Synthesis method of 4-pyrazolecarboxylic acid

Abstract

The invention belongs to the technical field of 4-pyrazolecarboxylic acid synthesis, and discloses a 4-pyrazolecarboxylic acid synthesis method, which comprises: S1, placing a mixed reaction system comprising 4-chloropyrazole, toluene, an inorganic base, palladium acetate, a ligand and water in a high-pressure reaction kettle, and vacuumizing the high-pressure reaction kettle; replacing with nitrogen for three times, and then replacing with carbon monoxide for two times; the pressure in the high-pressure reaction kettle is controlled to be 1.0 Mpa to 2.0 Mpa, the temperature is controlled to be 50 DEG C to 130 DEG C, and stirring is carried out for a carbonyl insertion reaction for 10 h to 20 h; s2, after the reaction, cooling to room temperature, emptying carbon monoxide, replacing with nitrogen for three times, and filtering; and S3, removing an organic phase in the filtrate, adjusting the pH value of a water phase to 1-4 by using an acid solution, stirring for 2 hours, filtering, recrystallizing a solid phase obtained by filtering by using ethanol / water, and drying to obtain the 4-pyrazolecarboxylic acid. According to the method, raw materials are easy to obtain, reaction conditions and reaction operation are simple, and the method has high application and popularization value.

Description

Technical Field

[0001] This invention belongs to the field of 4-pyrazole carboxylic acid synthesis technology, specifically relating to a method for synthesizing 4-pyrazole carboxylic acid. Background Technology

[0002] 4-Pyrazolic acid is a very important heterocyclic carboxylic acid pharmaceutical intermediate. Due to its molecular structure possessing both a pyrazol ring (a five-membered heterocycle containing two nitrogen atoms, exhibiting abundant biological activity) and a carboxyl group (easily undergoing functional group transformation and forming hydrogen bonds), it is widely used in the synthesis of various biologically active molecules, especially in medicinal chemistry and pesticide chemistry. However, this product suffers from easy decomposition, poor chemical stability, and inconvenient storage, often requiring immediate preparation before use.

[0003] Currently, the main synthetic methods for 4-pyrazolonic acid are as follows:

[0004] (1) Hydrolysis method: 4-pyrazole carboxylate is used as raw material and hydrolyzed under acidic or alkaline conditions to obtain 4-pyrazole carboxylic acid. This method is simple to operate and has a high yield, but the raw materials are expensive and not easy to obtain, so it cannot be applied to large-scale industrial production.

[0005] (2) Hydrazine cyclization hydrolysis method: 4-pyrazole carboxylate ethyl ester can be directly generated by cyclization reaction of ethoxyethynyl carboxylate with hydrazine hydrate, and then 4-pyrazole carboxylic acid can be obtained by hydrolysis. Although the raw materials are readily available, the unstable intermediates need to be purified during the reaction process, and the reaction operation is relatively complicated.

[0006] (3) Oxidation method: The aldehyde group of 4-pyrazole carboxaldehyde is oxidized to a carboxyl group using an oxidizing agent. This method has the disadvantages of harsh reaction conditions, easy destruction of the pyrazole ring, and low yield. Summary of the Invention

[0007] In view of this, in order to solve the problems mentioned in the background art, the object of the present invention is to provide a method for synthesizing 4-pyrazole carboxylic acid.

[0008] To achieve the above objectives, the present invention provides the following technical solution:

[0009] A method for synthesizing 4-pyrazole carboxylic acid, using 4-chloropyrazole and carbon monoxide as raw materials, and obtaining 4-pyrazole carboxylic acid by carbonyl insertion reaction under palladium acetate catalysis; wherein the carbonyl insertion reaction is carried out at a pressure of 1.0 MPa to 2.0 MPa, a temperature of 50℃ to 130℃, and a time of 10 h to 20 h.

[0010] In this invention, the molecular formula of 4-pyrazole carboxylic acid is C4H4N2O2, and its structural formula is:

[0011] .

[0012] The specific synthetic route of this invention is as follows:

[0013] .

[0014] A method for synthesizing 4-pyrazolic acid, comprising the following steps:

[0015] S1. A mixed reaction system comprising 4-chloropyrazole, toluene, inorganic base, palladium acetate, ligand, and water is placed in a high-pressure reactor, and the high-pressure reactor is evacuated; the reactor is first purged with nitrogen three times, and then purged with carbon monoxide twice; the pressure inside the high-pressure reactor is controlled at 1.0 MPa to 2.0 MPa and the temperature at 50°C to 130°C, and the reaction is carried out by stirring for 10 to 20 hours for carbonylation reaction.

[0016] S2. After the reaction, cool to room temperature, remove carbon monoxide, replace with nitrogen three times, and filter.

