Preparation method of fluoromethyl ether active hypoglycemic drug

Abstract

The invention provides a fluoromethylated compound of a natural phenolic compound. A preparation method of the fluoromethylated compound of the natural phenolic compound comprises the following step: by taking a phenolic natural product and fluoromethyl p-toluenesulfonate as raw materials, potassium carbonate as alkali and acetonitrile as a solvent, carrying out reflux to prepare the fluoromethylated compound. The reaction product is single and easy to separate, the reaction condition is mild, and the functional group tolerance is good. The product prepared by the invention is applied to anti-diabetic medicines, and a remarkable effect is achieved.

Description

Technical Field

[0001] The invention relates to a fluoromethylated compound of a natural phenol compound, belonging to the technical field of pharmaceuticals. Background Art

[0002] Over the past few decades, the development of efficient methods for introducing fluorine atoms or fluoroalkyl groups into organic molecules has attracted increasing attention in academia and the pharmaceutical industry. In particular, compounds bearing fluoroalkyl groups, which are potential targets in pharmaceutical and agricultural chemistry, have been the focus of recent research, primarily due to the high bond energy of the C-F bond (485 kJ / mol), which can significantly improve the pharmacokinetic properties of drug molecules. More specifically, as a strategic fluorinated substituent, the monofluoromethyl group is widely used in the pharmaceutical industry for numerous drugs and drug candidates, including the muscle relaxant fluoroquinolone, the anesthetic sevoflurane, the anti-inflammatory and asthma drug fluticasone propionate, and the clinical trial drug carmelliptin for hypoglycemic activity.

[0003] Among natural active ingredients, many have demonstrated promising anti-glycemic activity, including polysaccharides, steroids, alkaloids, flavonoids, chalcones, and peptides. These naturally derived anti-glycemic substances will become a potential resource for the research and treatment of type 2 diabetes. Natural flavonoids can regulate glucose absorption and homeostasis, targeting disulfide-binding enzymes. Chalcone compounds, precursors of flavonoids and isoflavones, are widely distributed in plants. Many natural chalcones and chalcone derivatives possess excellent anti-glycemic activity. However, structural defects in natural products often limit their application. Fluoromethyl groups, which generally possess strong electron-attracting properties, lipophilicity, and stable C-F bonds, can be introduced into drug molecules to prolong their in vivo action and enhance their metabolic stability. Furthermore, fluoromethyl groups can increase drug solubility and binding to target proteins, thereby improving drug bioavailability. Fluoromethyl modification of products with natural anti-glycemic activity can leverage these properties to alter the hypoglycemic activity of natural products. For example, in the 2010 Journal of Bioorganic and Pharmaceutical Sciences (Mattei, P.; Boehringer, M.; Di Giorgio, P. et al. Discovery of carmegliptin: a potent and long-acting dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes [J]. Bioorg. Med. Chem. Lett. 2010, 20(3), 1109-1113.) It was reported that carmelliptin is an effective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes and is currently in clinical trials. This patent aims to establish a synthetic route with readily available raw materials, simple operation, mild conditions, short route and high yield, in order to study the effects of structural changes of different natural active compounds on α-glucosidase inhibitory activity, screen out compounds with potential α-glucosidase inhibitory activity, and provide a class of natural small molecule α-glucosidase inhibitors. Summary of the Invention

[0004] The present invention relates to a fluoromethylated compound of a natural phenolic compound, the structural formula of which is: , the Ar includes any one of flavonoids, flavonols, chalcone, hydroxychalcone, dihydrochalcone, estrone, sesamol, vanillin, and zwitterion.

[0005] The flavonoids include any one of chrysin, apigenin, apigenin, and luteolin; the flavonols include quercetin or kaempferol; and the dihydrochalcone includes phloretin or hydroxyphloretin.

[0006] The method for preparing the fluoromethylated compounds of natural phenolic compounds comprises the following steps: Using phenolic natural products and fluoromethyl p-toluenesulfonate as raw materials, potassium carbonate as a base, and acetonitrile as a solvent, a reflux reaction is carried out under nitrogen protection to obtain fluoromethylated compounds of natural phenolic compounds; the specific reaction formula is as follows: .

[0007] The molar ratio of the phenolic natural product to fluoromethyl p-toluenesulfonate is 2:1.5-3.

[0008] The reflux reaction temperature is 80-100° C., and the reaction time is 3-5 hours.

[0009] The structural formula of the fluoromethylated compound prepared by the method includes any one of the following: .

[0010] The present invention also provides an application of the fluoromethylated natural phenolic compound in preparing a medicine for treating diabetes.

[0011] The invention relates to an application of the fluoromethylated natural phenolic compound in inhibiting the activity of α-glucosidase to prepare a medicine for treating diabetes.

[0012] The present invention also provides a medicine for treating diabetes, which comprises the fluoromethylated compound of the natural phenolic compound.

[0013] It is for those skilled in the art that it is anticipated that the drug also includes pharmaceutically acceptable salts.

