阅读说明：本技术 一种n-甲基化含氮芳香杂环化合物的制备方法 (Preparation method of N-methylated nitrogen-containing aromatic heterocyclic compound ) 是由 康传清 赵鸿宇 王禹 金日哲 于 2020-12-25 设计创作，主要内容包括：本发明的目的在于提供一种N-甲基化含氮芳香杂环化合物的制备方法。本发明提供的将芳香氮杂环进行N-甲基化的方法中,通过一定的酸的催化,采用特定的式Ⅲ所示脂肪醇甲醚为N-甲基化试剂,能够选择性地实现含氮芳香杂环的N-甲基化,且提高对含氮芳香杂环的选择性；同时,本发明采用的N-甲基化试剂安全无毒；另外,本发明无需使用碱性物质,而是在酸性催化剂作用下进行,能够避免使用碱性物质,对于那些对碱敏感的含氮芳香杂环化合物,本发明提供的方法更有适用性。(The invention aims to provide a preparation method of an N-methylated nitrogen-containing aromatic heterocyclic compound. According to the method for N-methylating the aromatic nitrogen heterocycle, disclosed by the invention, a specific aliphatic alcohol methyl ether shown as a formula III is used as an N-methylating reagent under the catalysis of a certain acid, so that the N-methylation of the nitrogen-containing aromatic heterocycle can be selectively realized, and the selectivity to the nitrogen-containing aromatic heterocycle is improved; meanwhile, the N-methylating agent adopted by the invention is safe and nontoxic; in addition, the method is carried out under the action of an acidic catalyst without using a basic substance, so that the method can avoid using the basic substance, and is more applicable to the nitrogenous aromatic heterocyclic compounds sensitive to alkali.)

1. A preparation method of an N-methylated nitrogen-containing aromatic heterocyclic compound is characterized by comprising the following steps:

in the presence of an acid substance HY, aliphatic alcohol methyl ether is used as an N-methylating reagent to carry out N-methylation on the nitrogen-containing aromatic heterocyclic compound to form an N-methylated nitrogen-containing aromatic heterocyclic compound;

the nitrogen-containing aromatic heterocyclic compound has a structure shown in a formula I and/or a formula II:

wherein the content of the first and second substances,

x is O, NH, S or S (O);

R₁、R₂、R₃each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl; or R₂And R₃And double bonds on the mother ring form a cyclic alkyl structure;

R₄、R₅、R₆、R₇each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl; or R₅And R₆Form a cyclic alkyl structure with a single bond on the mother ring; or R₆And R₇And double bonds on the mother ring form a cyclic alkyl structure;

the fatty alcohol methyl ether has a structure shown in a formula III:

wherein R is₈Selected from saturated alkyl groups, or alkyl groups containing a third group; the third group is a hydroxyl group, an ester group, an ether group or an aromatic group;

the N-methylated nitrogen-containing aromatic heterocyclic compound has a structure shown in a formula IV and/or a formula V:

wherein the content of the first and second substances,

x is O, NH, S or S (O);

is an acid radical ion from the acid substance HY;

R₁、R₂、R₃each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl; or R₂And R₃And double bonds on the mother ring form a cyclic alkyl structure;

R₄、R₅、R₆、R₇each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl; or R₅And R₆Form a cyclic alkyl structure with a single bond on the mother ring; or R₆And R₇And the double bond on the mother ring forms a cyclic alkyl structure.

2. The preparation method according to claim 1, wherein the acidic substance HY is one or more of inorganic acid and organic acid;

the inorganic acid is selected from HBr, HCl, HF, HBF₄、HPF₆、H₂SO₄、KHSO₄And NaHSO₄One or more of the above;

the organic acid is selected from CF₃CO₂H、CF₃SO₃H and CH₃SO₃H, one or more of H.

