Method for preparing dihalogenated pyridine

Abstract

The invention belongs to the technical field of fine chemical engineering, and particularly relates to a method for preparing dihalogenated pyridine shown in a formula (I). According to the preparation method, hydrochloride or hydrobromide of a compound shown in the formula (II) is subjected to diazotization and Sandmeyer reaction in a nitroso sulfuric acid solution at the same time to be converted into corresponding dihalogenated pyridine. According to the method, a copper catalyst with high chemical stability is used for replacing sulfamic acid with strong corrosivity, a palladium catalyst with high price and an iron catalyst with poor stability, and meanwhile, nitroso sulfuric acid which is low in price and easy to obtain is used for replacing a nitrite solution with high danger. The method is mild in reaction condition, simple and convenient to operate, few in by-products and suitable for industrial production, and the purity of a reaction post-treatment product reaches up to 99% or above. # imgabs0 #

Description

Technical Field

[0001] The invention relates to the technical field of fine chemicals, and in particular to a method for preparing dihalopyridine. Background Art

[0002] Dihalopyridine is an organic compound with high efficiency, stability, strong sensitization and unique chemical properties. It is widely used in the fields of medicine, pesticides and daily chemicals, and is often used as a synthetic organic intermediate and liquid crystal polymer. This type of compound is an important raw material for preparing compounds such as chlorfenapyr, α-carboline, and pyrazolopyridone derivatives; in addition, dihalopyridines can also undergo polymerization reactions and are widely used in polymer materials, composite materials, and organic electronic materials. It has a large market demand and high economic benefits.

[0003] There are many existing methods for synthesizing dihalopyridine, such as direct chlorination, alkyl halogenation, and reaction under specific conditions by specific chemical reagents. Among these reactions, the Sandmeyer reaction often requires the use of highly corrosive aminosulfonic acid (e.g., WO2009114589), expensive palladium catalysts (e.g., CN105418492A), or poorly stable iron catalysts (e.g., WO2013181592) to complete. Patent CN101959862A describes a method for synthesizing 2,3-dichloropyridine by adding nitrite to an inorganic solvent system. The method uses a nitrite solution that is easily oxidized, and the use of nitrite increases the safety risk, and it is very easy to synthesize carcinogenic nitrosamine compounds during its subsequent treatment. Summary of the invention

[0004] In view of this, the purpose of the present invention is to provide a new method for preparing dihalopyridine. The method uses cheap, easily available, safe and reliable nitrosylsulfuric acid as a diazotization reagent, uses a catalyst in a hydrochloride solution or a hydrobromide solution of a corresponding monohalopyridineamine, and simultaneously undergoes diazotization and Sandmeyer reaction, directly converting the hydrochloride or hydrobromide of a monohalopyridineamine into the corresponding dihalopyridine.

[0005] In the present invention, the hydrochloride or hydrobromide of a halogenated pyridinamine is prepared by directly reacting the halogenated pyridinamine in hydrogen chloride gas or hydrogen bromide gas, or reacting the halogenated pyridinamine with a hydrochloric acid aqueous solution or a hydrobromic acid aqueous solution, and a catalyst is added during the reaction, which significantly accelerates the reaction process and reduces impurities generated due to the hydrolysis of the diazonium salt. The method not only uses cheap, easily available, safe and reliable nitrosylsulfuric acid as a diazotization reagent, but also has a high yield and purity of the prepared product.

[0006] The present invention is achieved through the following technical solutions:

[0007] A method for preparing dihalopyridine represented by formula (I)

[0008]

[0009] in

[0010] X1 and X2 are each independently chlorine or bromine;

[0011] R1, R2 and R3 are each independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C6 haloalkenyl, C1-C6 alkylamino, C2-C6 alkenylamino, hydroxyl, cyano, carboxyl, nitro, amino.

