CN101514190B - Method for preparing heterocyclic compounds of methyl mercapto under ionic liquid catalysis - Google Patents

Abstract

The invention relates to a method for preparing heterocyclic compounds of methyl mercapto under ionic liquid catalysis, including the followings: (1) mercapto heterocyclic compound and methyl carbonate with the mole ratio of 1: 1.2 to 2 are added to ionic liquid, and are heated to the temperature of 50 to 150 DEG C while stirring during the reaction of 0.5 to 15 hours; (2) after reaction, the temperature is decreased to room temperature to extract products, and the solvent is recycled after vacuum concentration, thus obtaining the compound. The method has the advantages of easy, simple and safe operation as well as obviously improved substrate conversion and product selectivity, and the methyl carbonate used as methylating agent and the ionic liquid used as solvent are environmentally friendly; and simultaneously the ionic liquid is easy to recycle and can be in cycle use.

Description

Method for preparing methylthio heterocyclic compound under ionic liquid catalysis

technical field

The invention belongs to the field of preparation of methylthio heterocyclic compounds, in particular to a method for preparing methylthio heterocyclic compounds under ionic liquid catalysis.

Background technique

Methylthio heterocyclic compounds are an important class of chemical intermediates. For example, 2-methylthiobenzoxazole and 2-methylthiobenzothiazole have certain biological activities, and 4,6-disubstituted-2-methylthiopyrimidine is a synthetic plant growth regulator, herbicide, fungicide important intermediates for pharmaceuticals and pharmaceutical products. The synthesis method of this kind of compound generally uses the heterocyclic compound containing mercapto group as the substrate to carry out the methylation reaction, and the methylation reagent used is usually methyl iodide or dimethyl sulfate. However, methyl iodide and dimethyl sulfate are highly toxic, and methyl iodide is expensive, and these reagents have serious hidden dangers in actual reaction operations and environmental protection. Although there are reports (Synthesis1986, 382-383) using crown ethers to catalyze the methylation reaction of mercapto-containing heterocyclic compounds and dimethyl carbonate (DMC). Japanese patent JP2008184397 discloses that in the presence of sulfuric acid, microwaves are used to promote the reaction of 4,6-dimethyl-2-mercaptopyrimidine and methanol to methylate sulfhydryl groups. However, the yield is average or the catalyst is highly toxic, and the reaction conditions are not conducive to actual production. Therefore, there is a need for a method for the methylation of mercapto-containing heterocyclic compounds that is free from environmental pollution and is easy to operate in practice.

Room temperature ionic liquids have the advantages of low melting point, low toxicity, non-combustible and volatile, recyclable, etc., and are good catalysts and reaction solvents. Patent CN01808303.X shows that DMC can be used for N-methylation on nitrogen-containing heterocyclic rings, but no one has proposed to use DMC in ionic liquids to perform methylation reactions on sulfhydryl groups on heterocyclic compounds.

Contents of the invention

The technical problem to be solved by the present invention is to provide a method for preparing methylthio heterocyclic compounds under the catalysis of ionic liquids. The dimethyl carbonate and the ionic liquid as a solvent are environmentally friendly, and the ionic liquid is easy to recover and can be recycled.

The method for preparing a methylthio heterocyclic compound under ionic liquid catalysis of the present invention comprises:

(1) In the ionic liquid, add mercapto-containing heterocyclic compound and methylation reagent dimethyl carbonate in a molar ratio of 1:1.2~2, heat up to 50~150°C under stirring, react for 0.5~15 hours, TLC or HPLC monitor;

(2) After the reaction is completed, cool down to room temperature, extract the product, concentrate under reduced pressure, and recover the solvent to obtain the target product.

The step (1) ionic liquid doubles as a catalyst and a solvent.

The general formula of the thiol-containing heterocyclic compound in the step (1) is (I), (II), (III):

Wherein in general formula (I), R ¹ and R ² represent H, -CH ₃ , -Et or -OCH ₃ ; in general formula (II), X is O or S.

The mercapto-containing heterocyclic compound in the step (1) is 2-mercaptopyrimidine, 4,6-dimethyl-2-mercaptopyrimidine, 4,6-dimethoxy-2-mercaptopyrimidine, 4,6 - diethyl-2-mercaptopyrimidine, 2-mercaptobenzoxazole, 2-mercaptobenzothiazole or 2-mercaptobenzimidazole.

The ionic liquid in the step (1) is 1-butyl-3-methylimidazole chloride, 1-butyl-3-methylimidazole bromide, 1-ethyl-3-methylimidazole acetate, bromine 1-ethyl-3-methylimidazole, N-butyl-3-picoline bromide or N-ethyl-3-picoline bromide.

A preferred ionic liquid is 1-butyl-3-methylimidazole chloride.

The general formulas of the products in the step (2) are (IV), (V) and (VI).

Wherein the general formula (IV) R ¹ and R ² represent H, -CH ₃ , -Et or -OCH ₃ . In the general formula (V), X is O or S.

The product in the step (2) is 2-methylthiopyrimidine, 4,6-dimethyl-2-methylthiopyrimidine, 4,6-dimethoxy-2-methylthiopyrimidine, 4, 6-diethyl-2-methylthiopyrimidine, 2-methylthiobenzoxazole, 2-methylthiobenzothiazole or N-methyl-2-methylthiobenzimidazole.