[0014] The reaction product is single and easy to separate, the reaction conditions are mild, and the synthesis method is stable to functional groups such as ester groups, ketone carbonyl groups, double bonds and ethers, and has good functional group tolerance. The product prepared by the present invention is used in anti-diabetic drugs and has achieved significant results. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 This is the hydrogen spectrum of compound 3a.

[0016] Figure 2 This is the carbon spectrum of compound 3a.

[0017] Figure 3 This is the mass spectrum of compound 3a. DETAILED DESCRIPTION

[0018] Experimental reagents Chrysin (Shanghai MacLean Biochemical Technology Co., Ltd.), apigenin (Shanghai MacLean Biochemical Technology Co., Ltd.), sesamol (Shanghai MacLean Biochemical Technology Co., Ltd.), estrone (Shanghai MacLean Biochemical Technology Co., Ltd.), 4-methylumbelliferone (Shanghai MacLean Biochemical Technology Co., Ltd.), coumarin (Shanghai MacLean Biochemical Technology Co., Ltd.), potassium carbonate (Sinopharm Chemical Reagent Co., Ltd.), acetonitrile (analytical grade, Sinopharm Chemical Reagent Co., Ltd.), dichloromethane (analytical grade, Tianjin Komiou Chemical Reagent Co., Ltd.), petroleum ether (boiling range 60-90 °C, Tianjin Hengxing Chemical Reagent Manufacturing Co., Ltd.), ethyl acetate (analytical grade, Tianjin Komiou Chemical Reagent Co., Ltd.), anhydrous sodium sulfate (analytical grade, Sinopharm Chemical Reagent Co., Ltd.), deuterated chloroform (deuterium atomic content 99.8%, TMS content 0.03% v / v, 10*0.5 mL / box, ARMAR, Switzerland); nuclear magnetic resonance tube (5 mm 100 / pk² ST500-8, Norell, USA).

[0019] Experimental instruments ZXZ-4 rotary vane vacuum pump (Linhai Tan's Vacuum Equipment Co., Ltd.), DZF-6020 vacuum drying oven (Shanghai Xinmiao Medical Equipment Manufacturing Co., Ltd.), SHB-IIIA circulating water multi-purpose vacuum pump (Shanghai Yukang Science and Education Instrument Equipment Co., Ltd.), CL-4 flat magnetic stirrer (Zhengzhou Great Wall Science and Technology Industry and Trade Co., Ltd.), EYELA SB-1100 rotary evaporator (Shanghai Ailang Instrument Co., Ltd.), FA2104B analytical balance (Shanghai Yueping Technology Instrument Co., Ltd.), XRC-1 micro melting point meter (Sichuan University Science and Technology Instrument Factory), DF-101S thermal collector constant temperature heating magnetic stirrer (Gongyi Yingyu Yuhua Instrument Factory), ZF-6 three-purpose UV analyzer (Shanghai Jiapeng Technology Co., Ltd.), and Ultrashied 400 MHz Plus nuclear magnetic resonance spectrometer (Bruker, Switzerland).

[0020] Example 1 Phenolic natural products and fluoromethyl p-toluenesulfonate are used as raw materials, potassium carbonate is used as a base, and acetonitrile is used as a solvent to reflux at 80°C, as follows:

[0021] The technical route is as follows: Phenolic natural products 1a–1f (0.2 mmol, 1.0 equiv.) were added to a 5 mL reaction tube. 4.0 mL of acetonitrile was added as solvent, followed by potassium carbonate (2.0 mmol, 10.0 equiv.) and finally fluoromethyl p-toluenesulfonate (0.3 mmol, 1.5 equiv.). The reaction was allowed to react at 80°C for 4 h, and the reaction was monitored promptly by TLC. After completion, the reaction was quenched with water, extracted with ethyl acetate, and separated three times. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated on a rotary evaporator to afford the crude product. The crude product was separated by column chromatography using a 10:1 eluent system of PE:EA. After separation and vacuum drying, the fluoromethylated products 3a–3f were obtained in yields of 87.3%–93.2%. The yields of the products corresponding to different synthons varied, which may be related to factors such as the structural characteristics and reactivity of the synthons themselves.

[0022] Substrate range

[0023] The corresponding 1a-1f are the reaction raw materials of the corresponding 3a-3f, and the terminal is a hydroxyl structure.

[0024] Spectral data 7-(fluoromethoxy)-5-hydroxy-2-phenyl-4H-chromen-4-one (3a)

[0025] 1 H NMR (400 MHz, CDCl3) d 12.74 (s, 1H), 7.90–7.87 (m, 2H), 7.56–7.50 (m, 3H), 6.70–6.69 (m, 2H), 6.52 (d, J = 2.4 Hz, 1H), 5.78 (d, J = 53.5 Hz, 2H). 13 C{ 1 H} NMR (100 MHz, CDCl3) d 182.6, 164.4, 162.3, 162.0 ( J = 2.8 Hz), 157.5,132.0, 131.0, 129.1, 126.3, 107.2, 106.0, 100.1, 99.5 ( J = 220.5 Hz), 94.8. 19 FNMR (376 MHz, CDCl3) d -150.94. HRMS (ESI) m / z: calcd. for C 16 H 11 FO4Na + (M + Na) + ,309.0539, found 309.0534. Example 2 Phenolic natural products and methyl iodide were used as raw materials, potassium carbonate was used as a base, and acetonitrile was used as a solvent to reflux at 40°C, as follows: .