[0012] It is characterized in that the hydrochloride or hydrobromide of the compound of formula (II) wherein R1, R2 and R3 are each as defined above,

[0013]

[0014] In the presence of a copper catalyst, it reacts with nitrosylsulfuric acid to convert into the corresponding dihalopyridine.

[0015] Furthermore, R1, R2 and R3 are each independently hydrogen, methyl, ethyl, n-propyl, butyl and isobutyl.

[0016] Further, R1, R2 and R3 are hydrogen.

[0017] The concentration of the hydrochloric acid aqueous solution or the hydrobromic acid aqueous solution is 8%-48%, and the preferred concentration is 18%-48%.

[0018] The molar ratio of the hydrochloride or hydrobromide of the monohalogenated pyridinamine of formula (II) to nitrosylsulfuric acid is 1:0.6-3.0, preferably 1:0.9-1.3.

[0019] The copper catalyst is cuprous oxide, cuprous chloride, cuprous bromide, cupric oxide, cupric chloride, cupric bromide, and cupric hydroxide, preferably cuprous oxide.

[0020] The molar ratio of the hydrochloride or hydrobromide of the monohalogenated pyridinamine of formula (II) to the catalyst is 1:0.001-1, preferably 1:0.01-0.2.

[0021] The hydrochloride or hydrobromide of the monohalogenated pyridinamine of formula (II) is prepared by directly reacting the monohalogenated pyridinamine of formula (II) in hydrogen chloride gas or hydrogen bromide gas, or by reacting it with hydrochloric acid or hydrobromic acid aqueous solution.

[0022] The method for preparing the dihalopyridine represented by formula (I) is characterized in that the reaction temperature is 0-100°C, preferably 20-60°C.

[0023] Beneficial technical effects:

[0024] The method provided by the invention uses cheap and readily available nitrosylsulfuric acid to replace a highly toxic nitrite solution. Under the catalytic action of cuprous oxide, diazotization and Sandmeyer reaction are carried out simultaneously, and no diazonium salt is accumulated, so the process is safer. The byproduct aromatic phenol can be removed by conventional alkali washing in the post-treatment, and the operation is simple and suitable for industrial production. DETAILED DESCRIPTION

[0025] A method for preparing dihalopyridine according to the present invention (hereinafter referred to as "the method of the present invention") is described in detail below.

[0026] Example 1

[0027] 158g hydrochloric acid solution was added to a 500mL four-necked flask equipped with a condenser and a thermometer, and 27g of 2-bromo-3-aminopyridine was added in batches, and stirred. During the addition process, 2-bromo-3-aminopyridine rapidly generated pyridinamine hydrochloride, followed by 5g of cuprous oxide. The temperature in the reaction flask was lowered to 30-40°C, and 70g of nitrosylsulfuric acid with a specification of 42% was dripped into a constant pressure dropping funnel. It was dripped in about 2-4 hours, and the temperature during the dripping process was controlled at 35-40°C. After dripping, the reaction was continued at this temperature for 20 minutes. After the reaction was completed, the pH was adjusted to neutral with liquid caustic soda, and steam distillation was performed to obtain 27.2g of 2-bromo-3-chloropyridine as white crystals, and the liquid content was 92.3%.

[0028] Example 2

[0029] Add 200g hydrochloric acid solution to a 500mL four-necked flask equipped with a condenser and a thermometer, add 38g of 2-chloro-3-aminopyridine in batches, stir, during the addition process, 2-chloro-3-aminopyridine quickly generates pyridinamine hydrochloride, reduce the temperature in the reaction bottle to 30-40°C, and then add 6g of cuprous oxide. Drip 90g of nitrosylsulfuric acid with a specification of 42%, drip it in about 2-4 hours, control the temperature during the dripping process at 35-40°C, and continue to react at this temperature for 20 minutes. After the reaction is completed, adjust the pH to neutral with liquid alkali, steam distill, and obtain 35.9g of white crystal 2,3-dichloropyridine, with a liquid content of 89.1%.

