Synthesis of an antifungal pathogen agent

Abstract

The application discloses a method for synthesizing an antifungal pathogen reagent N-methyl-3-[(4-methylphenyl)thio]quinolinium iodide by realizing quinoline C3-H heteroatomization under nickel catalysis and mild conditions. The method comprises two steps, first, 3-(p-tolylthio)quinoline is synthesized under room temperature conditions, and then quinoline is N-methylated, so as to prepare the antifungal pathogen reagent N-methyl-3-[(4-methylphenyl)thio]quinolinium iodide. Compared with the past reports, the starting material is more cheap and easy to obtain, the steps are more simple, the atom utilization rate is higher, and the conditions are more mild, so the method is more suitable for kilogram scale amplification production.

Description

[Technical Field]

[0001] This invention belongs to the field of catalytic organic synthesis, specifically relating to the synthesis and gram-scale scale-up of N-methyl-3-[(4-methylphenyl)thio]quinoline iodide, an antifungal agent. [Background Technology]

[0002] Infections caused by pathogens remain a public health concern (J. Med. Mycol., 2000, 38, 225). Antifungal drugs are one of the most common treatment options for pathogen infections. Amphotericin B was previously commonly used intravenously; however, since amphotericin B cannot be taken orally, it is often used in combination with oral medications, such as flucytosine or one of the azoles. The oral form of amphotericin B, its severe nephrotoxicity and other side effects, the development of resistance, interactions with azoles, and the lack of biological targets support the need for new drugs.

[0003] Here, we reveal a method for synthesizing antifungal 3-(phenylthio)quinoline compounds by nickel-catalyzed, mild C3-H heteroatomic conversion of quinoline. The method comprises two steps: first, the synthesis of 3-(p-tolylthio)quinoline at room temperature, followed by N-methylation of the quinoline to prepare the antifungal agent N-methyl-3-[(4-methylphenyl)thio]quinoline onium iodide.

[0004] Compared to previous reports (Bioorg.Med.Chem.2011,19,458-470), this method uses cheaper and more readily available starting materials, has simpler procedures, higher atom utilization, and milder conditions, making it more suitable for gram-scale production. [Summary of the Invention]

[0005] Here, we reveal a method for synthesizing N-methyl-3-[(4-methylphenyl)thio]quinolineonium iodide, an antifungal agent with inexpensive and readily available starting materials, simple procedures, high atom utilization, mild conditions, and suitability for gram-scale production. The specific technical solution is as follows:

[0006] A method for synthesizing an antifungal pathogen comprises the following steps: synthesizing intermediate I.

[0007] The synthesis of intermediate I: using quinoline as a starting material, Ni catalyst and C7H were added under argon atmosphere. 15 MgBr and diethylene glycol dimethyl ether solvent. Stir at room temperature for 20 min. Then, add 4-methylphenyl disulfide, stir at room temperature for 20 min, then extract and dry the reaction solution, then add 1,2-dichloro-4,5-dicyanbenzidone (DDQ), stir for 10 min, and obtain intermediate I by column chromatography.

[0008]

[0009] In the synthesis of intermediate I, the amount of Ni(dppp)Cl used is 0.03 equivalents, and C7H 15 The amount of MgBr used was 1.5 equivalents, the amount of 4-methylphenyl disulfide used was 1.5 equivalents, and the amount of DDQ used was 1.0 equivalent. The reaction time was 50 min, and the reaction temperature was room temperature.

[0010] The antifungal pathogen reagent was synthesized as follows: Iodomethane and tetramethyl sulfone were added using intermediate I as a raw material. The mixture was heated at 110°C for 16 hours. After cooling to room temperature, ethyl acetate was added to precipitate the solid, and the mixture was filtered to obtain the antifungal pathogen reagent.

[0011]

[0012] The amount of iodomethane used in the synthesis of the antifungal pathogen reagent is 1.2 equivalents.

