Method for electrochemical synthesis of trifluoromethyl tellurium isoquinoline derivatives and medical use

Abstract

The present application relates to the technical field of organic synthesis, in particular to a method for electrochemical synthesis of trifluoromethyl tellurium isoquinoline derivatives and medical use. Trifluoromethyl tellurium tetramethyl ammonium salt and 1-(azidomethyl)-2-ethynyl areyl hydrocarbon are used as substrates, potassium iodide is used as an additive, and is added to an organic solvent to form a reaction system, a constant current reaction is carried out, after the reaction is completed, the reaction is treated, and trifluoromethyl tellurium isoquinoline derivatives are prepared. The present application has the advantages of mild conditions, wide substrate range and simple post-treatment, and provides a new synthesis method for trifluoromethyl tellurium isoquinoline derivatives. The obtained trifluoromethyl tellurium isoquinoline derivatives have the effect of GPR119 agonist activity, and provide a new drug candidate molecule for the treatment of abnormal glucose metabolism and related diseases.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for the electrochemical synthesis of trifluoromethyltelluronide isoquinoline derivatives and their pharmaceutical applications. Background Technology

[0002] Isoquinolines and their derivatives are core nitrogen-containing heterocyclic skeletons widely found in natural alkaloids, drug molecules, and functional materials, possessing multiple biological activities such as antitumor, antibacterial, antiviral, and enzyme inhibition, and have significant application value in drug development and fine chemical engineering. Trifluoromethyl (-CF3) exhibits strong electron-withdrawing effects, high lipophilicity, and metabolic stability; its introduction into the heterocyclic skeleton can significantly improve the molecule's lipid-water partition coefficient, membrane permeability, and in vivo metabolic stability. Tellurium, as a chalcogenide, possesses unique redox properties and coordination ability. Trifluoromethyl telluryl (-TeCF3) modification can further regulate molecular electron distribution and biological activity, providing new structural units for the development of novel lead compounds. Currently, research on compounds containing -TeCF3 is mainly limited to simple alkyl or aryl telluride ethers and their metal complexes, resulting in limited structural types, demanding synthetic methods, and poor functional group tolerance.

[0003] In recent years, organic electrosynthesis has utilized electrons as clean redox reagents, eliminating the need for external oxidizing / reducing agents. It allows for precise control of reaction pathways and selectivity through the regulation of current and potential, offering advantages such as mild conditions, environmental friendliness, and ease of scale-up. It has been successfully applied to the green synthesis of fluorine-containing heterocyclic and chalcogenide compounds. However, current electrochemical synthesis techniques are still focused on trifluoromethylation and trifluoromethylthio / selenization reactions. Effective reports on trifluoromethyl tellurization cyclization reactions targeting isoquinoline skeletons have not yet been found, hindering the research and application of such novel functional molecules.

[0004] GPR119 has garnered significant attention in recent years as an important potential target for the treatment of type 2 diabetes and related obesity. Activation of GPR119 can promote the secretion of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) by intestinal L cells and enhance the insulin release capacity of pancreatic β cells in the presence of glucose, thereby exerting a hypoglycemic effect. Although some progress has been made in the development of GPR119 agonists, such as filgrapese oral peptide agonists, their penetration efficiency across intestinal epithelial cells may still be limited. Furthermore, peptide drugs are easily degraded by gastrointestinal proteases or metabolized by the liver through first-pass metabolism, resulting in short half-lives and requiring multiple daily doses or high doses to maintain effective concentrations, which affects patient compliance. Therefore, there is still a need to develop selective GPR119 agonists with novel scaffolds and superior drug-like properties. Summary of the Invention

[0005] The purpose of this invention is to provide a method and application for the electrochemical synthesis of trifluoromethyltelluronide isoquinoline derivatives, in order to solve the problems mentioned in the background art.