[0026] The technical route is as follows: Phenolic natural products 1a–1f (0.2 mmol, 1.0 equiv.) were added to a 5 mL reaction tube. 4.0 mL of acetonitrile was added as solvent, followed by potassium carbonate (2.0 mmol, 10.0 equiv.), and finally iodomethane (0.3 mmol, 1.5 equiv.). The reaction was allowed to proceed at 40°C for 4 h, with prompt monitoring by TLC. Upon completion, the reaction was quenched with water, and the solution was extracted with ethyl acetate. This process was repeated three times, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated on a rotary evaporator to afford the crude product. The crude product was separated by column chromatography using a 10:1 PE:EA eluent. Following separation, the methylated products 4a–4f were obtained in 75%–84% yields.

[0027] Substrate range .

[0028] Spectral data 7-methoxy-5-hydroxy-2-phenyl-4H-chromen-4-one (4a)

[0029] 1 H NMR (400 MHz, CDCl3) d for C 16 H 12 O4Na + (M + Na) + , 291.0633, found 291.0636. Example 3 Evaluation of α-glucosidase inhibitory activity of fluoromethyl ether active molecules: Prepare the reaction solution: PBS solution (0.1 mM, pH 6.8), substrate PNPG solution (4 mM), α-glucosidase solution (0.2 U / mL), and Na2CO3 solution (0.2 mol / L).

[0030] The experiment was divided into an enzyme activity group (50 μL α-glucosidase solution and 20 μL PBS solution), an enzyme blank group (70 μL PBS solution), a sample group (50 μL α-glucosidase solution and 20 μL sample solution), a positive group (50 μL α-glucosidase solution and 20 μL positive drug solution), a sample blank group (50 μL PBS solution and 20 μL sample solution), and a positive blank group (50 μL PBS solution and 20 μL positive drug solution). Drugs in each group were added to a 96-well plate according to the above dosage, with three replicates per group. The plates were shaken for 2 min and reacted at 37°C for 10 min. 25 μL PNPG solution was added and shaken for 2 min. The plates were reacted at 37°C for 30 min. 100 μL Na2CO3 solution was added to terminate the reaction and the plates were shaken for 5 min. Since PNPG can be hydrolyzed to produce glucose and PNP under the action of α-glucosidase, and PNP has a maximum absorption at 405 nm, its absorbance is measured, and the inhibition rate and IC of α-glucosidase of each sample can be calculated according to the formula 50 value.

[0031] Calculation formula: Inhibition rate = (1-△ 样 / △ 酶 ) × 100% △ 样 = Average OD value of sample - OD value of sample blank △ 酶 = Average OD value of enzyme activity - OD value of enzyme blank Evaluation results of α-glucosidase inhibitory activity of fluoromethyl ether active molecules.

Claims

1. A fluoromethylated compound of a natural phenolic compound, characterized in that: The structural formula is: , the Ar includes any one of flavonoids, flavonols, chalcone, hydroxychalcone, dihydrochalcone, estrone, sesamol, vanillin, and zwitterion.

2. The fluoromethylated compound of natural phenolic compound according to claim 1, characterized in that The flavonoids include any one of chrysin, apigenin, apigenin, and luteolin; the flavonols include quercetin or kaempferol; and the dihydrochalcone includes phloretin or hydroxyphloretin.

3. The method for preparing a fluoromethylated compound of a natural phenolic compound according to claim 1 or 2, characterized in that: The steps include: Phenolic natural products and fluoromethyl p-toluenesulfonate are used as raw materials, potassium carbonate is used as a base, and acetonitrile is used as a solvent. Fluoromethylated compounds of natural phenolic compounds are obtained by reflux reaction under nitrogen protection.

4. The method for preparing the fluoromethylated compounds of natural phenolic compounds according to claim 3, characterized in that: The molar ratio of the phenolic natural product to fluoromethyl p-toluenesulfonate is 2:1.5-3.

5. The method for preparing the fluoromethylated compounds of natural phenolic compounds according to claim 3, characterized in that: The reflux reaction temperature is 80-100° C., and the reaction time is 3-5 hours.

6. The method for preparing fluoromethylated compounds of natural phenolic compounds according to claim 3, characterized in that: The structural formula of the fluoromethylated compound prepared by the method includes any one of the following: 。 7. Use of the fluoromethylated natural phenolic compound according to claim 1 or 2 in the preparation of a drug for treating diabetes.

8. The use according to claim 7, characterized in that The invention relates to an application of the fluoromethylated natural phenolic compound in inhibiting the activity of α-glucosidase to prepare a medicine for treating diabetes.

9. A drug for treating diabetes, characterized in that: The drug comprises the fluoromethylated compound of the natural phenolic compound according to claim 1 or 2.

10. The drug for treating diabetes according to claim 9, characterized in that The medicine also includes pharmaceutically acceptable salts.

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