1. A method for purifying 2-bromo-4-chloropyridine is characterized by comprising the following steps:

adding the 2-bromo-4-chloropyridine crude product into a first organic solvent, adding excessive sulfuric acid, fully reacting, and filtering to obtain a first filtrate;

washing the first filtrate in a second organic solvent, and filtering to obtain a second filtrate;

and adding the second filtrate into a third organic solvent, adding an excessive alkaline aqueous solution, fully reacting, separating liquid, and retaining an organic phase to obtain a 2-bromo-4-chloropyridine solution.

2. The method for purifying 2-bromo-4-chloropyridine according to claim 1, wherein the first organic solvent is one of an ester solvent, an alcohol solvent, a halogenated hydrocarbon solvent, a ketone solvent, an ether solvent, or a combination of at least two thereof.

3. The method for purifying 2-bromo-4-chloropyridine according to claim 2, wherein the first solvent is one of ethyl acetate, propyl acetate, acetone, butanone, dioxane, 2-methyl-tetrahydrofuran, dichloromethane, chlorobenzene, ethylene glycol dimethyl ether, methanol, ethanol, n-propanol, and isopropanol, or a combination of at least two of them.

4. The method of claim 3, wherein the first solvent is one or a combination of ethanol and acetone.

5. The method for purifying 2-bromo-4-chloropyridine according to claim 1, wherein the second solvent is one of ethyl acetate, propyl acetate, butanone, dioxane, 2-methyl-tetrahydrofuran, dichloromethane, chlorobenzene, ethylene glycol dimethyl ether, n-propanol, isopropanol, or a combination of at least two thereof.

6. The method according to claim 1, wherein the third solvent is an ethereal solvent having a solubility in water of not more than 51g/L at 20 ℃.

7. The method of claim 6, wherein the third solvent is isopropyl ether, methyl tert-butyl ether, or a combination thereof.

8. The process of claim 1, wherein the concentration of sulfuric acid is 98%.

9. A process for the purification of 2-bromo-4-chloropyridine according to claims 1 to 8 comprising the steps of:

adding the 2-bromo-4-chloropyridine crude product into a first organic solvent, adding excessive sulfuric acid, fully reacting, and filtering to obtain a first filtrate;

washing the first filtrate in a second organic solvent, and filtering to obtain a second filtrate;

adding the second filtrate into a third organic solvent, adding an excessive alkaline aqueous solution, fully reacting, separating liquid, and retaining an organic phase to obtain a 2-bromo-4-chloropyridine solution;

drying the obtained 2-bromo-4-chloropyridine solution, evaporating the solvent, and concentrating to obtain a refined 2-bromo-4-chloropyridine product.

Background

2-bromo-4-chloropyridine is an important medical intermediate. The 2-bromine has higher reactivity than 4-chlorine, and the 2-bromine can be subjected to functional group conversion, carbon-carbon bond coupling reaction or heteroatom substitution reaction, and then the 4-chlorine is utilized for other conversion, so that molecules with complex structures are constructed.

The synthesis of 2-bromo-4-chloropyridine is reported less: chopin Sabine reports in 2001 that 4-chloropyridine is adopted to generate negative ions under the action of butyl lithium, and the negative ions and carbon tetrabromide undergo substitution reaction to obtain 2-bromo-4-chloropyridine. The reaction selectivity is poor, column chromatography is required for purification, the efficiency is low, and the method is not suitable for industrial preparation; baishizibao company adopts 2-amido-4-chloropyridine (formula I) to generate diazonium salt in situ in 2003, and then adopts a bromination method to successfully obtain 2-bromo-4-chloropyridine (formula II), so that the problem of selectivity is solved, but column chromatography is still needed for purification; in 2008, the renitridation reaction was improved by the company schbeckmann, and the yield was greatly improved, but column chromatography was still required for purification.