[0006] To achieve the above objectives, the present invention provides the following technical solution: A method for the electrochemical synthesis of trifluoromethyltelluride isoquinoline derivatives is as follows: In an organic solvent, trifluoromethyltelluride tetramethylammonium salt having the structure shown in formula (I) and 1-(azidomethyl)-2-ethynyl aromatic hydrocarbon having the structure shown in formula (II) are used as reactants. Additives are added, and the reaction is carried out at room temperature and under constant current conditions. After the reaction is completed, the solvent is removed from the reaction solution under reduced pressure to obtain a crude product. The crude product is purified by column chromatography to obtain a trifluoromethyltelluride isoquinoline derivative having the structure shown in formula (III). The reaction equation is shown below:

[0007]

[0008] In compound (II), R is a hydrogen atom, a halogen, or a C1-C atom. 10 Alkyl, alkoxy, cyano, trifluoromethyl, nitro, acetyl; Ar is phenyl, naphthyl, anthracene, furanyl, thiophene, or an aryl group substituted with one or more substituents, wherein the substituents are alkoxy, alkyl, halogen, cyano, or nitro.

[0009] Preferably, the molar ratio of trifluoromethyltetramethylammonium telluride of formula (I) to 1-(azidomethyl)-2-ethynyl aromatic hydrocarbon of formula (II) is 1:1 to 2:1, preferably 1.5:1.

[0010] Preferably, the anode material for the constant current reaction is graphite felt, platinum sheet, or carbon rod, with carbon rod being preferred. The cathode material is one of copper, iron, nickel, chromium, or graphite, with iron sheet being preferred.

[0011] Preferably, the current for the constant current reaction is 5–10 mA, more preferably 8 mA, a diaphragm-free single-chamber electrolytic cell is used, the reaction time is 5–12 h, and the reaction temperature is room temperature.

[0012] Preferably, the organic solvent is any one of acetonitrile, dichloroethane, N,N-dimethylformamide or methanol, with acetonitrile being the most preferred.

[0013] Preferably, the electrolyte for the constant current reaction is any one of tetrabutylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroborate, sodium tetrafluoroborate, and tetrabutylammonium acetate, with tetrabutylammonium acetate being preferred. The molar concentration (electrolyte / organic solvent) of the electrolyte relative to the organic solvent in the reaction system is 0.1 mol / L to 0.2 mol / L.

[0014] Preferably, the additive is any one of potassium bromide, lithium bromide, and potassium iodide, with potassium iodide being the most preferred.

[0015] Preferably, after the reaction is completed, the solvent is removed under reduced pressure, and the crude product is purified by silica gel column chromatography. The eluent is a mixture of petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate is (100-1):1. The eluent is collected, and the solvent is evaporated by rotary evaporation to obtain the trifluoromethyltelluronide derivative shown in formula (III).

[0016] The trifluoromethyltelluron-isoquinoline derivative prepared in this invention has excellent GPR119 agonist activity and can be used to prepare drugs for treating diseases related to GPR119 activity, providing a new lead compound for the preparation of drugs for treating diabetes.

[0017] Furthermore, the trifluoromethyltelluronide isoquinoline derivatives obtained by this invention can be formulated into pharmaceutical preparations, alone or in combination with one or more pharmaceutically acceptable carriers, for drug delivery. For example, solvents, diluents, etc., can be used for oral dosage forms, such as tablets, capsules, dispersible powders, granules, etc. Various dosage forms of the pharmaceutical compositions of this invention can be prepared according to methods well known in the pharmaceutical field. These pharmaceutical preparations may contain, for example, 0.05% to 90% by weight of the active ingredient in combination with a carrier, more commonly about 15% to 50% by weight of the active ingredient. The dosage of the compounds of this invention can be from 0.005 to 5000 mg / kg / day, and may exceed this range depending on the severity of the disease or the dosage form.

