CN111072565A

CN111072565A - A kind of 3-alkylpyrazole and preparation method thereof

Info

Publication number: CN111072565A
Application number: CN201911320208.0A
Authority: CN
Inventors: 泮廷廷; 王海波; 韩强
Original assignee: Jinan Shaoyuan Medical Technology Co ltd
Current assignee: Jinan Shaoyuan Medical Technology Co ltd
Priority date: 2019-12-19
Filing date: 2019-12-19
Publication date: 2020-04-28

Abstract

本发明涉及一种3‑烷基吡唑及其制备方法，所述制备方法包括如下步骤：(1)使化合物A与化合物B反应，得到化合物C‑1和C‑2的混合物；(2)向所述化合物C‑1和C‑2的混合物中加入无机酸，无机酸与化合物C‑2反应，分离后得到化合物C‑1；(3)向所述化合物C‑1中加入水合肼，反应得到3‑烷基吡唑。本发明旨在步骤(2)中加入无机酸，无机酸不能与化合物C‑1反应，却能够与其异构体化合物C‑2进行反应，从而除去化合物C‑2，得到纯的化合物C‑1，再进行最后一步关环反应即可得到纯度较高的3‑烷基吡唑，纯度＞95％，且反应步骤简单，操作方便。The present invention relates to a 3-alkylpyrazole and a preparation method thereof. The preparation method comprises the following steps: (1) reacting compound A with compound B to obtain a mixture of compounds C-1 and C-2; (2) Add a mineral acid to the mixture of the compounds C-1 and C-2, and the mineral acid reacts with the compound C-2 to obtain compound C-1 after separation; (3) adding hydrazine hydrate to the compound C-1, The reaction obtains 3-alkylpyrazole. The present invention aims to add inorganic acid in step (2), and the inorganic acid cannot react with compound C-1, but can react with its isomer compound C-2, thereby removing compound C-2 to obtain pure compound C-1 3-alkylpyrazole with higher purity can be obtained by carrying out the final step of ring-closing reaction, the purity is more than 95%, and the reaction steps are simple and the operation is convenient.

Description

3-alkyl pyrazole and preparation method thereof

Technical Field

The invention relates to the technical field of organic synthesis, in particular to 3-alkyl pyrazole and a preparation method thereof.

Background

Pyrazole compounds have high biological activity and are attracting more and more attention as medicines, pesticides and the like. In particular to 3-alkyl pyrazole, one of important organic intermediates of a bifunctional chelating agent required to be used in time-resolved fluorescence immunoassay, 3-alkyl pyrazole and derivatives thereof can be used as a nitrogen fertilizer nitrification inhibitor, an acid gas absorbent, a precious metal extractant and a corrosion inhibitor, can also be used for separating and recovering alkyne, preparing pesticides with weeding performance and antibiotic action and fruit growth hormone, and can be used as an organic intermediate for synthesizing luminescent materials, the pyrazole derivatives have wide application, become a hotspot of development in recent years, and the synthesis of the pyrazole compounds is also concerned by the industry.

The synthesis method in the prior art comprises the following steps: the synthesis method comprises the steps of firstly synthesizing methyl formate by using formic acid and absolute ethyl alcohol and using calcium chloride as a catalyst, synthesizing formylacetone by using the methyl formate as a raw material and performing aldol condensation reaction on the methyl formate and acetone by using metal sodium and the absolute ethyl alcohol as catalysts, and finally adding hydrazine hydrate into the formylacetone to perform cyclization reaction to generate the product 3-methylpyrazole.

