Synthesis method of pyridine salt compound

Abstract

The invention provides a synthesis method of a pyridine salt compound. A 2-(trimethylsilyl) phenyl trifluoromethanesulfonate compound is used as a benzyne precursor, cesium fluoride is used as alkali, and the 2-(trimethylsilyl) phenyl trifluoromethanesulfonate compound reacts with 6-azaindole in acetonitrile without additional catalysts or under the protection of special conditions to prepare the pyridine salt compound. The reaction overcomes the defects of overlong route, harsh requirements on substrates and reaction conditions, limited expansion of substituted functional groups and the like in the previous reaction. According to the reaction, substrate synthesis is simple, reagents are cheap, the operation method is simple, and an efficient and practical novel method is provided for synthesis of pyridine salt compounds with important value in industrial production and bioactive compounds.

Description

Technical Field

[0001] The present invention relates to compound preparation, belonging to the field of organic compound synthesis, and specifically to a method for synthesizing a pyridinium salt compound. Background Art

[0002] Pyridinium salt compounds are an important class of heterocyclic compounds, present in many natural products and bioactive compounds (ACS Infect.Dis.2015, 1, 288-303). In addition, they are also an effective, irreversible acetylcholinesterase inhibitor, and are well-known for their bactericidal properties, and can be used for various other biological activities, such as drug delivery, gene therapy, biofilm stable transfection, etc. (Bioconjugate Chem.2008, 19, 2499-2512). More importantly, pyridinium salt compounds have a wider range of applications in industry, and can be used as acylating agents, phase transfer catalysts, dyes, surfactants, cosmetics, drugs, polymerization, catalysis, sensors and electrolytes, etc. (Energy Environ.Sci.2014, 7, 3135-3191). Pyridinium salts are quite abundant, and the synthesis methods are varied (Formula 1), specifically including: metal-catalyzed multi-component reaction (Formula 1a), microwave-assisted nucleophilic substitution reaction (Formula 1b), Katritzky reaction (Formula 1c) and other three.

[0003]

[0004] However, these reactions often require the addition of organic acids, bases or transition metals as catalysts. The harsh reaction conditions, lengthy reaction routes and the reality that the catalysts are non-recyclable are huge challenges for environmental protection and controlling reaction costs. Therefore, it is crucial to develop a cheap and efficient method for synthesizing pyridinium salt compounds. Summary of the invention

[0005] In view of the important value of pyridinium salt compounds in industrial production and biologically active compounds, the present invention provides a method for preparing pyridinium salt compounds, which is simple and does not require an external catalyst or special conditions for protection, and provides a new method for developing pyridinium salt compounds.

[0006] The specific technical solutions of the present invention are as follows:

[0007] A method for synthesizing a pyridinium salt compound, specifically comprising:

[0008] Using cesium fluoride as a base, 6-azaindole and 2-(trimethylsilyl)phenyl trifluoromethanesulfonate compounds react in acetonitrile at room temperature. After the reaction is completed, separation and purification are performed to obtain pyridinium salt compounds.

[0009]

[0010] The room temperature reaction refers to a reaction at 20-30°C for 1-2 hours.

[0011] The chemical structural formula of the 6-azaindole is:

[0012] The chemical structural formula of the 2-(trimethylsilyl)phenyl trifluoromethanesulfonate compound is:

[0013]

[0014] Wherein, R is a halogen, an alkyl, an alkoxy, a cycloalkane or an aromatic hydrocarbon group; R can be at any position of the benzene ring;

[0015] Furthermore, the R is preferably a hydrogen atom or a methyl group.

[0016] The molar ratio of the 6-azaindole, 2-(trimethylsilyl)phenyl trifluoromethanesulfonate compound and cesium fluoride is 1.2:1:2.

[0017] The concentration of the 6-azaindole in acetonitrile is 0.2-0.5 mol / L.

[0018] The separation and purification method comprises the following steps: quenching the reaction with dichloromethane, drying the mixture under reduced pressure, and then performing column chromatography separation and purification using methanol: dichloromethane: acetic acid in a volume ratio of 1:20:2 as an eluent.

[0019] The structural formula of the synthesized pyridinium salt compound is:

[0020] Reaction mechanism: 2-(Trimethylsilyl)phenyl trifluoromethanesulfonate compounds can generate benzyne intermediates in situ by leaving the trimethylsilyl (-TMS) group and the trifluoromethanesulfonate (-OTf) group under the action of fluoride ions in cesium fluoride; then they are captured by 6-azaindole in the form of nucleophilic attack to form zwitterions; finally, the zwitterions obtain a proton from the reaction solvent to obtain pyridinium salt compounds.