[0018] Compared with the prior art, the beneficial effects of the present invention are:

[0019] 1. A novel electrochemical method for the synthesis of trifluoromethyltelluride isoquinoline derivatives has been developed for the first time. This method uses electrons as a clean reagent, requires no external oxidant, and has advantages such as mild conditions, environmental friendliness, and simple steps, opening up a new route for the synthesis of heterocyclic compounds containing trifluoromethyltelluride groups.

[0020] 2. Trifluoromethyl telluryl group was successfully introduced into the isoquinoline skeleton to construct a novel functional molecule with the triple advantages of heterocycle, fluorine atom and chalcogen elements, providing a brand-new structural unit for drug development.

[0021] 3. The synthesized compound exhibits excellent GPR119 agonist activity, can promote insulin secretion, and has the potential to be developed into a hypoglycemic drug. Detailed Implementation

[0022] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0023] This invention provides the following technical solution: a method for electrochemically synthesizing trifluoromethyltelluride isoquinoline derivatives, comprising the following steps:

[0024] In an organic solvent, trifluoromethyltelluric tetramethylammonium salt having the structure shown in formula (I) and 1-(azidomethyl)-2-ethynyl aromatic hydrocarbon having the structure shown in formula (II) were used as reactants. Additives were added, and the reaction was carried out at room temperature and under constant current conditions. After the reaction was completed, the solvent was removed from the reaction solution under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain a trifluoromethyltelluric isoquinoline derivative having the structure shown in formula (III). The reaction equation is shown below:

[0025]

[0026] In compound (II), R is a hydrogen atom, a halogen, or a C1-C atom. 10 Alkyl, alkoxy, cyano, trifluoromethyl, nitro, acetyl; Ar is phenyl, naphthyl, anthracene, furanyl, thiophene, or an aryl group substituted with one or more substituents, wherein the substituents are alkoxy, alkyl, halogen, cyano, or nitro.

[0027] Compound (II) is prepared by the following route:

[0028]

[0029] The operation steps are as follows:

[0030] o-Iodobenzoic acid S1 (1.0 equivalent) was dissolved in anhydrous THF. After cooling to 0 °C, NaBH4 (3.0 equivalent) was added in portions. Subsequently, a THF solution containing dissolved I2 (0.75 equivalent) was slowly added dropwise to the resulting mixture over a period of more than 5 hours. After the addition was complete, the mixture was allowed to warm to room temperature and stirred overnight. After the reaction was complete, the mixture was cooled to 0 °C, and water was carefully added. Then, 3M hydrochloric acid was slowly added until the pH of the solution reached 2. The resulting mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to give product S2.

[0031] Under an argon atmosphere at room temperature, Pd(PPh3)2Cl2 (1 mol%) and CuI (2 mol%) were added sequentially to a stirred solution of triethylamine (2 mL) containing 1.2 equivalents of aromatic yne. The mixture was stirred for 10 minutes. Then, S2 (1.2 equivalents) was added. The mixture was stirred overnight. A saturated aqueous solution of NH4Cl was added to the resulting mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain product S3.

[0032] S3 (1 equivalent) was dissolved in 2 mL of toluene, and DBU (1.3 equivalent) and diphenylphosphoazide (DPPA) (1.2 equivalent) were added. The mixture was stirred at room temperature for 14 hours. The reaction mixture was posttreated with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and purified by column chromatography to give product (III).

[0033] Example 1

[0034] The reaction equation is shown below:

[0035]

[0036] In an air atmosphere, trifluoromethyltelluric tetramethylammonium salt (0.3 mmol), 1-(azidomethyl)-2-(phenylethynyl)benzene (0.2 mmol), KI (0.4 mmol), nBu4OAc (2 mmol), and acetonitrile (10 mL) were sequentially added to a 25 mL diaphragm-free three-necked flask equipped with a magnetic stirrer. After the addition was complete, a carbon rod anode (1.5 cm × 1.5 cm) and an iron cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, and the current was set to 8 mA. The electrolysis reaction was carried out continuously for 10 hours in an air atmosphere at room temperature. After the reaction was completed, the solvent was removed from the reaction solution by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 15:1) to obtain the target compound 1a in 65% yield.