In order to achieve the above purpose, the embodiment of the invention adopts the following technical scheme: diazotizing and brominating 2-amido-4-chloropyridine, wherein the main byproduct is dibromide (formula III), the Rf values of the dibromide and the dibromide are relatively close, the column chromatography has certain separation degree, but the product with the purity of more than 93 percent can be obtained by multiple column chromatography. The technical bottleneck that needs to be broken through at present: and the method avoids inefficient column chromatography, and finds a simple, convenient and feasible industrialized purification method for purifying the product.

Disclosure of Invention

In view of the defects, the invention provides a purification method of 2-bromo-4-chloropyridine, which can achieve the effects of simplicity, feasibility and industrialization.

In order to achieve the above purpose, the embodiment of the invention adopts the following technical scheme:

a method for purifying 2-bromo-4-chloropyridine comprises the following steps:

adding the 2-bromo-4-chloropyridine crude product into a first organic solvent, adding excessive sulfuric acid, fully reacting, and filtering to obtain a first filtrate;

washing the first filtrate in a second organic solvent, and filtering to obtain a second filtrate;

and adding the second filtrate into a third organic solvent, adding an excessive alkaline aqueous solution, fully reacting, and extracting and separating to obtain a 2-bromo-4-chloropyridine solution.

According to an aspect of the present invention, the first organic solvent is any one of an ester solvent, an alcohol solvent, a halogenated hydrocarbon solvent, a ketone solvent, an ether solvent, or a combination of at least two thereof.

According to an aspect of the present invention, the first solvent is any one of ethyl acetate, propyl acetate, acetone, methyl ethyl ketone, dioxane, 2-methyl-tetrahydrofuran, dichloromethane, chlorobenzene, ethylene glycol dimethyl ether, methanol, ethanol, n-propanol, isopropanol, or a combination of at least two thereof.

According to one aspect of the present invention, the first solvent used is one of ethanol, acetone, or a combination of both.

According to an aspect of the present invention, the second solvent is any one of ethyl acetate, propyl acetate, butanone, dioxane, 2-methyl-tetrahydrofuran, dichloromethane, chlorobenzene, ethylene glycol dimethyl ether, n-propanol, isopropanol, or a combination of at least two thereof.

According to one aspect of the present invention, the third solvent is an ether-based solvent having a solubility in water of not more than 51g/L at 20 ℃.

According to one aspect of the invention, the third solvent is any one of isopropyl ether, methyl tert-butyl ether, or a combination of the two.

According to one aspect of the invention, the concentration of sulfuric acid is 98%.

In accordance with one aspect of the present invention, a process for the purification of 2-bromo-4-chloropyridine comprises the steps of:

adding the 2-bromo-4-chloropyridine crude product into a first organic solvent, adding excessive sulfuric acid, fully reacting, and filtering to obtain a first filtrate;

washing the first filtrate in a second organic solvent, and filtering to obtain a second filtrate;

adding the second filtrate into a third organic solvent, adding an excessive alkaline aqueous solution, fully reacting, separating liquid, and retaining an organic phase to obtain a 2-bromo-4-chloropyridine solution;

drying the obtained 2-bromo-4-chloropyridine solution with anhydrous sodium sulfate, drying, evaporating the solvent, and concentrating to obtain refined 2-bromo-4-chloropyridine product.

The chemical reactions and reaction formulas involved in the above process are as follows:

(1) adding a 2-bromo-4-chloropyridine (formula II) crude product into a first solvent, adding concentrated sulfuric acid at low temperature, and salifying the 2-bromo-4-chloropyridine with sulfuric acid, wherein impurities do not participate in salifying, and the reaction equation is as follows:

(2) after the sulfate (formula IV) is pulped by a second solvent and impurities are washed away, alkaline water is added for dissociation, and the high-purity 2-bromo-4-chloropyridine (formula II) is obtained, wherein the reaction equation is as follows:

the implementation of the invention has the advantages that: adding a 2-bromo-4-chloropyridine crude product and sulfuric acid into a first solvent to form 2-bromo-4-chloropyridine sulfate which is insoluble in the first solvent; pulping, washing and filtering the 2-bromo-4-chloropyridine sulfate by using a second solvent; adding the filtrate into a third solvent, adding alkali liquor to neutralize sulfuric acid, extracting 2-bromo-4-chloropyridine, and separating liquid to obtain a high-purity 2-bromo-4-chloropyridine solution, wherein the whole process only involves operations such as stirring, pulping, extracting and the like, and the method is simple, convenient and feasible and is suitable for industrial production.

