2356 g, 1.4 mmol) were mixed in a reaction device in a molar ratio of 1:2; 3.5 mL of DMF was added to the reaction device and 1.5 MPa of trifluoromethane was charged, and stirred at room temperature for 10 min; the trifluoromethane was discharged to obtain a mixed solution A; an equimolar amount of triethylamine hydrochloride (0.0966 g, 0.7 mmol) with cuprous thiocyanate was added to the reaction device, mixed with the obtained mixed solution A, and then benzofuran-2-boronic acid (0.0324 g, 0.2 mmol) dissolved in 1 mL of DMF was added and 1.5 MPa of trifluoromethane was charged, and reacted at 25°C for 60 min to obtain a reaction product B; the reaction device was ice-bathed for 15 min, and then separated, extracted with ether, washed with water, and dried with magnesium sulfate to remove water, filtered, and evaporated; the solvent was removed with a rotary evaporator to obtain a solid powder, which was then separated by column chromatography with an eluent to obtain a trifluoromethyl benzofuran derivative (2-trifluoromethyl benzofuran) after rotary evaporation.
[0050] Example 4
[0051] A method of preparing a trifluoromethyl benzofuran derivative, comprising the steps of:
[0052] Cuprous thiocyanate (0.0851 g, 0.7 mmol) and potassium tert-butoxide (0.2356 g, 2.1 mmol) were mixed in a reaction device in a molar ratio of 1:3; 3.5 mL of DMF was added to the reaction device and 2 MPa of trifluoromethane was charged, and stirred at room temperature for 30 min; the trifluoromethane was discharged to obtain a mixed solution A; triethylamine hydrochloride (0.0966 g, 0.7 mmol) in an equimolar amount of cuprous thiocyanate was added to the reaction device, mixed with the obtained mixed solution A, and then benzofuran-2-boronic acid (0.0032 g, 0.02 mmol) dissolved in 1 mL of DMF was added and 2 MPa of trifluoromethane was charged, and reacted at 110°C for 5 min to obtain a reaction product B; the reaction device was ice-bathed for 15 min, and then separated, extracted with ether, washed with water, and dried with magnesium sulfate to remove water, filtered, and evaporated; the solvent was removed with a rotary evaporator and a solid powder was obtained, which was then separated by column chromatography with an eluent to obtain a trifluoromethyl benzofuran derivative (2-trifluoromethyl benzofuran) after spin-drying.
[0053] Example 5
[0054] A method of preparing a trifluoromethyl benzofuran derivative, comprising the steps of:
[0055] Cuprous thiocyanate (0.0851 g, 0.7 mmol) and potassium tert-butoxide (0.2356 g, 2.1 mmol) were mixed in a reaction device in a molar ratio of 1:3; 3.5 mL of DMF was added to the reaction device and 2 MPa of trifluoromethane was charged, and stirred at room temperature for 30 min; the trifluoromethane was discharged to obtain a mixed solution A; triethylamine hydrochloride (0.0966 g, 0.7 mmol) in an equimolar amount of cuprous thiocyanate was added to the reaction device, mixed with the obtained mixed solution A, and then benzofuran-2-boronic acid (0.0032 g, 0.02 mmol) dissolved in 1 mL of DMF was added and 2 MPa of trifluoromethane was charged, and reacted at 110°C for 5 min to obtain a reaction product B; the reaction device was ice-bathed for 15 min, and then separated, extracted with ether, washed with water, and dried with magnesium sulfate to remove water, filtered, and evaporated; the solvent was removed with a rotary evaporator and a solid powder was obtained, which was then separated by column chromatography with an eluent to obtain a trifluoromethyl benzofuran derivative (2-trifluoromethyl benzofuran) after spin-drying.
[0056] Figure 2 NMR spectra of the trifluoromethyl benzofuran derivatives prepared in Examples 1 to 5 are shown, and the spectrum analysis data are as follows:
[0057] 1 H NMR (600 MHz, CDC13) δ 7.68 (d, J = 7.8 Hz, 1 H), 7.58 (d, J = 8.4 Hz,1 H), 7.50-7.40 (m, 1 H), 7.34(t, J=7.5Hz, 1 H), 7.17(d, J=1.2Hz, 1 H). 13 C NMR (151MHz, CDCl3) δ126.94,126.03,123.99,122.50,120.25,112.12,108.16. 19 F NMR (565MHz, CDCl3) δ-64.84.
[0058] The above content is only for illustrating the technical concept of the present invention and should not be construed as limiting the scope of protection of the present invention. Any modifications made to the technical solution based on the technical concept proposed in this invention shall fall within the scope of protection of the claims of this invention.
Claims
1. A method for preparing a trifluoromethylbenzofuran derivative, characterized in that, The target product is obtained by a one-pot reaction using trifluoromethane and a borate-containing benzofuran derivative as starting materials, including the following steps: S1: After mixing cuprous thiocyanate, potassium tert-butoxide and DMF in the reaction apparatus, trifluoromethane is then introduced into the reaction apparatus for mixing. After stirring, the trifluoromethane is discharged to obtain mixed solution A. S2: Mix solution A with triethylamine hydrochloride, then mix with borate-containing benzofuran derivative, then introduce trifluoromethane into the reaction apparatus, stir and react to obtain reaction product B; S3: Post-processing reaction product B yields a trifluoromethylbenzofuran derivative; In S1, the molar ratio of cuprous thiocyanate to potassium tert-butoxide is 1:(1~4); the DMF is 3.5 mL; the stirring is carried out at room temperature for (5~30) min; the amount of trifluoromethane introduced is (0.25~2) MPa. In S2, the amount of triethylamine hydrochloride used is equal to the molar amount of cuprous thiocyanate; the molar amount of borate-based benzofuran derivative is (0.02~0.2) mmol; the reaction temperature is (25~110) °C, and the time is (5~60) min; the amount of trifluoromethane introduced is (0.25~2) MPa. In S3, the post-processing includes sequentially subjecting the reaction product B to ice bath, separation, extraction, washing, drying to remove water, filtration, evaporation, solvent removal, column separation, and rotary evaporation; the drying to remove water is performed using magnesium sulfate; and the column separation is performed using an eluent.