3. The preparation method according to claim 1, wherein the fatty alcohol methyl ether represented by the formula III is one or more selected from dimethyl ether, methyl ethyl ether, methyl n-propyl ether, methyl isopropyl ether, methyl n-butyl ether, methyl isobutyl ether, methyl tert-butyl ether, methyl anisole, methyl phenetole, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, diethylene glycol monomethyl ether, diethylene glycol dimethyl ether, triethylene glycol monomethyl ether, triethylene glycol dimethyl ether, ethyl 3-methoxypropionate and ethyl 4-methoxybutyrate.

4. The method according to claim 1, wherein the alkyl group in the substituted or unsubstituted alkyl group is a C1-C18 alkyl group.

5. The preparation method according to claim 1 or 4, wherein the nitrogen-containing aromatic heterocyclic compound represented by formula I is one or more selected from 2-methylthiazole, 2-ethylthiazole, 2-phenylthiazole, 4, 5-dimethylthiazole, 2,4, 5-trimethylthiazole, benzothiazole, 2-methylbenzothiazole, 2-methylimidazole, benzimidazole, benzoxazole, N-pentylbenzothiazol-6-amine, N-dimethylbenzothiazole-6-amine and 2-dimethylaminobenzothiazole.

6. The preparation method according to claim 1 or 4, wherein the nitrogen-containing aromatic heterocyclic compound represented by the formula II is one or more selected from pyrimidine, 2-methylpyrimidine, 2-chloropyrimidine, 4-methylpyrimidine, 5-chloropyrimidine, quinazoline, 5-dimethylamino pyrimidine and N-methyl-pyrimidine-5-methylamine.

7. The preparation method according to claim 1, wherein the dosage ratio of the aliphatic alcohol methyl ether to the nitrogen-containing aromatic heterocyclic compound is (4-30) mL: 1 g;

the molar ratio of the acidic substance HY to the nitrogen-containing aromatic heterocyclic compound is 0.05-20.0: 1.

8. The preparation method according to claim 1, wherein the reaction temperature is 20-160 ℃ and the reaction time is 2-120 h.

9. The method of claim 1, comprising the steps of:

a) mixing and reacting a nitrogen-containing aromatic heterocyclic compound, an acidic substance HY and aliphatic alcohol methyl ether to obtain a reaction mixture;

b) and (3) evaporating the reaction mixture to recover the residual aliphatic alcohol methyl ether, and then carrying out precipitation and solid-liquid separation to obtain the N-methylated nitrogen-containing aromatic heterocyclic compound.

10. The method according to claim 1 or 9, wherein the atmosphere of the reaction is an air atmosphere or a protective atmosphere.

Technical Field

The invention relates to the technical field of organic synthesis, in particular to a preparation method of an N-methylated nitrogen-containing aromatic heterocyclic compound.

Background

The N-methylation reaction of the nitrogen-containing aromatic heterocycle is widely applied to fine chemical synthesis, and has wide application in the fields of synthesizing photoelectric functional materials, medicines, pesticides, veterinary chemicals and the like. The methylation reagent used in the commonly used N-methylation method of the nitrogenous aromatic heterocycle is methyl iodide or dimethyl sulfate, and the two methylation reagents are extremely toxic and limited in use. The N-methylation reaction using these two methylating agents is carried out in a solvent selected from acetone, acetonitrile, DMSO, DMF or water, depending on the substrate. The methylation reaction is usually carried out at a temperature between room temperature and the reflux temperature of the solvent without using a base or using potassium carbonate, sodium hydroxide, sodium hydride or the like as a base in the reaction. In addition, the N-methylation reaction using methyl iodide or dimethyl sulfate lacks selectivity and has methylation effects on both nitrogen-containing aromatic heterocycles and non-aromatic aliphatic amines (such as primary, secondary and tertiary amines).

Therefore, the above methylation methods of the prior art have the following problems: the adopted methylation reagent has great toxicity to human bodies and is limited to purchase and use; moreover, the two methylating agents can methylate nitrogen-containing aromatic heterocycles and other primary amines, secondary amines and tertiary amines, lack sufficient selectivity in the reaction, even have higher activity on the latter, and cannot efficiently obtain the N-methylated nitrogen-containing aromatic heterocyclic compounds.