[0017] S3. Remove the organic phase from the filtrate, adjust the pH of the aqueous phase to 1-4 with an acid solution, stir for 2 hours and then filter. Recrystallize the obtained solid phase with ethanol / water and dry it to obtain 4-pyrazole carboxylic acid.

[0018] Preferably, the molar ratio of 4-chloropyrazole, inorganic base, palladium acetate, and ligand is 1:1 to 5:0.1% to 2%:0.5% to 2.5%.

[0019] Preferably, in step S1, the pressure inside the high-pressure reactor is controlled at 1.5±0.1 MPa and the temperature at 100°C, and the carbonylation reaction is carried out for 20 hours with stirring.

[0020] Preferably, in step S1, the pH of the aqueous phase is adjusted to 3-4 using an acid solution.

[0021] Preferably, the acid solution is a sulfuric acid solution, a hydrochloric acid solution, or a phosphoric acid solution.

[0022] Preferably, the acid solution is a 2 mol / L hydrochloric acid solution.

[0023] Preferably, in step S3, the drying temperature is 40℃~70℃.

[0024] Compared with the prior art, the present invention has the following advantages:

[0025] The method of the present invention uses 4-chloropyrazole and carbon monoxide as raw materials to prepare 4-pyrazole carboxylic acid through a carbonyl insertion reaction. The raw materials are readily available and the reaction conditions and operation are simple, making it highly valuable for widespread application. Detailed Implementation

[0026] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0027] This invention provides a method for synthesizing 4-pyrazolonic acid, using 4-chloropyrazole and carbon monoxide as raw materials, and reacting them via a carbonylation reaction in the presence of toluene, sodium acetate, palladium acetate, triphenylphosphine, and water to obtain 4-pyrazolonic acid; the carbonylation reaction is carried out at a pressure of 1.0 MPa to 2.0 MPa, a temperature of 50°C to 130°C, and a time of 10 to 20 hours. Therefore, the synthetic route of this invention is as follows:

[0028]

[0029] Example 1

[0030] A method for synthesizing 4-pyrazolic acid, comprising the following steps:

[0031] S1. In a 500 mL high-pressure reactor, add 25 g of 4-chloropyrazole (243.9 mmol), 100 mL of toluene, 42 g of sodium acetate (1219 mmol), 0.55 g of palladium acetate (2.45 mmol, 1% mmol), 1.28 g of triphenylphosphine (4.9 mmol), and 50 mL of water; evacuate the high-pressure reactor, purge it three times with nitrogen, and then purge it twice with carbon monoxide; control the pressure inside the high-pressure reactor at 1.4 MPa and the temperature at 100 °C, and stir for 20 h for the carbonylation reaction;

[0032] S2. After the reaction, cool to room temperature, remove carbon monoxide, replace with nitrogen three times, and filter.

[0033] S3. Remove the organic phase from the filtrate, adjust the pH of the aqueous phase to 3-4 with 2 mol / L hydrochloric acid solution, stir for 2 h, filter, recrystallize the obtained solid phase (pale yellow solid) with ethanol / water, and dry at 60 °C to obtain a white solid 4-pyrazolonic acid (21 g). Product yield 77%, HPLC purity 99.2%.

[0034] Example 2

[0035] S1. In a 500 mL high-pressure reactor, add 25 g of 4-chloropyrazole (243.9 mmol), 100 mL of toluene, 51.7 g of sodium carbonate (487.8 mmol), 0.55 g of palladium acetate (2.45 mmol, 1% mmol), 1.28 g of triphenylphosphine (4.9 mmol), and 50 mL of water; evacuate the high-pressure reactor, purge it three times with nitrogen, and then purge it twice with carbon monoxide; control the pressure inside the high-pressure reactor at 1.4 MPa and the temperature at 100 °C, and stir for 20 h for the carbonylation reaction;

[0036] S2. After the reaction, cool to room temperature, remove carbon monoxide, replace with nitrogen three times, and filter.

[0037] S3. Remove the organic phase from the filtrate, adjust the pH of the aqueous phase to 3-4 with 2 mol / L hydrochloric acid solution, stir for 2 h, filter, recrystallize the obtained solid phase (pale yellow solid) with ethanol / water, and dry at 60℃ to obtain 18.5 g of white solid 4-pyrazolonic acid. Product yield 68%, HPLC purity 99.5%.

[0038] Example 3

[0039] S1. In a 500 mL high-pressure reactor, add 25 g of 4-chloropyrazole (243.9 mmol), 100 mL of toluene, 19.5 g of sodium hydroxide (487.8 mmol), 0.55 g of palladium acetate (2.45 mmol, 1% mmol), 1.28 g of triphenylphosphine (4.9 mmol), and 50 mL of water; evacuate the high-pressure reactor, first purging it three times with nitrogen, then purging it twice with carbon monoxide; control the pressure inside the high-pressure reactor at 1.4 MPa and the temperature at 100 °C, and stir for 20 h for the carbonylation reaction.