[0037] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.54 (s, 1H), 8.53 (d, J= 8.6 Hz, 1H), 8.27 (d, J = 8.1 Hz, 1H), 7.98–7.88 (m, 1H), 7.85–7.77 (m,1H), 7.59–7.56 (m, 2H), 7.55–7.48 (m, 3H). 13 C NMR (100 MHz, CDCl3) δ 165.9,162.6, 158.9, 143.3, 141.8, 135.4, 134.0, 130.8, 129.3, 128.2, 123.1, 119.5,118.1, 117.8.

[0038] Example 2

[0039] In an air atmosphere, trifluoromethyltelluric tetramethylammonium salt (0.2 mmol), 1-(azidomethyl)-2-(phenylethynyl)benzene (0.2 mmol), KI (0.4 mmol), nBu4OAc (2 mmol), and acetonitrile (10 mL) were sequentially added to a 25 mL diaphragm-free three-necked flask equipped with a magnetic stirrer. After the addition was complete, a carbon rod anode (1.5 cm × 1.5 cm) and an iron cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, and the current was set to 8 mA. The electrolysis reaction was carried out continuously for 10 hours in an air atmosphere at room temperature. After the reaction was completed, the solvent was removed from the reaction solution by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 15:1) to obtain the target compound 1a in 50% yield.

[0040] Example 3

[0041] In an air atmosphere, trifluoromethyltelluric tetramethylammonium salt (0.3 mmol), 1-(azidomethyl)-2-(phenylethynyl)benzene (0.2 mmol), KI (0.4 mmol), nBu4OAc (2 mmol), and methanol (10 mL) were sequentially added to a 25 mL diaphragm-free three-necked flask equipped with a magnetic stirrer. After the addition was complete, a carbon rod anode (1.5 cm × 1.5 cm) and an iron cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, and the current was set to 8 mA. The electrolysis reaction was carried out continuously for 10 hours in an air atmosphere at room temperature. After the reaction was completed, the solvent was removed from the reaction solution by a rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 15:1) to obtain the target compound 1a in a yield of 44%.

[0042] Example 4

[0043] In an air atmosphere, trifluoromethyltelluric tetramethylammonium salt (0.3 mmol), 1-(azidomethyl)-2-(phenylethynyl)benzene (0.2 mmol), KI (0.4 mmol), nBu4NPF6 (2 mmol), and acetonitrile (10 mL) were sequentially added to a 25 mL diaphragm-free three-necked flask equipped with a magnetic stirrer. After the addition was complete, a carbon rod anode (1.5 cm × 1.5 cm) and an iron cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, and the current was set to 8 mA. The electrolysis reaction was continued for 10 hours in an air atmosphere at room temperature. After the reaction was completed, the solvent was removed from the reaction solution by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 15:1) to obtain the target compound 1a in 56% yield.

[0044] Example 5

[0045] The reaction equation is shown below:

[0046]

[0047] In an air atmosphere, trifluoromethyltelluryltetramethylammonium salt (0.3 mmol), 2-((4-fluorophenyl)ethynyl)-1-(azidomethyl)benzene (0.2 mmol), KI (0.4 mmol), nBu4OAc (2 mmol), and acetonitrile (10 mL) were sequentially added to a 25 mL diaphragm-free three-necked flask equipped with a magnetic stirrer. After the addition was complete, a carbon rod anode (1.5 cm × 1.5 cm) and an iron cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, and the current was set to 8 mA. The electrolysis reaction was continued for 10 hours in an air atmosphere at room temperature. After the reaction was completed, the solvent was removed from the reaction solution by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 15:1) to obtain the target compound 1b in 72% yield.