Disclosure of Invention

In view of the above, the present invention provides a method for preparing an N-methylated nitrogen-containing aromatic heterocyclic compound. The preparation method provided by the invention can realize N-methylation of the N-methylated nitrogen-containing aromatic heterocyclic compound under the condition of avoiding toxic methylation reagents, can effectively improve the selectivity of aromatic heterocyclic nitrogen for the nitrogen heterocyclic aromatic compound simultaneously containing an aliphatic amine structure, and is safe and environment-friendly.

The invention provides a preparation method of an N-methylated nitrogen-containing aromatic heterocyclic compound, which comprises the following steps:

in the presence of an acid substance HY, aliphatic alcohol methyl ether is used as an N-methylating reagent to carry out N-methylation on the nitrogen-containing aromatic heterocyclic compound to form an N-methylated nitrogen-containing aromatic heterocyclic compound;

the nitrogen-containing aromatic heterocyclic compound has a structure shown in a formula I and/or a formula II:

wherein the content of the first and second substances,

x is O, NH, S or S (O);

R₁、R₂、R₃each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl; or R₂And R₃And double bonds on the mother ring form a cyclic alkyl structure;

R₄、R₅、R₆、R₇each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl; or R₅And R₆Form a cyclic alkyl structure with a single bond on the mother ring; or R₆And R₇And double bonds on the mother ring form a cyclic alkyl structure;

the fatty alcohol methyl ether has a structure shown in a formula III:

wherein R is₈Selected from saturated alkyl groups, or alkyl groups containing a third group; the third group is a hydroxyl group, an ester group, an ether group or an aromatic group;

the N-methylated nitrogen-containing aromatic heterocyclic compound has a structure shown in a formula IV and/or a formula V:

wherein the content of the first and second substances,

x is O, NH, S or S (O);

is an acid radical ion from the acid substance HY;

R₁、R₂、R₃each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl; or R₂And R₃And double bonds on the mother ring form a cyclic alkyl structure;

R₄、R₅、R₆、R₇each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl; or R₅And R₆Form a cyclic alkyl structure with a single bond on the mother ring; or R₆And R₇And the double bond on the mother ring forms a cyclic alkyl structure.

Preferably, the acidic substance HY is one or more of inorganic acid and organic acid;

the inorganic acid is selected from HBr, HCl, HF, HBF₄、HPF₆、H₂SO₄、KHSO₄And NaHSO₄One or more of the above;

the organic acid is selected from CF₃CO₂H、CF₃SO₃H and CH₃SO₃H, one or more of H.

Preferably, the fatty alcohol methyl ether shown in the formula III is one or more selected from dimethyl ether, methyl ethyl ether, methyl n-propyl ether, methyl isopropyl ether, methyl n-butyl ether, methyl isobutyl ether, methyl tert-butyl ether, methyl anisole, methyl phenetole, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, diethylene glycol monomethyl ether, diethylene glycol dimethyl ether, triethylene glycol monomethyl ether, triethylene glycol dimethyl ether, ethyl 3-methoxypropionate and ethyl 4-methoxybutyrate.

Preferably, in the substituted or unsubstituted alkyl group, the alkyl group is a C1-C18 alkyl group.

Preferably, the nitrogen-containing aromatic heterocyclic compound shown in the formula I is selected from one or more of 2-methylthiazole, 2-ethylthiazole, 2-phenylthiazole, 4, 5-dimethylthiazole, 2,4, 5-trimethylthiazole, benzothiazole, 2-methylbenzothiazole, 2-methylimidazole, benzimidazole, benzoxazole, N-pentylbenzothiazole-6-amine, N-dimethylbenzothiazole-6-amine and 2-dimethylaminobenzothiazole.

Preferably, the nitrogen-containing aromatic heterocyclic compound shown in the formula II is selected from one or more of pyrimidine, 2-methylpyrimidine, 2-chloropyrimidine, 4-methylpyrimidine, 5-chloropyrimidine, quinazoline, 5-dimethylamino pyrimidine and N-methyl-pyrimidine-5-methylamine.