Drawings

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

FIG. 1 is an HPLC chromatogram of the crude 2-bromo-4-chloropyridine prepared in example 1;

FIG. 2 is an HPLC chromatogram of a purified 2-bromo-4-chloropyridine product prepared in example 2;

FIG. 3 is an HPLC chromatogram of a purified 2-bromo-4-chloropyridine product prepared in example 3;

FIG. 4 is an HPLC chromatogram of the purified 2-bromo-4-chloropyridine prepared in example 9.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Example 1

An aqueous HBr solution (concentration: 48%, 300 ml) was charged into a 1L three-necked flask, and 2-amino-4-chloropyridine (128 g) was added dropwise thereto at a system temperature of 10 ℃; reducing the temperature, keeping the system temperature at 0 ℃, dropwise adding liquid bromine (400 g), slowly dropwise adding NaNO2 aqueous solution at 0 ℃ after dropwise adding, stirring for 2h at 0 ℃ after dropwise adding, dropwise adding 35% sodium hydroxide aqueous solution at 0 ℃ to adjust the pH to 9-10, filtering, extracting and separating MTBE twice, combining organic phases, washing the organic phases with water once, washing with saturated salt solution once, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product of 2-bromo-4-chloropyridine.

The obtained crude 2-bromo-4-chloropyridine product is light yellow oil with the mass of 88.6g and the HPLC purity of 72.4 percent, and the HPLC chromatogram is shown in figure 1.

Example 2

A50 mL three-necked flask was charged with the crude 2-bromo-4-chloropyridine (5.6g, purity 72.4%) prepared in example 1, followed by addition of a first solvent acetone (14 mL), stirring, cooling to 5 deg.C, dropwise addition of concentrated sulfuric acid (1.2mL, concentration: 98%), and heat preservation at 5 deg.C for 1 hour.

It should be noted that, in the present step, the sulfuric acid mainly forms a salt with 2-bromo-4-chloropyridine and precipitates out, so that the use amount of the sulfuric acid is excessive; however, in practical application, 98% concentrated sulfuric acid is generally preferred, because 98% concentrated sulfuric acid is a mature industrial product and raw materials are easily available; under the condition of achieving the same salifying effect, the higher the concentration of the sulfuric acid is, the smaller the volume of the required sulfuric acid is naturally, the smaller the volume of the solution in the reaction system is, and the operation is more convenient. In other embodiments, sulfuric acid with any concentration can be selected according to actual conditions, and the implementation of the invention is not affected.

Followed by filtration to give a cake of sulfate salt whose main component is 2-bromo-4-chloropyridine. Pulping the obtained filter cake for 1 hour at 5 ℃ in a second solvent of ethyl acetate (10 ml), filtering, removing the filtrate, reserving the filtrate, adding the obtained filtrate into a third solvent of isopropyl ether (5 ml), adding an aqueous solution of sodium hydroxide for neutralizing until the pH value is 8, separating the solution and reserving an organic phase to obtain the 2-bromo-4-chloropyridine solution.