Beneficial effect

The preparation method of the present invention has the advantages of simple and safe operation, recyclable ionic liquid serving as solvent and catalyst, high product yield, and more importantly, environmental protection and easy practical production.

Detailed ways

Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that after reading the teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Example 1

Preparation of 2-methylthiopyrimidine

Dissolve 2-mercaptopyrimidine (5.6g, 0.05mol) in 1-butyl-3-methylimidazole chloride (3.5g, 0.02mol), add dimethyl carbonate (5.4g, 0.06mol), and heat up under stirring to 90-130°C, react for 3-5 hours, and monitor by TLC or HPLC. After the reaction was completed, the product was cooled down to room temperature, extracted with ethyl acetate (10-30 ml), concentrated under reduced pressure, and the solvent was recovered to obtain the product as a colorless oil with a content of 97.6%. Add 2-mercaptopyrimidine and dimethyl carbonate to the ionic liquid, react under the same conditions, and cycle 5 times, the reaction results are shown in the following table:

Example 2

Preparation of 2-Methylthiobenzoxazole

Dissolve 2-mercaptobenzoxazole (12.1g, 0.08mol) in 1-butyl-3-methylimidazole chloride (7.0g, 0.04mol), add dimethyl carbonate (8.1g, 0.09mol), Heat up to 90-130°C with stirring, react for 2-4 hours, and monitor by TLC or HPLC. After the reaction was completed, it was lowered to room temperature, the product was extracted with ethyl acetate (10-30 ml), concentrated under reduced pressure, and the solvent was recovered. The product was vacuum-dried to obtain 10.0 g with a content of 95.2%. Yield 75.6%.

Example 3

Preparation of 2-Methylthiobenzothiazole

Dissolve 2-mercaptobenzothiazole (16.7g, 0.1mol) in 1-butyl-3-methylimidazole chloride (10.5g, 0.06mol), add dimethyl carbonate (10.8g, 0.12mol), and stir Lower the temperature to 90-130°C, react for 2-4 hours, and monitor by TLC or HPLC. After the reaction was completed, it was lowered to room temperature, the product was extracted with ethyl acetate (10-30 ml), concentrated under reduced pressure, and the solvent was recovered. The product was vacuum-dried to obtain 14.9 g with a content of 95.0%. Yield 82.2%.

Example 4

Preparation of N-methyl-2-methylthiobenzimidazole

Dissolve 2-mercaptobenzimidazole (7.5g, 0.05mol) in 1-butyl-3-methylimidazole chloride (8.7g, 0.05mol), add dimethyl carbonate (9.0g, 0.1mol), and stir Lower the temperature to 90-130°C, react for 8-14 hours, and monitor by TLC or HPLC. After the reaction was completed, it was lowered to room temperature, the product was extracted with ethyl acetate (10-30 ml), concentrated under reduced pressure, and the solvent was recovered. The product was vacuum-dried to obtain 5.4 g with a content of 96.5%. Yield 65.8%.

Claims (4)

1. the method for the heterogeneous ring compound of the ionic liquid-catalyzed methylthio group of preparation down comprises:

(1) in ionic liquid, what add 1: 1.2～2 mol ratios contains sulfhydryl heterocycle compound and methylcarbonate, is warming up to 50～150 ℃ under stirring, and reacts 0.5～15 hour; Described ionic liquid is chlorination 1-butyl-3-Methylimidazole, bromination 1-butyl-3-Methylimidazole, acetate 1-ethyl-3-Methylimidazole, bromination 1-ethyl-3-Methylimidazole, bromination N-butyl-3-picoline or bromination N-ethyl-3-picoline;

(2) after reaction finishes, reduce to room temperature, extract product, concentrating under reduced pressure reclaims solvent, promptly.

2. the method for the heterogeneous ring compound of the ionic liquid-catalyzed methylthio group of preparation down according to claim 1, it is characterized in that: the heterogeneous ring compound that contains sulfydryl in the described step (1) is a 2-mercaptopyrimidine, 4,6-dimethyl-2-mercaptopyrimidine, 4,6-dimethoxy-2-mercaptopyrimidine, 4,6-diethyl-2-mercaptopyrimidine, 2-mercaptobenzoxazole, 2-mercaptobenzothiazole or 2-mercaptobenzimidazole.

3. the method for the heterogeneous ring compound of ionic liquid-catalyzed down preparation methylthio group according to claim 1 is characterized in that: the product general formula in the described step (2) for (IV), (V) and (VI)

Its formula of (IV) R ¹And R ²Represent H ,-CH ₃,-Et or-OCH ₃X is O or S in the logical formula V.

4. the method for the heterogeneous ring compound of the ionic liquid-catalyzed methylthio group of preparation down according to claim 1, it is characterized in that: the product in the described step (2) is a 2-methylthiopyrimidine, 4,6-dimethyl-2-methylthiopyrimidine, 4,6-dimethoxy-2-methylthiopyrimidine, 4,6-diethyl-2-methylthiopyrimidine, 2-methylthio group benzo oxazole, 2-methylthio group benzo thiazole or N-methyl-2-methylthio group benzo imidazoles.