In addition, the prior art also discloses a simple preparation method of 3-alkyl pyrazole by the following two steps:

(1) the literature reports (Journal of Organic Chemistry,1955, vol.20, p.1681,1682) that starting from monoalkyl-substituted acetone, ethyl formate gives intermediate A1, and that A1 is cyclized with hydrazine hydrate to give 3-alkylpyrazole B1, the reaction is shown in scheme one below:

route one:

(2) KR101798840 discloses the reaction of monoalkyl-substituted acetone with N, N-dimethylformamide dimethyl acetal to obtain intermediate C1, and cyclization of C1 with hydrazine hydrate to obtain 3-alkylpyrazole B1, as shown in scheme II below:

both of the above-mentioned preparation methods, although simple in steps, have the drawback that 10-20% of the isomer A2 or C2 is produced in the first reaction step, followed by 10-20% of the isomer B2 in the second reaction step. The properties of B1 and B2 are very similar, so that the isomer impurity B2 is difficult to remove to obtain pure B1, and the purity of the obtained 3-alkyl pyrazole product is low.

Therefore, there is a need in the art to develop a method for preparing 3-alkylpyrazole with simple steps to improve the purity of the product.

Disclosure of Invention

The invention aims to provide a preparation method of 3-alkyl pyrazole, which has high purity of the 3-alkyl pyrazole and simple steps.

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

the invention provides a preparation method of 3-alkyl pyrazole, which comprises the following steps:

(1) reacting compound A with compound B to obtain a mixture of compounds C-1 and C-2, according to the following reaction formula:

r is selected from C1-C10 (such as C2, C3, C4, C5, C6, C7, C8, C9 and the like) alkyl; C1-C10 represent the number of carbons in the alkyl group;

(2) adding inorganic acid into the mixture of the compounds C-1 and C-2, reacting the inorganic acid with the compound C-2, and separating to obtain a compound C-1;

(3) adding hydrazine hydrate into the compound C-1, and reacting to obtain 3-alkyl pyrazole, wherein the reaction formula is as follows:

the invention provides a novel method for synthesizing 3-alkyl pyrazole, which comprises the steps of adding inorganic acid into the step (2), wherein the inorganic acid can not react with a compound C-1 but can react with an isomer compound C-2 thereof, so that the compound C-2 is removed to obtain a pure compound C-1, and then carrying out a final ring-closing reaction to obtain the 3-alkyl pyrazole with higher purity, wherein the purity is more than 95 percent, and the reaction steps are simple and convenient to operate.

Preferably, the inorganic acid comprises any one or a combination of at least two of hydrochloric acid, sulfuric acid or nitric acid, preferably hydrochloric acid.

The invention preferably uses hydrochloric acid to react with the compound C-2, and can react with the compound C-2 more completely, thereby further improving the purity of the 3-alkyl pyrazole.

Preferably, the concentration of the hydrochloric acid is 2-5 mol/L, such as 2.1mol/L, 2.2mol/L, 2.3mol/L, 2.5mol/L, 2.6mol/L, 2.8mol/L, 2.9mol/L, 3mol/L, 3.2mol/L, 3.5mol/L, 3.7mol/L, 3.9mol/L, 4mol/L, 4.2mol/L, 4.6mol/L, 4.8mol/L, and the like, and 3mol/L is preferred.

The hydrochloric acid preferably has the specific concentration, the purity of the 3-alkyl pyrazole can be further improved within the concentration range, the concentration of the hydrochloric acid is too high, C-1 is damaged, the selectivity of the reaction is poor, the purity of the final product is reduced, the concentration of the hydrochloric acid is too low, the reaction with C-2 cannot be carried out, and the subsequent extraction difficulty is increased due to too much added water.

Preferably, the molar ratio of the inorganic acid to the compound a is (0.05-0.20): 1, for example, 0.06:1, 0.07:1, 0.08:1, 0.09:1, 0.1:1, 0.11:1, 0.12:1, 0.13:1, 0.14:1, 0.15:1, 0.16:1, 0.17:1, 0.18:1, 0.19:1, and the like.

In the present invention, it is preferable to add the inorganic acid in the above-mentioned addition ratio, and within this ratio, the purity of the 3-alkylpyrazole can be further improved, and too much inorganic acid causes C-1 loss, while too little inorganic acid causes a decrease in yield and a decrease in purity.