Preferably, the dosage ratio of the aliphatic alcohol methyl ether to the nitrogen-containing aromatic heterocyclic compound is (4-30) mL: 1 g;

the molar ratio of the acidic substance HY to the nitrogen-containing aromatic heterocyclic compound is 0.05-20.0: 1.

Preferably, the reaction temperature is 20-160 ℃, and the reaction time is 2-120 h.

Preferably, the preparation method comprises the following steps:

a) mixing and reacting a nitrogen-containing aromatic heterocyclic compound, an acidic substance HY and aliphatic alcohol methyl ether to obtain a reaction mixture;

b) and (3) evaporating the reaction mixture to recover the residual aliphatic alcohol methyl ether, and then carrying out precipitation and solid-liquid separation to obtain the N-methylated nitrogen-containing aromatic heterocyclic compound.

Preferably, the atmosphere of the reaction is an air atmosphere or a protective atmosphere.

According to the method for N-methylating the aromatic nitrogen heterocycle, disclosed by the invention, a specific aliphatic alcohol methyl ether shown as a formula III is used as an N-methylating reagent under the catalysis of a certain acid, so that the N-methylation of the nitrogen-containing aromatic heterocycle can be selectively realized, and the selectivity to the nitrogen-containing aromatic heterocycle is improved; meanwhile, the N-methylating agent adopted by the invention is safe and nontoxic; in addition, the method is carried out under the action of an acidic catalyst without using a basic substance, so that the method can avoid using the basic substance, and is more applicable to the nitrogenous aromatic heterocyclic compounds sensitive to alkali.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.

FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of the product obtained in example 1;

FIG. 2 is a NMR spectrum of the product obtained in example 3;

FIG. 3 is a NMR spectrum of the product obtained in example 5.

Detailed Description

The invention provides a preparation method of an N-methylated nitrogen-containing aromatic heterocyclic compound, which comprises the following steps:

in the presence of an acid substance HY, aliphatic alcohol methyl ether is used as an N-methylating reagent to carry out N-methylation on the nitrogen-containing aromatic heterocyclic compound to form an N-methylated nitrogen-containing aromatic heterocyclic compound;

the nitrogen-containing aromatic heterocyclic compound has a structure shown in a formula I and/or a formula II:

wherein the content of the first and second substances,

x is O, NH, S or S (O);

R₁、R₂、R₃each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl; or R₂And R₃And on the mother ringThe bond forms a cyclic hydrocarbyl structure;

R₄、R₅、R₆、R₇each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl; or R₅And R₆Form a cyclic alkyl structure with a single bond on the mother ring; or R₆And R₇And double bonds on the mother ring form a cyclic alkyl structure;

the fatty alcohol methyl ether has a structure shown in a formula III:

wherein R is₈Selected from alkyl, or alkyl containing a third group; the third group is a hydroxyl group, an ester group, an ether group or an aromatic group;

the N-methylated nitrogen-containing aromatic heterocyclic compound has a structure shown in a formula IV and/or a formula V:

wherein the content of the first and second substances,

x is O, NH, S or S (O);

is an acid radical ion from the acid substance HY;

R₁、R₂、R₃each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl; or R₂And R₃And double bonds on the mother ring form a cyclic alkyl structure;

R₄、R₅、R₆、R₇each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl; or R₅And R₆Form a cyclic alkyl structure with a single bond on the mother ring; or R₆And R₇Form a cyclic alkyl structure with a double bond on the mother ring。

According to the method for N-methylating the aromatic nitrogen heterocycle, disclosed by the invention, a specific aliphatic alcohol methyl ether shown as a formula III is used as an N-methylating reagent under the catalysis of a certain acid, so that the N-methylation of the nitrogen-containing aromatic heterocycle can be selectively realized, and the selectivity to the nitrogen-containing aromatic heterocycle is improved; meanwhile, the N-methylating agent adopted by the invention is safe and nontoxic; in addition, the method is carried out under the action of an acidic catalyst without using a basic substance, so that the method can avoid using the basic substance, and is more applicable to the nitrogenous aromatic heterocyclic compounds sensitive to alkali.