[0021] Compared with the prior art, this method is simple to operate, has simple steps and does not require an external catalyst or special conditions for protection, providing an efficient and practical new method for the synthesis of valuable pyridinium salt compounds. DETAILED DESCRIPTION

[0022] The technical solution of the present invention is further described below through specific implementation modes:

[0023] Example 1

[0024] The reaction of this example is as follows:

[0025]

[0026] The synthesis method of this embodiment comprises the following steps:

[0027] Raw materials preparation:

[0028] 6-Azaindole, purity >97%, Shanghai Adamas Reagent Co., Ltd.;

[0029] 2-(Trimethylsilyl)phenyl trifluoromethanesulfonate, purity>95%, Shanghai Adamas Reagent Co., Ltd.;

[0030] Specific synthesis process:

[0031] At room temperature, 1.2 mmol of 6-azaindole, 1 mmol of 2-(trimethylsilyl)phenyl trifluoromethanesulfonate and 2 mmol of cesium fluoride were reacted in 4 mL of acetonitrile solvent for 1 hour to obtain a crude product of a pyridinium salt compound; the prepared crude product of the pyridinium salt compound was washed with dichloromethane, dried under reduced pressure, and separated by column chromatography using methanol: dichloromethane: acetic acid in a volume ratio of 1:20:2 to obtain an off-white solid product, namely, a pyridinium salt compound 3a, and the column chromatography yield was about 72%.

[0032] The product structure is 1 H NMR, 13 C NMR was used to determine the results, and the results are as follows:

[0033] 1 H NMR (400MHz, CDCl3) δ12.68(s,1H),9.63(s,1H),8.18-8.16(m,1H),8.13-8.12(m,1H),8.09-8.07(m,1H),7.67-7.62(m,5H),6.95(s,1H);

[0034] 13 C NMR (100MHz, CDC13) δ143.3,140.9,136.7,132.7,131.3,131.0,130.9,130.3,124.2,117.7,104.3 。

[0035] Example 2

[0036] The reaction of this example is as follows:

[0037]

[0038] The synthesis method of this embodiment comprises the following steps:

[0039] Raw materials preparation:

[0040] 6-Azaindole, purity >97%, Shanghai Adamas Reagent Co., Ltd.;

[0041] 6-Methyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate, purity>94%, Shanghai Adamas Reagent Co., Ltd.;

[0042] Specific synthesis process:

[0043] At room temperature, 1.2 mmol of 6-azaindole, 1 mmol of 6-methyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate and 2 mmol of cesium fluoride were reacted in 4 mL of acetonitrile solvent for 1 hour to obtain a crude product of a pyridinium salt compound; the prepared crude product of the pyridinium salt compound was washed with dichloromethane, dried under reduced pressure, and separated by column chromatography using methanol: dichloromethane: acetic acid in a volume ratio of 1:20:2 to obtain an off-white solid product, namely, a pyridinium salt compound 3b, and the column chromatography yield was about 64%.

[0044] The product structure is 1 H NMR, 13 C NMR was used to determine the results, and the results are as follows:

[0045] 1 H NMR (400MHz, CDCl3) δ12.70(s,1H),9.61(s,1H),8.14-8.12(m,3H),7.56-7.52(m,1H),7.46-7.40(m,3H),6.94-6.93(m,1H),2.51(s,3H);

[0046] 13 C NMR (100MHz, CDCl3) δ143.3,141.7,140.7,136.6,132.7,131.8,131.0,130.7,130.3,124.7,121.2,117.6,104.2,21.5. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 The synthetic route of pyridinium salt compounds is shown in FIG.

[0048] Figure 2 Schematic diagram of the reaction mechanism of the present invention;

[0049] Figure 3 The XRD single crystal diffraction pattern of the pyridinium salt compound 3a prepared in Example 1;

[0050] Figure 4 The H NMR spectrum of the pyridinium salt compound 3a prepared in Example 1;

[0051] Figure 5 The carbon NMR spectrum of the pyridinium salt compound 3a prepared in Example 1;

[0052] Figure 6 The H NMR spectrum of the pyridinium salt compound 3b prepared in Example 2;

[0053] Figure 7 This is the carbon NMR spectrum of the pyridinium salt compound 3b prepared in Example 2.

Claims

1. A method for synthesizing a pyridinium salt compound, It is characterized in that The synthesis method is specifically: 2-(Trimethylsilyl)phenyl trifluoromethanesulfonate compounds are used as benzylene precursors, cesium fluoride is used as a base, and 6-azaindole is reacted in acetonitrile solvent at room temperature according to the following reaction formula. After the reaction is completed, the pyridinium salt compounds are separated and purified. Wherein, R is a halogen, an alkyl, an alkoxy, a cycloalkane or an aromatic hydrocarbon group.

2. The synthesis method according to claim 1, It is characterized in that The room temperature reaction refers to a reaction at 20-30°C for 1-2 hours.

3. The synthesis method according to claim 1, It is characterized in that The molar ratio of the 6-azaindole, 2-(trimethylsilyl)phenyl trifluoromethanesulfonate compound and cesium fluoride is 1.2:1:

2.

4. The synthesis method according to claim 1, It is characterized in that The concentration of the 6-azaindole in acetonitrile is 0.2-0.5 mol / L.

5. The synthesis method according to claim 1, It is characterized in that The separation and purification method comprises the following steps: quenching the reaction with dichloromethane, drying the mixture under reduced pressure, and then performing column chromatography separation and purification using methanol: dichloromethane: acetic acid in a volume ratio of 1:20:2 as an eluent.

6. The synthesis method according to claim 1, It is characterized in that The structural formula of the synthesized pyridinium salt compound is:

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