Preferably, in the step (2), the inorganic acid is added in a dropwise manner to the mixture of the compounds C-1 and C-2.

Preferably, in step (2), the solvent of the reaction comprises water.

Preferably, in step (2), the temperature of the reaction is < 10 ℃, e.g., 0 ℃,1 ℃, 2 ℃, 3 ℃,4 ℃, 5 ℃, 6 ℃, 7 ℃, 8 ℃, 9 ℃, etc.

The reaction of step (2) is preferably carried out at a low temperature (< 10 ℃) in the present invention because, when the temperature is too high, the inorganic acid reacts with both C-1 and C-2, the selectivity is deteriorated, resulting in a decrease in yield and a decrease in purity of the final product.

Preferably, in the step (2), the reaction time is 20-40 min, such as 21min, 22min, 23min, 24min, 25min, 26min, 27min, 28min, 29min, 30min, 31min, 32min, 33min, 34min, 35min, 36min, 37min, 38min, 39min, and the like, and preferably 30 min.

Preferably, in the step (2), after the reaction is completed, a base is added to the reaction system to adjust the pH.

Preferably, the base comprises any one or a combination of at least two of potassium carbonate, sodium hydroxide, strong potassium oxide or lithium hydroxide.

Preferably, the pH is adjusted to 10-11.

Preferably, the extraction, washing, drying, distillation is carried out after the pH adjustment.

Preferably, the solvent of the extraction comprises ethyl acetate.

Preferably, the washing detergent comprises a saturated saline solution.

Preferably, the step (2) specifically comprises the following steps:

dispersing a mixture of the compounds C-1 and C-2 in water, dropwise adding hydrochloric acid with the concentration of 2-5 mol/L at the temperature of less than 10 ℃, stirring for 20-40 min, then adding alkali to adjust the pH value to 10-11, extracting, washing, drying and distilling to obtain the compound C-1.

Preferably, in the step (1), the solvent for the reaction includes any one or a combination of at least two of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, or dimethylsulfoxide.

Preferably, in step (1), the reaction is carried out under nitrogen protection.

Preferably, in the step (1), the reaction temperature is 100 to 150 ℃, for example 105 ℃, 110 ℃, 115 ℃, 120 ℃, 125 ℃, 130 ℃, 135 ℃, 140 ℃, 145 ℃, 148 ℃ and the like, preferably 125 ℃.

Preferably, in the step (1), the reaction time is 20-25 h, such as 21h, 22h, 23h, 24h, 25h and the like, and preferably 24 h.

Preferably, the step (1) specifically comprises the following steps:

and mixing the compound A, the compound B and a solvent, heating to 100-150 ℃ under the protection of nitrogen, and stirring for 20-25 h to obtain a mixture of the compounds C-1 and C-2.

Preferably, in the step (3), the solvent for the reaction includes any one or a combination of at least two of ethanol, methanol, isopropanol, 1, 4-dioxane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, or n-butanol.

Preferably, in step (3), the temperature of the reaction is 70 to 90 ℃, such as 71 ℃, 72 ℃, 73 ℃, 74 ℃, 75 ℃, 76 ℃, 77 ℃, 78 ℃, 79 ℃, 80 ℃, 81 ℃, 82 ℃, 83 ℃, 84 ℃, 85 ℃, 86 ℃, 87 ℃, 88 ℃, 89 ℃, preferably 85 ℃.

Preferably, in step (3), the reaction time is 4-6 h, such as 4.1h, 4.2h,. 3h,. 4h, 4.5h, 4.6h, 4.7h, 4.8h, 4.9h, 5h, 5.1h, 5.2h, 5.3h, 5.4h, 5.5h, 5.6h, 5.7h, 5.8h, 5.9h, and the like, preferably 5 h.

Preferably, the step (3) specifically comprises the following steps:

and mixing the compound C-1, hydrazine hydrate and a solvent, heating to 70-90 ℃, and stirring for 4-6 hours to obtain the 3-alkyl pyrazole.