According to the invention, acid is adopted to activate fatty alcohol methyl ether, so that methyl in methyl ether has electrophilic activity and is easy to be subjected to nucleophilic attack by nitrogen on a nitrogen-containing aromatic heterocyclic ring, and the methyl is transferred to the aromatic heterocyclic ring, thereby realizing N-methylation of the nitrogen-containing aromatic heterocyclic ring. The synthetic route of the N-methylation reaction of the nitrogenous aromatic heterocyclic compound raw material and the fatty alcohol methyl ether is as follows:

in the invention, the nitrogen-containing aromatic heterocyclic compound serving as a reaction raw material has a structure shown in a formula I and/or a formula II:

for compounds of formula I:

the compound I is a five-membered heterocyclic compound, a benzo five-membered heterocyclic compound and derivatives thereof, wherein:

x is O, NH, S or S (O); said S (O) is a sulfoxide structure,

R₁、R₂、R₃each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl; or R₂And R₃And the double bond on the mother ring forms a cyclic alkyl structure. Among the substituted or unsubstituted alkyl groups, the alkyl group is preferably a C1-C18 alkyl group. The cyclic hydrocarbon structure is preferably a cycloalkane or a cyclic aromatic hydrocarbon. Compound I may be X, R₁、R₂And R₃Any combination of (a), for example: x is S, R₁Is methyl, R₂And R₃Is hydrogen, then compound I is 2-methylthiazole; x is S, R₁Is hydrogen, R₂And R₃And the double bond on the mother ring forms a benzene ring, then the compound I is benzothiazole.

More preferably, the compound of formula I is selected from one or more of 2-methylthiazole, 2-ethylthiazole, 2-phenylthiazole, 4, 5-dimethylthiazole, 2,4, 5-trimethylthiazole, benzothiazole, 2-methylbenzothiazole, 2-methylimidazole, benzimidazole and benzoxazole, N-pentylbenzothiazol-6-amine, N-dimethylbenzothiazole-6-amine and 2-dimethylaminobenzothiazole.

For compounds of formula ii:

the compound of the formula II is a pyrimidine compound and a derivative thereof, wherein:

R₄、R₅、R₆、R₇each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl; or R₅And R₆Form a cyclic alkyl structure with a single bond on the mother ring; or R₆And R₇And the double bond on the mother ring forms a cyclic alkyl structure. Among the substituted or unsubstituted alkyl groups, the alkyl group is preferably a C1-C18 alkyl group. The cyclic hydrocarbon structure is preferably a cycloalkane or a cyclic aromatic hydrocarbon.

More preferably, the compound of formula II is selected from one or more of pyrimidine, 2-methylpyrimidine, 2-chloropyrimidine, 4-methylpyrimidine, 5-chloropyrimidine, quinazoline, 5-dimethylamino pyrimidine and N-methyl-pyrimidine-5-methylamine.

In the invention, the N-methylating agent fatty alcohol methyl ether has a structure shown in a formula III:

wherein R is₈Selected from saturated alkyl groups, or alkyl groups containing a third group; the third group is a hydroxyl group, an ester group, an ether group or an aromatic group.

More preferably, the compound of formula iii is one or more selected from dimethyl ether, methyl ethyl ether, methyl n-propyl ether, methyl isopropyl ether, methyl n-butyl ether, methyl isobutyl ether, methyl tert-butyl ether, methyl anisole, methyl phenetole, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, diethylene glycol monomethyl ether, diethylene glycol dimethyl ether, triethylene glycol monomethyl ether, triethylene glycol dimethyl ether, ethyl 3-methoxypropionate and ethyl 4-methoxybutyrate.

In the invention, the dosage ratio of the aliphatic alcohol methyl ether shown in the formula III to the nitrogen-containing aromatic heterocyclic compound is preferably (4-30) mL to 1g, and more preferably (6-20) mL to 1 g.