[0048] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.45 (s, 1H), 8.69 (d, J= 8.6 Hz, 1H), 8.36 (d, J = 8.1 Hz, 1H), 7.99–7.88 (m, 1H), 7.74–7.70 (m,1H), 7.56–7.54 (m, 2H), 7.18 (t, J = 8.7 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ164.9, 158.6, 157.8, 140.3, 139.2, 137.4, 136.3, 129.4, 128.6, 128.1, 121.2,118.2, 118.0, 116.6.

[0049] Example 6

[0050] The reaction equation is shown below:

[0051]

[0052] In an air atmosphere, trifluoromethyltelluryltetramethylammonium salt (0.3 mmol), 2-((4-methylphenyl)ethynyl)benzyl azide (0.2 mmol), KI (0.4 mmol), nBu4OAc (2 mmol), and acetonitrile (10 mL) were sequentially added to a 25 mL diaphragm-free three-necked flask equipped with a magnetic stirrer. After the addition was complete, a carbon rod anode (1.5 cm × 1.5 cm) and an iron cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, and the current was set to 8 mA. The electrolysis reaction was continued for 10 hours in an air atmosphere at room temperature. After the reaction was completed, the solvent was removed from the reaction solution by a rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 15:1) to obtain the target compound 1c in 73% yield.

[0053] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.38 (s, 1H), 8.59 (d, J= 8.6 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.99–7.95 (m, 1H), 7.87 (t, J = 7.5Hz, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 7.9 Hz, 2H), 2.66 (s, 3H). 13 CNMR (100 MHz, CDCl3) δ 163.7, 155.7, 154.4, 149.0, 145.7, 139.4, 137.2,136.4, 135.6, 132.5, 130.9, 129.8, 128.4, 117.2, 22.6.

[0054] Example 7

[0055] The reaction equation is shown below:

[0056]

[0057] In an air atmosphere, trifluoromethyltelluryltetramethylammonium salt (0.3 mmol), 2-((2-azidomethylphenyl)ethynyl)naphthalene (0.2 mmol), KI (0.4 mmol), nBu4OAc (2 mmol), and acetonitrile (10 mL) were sequentially added to a 25 mL diaphragm-free three-necked flask equipped with a magnetic stirrer. After the addition was complete, a carbon rod anode (1.5 cm × 1.5 cm) and an iron cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, and the current was set to 8 mA. The electrolysis reaction was carried out continuously for 10 hours in an air atmosphere at room temperature. After the reaction was completed, the solvent was removed from the reaction solution by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 15:1) to obtain the target compound 1d, with a yield of 65%.

[0058] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ9.77 (s, 1H), 9.62 (d, J =8.8 Hz, 1H), 9.07 (d, J = 8.0 Hz, 1H), 8.98–8.88 (m, 3H), 8.71 (t, J = 7.6Hz, 1H), 8.56 (t, J = 7.6 Hz, 1H), 7.68 (d, J = 6.8 Hz, 1H), 7.43–7.34 (m,3H). 13 C NMR (100 MHz, CDCl3) δ 168.8, 147.7, 136.7, 134.5, 133.9, 132.6,131.8, 130.9, 130.5, 128.9, 128.7, 128.5, 125.4, 124.3, 122.3, 121.1, 113.9,100.4.

[0059] Example 8

[0060] The reaction equation is shown below:

[0061]

[0062] In an air atmosphere, trifluoromethyltelluryltetramethylammonium salt (0.3 mmol), 2-(2-azidomethylphenylethynyl)thiophene (0.2 mmol), KI (0.4 mmol), nBu4OAc (2 mmol), and acetonitrile (10 mL) were sequentially added to a 25 mL diaphragm-free three-necked flask equipped with a magnetic stirrer. After the addition was complete, a carbon rod anode (1.5 cm × 1.5 cm) and an iron cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, respectively. The current was set to 8 mA, and the electrolysis reaction was continued for 10 hours in an air atmosphere at room temperature. After the reaction was completed, the solvent was removed from the reaction solution by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 15:1) to obtain the target compound 1e in 61% yield.