Preferably, the preparation method specifically comprises the following steps:

(1) mixing the compound A, the compound B and a solvent, heating to 100-150 ℃ under the protection of nitrogen, and stirring for 20-25 h to obtain a mixture of compounds C-1 and C-2;

(2) dispersing a mixture of a compound C-1 and a compound C-2 in water, dropwise adding hydrochloric acid with the concentration of 2-5 mol/L at the temperature of less than 10 ℃, stirring for 20-40 min, then adding alkali to adjust the pH value to 10-11, extracting, washing, drying and distilling to obtain a compound C-1;

(3) and mixing the compound C-1, hydrazine hydrate and a solvent, heating to 70-90 ℃, and stirring for 4-6 hours to obtain the 3-alkyl pyrazole.

It is a second object of the present invention to provide a 3-alkylpyrazole, which is produced by the production method described in the first object.

Preferably, the 3-alkylpyrazole is > 95% pure, e.g., 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, 99.5%, 99.8%, etc.

Compared with the prior art, the invention has the following beneficial effects:

the invention provides a new method for synthesizing 3-alkyl pyrazole, which is characterized in that inorganic acid is added in the step (2), the inorganic acid can not react with a compound C-1 but can react with an isomer compound C-2 thereof, so that the compound C-2 is removed to obtain a pure compound C-1, and then hydrazine hydrate cyclization reaction is carried out in the last step to obtain the 3-alkyl pyrazole with higher purity, wherein the purity is more than 95 percent, and the reaction steps are simple and the operation is convenient.

Detailed Description

The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.

In the present invention, the compounds were characterized using a gas chromatograph model 7890B from Agilent and a nuclear magnetic resonance spectrometer model 400-MR from Warran.

Example 1

This example provides a preparation method of 3-propylpyrazole, which comprises the following steps:

(1) 2500g of N, N-dimethylformamide dimethyl acetal (21mol, 1.0eq), 2000g of 2-pentanone (23.1mol, 1.1eq) and 2.0L of N, N-Dimethylformamide (DMF) are mixed, the temperature is raised to 125 ℃ under the protection of nitrogen, the mixture is stirred for 24 hours, Gas Chromatography (GC) detects that the N, N-dimethylformamide dimethyl acetal has little residue and is completely reacted basically, and the isomer C-2 accounts for about 16 percent. Heating was stopped, the mixture was cooled to 60 ℃ and the solvent was removed by rotary evaporation to obtain 1420g of crude product.

(2) Dispersing 1420g (10.1mol, 1.0eq) of crude product obtained in the step (1) in 6.0L of ice water, keeping the temperature within 10 ℃, slowly adding 600mL of 3mol/L hydrochloric acid (1.8mol, 0.18eq) dropwise, keeping the temperature and stirring for 30min, sampling and detecting by thin layer chromatography (TLC, developing agent: dichloromethane, Rf product is 0.3, tailing, Rf isomer is 0.45), remaining a small amount of isomer C-2, continuing to add 50mL of 3mol/L hydrochloric acid dropwise, stirring for 30min, and detecting by TLC that the isomer C-2 is completely reacted. 1kg of potassium carbonate solid was added to the system directly in portions, the pH was adjusted to 10, and 2.5 L.times.3 extraction with ethyl acetate was carried out. The organic phases are combined, washed twice with saturated salt water, dried and spin-dried. 1030g of compound C-1 are obtained. The purity is 95% by GC detection, and the isomer C-2 accounts for less than 1%.

(3) Adding 1030g (7.31mol, 1.0eq) of the mixture into a 10L three-necked bottle, mechanically stirring, adding 4.85L of ethanol, adding 385g of 85% hydrazine hydrate (10.22mol, 1.4eq), heating to 85 ℃, refluxing and stirring for more than 5 hours, carrying out GC detection until the raw materials disappear, carrying out rotary evaporation to remove the solvent after the reaction is finished, carrying out oil pump drying, carrying out reduced pressure distillation, collecting fractions (0.5torr) at 85-100 ℃, obtaining 680g of light yellow liquid, namely 3-propylpyrazole, wherein the purity is 97.5% by GC detection.