In the invention, the acidic substance HY is one or more of inorganic acid and organic acid. Wherein the inorganic acid is preferably HBr, HCl, HF, HBF₄、HPF₆、H₂SO₄、KHSO₄And NaHSO₄One or more of them. The organic acid is preferably CF₃CO₂H、CF₃SO₃H and CH₃SO₃H, one or more of H. From the viewpoint of easy handling, the acidic substance is more preferably KHSO₄And/or NaHSO₄. By using the above acidic substance, hydrogen ions can be supplied to the reaction system to activate the fatty alcohol methyl ether shown in the formula III, and anions can be supplied to the product, and the reaction can be promoted better by using the above acidic substance to obtain the corresponding N-methylated product, for example, if other acidic substance such as acetic acid is used, the effect is poor.

In the present invention, the molar ratio of the acidic substance HY to the nitrogen-containing heteroaromatic compound is preferably (0.05-20.0) to 1, more preferably (0.1-10.0) to 1, even more preferably (1.0-5.0) to 1, and most preferably (1.5-3.0) to 1.

In the present invention, the atmosphere of the N-methylation reaction is preferably an air atmosphere or a protective atmosphere. The type of protective gas used to provide the protective atmosphere is not particularly limited in the present invention, and may be any conventional type known to those skilled in the art, such as nitrogen or argon.

In the invention, the temperature of the N-methylation reaction is preferably room temperature to 160 ℃, specifically 20 to 160 ℃, and more preferably 80 to 140 ℃. In the invention, the time of the N-methylation reaction is preferably 2-120 h, more preferably 4-96 h, and further preferably 8-48 h. In the present invention, the mode of the N-methylation reaction is preferably a heated reflux method.

In the present invention, the specific process of the preparation method preferably includes:

a) mixing and reacting a nitrogen-containing aromatic heterocyclic compound, an acidic substance HY and aliphatic alcohol methyl ether to obtain a reaction mixture;

b) and (3) evaporating the reaction mixture to recover the residual fatty alcohol methyl ether, and then carrying out precipitation and solid-liquid separation to obtain the N-methylated heterocyclic compound.

With respect to step a): the preparation method has higher selectivity on nitrogen heterocycles in the raw materials of the nitrogen-containing aromatic heterocyclic compound, and can efficiently form the N-methylated nitrogen-containing aromatic heterocyclic compound. The types, reaction conditions and the like of the nitrogen-containing aromatic heterocyclic compound, the acidic substance HY and the aliphatic alcohol methyl ether are consistent with those in the technical scheme, and are not described herein again.

With respect to step b): after the N-methylation reaction, the post-treatment of step b) is carried out. Among them, the distillation method for recovering the residual fatty alcohol methyl ether is preferably vacuum distillation. The temperature of the reduced pressure distillation is preferably 20-70 ℃, and the air pressure is preferably-0.01 to-0.09 MPa. The distillation residue was dissolved with a small amount of methanol, followed by precipitation. The type of the reagent used for the precipitation is not particularly limited, and may be any conventional precipitation reagent known to those skilled in the art, for example, precipitation with diethyl ether. After precipitation, carrying out solid-liquid separation; the solid-liquid separation method is not particularly limited in the present invention, and may be a conventional separation means known to those skilled in the art, such as filtration. After solid-liquid separation, the precipitate is collected and preferably recrystallized. In the invention, the solvent for recrystallization is preferably one or more of diethyl ether, acetonitrile and acetone. After the post-treatment, the N-methylated nitrogenous aromatic heterocyclic compound is obtained.

In the invention, the obtained N-methylated nitrogen-containing aromatic heterocyclic compound has a structure shown in a formula IV and/or a formula V:

wherein the content of the first and second substances,is an acid radical ion derived from the acidic substance HY. X, R₁、R₂、R₃、R₄、R₅、R₆、R₇The above technical solutions are the same, and are not described herein again.