[0063] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.32 (s, 1H), 8.79 (d, J= 8.4 Hz, 1H), 8.76 (d, J = 7.2 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.95 (t, J= 7.2 Hz, 1H), 7.85 (t, J = 7.2 Hz, 1H), 7.74−7.73 (m, 1H), 7.58 (dd, J =4.8, 4.0 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 167.1, 153.2, 144.1, 135.7,132.6, 130.8, 129.8, 128.8, 127.1, 126.7, 124.3, 121.0, 113.0, 105.4.

[0064] Example 9

[0065] The reaction equation is shown below:

[0066]

[0067] In an air atmosphere, trifluoromethyltelluryltetramethylammonium salt (0.3 mmol), 2-(azidomethyl)-4-bromo-1-(phenylethynyl)benzene (0.2 mmol), KI (0.4 mmol), nBu4OAc (2 mmol), and acetonitrile (10 mL) were sequentially added to a 25 mL diaphragm-free three-necked flask equipped with a magnetic stirrer. After the addition was complete, a carbon rod anode (1.5 cm × 1.5 cm) and an iron cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, and the current was set to 8 mA. The electrolysis reaction was continued for 10 hours in an air atmosphere at room temperature. After the reaction was completed, the solvent was removed from the reaction solution by a rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 15:1) to obtain the target compound 1f in 60% yield.

[0068] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.36 (s, 1H), 8.90 (s,1H), 7.96 (dd, J = 8.5, 3.7 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.53 – 7.49(m, 5H). 13 C NMR (100 MHz, CDCl3) δ 167.6, 159.6, 157.4, 149.5, 138.8, 137.9,136.7, 135.8, 133.6, 131.7, 129.8, 128.9, 125.1, 119.1.

[0069] Example 10

[0070]

[0071] In an air atmosphere, trifluoromethyltelluryltetramethylammonium salt (0.3 mmol), 4-methyl-2-(azidomethyl)phenylethynylbenzene (0.2 mmol), KI (0.4 mmol), nBu4OAc (2 mmol), and acetonitrile (10 mL) were sequentially added to a 25 mL diaphragm-free three-necked flask equipped with a magnetic stirrer. After the addition was complete, a carbon rod anode (1.5 cm × 1.5 cm) and an iron cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, and the current was set to 8 mA. The electrolysis reaction was continued for 10 hours in an air atmosphere at room temperature. After the reaction was completed, the solvent was removed from the reaction solution by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 15:1) to obtain 1 g of the target compound, with a yield of 68%.

[0072] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.47 (s, 1H), 8.92 (s,1H), 8.83 (dd, J = 8.5, 3.7 Hz, 1H), 8.71 (d, J = 8.5 Hz, 1H), 7.56 – 7.43(m, 5H), 2.50 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 154.2, 148.0, 144.9, 138.8,129.8, 129.7, 128.4, 126.7, 126.2, 124.8, 25.6.

[0073] Example 11

[0074]

[0075] In an air atmosphere, trifluoromethyltelluryltetramethylammonium salt (0.3 mmol), 4-methoxy-2-(azidomethyl)phenylethynylbenzene (0.2 mmol), KI (0.4 mmol), nBu4OAc (2 mmol), and acetonitrile (10 mL) were sequentially added to a 25 mL diaphragm-free three-necked flask equipped with a magnetic stirrer. After the addition was complete, a carbon rod anode (1.5 cm × 1.5 cm) and an iron cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, respectively. The current was set to 8 mA, and the electrolysis reaction was continued for 10 hours in an air atmosphere at room temperature. After the reaction was completed, the solvent was removed from the reaction solution by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 15:1) to obtain the target compound in 1 h, with a yield of 72%.

[0076] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.38 (dd, J = 7.2, 1.4Hz, 1H), 7.78 (d, J = 7.1 Hz, 1H), 7.55–7.51 (m, 3H), 7.48–7.40 (m, 4H), 3.90 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 171.3, 148.6, 146. 8, 138.2, 135.5, 134.8, 132.9, 129.4, 128.7, 124.7, 123.2, 122.4, 121.2, 119.4, 57.3.