Mass spectrum of compound 3-propylpyrazole: [ M +1] + ═ 111.2;

nuclear magnetic resonance hydrogen spectrum of compound 3-propylpyrazole:¹HNMR(400MHz，CD₃OD)δ：7.47(s，1H)，6.09(s，1H)，2.63(t，J＝7.5Hz，1H)，1.80–1.56(m，1H)，0.96(t，J＝7.4Hz，2H)。

example 2

The difference from example 1 is that the concentration of hydrochloric acid was 2mol/L and the purity of 3-methylpyrazole was 97.3%.

Example 3

The difference from example 1 is that the concentration of hydrochloric acid was 5mol/L and the purity of 3-methylpyrazole was 97.1%.

Example 4

The difference from example 1 is that the concentration of hydrochloric acid was 1mol/L and the purity of 3-methylpyrazole was 95.1%.

Example 5

The difference from example 1 is that the concentration of hydrochloric acid was 6mol/L and the purity of 3-methylpyrazole was 95.0%.

Example 6

The difference from example 1 is that, in step (2), hydrochloric acid was added dropwise at a temperature of 15 ℃ and the purity of 3-methylpyrazole was 95.2%.

Example 7

(1) 2500g of N, N-dimethylformamide dimethyl acetal (21mol, 1.0eq), 2000g of 2-pentanone (23.1mol, 1.1eq) and 2.0L of N, N-Dimethylformamide (DMF) are mixed, the temperature is raised to 100 ℃ under the protection of nitrogen, the mixture is stirred for 25 hours, Gas Chromatography (GC) detects that the N, N-dimethylformamide dimethyl acetal has little residue and is completely reacted basically, and the isomer C-2 accounts for about 15%. Heating is stopped, the temperature is cooled to 60 ℃, and the solvent is removed by rotary evaporation to obtain 1390g of crude product.

(2) 1390g (9.8mol, 1.0eq) of crude product obtained in the step (1) is dispersed in 6.0L of ice water, 600mL of 3mol/L hydrochloric acid (1.81mol, 0.18eq) is slowly added dropwise while keeping the temperature within 10 ℃, the mixture is kept and stirred for 20min, sampling thin layer chromatography (TLC, developing agent: dichloromethane, Rf product is 0.3, tailing, Rf isomer is 0.45) is detected, a small amount of isomer C-2 is remained, 50mL of 3mol/L hydrochloric acid is continuously added dropwise, stirring is carried out for 30min, and the isomer C-2 is detected by TLC to be completely reacted. 1kg of potassium carbonate solid was added to the system directly in portions, the pH was adjusted to 11, and 2.5 L.times.3 extraction with ethyl acetate was carried out. The organic phases are combined, washed twice with saturated salt water, dried and spin-dried. 1010g of compound C-1 were obtained. The purity is 96 percent by GC detection, and the isomer C-2 accounts for less than 1 percent.

(3) Adding 1010g (7.15mol, 1.0eq) of the crude product into a 10L three-necked bottle, mechanically stirring, adding 4.85L of ethanol, adding 377g of 85% hydrazine hydrate (10.01mol, 1.4eq), heating to 70 ℃, refluxing and stirring for more than 6h, carrying out GC detection until the raw materials disappear, carrying out rotary evaporation to remove the solvent after the reaction is finished, carrying out oil pump drying, carrying out reduced pressure distillation, collecting fractions (0.5torr) at 85-100 ℃, obtaining 674g of light yellow liquid, namely 3-propylpyrazole, wherein the GC detection purity is 97.0%.