For a further understanding of the invention, reference will now be made to the preferred embodiments of the invention by way of example, and it is to be understood that the description is intended to further illustrate features and advantages of the invention, and not to limit the scope of the claims.

Example 1

Adding 149mg (1.0mmol) of 2-methylbenzothiazole, 288mg (2.4mmol) of sodium bisulfate and 3mL of ethylene glycol monomethyl ether into a reactor, heating to 135 ℃ under a nitrogen atmosphere for reaction for 48 hours, distilling and recovering the solvent after the reaction is finished, dissolving by using a small amount of methanol, adding diethyl ether into the solution for precipitation, filtering and collecting the precipitate to obtain the product 1-methyl-2-methylbenzothiazole hydrogen sulfate. At the end of the reaction, the yield of the reaction product was 87% calculated according to 1HNMR or HPLC.

Nuclear magnetic resonance hydrogen spectrum (1H NMR) of the obtained product referring to fig. 1, fig. 1 is a nuclear magnetic resonance hydrogen spectrum of the product obtained in example 1.

Example 2

Adding 149mg (1.0mmol) of 2-methylbenzothiazole, 136mg (1.0mmol) of potassium hydrogen sulfate and 3mL of ethylene glycol monomethyl ether into a reactor, heating to 135 ℃ under a nitrogen atmosphere for reacting for 24 hours, distilling and recovering a solvent after the reaction is finished, dissolving by using a small amount of methanol, adding diethyl ether into the solution for precipitation, filtering and collecting the precipitate to obtain a product, namely 2, 3-dimethylbenzothiazolium bisulfate. At the end of the reaction, the yield of the reaction product was 84% calculated according to 1HNMR or HPLC.

Example 3

Adding 85mg (1.0mmol) of thiazole, 288mg (2.4mmol) of sodium bisulfate and 3mL of ethylene glycol monomethyl ether into a reactor, heating to 128 ℃ under the nitrogen atmosphere for reaction for 72 hours, distilling and recovering the solvent after the reaction is finished, dissolving by using a small amount of methanol, adding diethyl ether into the solution for precipitation, filtering and collecting the precipitate to obtain the product, namely the 3-methylthiazolium bisulfate. At the end of the reaction, the yield of the reaction product was 50% according to 1H NMR or HPLC.

Nuclear magnetic resonance hydrogen spectrum (1H NMR) of the obtained product referring to fig. 2, fig. 2 is a nuclear magnetic resonance hydrogen spectrum of the product obtained in example 3.

Example 4

Adding 85mg (1.0mmol) of thiazole, 163mg (1.2mmol) of potassium bisulfate and 3mL of ethylene glycol monomethyl ether into a reactor, heating to 135 ℃ under the nitrogen atmosphere for reaction for 48 hours, after the reaction is finished, distilling and recovering the solvent, dissolving by using a small amount of methanol, precipitating the solution by using diethyl ether, filtering and collecting the precipitate to obtain the product, namely the 3-methylthiazolium bisulfate. At the end of the reaction, the yield of the reaction product was 42% according to 1H NMR or HPLC.

Example 5 pyrimidine 80mg (1mmol), potassium hydrogen sulfate 163mg (1.2mmol) and 3mL of ethylene glycol monomethyl ether were added to a reactor, heated to 135 ℃ under nitrogen atmosphere for reaction for 16 hours, after the reaction was completed, the solvent was drained, dissolved with a small amount of methanol, and then precipitated by ether precipitation and filtration to obtain the product 1-methylpyrimidinium bisulfate. At the end of the reaction, the product yield was 30% according to 1H NMR or HPLC.

The hydrogen nuclear magnetic resonance spectrum (1HNMR) of the obtained product is shown in figure 3, and figure 3 is the hydrogen nuclear magnetic resonance spectrum of the product obtained in example 5.

