阅读说明：本技术 一种制备吡啶-2-硫醇的方法 (Method for preparing pyridine-2-thiol ) 是由 孙绍光 周勇 于 2019-10-30 设计创作，主要内容包括：本发明提供了一种制备吡啶-2-硫醇的方法,属于药物合成技术领域,以2-卤代吡啶为原料,与硫脲反应,制备出吡啶-2-硫醇,其工艺路线如下图：<Image he="278" wi="700" file="DDA0002253399520000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中,式II为2-卤代吡啶的化学式,式II中R为H、C1-C6脂肪烃或C1-C6取代的苯基；式II中X为氟、氯、溴或者碘原子；在硫脲酸水溶液中,以2-卤代吡啶为原料,在80-120℃下,使2-卤代吡啶转化完全,控制反应温度在50-100℃,再加入碱水溶液,继续反应至中间态完全转化为吡啶-2-硫醇,再调节溶液至pH为3.6-6.5,之后加入有机溶剂萃取,萃取的次数为3-5次,分液,有机相浓缩至干,得到吡啶-2-硫醇粗品,将粗品加入有机溶剂中重结晶得到吡啶-2-硫醇纯品。(The invention provides a method for preparing pyridine-2-thiol, belonging to the technical field of drug synthesis, wherein 2-halogenated pyridine is used as a raw material to react with thiourea to prepare the pyridine-2-thiol, and the process route is as follows: wherein, the formula II is the chemical formula of 2-halogenated pyridine, R in the formula II is H, C1-C6 aliphatic hydrocarbon or C1-C6 substituted phenyl; in the formula II, X is fluorine, chlorine, bromine or iodine atom; in thiourea acid aqueous solution, 2-halopyridine is used as a raw material, the 2-halopyridine is completely converted at 80-120 ℃, the reaction temperature is controlled at 50-100 ℃, alkaline aqueous solution is added, the reaction is continued until the intermediate state is completely converted into pyridine-2-thiol, the pH of the solution is adjusted to 3.6-6.5, then organic solvent is added for extraction, the extraction frequency is 3-5 times, liquid separation is carried out, the organic phase is concentrated to dryness, a crude product of pyridine-2-thiol is obtained, and the crude product is added into the organic solvent for recrystallization to obtain a pure product of pyridine-2-thiol.)

1. A method for preparing pyridine-2-thiol is characterized in that 2-halogenated pyridine is used as a raw material and reacts with thiourea to prepare the pyridine-2-thiol, and the process route is as follows:

wherein, the formula II is the chemical formula of 2-halogenated pyridine, R in the formula II is H, C1-C6 aliphatic hydrocarbon or C1-C6 substituted phenyl; in the formula II, X is fluorine, chlorine, bromine or iodine atom.

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

s1: dissolving thiourea in an acid water solution, and stirring to form a suspension;

s2: adding 2-halogenated pyridine into the suspension, and controlling the reaction temperature to completely convert the 2-halogenated pyridine to obtain a first reaction solution;

s3: controlling the reaction temperature, adding an alkali aqueous solution into the first reaction solution, and continuously reacting until the intermediate state is completely converted into pyridine-2-thiol to obtain an alkali solution;

s4: adding acid into the alkaline solution until the solution is slightly acidic to obtain a second reaction solution;

s5: adding an organic solvent into the second reaction solution, stirring and extracting until the product completely enters the organic solvent, namely extracting;

s6: separating liquid, and concentrating an organic phase to be dry to obtain a pyridine-2-thiol crude product;

s7: and adding the crude product into an organic solvent for recrystallization to obtain a pure pyridine-2-thiol product.

3. The method according to claim 2, wherein in S1, the acid aqueous solution is hydrochloric acid, sulfuric acid, methanesulfonic acid or trifluoroacetic acid, and the concentration of the acid aqueous solution is 10-50%.

4. The method of claim 2, wherein the molar ratio of 2-halopyridine to thiourea in S2 to the aqueous acid solution is from 1:1 to 3.

5. The method of claim 2, wherein the reaction temperature in S2 is 80-120 ℃.

6. The method of claim 2, wherein the reaction temperature in S3 is 50-100 ℃.

7. The method according to claim 2, wherein the alkaline water in S3 is sodium hydroxide or potassium hydroxide solution, the concentration of the alkaline water is 10-100%, and the dosage of the alkaline water is 3-5 equivalent of 2-halogenated pyridine.

8. The method according to claim 2, wherein in S4, the acid is hydrochloric acid, sulfuric acid, methanesulfonic acid or trifluoroacetic acid, wherein the hydrochloric acid is concentrated hydrochloric acid, the sulfuric acid concentration is 25-65%, the methanesulfonic acid and the trifluoroacetic acid are pure products, and the pH of the slightly acidic solution is 3.6-6.5.

9. The method according to claim 2, wherein in S5, the organic solvent is one or more of chloroform, dichloromethane, ethyl acetate, isopropyl acetate, toluene, methyl tert-butyl ether, petroleum ether, n-heptane and n-octane; the organic solvent accounts for 20-50% of the volume of the second reaction solution; the extraction times are 3-5 times.

10. The method according to claim 2, wherein in S7, the organic solvent is one or more of chloroform, dichloromethane, ethyl acetate, isopropyl acetate, toluene, methyl tert-butyl ether, petroleum ether, n-heptane and n-octane; the weight ratio of the crude product to the organic solvent is 1:2-5, and the crude product is recrystallized for 1-3 times.