[0077] Example 12

[0078]

[0079] In an air atmosphere, trifluoromethyltelluric tetramethylammonium salt (0.3 mmol), 4-nitro-2-(azidomethyl)phenylethynylbenzene (0.2 mmol), KI (0.4 mmol), nBu4OAc (2 mmol), and acetonitrile (10 mL) were sequentially added to a 25 mL diaphragm-free three-necked flask equipped with a magnetic stirrer. After the addition was complete, a carbon rod anode (1.5 cm × 1.5 cm) and an iron cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, and the current was set to 8 mA. The electrolysis reaction was continued for 10 hours in an air atmosphere at room temperature. After the reaction was completed, the solvent was removed from the reaction solution by a rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 15:1) to obtain the target compound 1i in 70% yield.

[0080] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.86 (s, 1H), 9.44 (d, J= 9.2 Hz, 2H), 8.86-8.79 (m, 3H), 7.95 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ196.3, 154.3, 143.4, 138.6, 136.1, 134.6, 130.9, 129.8, 125.2, 124.7, 123.2,120.5, 119.7, 116.7.

[0081] Example 13: Activity Study

[0082] The trifluoromethyltellurium-substituted isoquinoline derivative provided by this invention can effectively activate the GPR119 receptor. The GPR119 receptor plays a crucial role in regulating glucose metabolism; its activation can improve insulin sensitivity, reduce insulin resistance, and enhance the secretion of glucose-dependent GLP-1, thereby inhibiting abnormal blood glucose elevation. Therefore, it can serve as a novel drug candidate molecule for the treatment of diabetes and related metabolic diseases.

[0083] The procedure was as follows: Cells were seeded at a density of 10,000 cells per well in 384-well opaque white plates using MEMα medium containing streptomycin (500 μg / mL genimycin) and cultured overnight at 37°C, 5% CO2, and saturated humidity. Subsequently, the cells were washed once with analysis buffer (MEMα medium containing 20 mmol / L HEPES, 0.1% bovine serum albumin, 100 U / mL penicillin, and 100 μg / mL streptomycin), and then serially diluted compound 1a-1i was added, followed by incubation for 2 hours. After removing the culture supernatant, cAMP-induced luciferase activity was detected using Steady-Glo reagent and an EnVision multi-mode microplate reader. The agonistic activity of the test compound against GPR119 cells is expressed as [(A-B) / (C-B)]×100, where A represents the luciferase activity of cells treated with the test compound, B represents the activity of cells treated with the solvent, and C represents the activity of cells treated with 10 μM N-[4-(methanesulfonyl)phenyl]-5-nitro-6-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}pyrimidin-4-amine. The half-maximal effective concentration (EC50) was calculated using XLfit software. 50 )value.

[0084] Detailed test results are shown in Table 1 below:

[0085] Table 1

[0086] compound <![CDATA[hGPR119 EC 50 (nM)]]> Filgrape 0.9 APD668 2.7 1a 21 1b 14 1c 18 1d 51 1e 129 1f 2.5 1g 22 1h 38 1i 64

[0087] The test results show that, compared with the positive references filgrape and APD668, the series of compounds of this invention (1a–1i) all exhibited agonistic activity against GPR119. Among them, the EC50 of compounds 1b, 1c, and 1f were at a low level. Compound 1f, for example, had an EC50 of as low as 2.5 nM against hGPR119, and has the potential to be further developed into a candidate drug.