After pulping and impurity washing, adding alkali to neutralize hydrogen ions in sulfate of 2-bromo-4-chloropyridine to generate 2-bromo-4-chloropyridine. The alkali added is preferably sodium hydroxide generally, because sodium hydroxide is a mature industrial product and the raw materials are easily available and cheap. The principle of action of the base will be such that it will neutralize hydrogen ions, will not react with 2-bromo-4-chloropyridine, will not react with an organic phase, and will not dissolve in an organic phase, and can be used in the practice of the present invention. For example, in other embodiments, ammonia, sodium carbonate, etc. may be used as the base, without affecting the practice of the present invention. The amount of base is preferably such that the system has a pH of 8. In principle, the alkali is excessive, the sulfate of the 2-bromo-4-chloropyridine completely reacts when the pH of the system is more than 7, and the implementation of the method is not influenced when the pH of the system reaches 9, 10 or even more, but the alkali is wasted; in actual operation, the PH test has errors, and is often difficult to accurately control, and in order to ensure that the system is alkaline, the dosage of the alkali is preferably the dosage which enables the system PH to be 8, so that even if the measurement error exists, the actual PH of the system can be ensured to be more than 7, and the waste of the alkali is reduced as much as possible.

The reaction temperature in this example was controlled at 5 ℃ to explore the effect of specific factors on the overall purification process and to make strict reaction condition control; when the method is implemented, the temperature does not need to be kept unchanged in the whole reaction process, and the reaction can be carried out naturally. The preferred implementation temperature of the invention is 0-50 ℃, if the temperature is higher than 50 ℃, the risk of bumping can be caused by adding concentrated sulfuric acid; however, this does not mean that the invention cannot be carried out above 50 ℃ and that the invention can be carried out at temperatures of from 0 to 100 ℃ as long as the safety measures are adequate.

In the present invention, the first organic solvent has a central role in precipitating the sulfate salt of 2-bromo-4-chloropyridine, and therefore, any one of an ester solvent, an alcohol solvent, a halogenated hydrocarbon solvent, a ketone solvent, and an ether solvent, or a combination of at least two thereof may be used as the first organic solvent, and the above requirements can be satisfied. The first organic solvent has the secondary function of dissolving the 2-bromo-4-chloropyridine in the crude 2-bromo-4-chloropyridine product, and the contact between the 2-bromo-4-chloropyridine dispersed in the solvent and sulfuric acid molecules is increased, so that the reaction rate can be increased. Therefore, in the present invention, the first organic solvent is preferably any one of ethyl acetate, propyl acetate, acetone, methyl ethyl ketone, dioxane, 2-methyl-tetrahydrofuran, dichloromethane, chlorobenzene, ethylene glycol dimethyl ether, methanol, ethanol, n-propanol, and isopropanol, or a combination of at least two thereof. Ethanol and acetone are common and easily available solvents, and the application effect of the invention is good, so one or the combination of two of ethanol and acetone is a further preferable scheme.

The second organic solvent is used for washing off impurities in the sulfate of the 2-bromo-4-chloropyridine, and when any one or a combination of at least two of ethyl acetate, propyl acetate, butanone, dioxane, 2-methyl-tetrahydrofuran, dichloromethane, chlorobenzene, ethylene glycol dimethyl ether, n-propanol and isopropanol is observed as the second organic solvent in practical experiments, the yield and the purity of the obtained 2-bromo-4-chloropyridine are high, so the second organic solvent is a preferable scheme.

The third organic solvent is selected mainly in consideration that the dissolving capacity of the third organic solvent to the 2-bromo-4-chloropyridine is far higher than that of water to the 2-bromo-4-chloropyridine, and meanwhile, the third organic solvent has low solubility in water to ensure higher yield. In practical experiments, the ether solvent can better meet the requirements, the ether is stable in alkali, and the implementation of the invention is not influenced even if more alkali is added during operation; among ether solvents, methyl t-butyl ether and isopropyl ether show the best performance. The solubility of methyl tert-butyl ether in water reaches 51g/L (20 ℃), which is at a high level in etheric solvents. However, the methyl tert-butyl ether has good effect even if the solubility of the methyl tert-butyl ether in water is higher due to the excellent dissolving capacity of the methyl tert-butyl ether to the 2-bromo-4-chloropyridine. Since the ether solvent has a good dissolving power for 2-bromo-4-chloropyridine, an ether solvent having a solubility in water of not more than 51g/L at 20 ℃ may be used as a preferred embodiment of the present invention.