Example 6

Adding 149mg (1.0mmol) of 2-methylbenzothiazole, 163mg (1.2mmol) of potassium hydrogen sulfate and 3mL of ethylene glycol dimethyl ether into a reactor, heating to 135 ℃ under a nitrogen atmosphere for reacting for 48 hours, distilling to remove the solvent after the reaction is finished, dissolving by using a small amount of methanol, precipitating the solution by using ether, filtering and collecting the precipitate to obtain the product, namely 2, 3-dimethylbenzothiazole hydrogen sulfate. At the end of the reaction, the yield of the reaction product was 91% calculated according to 1H NMR or HPLC.

Example 7

Adding 149mg (1.0mmol) of 2-methylbenzothiazole, 1.36g (10.0mmol) of potassium bisulfate and 4mL of ethylene glycol monomethyl ether into a reactor, heating to 135 ℃ under a nitrogen atmosphere for reaction for 24 hours, distilling and recovering a solvent after the reaction is finished, dissolving by using a small amount of methanol, adding diethyl ether into the solution for precipitation, filtering and collecting the precipitate to obtain a product, namely 2, 3-dimethylbenzothiazolium bisulfate. At the end of the reaction, the yield of the reaction product was 94% according to 1H NMR or HPLC.

Example 8

Adding 149mg (1.0mmol) of 2-methylbenzothiazole, 816mg (6.0mmol) of potassium hydrogen sulfate and 4mL of ethylene glycol monomethyl ether into a reactor, heating to 135 ℃ under a nitrogen atmosphere for reacting for 24 hours, distilling and recovering a solvent after the reaction is finished, dissolving by using a small amount of methanol, adding diethyl ether into the solution for precipitation, filtering and collecting the precipitate to obtain a product, namely 2, 3-dimethylbenzothiazolium bisulfate. At the end of the reaction, the yield of the reaction product was 90% according to 1H NMR or HPLC.

Example 9

Under a nitrogen atmosphere, 118mg (0.50mmol) of N-pentylbenzothiazol-6-amine, NaHSO₄300mg (2.50mmol) and 3mL of ethylene glycol monomethyl ether were charged into a reactor, reacted at 135 ℃ for 72 hours under a nitrogen atmosphere, and after the reaction was completed, the solvent was distilled off under reduced pressure, dissolved with a small amount of methanol, and then precipitated by ether precipitation and filtration. The product 6-pentylamino-3-methylbenzothiazolium hydrogen sulfate is obtained. At the end of the reaction, the yield of the reaction product was 89% as calculated by 1H NMR or HPLC, and the selectivity was 100%, i.e. only the N on the nitrogen heterocycle was methylated and the N on the side chain was not methylated, all forming a product with methylated nitrogen heterocycles.

Comparative example 1

Preparation according to example 8The process is carried out by reacting NaHSO₄The equimolar amount of acetic acid was replaced. The results showed that no nitrogen-containing heteroaromatic compound was formed and 85% of the reaction raw material could be recovered.

Comparative example 2

The procedure was carried out as in example 8, except that an equimolar amount of N, N-diethylbenzylamine was used instead of 2-methylbenzothiazole. The results show that no reaction takes place and no N-methylated product is formed.

Comparative example 3

The procedure was carried out according to the preparation of example 8, except that an equimolar amount of N, N-diethylaniline was used instead of 2-methylbenzothiazole. The results show that no reaction takes place and no N-methylated product is formed.

According to the embodiments, the preparation method of the invention can avoid using toxic methylating reagent under acidic condition, and adopts safe and environment-friendly aliphatic alcohol methyl ether shown in formula III to methylate the nitrogen-containing aromatic heterocyclic compound; moreover, for aromatic compounds containing nitrogen heterocycles and aliphatic amine structures, the selectivity of N-methylation on the nitrogen heterocycles can be effectively improved. The comparison with the effect of comparative example 1 proves that N-methylation of nitrogen heterocycles can be effectively realized under the catalysis of the acidic substance. In addition, as can be seen from the above examples, the preparation method of the present invention does not require the use of basic substances, and the method provided by the present invention is more applicable to nitrogen-containing heteroaromatic compounds sensitive to bases.

The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.