[0040] S2. After the reaction, cool to room temperature, remove carbon monoxide, replace with nitrogen three times, and filter.

[0041] S3. Remove the organic phase from the filtrate, adjust the pH of the aqueous phase to 3-4 with 2 mol / L hydrochloric acid solution, stir for 2 h, filter, recrystallize the obtained solid phase (pale yellow solid) with ethanol / water, and dry at 60℃ to obtain a white solid 4-pyrazolonic acid (13.6 g). Product yield 50%, HPLC purity 97.3%.

[0042] Example 4

[0043] S1. In a 500 mL high-pressure reactor, add 25 g of 4-chloropyrazole (243.9 mmol), 100 mL of toluene, 42 g of sodium acetate (1219 mmol), 0.55 g of palladium acetate (2.45 mmol, 1% mmol), 1.28 g of triphenylphosphine (4.9 mmol), and 50 mL of water; evacuate the high-pressure reactor, first purging it three times with nitrogen, then purging it twice with carbon monoxide; control the pressure inside the high-pressure reactor at 1.4 MPa and the temperature at 150 °C, and stir for 20 h for the carbonylation reaction;

[0044] S2. After the reaction, cool to room temperature, remove carbon monoxide, replace with nitrogen three times, and filter.

[0045] S3. Remove the organic phase from the filtrate, adjust the pH of the aqueous phase to 3-4 with 2 mol / L hydrochloric acid solution, stir for 2 h, filter, recrystallize the obtained solid phase (pale yellow solid) with ethanol / water, and dry at 60 °C to obtain a white solid 4-pyrazolonic acid (19.4 g). Product yield 71%, HPLC purity 99.3%.

[0046] In the description of this invention, the references to terms such as "one embodiment," "some embodiments," "illustrative embodiment," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0047] Note that the above description is merely a preferred embodiment of the present invention and the technical principles employed. Those skilled in the art will understand that the present invention is not limited to the specific embodiments described herein, and various obvious changes, readjustments, and substitutions can be made without departing from the scope of protection of the present invention. Therefore, although the present invention has been described in detail through the above embodiments, the present invention is not limited to the above embodiments, and may include many other equivalent embodiments without departing from the concept of the present invention, the scope of which is determined by the scope of the appended claims.

Claims

1. A method for synthesizing 4-pyrazolic acid, characterized in that: 4-Pyrazole carboxylic acid was prepared by carbonylation reaction using 4-chloropyrazole and carbon monoxide as raw materials in the presence of toluene, inorganic base, palladium acetate, ligand and water; the carbonylation reaction was carried out at a pressure of 1.0 MPa to 2.0 MPa, a temperature of 50℃ to 130℃ and a time of 10h to 20h.

2. The method for synthesizing 4-pyrazolonic acid according to claim 1, characterized in that, Includes the following steps: S1. A mixed reaction system comprising 4-chloropyrazole, toluene, inorganic base, palladium acetate, ligand, and water is placed in a high-pressure reactor, and the high-pressure reactor is evacuated; the reactor is first purged with nitrogen three times, and then purged with carbon monoxide twice; the pressure inside the high-pressure reactor is controlled at 1.0 MPa to 2.0 MPa and the temperature at 50°C to 130°C, and the reaction is carried out by stirring for 10 to 20 hours for carbonylation reaction. S2. After the reaction, cool to room temperature, remove carbon monoxide, replace with nitrogen three times, and filter. S3. Remove the organic phase from the filtrate, adjust the pH of the aqueous phase to 1-4 with an acid solution, stir for 2 hours and then filter. Recrystallize the obtained solid phase with ethanol / water and dry it to obtain 4-pyrazole carboxylic acid.

3. The method for synthesizing 4-pyrazolonic acid according to claim 1 or 2, characterized in that: The molar ratio of 4-chloropyrazole, inorganic base, palladium acetate, and ligand is 1:1 to 5:0.1% to 2%:0.5% to 2.5%.

4. The method for synthesizing 4-pyrazolic acid according to claim 2, characterized in that: The inorganic bases are: sodium acetate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium phosphate, etc.

5. The method for synthesizing 4-pyrazolic acid according to claim 2, characterized in that: The ligands are: triphenylphosphine, tri-n-butylphosphine, tri-tert-butylphosphine, etc.

6. The method for synthesizing 4-pyrazolic acid according to claim 2, characterized in that: In step S1, the pressure inside the high-pressure reactor is controlled at 1.5±0.1 MPa and the temperature at 100°C, and the carbonylation reaction is carried out for 20 hours with stirring.

7. The method for synthesizing 4-pyrazolic acid according to claim 2, characterized in that: The acid solution is a sulfuric acid solution, a hydrochloric acid solution, or a phosphoric acid solution.

Images