Example 8

(1) 2500g of N, N-dimethylformamide dimethyl acetal (21mol, 1.0eq), 2000g of 2-pentanone (23.1mol, 1.1eq) and 2.0L of N, N-Dimethylformamide (DMF) are mixed, the temperature is raised to 150 ℃ under the protection of nitrogen, the mixture is stirred for 20 hours, Gas Chromatography (GC) detects that the N, N-dimethylformamide dimethyl acetal has little residue and is completely reacted basically, and the isomer C-2 accounts for about 16 percent. Stopping heating, cooling to 60 ℃, and removing the solvent by rotary evaporation to obtain 1480g of a crude product.

(2) Dispersing 1480g (10.5mol, 1.0eq) of the crude product obtained in the step (1) in 6.0L of ice water, keeping the temperature within 10 ℃, slowly adding 600mL of 3mol/L hydrochloric acid (1.81mol, 0.17eq) dropwise, keeping the temperature and stirring for 40min, sampling and detecting by thin layer chromatography (TLC, developing agent: dichloromethane, Rf product is 0.3, tailing, Rf isomer is 0.45), remaining a small amount of isomer C-2, continuing adding 50mL of 3mol/L hydrochloric acid dropwise, stirring for 30min, and detecting by TLC that the isomer C-2 is completely reacted. 1kg of potassium carbonate solid was added to the system directly in portions, the pH was adjusted to 11, and 2.5 L.times.3 extraction with ethyl acetate was carried out. The organic phases are combined, washed twice with saturated salt water, dried and spin-dried. 1120g of Compound C-1 were obtained. The purity is 94% by GC detection, and the isomer C-2 accounts for less than 1%.

(3) 1120g (7.93mol, 1.0eq) is added into a 10L three-necked bottle, mechanical stirring is carried out, 4.85L of ethanol is added, 418g of 85% hydrazine hydrate (11.10mol, 1.4eq) is added, the temperature is raised to 70 ℃, reflux stirring is carried out for more than 6h, GC detection is carried out until the raw materials disappear, the reaction is finished, the solvent is removed by rotary evaporation, an oil pump is used for drying, reduced pressure distillation is carried out, fraction (0.5torr) at 85-100 ℃ is collected, and 689g of light yellow liquid, namely 3-propylpyrazole, is obtained, and the purity is 97.2% by GC detection.

The mass spectrum and nuclear magnetic characterization data of examples 2-8 are similar to those of example 1, which shows that 3-propylpyrazole is successfully synthesized, and are not repeated.

Example 9

This example provides a preparation method of 3-ethylpyrazole, which specifically includes the following steps:

(1) 420g of 2-butanone (5.8mol, 1.1eq), 622g N, N-dimethylformamide dimethyl acetal (5.22mol, 1.0eq) and 500ml of DMF are uniformly mixed, the temperature is raised to 125 ℃ under the protection of nitrogen, the mixture is stirred for 24 hours, Gas Chromatography (GC) detects that the N, N-dimethylformamide dimethyl acetal has little residue and complete basic reaction, and the isomer C-2 accounts for about 15 percent. Stopping heating, cooling to 60 ℃, and removing the solvent by rotary evaporation to obtain 311g of crude product;

(2) dispersing 311g (2.45mol, 1.0eq) crude product obtained in the step (1) in 1.5L of ice water, keeping the temperature within 10 ℃, slowly adding 150mL of 3mol/L hydrochloric acid (0.45mol, 0.18eq) dropwise, keeping the temperature and stirring for 30min, sampling and detecting by thin layer chromatography (TLC, developing agent: dichloromethane, Rf product is 0.3, tailing, Rf isomer is 0.45), remaining a small amount of isomer C-2, continuing to add 12mL of 3mol/L hydrochloric acid dropwise, stirring for 30min, and detecting by TLC that the isomer C-2 is completely reacted. 0.25kg of potassium carbonate solid was added to the system in portions directly, the pH was adjusted to 10, and ethyl acetate was extracted at 0.6 L.times.3. The organic phases are combined, washed twice with saturated salt water, dried and spin-dried. 226g of compound C-1 are obtained. The purity is 96 percent by GC detection, and the isomer C-2 accounts for less than 1 percent.