The obtained 2-bromo-4-chloropyridine solution was dried over anhydrous sodium sulfate, and the solvent was evaporated and concentrated to give a purified 2-bromo-4-chloropyridine product (3.6 g, colorless oily substance, HPLC purity 99.2%, HPLC chromatogram shown in fig. 2.

Example 3

A50 mL three-necked flask was charged with the crude 2-bromo-4-chloropyridine (5.6g, purity 72.4%) prepared in example 1, followed by addition of ethanol (14 mL) as a solvent, stirring, cooling to 5 deg.C, dropwise addition of concentrated sulfuric acid (1.2mL, concentration: 98%), heat preservation at 5 deg.C for 1 hour, and filtration to obtain a cake containing 2-bromo-4-chloropyridine as a main component as a sulfate salt. Pulping the filter cake in ethyl acetate (10 ml) at 5 ℃ for 1 hour, filtering, discarding the filtrate to retain the filtrate, adding the obtained filtrate into isopropyl ether (5 ml), adding sodium hydroxide aqueous solution to neutralize until the pH value is 8, separating the solution and retaining the organic phase to obtain the 2-bromo-4-chloropyridine solution.

The obtained 2-bromo-4-chloropyridine solution was dried over anhydrous sodium sulfate, and the solvent was evaporated and concentrated to give a purified 2-bromo-4-chloropyridine product (2.8 g, colorless oily substance, HPLC purity 96.9%) having an HPLC chromatogram shown in fig. 3.

Example 4

A50 mL three-necked flask was charged with the crude 2-bromo-4-chloropyridine (5.6g, purity 72.4%) prepared in example 1, followed by addition of acetone (14 mL) as a solvent, stirring, cooling to 5 ℃ and dropwise addition of concentrated sulfuric acid (1.2mL, concentration: 98%), heat preservation at 5 ℃ for 1 hour, and filtration to obtain a cake containing 2-bromo-4-chloropyridine as a main component as a sulfate salt. Pulping the obtained filter cake in ethyl acetate (10 ml) at 5 ℃ for 1 hour, filtering, discarding the filtrate to retain the filtrate, adding the obtained filtrate into isopropyl ether (5 ml), adding sodium hydroxide aqueous solution to neutralize until the pH value is 8, separating the solution and retaining the organic phase to obtain the 2-bromo-4-chloropyridine solution. The resulting 2-bromo-4-chloropyridine solution was dried over anhydrous sodium sulfate, and the solvent was evaporated and concentrated to give a refined 2-bromo-4-chloropyridine product (3.3 g, colorless oily substance, HPLC purity 98.1%)

Example 5

A50 mL three-necked flask was charged with the crude 2-bromo-4-chloropyridine (5.6g, purity 72.4%) prepared in example 1, followed by addition of acetone (14 mL) as a solvent, stirring, heating to 25 deg.C, dropwise addition of concentrated sulfuric acid (1.2mL, concentration: 98%), heat preservation at 25 deg.C for 1 hour, and filtration to obtain a cake containing 2-bromo-4-chloropyridine as a main component as a sulfate salt. The obtained filter cake is pulped for 1 hour at the temperature of 5 ℃ in ethyl acetate (10 ml), filtered, filtrate is discarded, filter mass is reserved, the obtained filter mass is suspended in methyl tert-butyl ether (5 ml), sodium hydroxide aqueous solution is added for neutralization till the pH value is 8, and liquid separation is carried out to reserve an organic phase, so that 2-bromine-4-chloropyridine solution is obtained. The resulting 2-bromo-4-chloropyridine solution was dried over anhydrous sodium sulfate, and the solvent was evaporated and concentrated to give a purified 2-bromo-4-chloropyridine product (2.2 g, colorless oily substance, HPLC purity 97.2%)