[0088] In summary, this invention develops a novel electrochemical synthesis method for trifluoromethyltelluride isoquinoline derivatives. Using trifluoromethyltelluride tetramethylammonium salt and 1-(azidomethyl)-2-ethynyl aromatic hydrocarbon as raw materials, the reaction is carried out under constant current conditions at room temperature, followed by purification by column chromatography to obtain the target compound. This method requires no external oxidant and has advantages such as mild conditions, environmental friendliness, high yield, and broad substrate scope. It successfully constructs a novel molecular skeleton containing heterocycles, fluorine atoms, and tellurium elements. Bioactivity evaluation shows that these compounds possess GPR119 agonist activity. GPR119 agonism can promote insulin secretion and improve insulin resistance. Therefore, this invention provides a novel drug candidate molecule with development potential for the clinical treatment of diabetes and related metabolic diseases.

[0089] Any aspects of this invention not described in detail are well-known to those skilled in the art.

[0090] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, it is intended that all variations falling within the meaning and scope of equivalents of the claims be included within the present invention.

Claims

1. A method for the electrochemical synthesis of trifluoromethyltelluron isoquinoline derivatives, characterized in that: The method is as follows: Trifluoromethyltelluryltetramethylammonium salt of formula (I) and 1-(azidomethyl)-2-ethynyl aromatic hydrocarbon of formula (II) are added to an organic solvent, and then an additive is added. The reaction is carried out at room temperature and under constant current conditions. After the reaction is completed, the solvent is removed from the reaction solution under reduced pressure to obtain a crude product. The crude product is purified by column chromatography to obtain a trifluoromethyltellurylisoquinoline derivative of formula (III). The reaction equation is shown below: In compound (II), R is a hydrogen atom, a halogen, or a C1-C atom. 10 Alkyl, alkoxy, cyano, trifluoromethyl, nitro, acetyl; Ar is phenyl, naphthyl, anthracene, furanyl, thiophene, or an aryl group substituted with one or more substituents, wherein the substituents are alkoxy, alkyl, halogen, cyano, or nitro.

2. The method for electrochemically synthesizing trifluoromethyltelluron isoquinoline derivatives according to claim 1, characterized in that: The molar ratio of trifluoromethyltelluryltetramethylammonium salt to 1-(azidomethyl)-2-ethynyl aromatic hydrocarbon is 1:1 to 2:

1.

3. The method for electrochemically synthesizing trifluoromethyltelluron isoquinoline derivatives according to claim 1, characterized in that: The anode material of the constant current reaction is one of graphite felt, platinum sheet or carbon rod, and the cathode material is one of copper, iron, nickel, chromium or graphite.

4. The method for electrochemically synthesizing trifluoromethyltelluronide isoquinoline derivatives according to claim 1, characterized in that: The constant current reaction time is 5–12 h, and the current is 5–10 mA; a diaphragmless single-chamber electrolytic cell is used for the constant current reaction.

5. The method for electrochemically synthesizing trifluoromethyltelluron isoquinoline derivatives according to claim 1, characterized in that: The organic solvent is any one of acetonitrile, dichloroethane, N,N-dimethylformamide, or methanol.

6. The method for electrochemically synthesizing trifluoromethyltelluron isoquinoline derivatives according to claim 1, characterized in that: The electrolyte for the galvanostatic reaction is any one of tetrabutylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroborate, sodium tetrafluoroborate, and tetra-n-butylammonium acetate, and the concentration of the electrolyte in the reaction system is 0.1–0.2 mol / L.

7. The method for electrochemically synthesizing trifluoromethyltelluronide isoquinoline derivatives according to claim 1, characterized in that: The additive is any one of potassium bromide, lithium bromide, and potassium iodide.

8. The method for electrochemically synthesizing trifluoromethyltelluron isoquinoline derivatives according to claim 1, characterized in that: Purification was performed by silica gel column chromatography, using a mixture of petroleum ether and ethyl acetate as the eluent, wherein the volume ratio of petroleum ether to ethyl acetate was 100 to 1:

1.

9. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a trifluoromethyltelluron-isoquinoline derivative prepared according to the method of claim 1, a medically acceptable salt, solvate or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.

10. Use of the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating diseases related to GPR119 activity.

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