[0013] Compared with existing technologies, the advantages of this invention are as follows: It provides a novel method for synthesizing antifungal pathogen reagents, starting from readily available quinoline, achieving highly selective thioetherification of quinoline C-3 to generate intermediate I, followed by simple quaternary ammonium salting to generate the antifungal pathogen reagent. Furthermore, the generation of intermediate I is achieved through Ni catalysis. [Attached Image Description]

[0014] The attached figure shows the specific synthesis method of the antifungal pathogen reagent, as well as the spectrum of the corresponding compound.

Detailed Implementation Methods

[0015] The invention will be further illustrated below with specific preparation examples:

[0016] Preparation of intermediate I

[0017] Under argon atmosphere, 0.15 mmol of Ni(dppp)Cl2, 5 mmol of quinoline, and 25.0 mL of anhydrous DEDM were added sequentially. 7.5 mmol of magnesium heptabromide solution was added dropwise using a syringe, and the solution was stirred at room temperature for 20 min. Then, 7.5 mmol of 4-methylphenyl disulfide was added, and the mixture was stirred at room temperature for 20 min. The reaction was quenched by the addition of 60 mL of saturated ammonium chloride aqueous solution. The aqueous layer was separated by extraction with ethyl acetate (3 × 120 mL), and the combined organic layer was dried on anhydrous sodium sulfate. Then, 0.5 mmol of 1,2-dichloro-4,5-dicyanbenzidone (DDQ) was added. Finally, the solvent was removed under reduced pressure, and the solution was purified by silica gel chromatography (5%–10% ethyl acetate, n-hexane) to give 1.03 g of a yellow oily liquid in 82% yield.

[0018] Preparation of antifungal pathogen reagents

[0019] Starting with intermediate I (4.00 mmol, 1.01 g), iodomethane (0.71 g, 5.00 mmol) and tetramethyl sulfone (5.0 mL) were added. The mixture was heated at 110 °C for 16 hours. After cooling to room temperature, EtOAc (30 mL) was added to precipitate the solid. The precipitate was collected, washed with additional ethyl acetate, and dried. 1.26 g of orange powder was given, with a yield of 80%. 1 HNMR(400MHz, CDCl3)δ9.85(d,J=1.5Hz,1H),8.42(d,J=8.9Hz,1H),8.33(s,1H),8.10(ddd,J=8.7,7.1,1.2Hz,1 H),8.01-7.96(m,1H),7.90-7.83(m,1H),7.59(d,J=8.1Hz,2H),7.30(d,J=8.9Hz,2H),4.88(s,3H),2.41(s,3H).

[0020] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method of synthesis of the antifungal pathogen agent N-methyl-3-[(4- methylphenyl)thio]quinolinium iodide, characterized by, The synthesis method comprises the following steps: synthesizing intermediate I, and synthesizing the antifungal pathogen agent. The synthesis of the intermediate I: quinoline as raw material, under argon, the addition of Ni catalyst, C7H 15 MgBr and solvent diglyme, stirring at room temperature for 20 min; then, the addition of 4-methyl phenyl disulfide, stirring at room temperature for 20 min, then the reaction liquid is extracted, dried, then the addition of 1,2-dichloro-4,5-dicyanoquinone DDQ, stirring for 10 min, column chromatography to obtain the intermediate I; the synthesis of the antifungal pathogen agent: the intermediate I as raw material, the addition of iodomethane and tetramethyl sulfone, the mixture is heated at 110℃ for 16h, after cooling to room temperature, the addition of ethyl acetate to precipitate the solid, filtration to obtain the antifungal pathogen agent.

2. The method of synthesis of the antifungal pathogen agent N-methyl-3-[(4- methylphenyl)thio]quinolinium iodide according to claim 1, characterized in that, The amount of Ni(dppp)Cl used in the synthesis of the intermediate I is 0.03 equivalent, the amount of C7H 15 The amount of MgBr used is 1.5 equivalents, the amount of 4-methylphenyl disulfide used is 1.5 equivalents, and the amount of DDQ used is 1.0 equivalent; the reaction time is 50 min, and the reaction temperature is room temperature.

3. The method of synthesis of the antifungal pathogen agent N-methyl-3-[(4- methylphenyl)thio]quinolinium iodide according to claim 1, characterized in that, In the synthesis of the antifungal pathogen agent, the amount of iodomethane is 1.2 equivalent.

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