Example 6

A50 mL three-necked flask was charged with the crude 2-bromo-4-chloropyridine (5.6g, purity 72.4%) prepared in example 1, followed by addition of acetone (14 mL) as a solvent, stirring, heating to 25 deg.C, dropwise addition of concentrated sulfuric acid (1.5 mL, concentration: 80%), heat preservation at 25 deg.C for 1 hour, and filtration to obtain a cake containing 2-bromo-4-chloropyridine as a main component as a sulfate salt. The obtained filter cake is pulped for 1 hour at the temperature of 5 ℃ in ethyl acetate (10 ml), filtered, filtrate is discarded, filter mass is reserved, the obtained filter mass is suspended in methyl tert-butyl ether (5 ml), sodium hydroxide aqueous solution is added for neutralization till the pH value is 8, and liquid separation is carried out to reserve an organic phase, so that 2-bromine-4-chloropyridine solution is obtained. The resulting 2-bromo-4-chloropyridine solution was dried over anhydrous sodium sulfate, and the solvent was evaporated and concentrated to give a purified 2-bromo-4-chloropyridine product (1.9 g, colorless oily substance, HPLC purity 97.3%)

Example 7

A50 mL three-necked flask was charged with the crude 2-bromo-4-chloropyridine (5.6g, HPLC purity 72.4%) prepared in example 1, dioxane (20mL) was added, and after stirring, sulfuric acid (1.4mL, 90%) was added dropwise at 30 ℃ for 1 hour. Filtering to obtain a filter cake of sulfate with the main component of 2-bromo-4-chloropyridine. Pulping the obtained filter cake with tetrahydrofuran at 30 ℃ for 1 hour, filtering, discarding the filtrate to retain the filtrate, suspending the obtained filtrate in diethyl ether, adding aqueous sodium hydroxide solution to neutralize the filtrate until the pH is 11, separating the liquid to retain an organic phase, drying the organic phase with calcium chloride, evaporating the solvent, and concentrating to obtain a refined 2-bromo-4-chloropyridine product (2.0 g, colorless oily substance, HPLC purity 96.5%)

Example 8

A50 mL three-necked flask was charged with the crude 2-bromo-4-chloropyridine (5.6g, HPLC purity 72.4%) prepared in example 1, followed by addition of dichloromethane (17mL), stirring, temperature-controlled 50 ℃, dropwise addition of sulfuric acid (1.2mL, 98%), and heat-preservation at 50 ℃ for 1 hour. Filtering to obtain a filter cake of sulfate with the main component of 2-bromo-4-chloropyridine. Pulping the obtained filter cake with ethylene glycol dimethyl ether at 50 ℃ for 1 hour, filtering, discarding the filtrate to retain the filtrate, suspending the obtained filtrate in petroleum ether, adding sodium hydroxide aqueous solution to neutralize to pH 9, separating the liquid to retain an organic phase, drying the organic phase with calcium oxide, evaporating the solvent, and concentrating to obtain a refined 2-bromo-4-chloropyridine product (1.5 g, colorless oily substance, HPLC purity 95.9%)

Example 9

The crude 2-bromo-4-chloropyridine (5.6g, HPLC purity 72.4%) prepared in example 1 was subjected to column chromatography to give a refined 2-bromo-4-chloropyridine product having an HPLC purity of 92.8%, and the HPCL chromatogram was shown in fig. 4.

A comparison of the HPLC purities of examples 2-6 and example 9 is given in Table 1.

TABLE 1 sample purity table after purification

Item	Purity before purification	Purity after purification
			Example 2	72.4％	99.1％
Example 3	72.4％	98.1％
			Example 4	72.4％	96.8％
Example 5	72.4％	97.2％
			Example 6	72.4％	97.3％
Example 9	72.4％	92.8％

It can be seen that the purity of the method of the present invention is higher than that of the general column chromatography method. On the basis, the operation steps of the invention only involve mixing, filtering, extracting and separating, and the method is obviously more suitable for industrial application than column chromatography.

The above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention disclosed herein are intended to be covered by the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.