[0030] Example 3

[0031] Add 158g of hydrochloric acid solution to a 500mL four-necked flask equipped with a condenser and a thermometer, add 36g of 2-chloro-3-aminopyridine in batches, stir, during the addition process, 2-chloro-3-aminopyridine quickly generates pyridinamine hydrochloride, adjust the temperature in the reaction bottle to 40-50°C, and then add 5g of cuprous oxide. Add 70g of nitrosylsulfuric acid with a specification of 42% dropwise, and add it dropwise in about 2-4 hours. The temperature during the addition process is controlled at 45-50°C. After the dropwise addition is completed, continue to react at this temperature for 20 minutes. After the reaction is completed, adjust the pH to neutral with liquid caustic soda, and steam distill to obtain 35.7g of white crystal 2,3-dichloropyridine with a liquid content of 87.7%.

[0032] Example 4

[0033] Add 255g of hydrobromic acid aqueous solution to a 500mL four-necked flask equipped with a condenser and a thermometer, add 45g of 2-bromo-3-aminopyridine in batches, stir, during the addition process, 2-bromo-3-aminopyridine quickly generates pyridinamine hydrochloride, adjust the temperature in the reaction bottle to 40-50°C, then add 6.5g of cuprous oxide, drop into 95g of nitrosylsulfuric acid with a specification of 42%, add dropwise, add dropwise in about 2-4 hours, control the temperature during the addition process at 45-50°C, and continue to react at this temperature for 20 minutes. After the reaction is completed, adjust the pH to neutral with liquid caustic soda, steam distill, and obtain 52.6g of 2,3-dibromopyridine as white crystals with a liquid content of 93.5%.

[0034] Example 5

[0035] 54.1g of 2-chloro-3-aminopyridine was added to a 500mL four-necked flask equipped with a condenser and a thermometer, stirred, and at room temperature, 18g of HCl gas was introduced, and the process was passed, and 2-chloro-3-aminopyridine rapidly generated 2-chloro-3-aminopyridineamine hydrochloride, and the temperature in the reaction flask was raised to 30-40°C, 9g of cuprous oxide was added, and 139.8g of specification was dripped into a constant pressure dropping funnel and 42% nitrosylsulfuric acid was added, and the addition was completed in about 2-4 hours, and the temperature of the dripping process was controlled at 45-50°C, and the dripping was completed, and the reaction was continued at this temperature for 20 minutes. After the reaction was completed, the pH was adjusted to neutral with liquid caustic soda, and steam distillation was performed to obtain 55.4g of 2,3-dichloropyridine as white crystals, and the liquid content was 94.2%.

[0036] Example 6

[0037] 2-bromo-3-aminopyridine 45g was added to a 500mL four-necked flask equipped with a condenser and a thermometer, stirred, and 32.8g HBr gas was introduced at room temperature. During the introduction, 2-bromo-3-aminopyridine rapidly generated 2-bromo-3-aminopyridine amine hydrobromide, and the temperature in the reaction flask was raised to 30-40°C. 6.5g cuprous oxide was added, and 105g of specifications were dripped into a constant pressure dropping funnel, and 42% nitrosylsulfuric acid was added. The addition process was temperature-controlled at 45-50°C, and the reaction was continued at this temperature for 20 minutes. After the reaction was completed, the pH was adjusted to neutral with liquid caustic soda, and steam distillation was performed to obtain 52.3g of 2,3-dibromopyridine as white crystals, and the liquid content was 92.2%.