Disclosure of Invention

Aiming at the defects of high reaction temperature, high energy consumption, large amount of organic waste liquid and low yield existing in the existing method for preparing pyridine-2-thiol.

A method for preparing pyridine-2-thiol takes 2-halogenated pyridine as raw material to react with thiourea to prepare the pyridine-2-thiol, and the process route is as follows:

wherein, the formula II is the chemical formula of 2-halogenated pyridine, R in the formula II is H, C1-C6 aliphatic hydrocarbon or C1-C6 substituted phenyl; in the formula II, X is fluorine, chlorine, bromine or iodine atom.

In the technical scheme, 2-halogenated pyridine is used as a raw material and reacts with thiourea in an aqueous solution to prepare pyridine-2-thiol, the reaction condition is mild, the method is green and environment-friendly, and the obtained pyridine-2-thiol has high yield and is suitable for industrial production.

A process for preparing pyridine-2-thiol comprising the steps of:

s1: dissolving thiourea in an acid water solution, and stirring to form a suspension;

s2: adding 2-halogenated pyridine into the suspension, and controlling the reaction temperature to completely convert the 2-halogenated pyridine to obtain a first reaction solution;

s3: controlling the reaction temperature, adding an alkali aqueous solution into the first reaction solution, and continuously reacting until the intermediate state is completely converted into pyridine-2-thiol to obtain an alkali solution; the intermediate state is shown as a formula III;

s4: adding acid into the alkaline solution until the solution is slightly acidic to obtain a second reaction solution;

s5: adding an organic solvent into the second reaction solution, stirring and extracting until the product completely enters the organic solvent, namely extracting;

s6: separating liquid, and concentrating an organic phase to be dry to obtain a pyridine-2-thiol crude product;

s7: and adding the crude product into an organic solvent for recrystallization to obtain a pure pyridine-2-thiol product.

Preferably, in S1, the acid aqueous solution is hydrochloric acid, sulfuric acid, methanesulfonic acid or trifluoroacetic acid, and the concentration of the acid aqueous solution is 10 to 50%.

More preferably, the concentration of the hydrochloric acid is 10-35%; the concentration of the sulfuric acid is 25-85%.

Preferably, the molar ratio of the 2-halopyridine to the thiourea and the aqueous acid solution in S2 is 1:1-3: 1-3.

More preferably, the molar ratio of the 2-halopyridine to the thiourea and the aqueous acid solution in S2 is 1:2: 2.

Preferably, the reaction temperature in S2 is 80-120 ℃.

More preferably, the reaction temperature in S2 is 100 ℃.

Preferably, the reaction temperature in S3 is 50-100 ℃.

More preferably, the reaction temperature in S3 is 70 ℃.

Preferably, the alkaline water in S3 is sodium hydroxide or potassium hydroxide solution, the concentration of the alkaline water is 10-100%, and the dosage of the alkaline water is 3-5 equivalent of 2-halogenated pyridine.

More preferably, the concentration of the alkaline water is 40-60%.

Preferably, in S4, the acid is hydrochloric acid, sulfuric acid, methanesulfonic acid or trifluoroacetic acid, wherein the hydrochloric acid is concentrated hydrochloric acid, the sulfuric acid concentration is 25-65%, the methanesulfonic acid and the trifluoroacetic acid are pure products, and the pH of the slightly acidic solution is 3.6-6.5.

More preferably, the pH of the slightly acidic solution is 6.

Preferably, in S5, the organic solvent is one or more of chloroform, dichloromethane, ethyl acetate, isopropyl acetate, toluene, methyl tert-butyl ether, petroleum ether, n-heptane, and n-octane; the organic solvent accounts for 20-50% of the volume of the second reaction solution; the extraction times are 3-5 times.

More preferably, the number of extractions is 4.

Preferably, in S7, the organic solvent is one or more of chloroform, dichloromethane, ethyl acetate, isopropyl acetate, toluene, methyl tert-butyl ether, petroleum ether, n-heptane, and n-octane; the weight ratio of the crude product to the organic solvent is 1:2-5, and the crude product is recrystallized for 1-3 times. The weight ratio of crude product to solvent was the same for each recrystallization.

More preferably, the weight ratio of crude product to organic solvent is 1: 3.5.

More preferably, the number of recrystallization is 2.

In the method scheme of the application:

compared with the prior art, the method has the beneficial effects that:

(1) in thiourea acid aqueous solution, 2-halopyridine is used as a raw material, the 2-halopyridine is completely converted at 80-120 ℃, the reaction temperature is controlled at 50-100 ℃, alkaline aqueous solution is added, the reaction is continued until the intermediate state is completely converted into pyridine-2-thiol, the solution is adjusted to pH 5.5-6.5, then organic solvent is added for extraction, the extraction frequency is 3-5 times, liquid separation is carried out, the organic phase is concentrated to be dry, crude pyridine-2-thiol is obtained, and the crude pyridine-2-thiol is added into the organic solvent for recrystallization to obtain pure pyridine-2-thiol;

(2) the process route of the application is not reported;

(3) the preparation method has the advantages that the temperature is 50-120 ℃, the condition is mild, the materials required by the reaction are easy to obtain, the preparation method is safe and environment-friendly, and the preparation process is simple and easy to implement;

(4) the yield is as high as 85 percent;

(5) the method is green and environment-friendly and is suitable for industrial production.

Drawings

FIG. 1 is a HNMR map of pyridine-2-thiol, DMSO-6, a solvent, according to example 3 of the present invention.

Detailed Description

In order that those skilled in the art will better understand the method embodiments of the present invention, the present invention will be further described in detail with reference to the following specific examples.