[0038] Comparative Example 1

[0039] 158g hydrochloric acid solution was added to a 500mL four-necked flask equipped with a condenser and a thermometer, and 27g of 2-chloro-3-aminopyridine was added in batches, and stirred. During the addition process, 2-chloro-3-aminopyridine quickly generated pyridinamine hydrochloride, and 70g of 42% nitrosylsulfuric acid was dripped into the constant pressure dropping funnel. The addition was completed in about 2-4 hours, and the temperature was controlled at 30-45°C during the dripping process. After the dripping was completed, the reaction was continued at this temperature for 20 minutes. After the reaction was completed, the pH was adjusted to neutral with liquid caustic soda, and steam distillation was performed to obtain 16.3g of white crystal 2,3-dichloropyridine, and the liquid phase content was 58.3%.

[0040] Comparative Example 2

[0041] 158g hydrochloric acid solution was added to a 500mL four-necked flask equipped with a condenser and a thermometer, 27g of 2-chloro-3-aminopyridine was added in batches, and stirred. During the addition process, 2-chloro-3-aminopyridine rapidly generated pyridinamine hydrochloride, and the temperature in the reaction bottle was raised to 30-40°C, and 5.28g of aminosulfonic acid was added. 70g of nitrosylsulfuric acid with a constant pressure dropping funnel was dripped in, and the addition was completed in about 2-4 hours. The temperature of the dripping process was controlled at 35-40°C, and the dripping was completed. The reaction was continued at this temperature for 20 minutes. After the reaction was completed, the pH was adjusted to neutral with liquid caustic soda, and steam distillation was performed to obtain 20.1g of 2,3-dichloropyridine as white crystals, and the liquid content was 75.4%.

Claims

1. A method for preparing a dihalopyridine represented by formula (I), wherein X1 and X2 are each independently chlorine or bromine; R1, R2 and R3 are each independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C6 haloalkenyl, C1-C6 alkylamino, C2-C6 alkenylamino, hydroxyl, cyano, carboxyl, nitro, amino; It is characterized in that wherein R1, R2 and R3 are each as defined above, the hydrochloride or hydrobromide of a compound of formula (II), In the presence of a copper catalyst, it reacts with a diazotizing agent in the hydrochloride or hydrobromide of the pyridinamine of formula (II) to convert it into the corresponding dihalopyridine.

2. The method for preparing a dihalopyridine represented by formula (I) according to claim 1, characterized in that: R1, R2 and R3 are each independently hydrogen, methyl, ethyl, n-propyl, butyl and isobutyl.

3. The method for preparing a dihalopyridine represented by formula (I) according to claim 1, characterized in that: R1, R2 and R3 are hydrogen.

4. The method for preparing a dihalopyridine represented by formula (I) according to claim 1, characterized in that: The copper catalyst is cuprous oxide, cuprous bromide, cuprous chloride, cuprous iodide, cupric oxide, cupric chloride, cupric bromide, or cupric hydroxide. The molar ratio of the hydrochloride or hydrobromide of the pyridinamine of formula (II) to the copper catalyst is 1:0.001-1.

5. The method for preparing a dihalopyridine represented by formula (I) according to claim 1, characterized in that: The diazotizing agent is nitrosylsulfuric acid.

6. The method for preparing a dihalopyridine represented by formula (I) according to claim 1, characterized in that: The molar ratio of the hydrochloride or hydrobromide of the pyridinamine of formula (II) to nitrosylsulfuric acid is 1:0.6-3.

0.

7. The method for preparing a dihalopyridine represented by formula (I) according to claim 1, characterized in that: The hydrochloride or hydrobromide of the pyridinamine of formula (II) is prepared by directly reacting the pyridinamine of formula (II) in hydrogen chloride gas or hydrogen bromide gas, or by reacting it in a hydrochloric acid aqueous solution or a hydrobromic acid aqueous solution.

8. The method for preparing a dihalopyridine represented by formula (I) according to claim 1, characterized in that: The reaction temperature is 0-100°C.

9. The method for preparing a dihalopyridine represented by formula (I) according to claim 7, characterized in that: The concentration of the aqueous hydrochloric acid solution is 18%-38% and the concentration of the hydrobromic acid is 28%-48%.

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