(3) 226g (1.78mol, 1.0eq) of the mixture is added into a 10L three-necked bottle, the mixture is mechanically stirred, 1.2L of ethanol is added, 94g of 85 percent hydrazine hydrate (2.49mol, 1.4eq) is added, the mixture is heated to 85 ℃, the reflux stirring is carried out for more than 5 hours, GC detection is carried out until the raw materials disappear, the reaction is finished, the solvent is removed by rotary evaporation, an oil pump is used for drying, reduced pressure distillation is carried out, fractions at 85-100 ℃ are collected (0.5torr), 142g of light yellow liquid, namely 3-ethylpyrazole is obtained, and the purity of GC detection is 97.8%.

Mass Spectrometry of Compound 3-ethylpyrazole: [ M +1]]⁺＝97.1；

Nuclear magnetic resonance hydrogen spectrum of compound 3-ethylpyrazole:¹HNMR(400MHz，CD₃OD)δ：7.49(s，1H)，6.09(s，1H)，2.71(t，J＝7.5Hz，1H)，1.27(t，J＝7.4Hz，2H)。

comparative example 1

The difference from example 1 is that, without carrying out step (2), the 3-methylpyrazole purity was 83.2%.

As is clear from the above examples and comparative examples, the present invention can remove the isomer C-2 by introducing the step (2), and further improve the purity (> 95%) of the final product 3-methylpyrazole, and further, the purity can be more than 97% under preferable conditions.

As is clear from comparative examples 1 to 5, when the concentration of hydrochloric acid is 2 to 5mol/L (examples 1 to 3), the purity of the finally obtained 3-methylpyrazole is further improved, and the purity is lowered both when the concentration is too low (example 4) and when the concentration is too high (example 5).

Comparing example 1 with example 6, it can be seen that the purity can be further improved by controlling the temperature of the dropwise addition hydrochloric acid to 10 ℃ or lower (example 1), and increasing the dropwise addition temperature to 15 ℃ (example 6).

The present invention is illustrated in detail by the examples described above, but the present invention is not limited to the details described above, i.e., it is not intended that the present invention be implemented by relying on the details described above. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.

Claims

1. a preparation method of 3-alkylpyrazole, is characterized in that, described preparation method comprises the steps:

(1) make compound A react with compound B, obtain the mixture of compound C-1 and C-2, reaction formula is as follows:

Described R is selected from C1～C10 alkyl;

(2) adding an inorganic acid to the mixture of the compounds C-1 and C-2, the inorganic acid reacts with the compound C-2, and after separation, the compound C-1 is obtained;

(3) adding hydrazine hydrate to the compound C-1, the reaction obtains 3-alkylpyrazole, and the reaction formula is as follows:

2. preparation method according to claim 1, is characterized in that, described mineral acid comprises any one or at least two combinations in hydrochloric acid, sulfuric acid or nitric acid, preferably hydrochloric acid;

Preferably, the concentration of the hydrochloric acid is 2～5mol/L, preferably 3mol/L;

Preferably, the molar ratio of the inorganic acid to compound A is (0.05-0.20):1.

3. The preparation method according to claim 1 or 2, characterized in that, in step (2), the inorganic acid is added dropwise to the mixture of compounds C-1 and C-2.

4. The preparation method according to any one of claims 1 to 3, wherein in step (2), the solvent of the reaction comprises water;

Preferably, in step (2), the temperature of the reaction is less than 10°C;

Preferably, in step (2), the reaction time is 20-40 min, preferably 30 min.

5. The preparation method according to any one of claims 1 to 4, wherein in step (2), after the reaction is completed, an alkali is added to the reaction system to adjust pH;

Preferably, the alkali comprises any one or a combination of at least two of potassium carbonate, sodium carbonate, sodium hydroxide, strong potassium oxide or lithium hydroxide;

Preferably, the pH is adjusted to 10-11;

Preferably, extraction, washing, drying, distillation are carried out after adjusting the pH;

Preferably, the solvent of the extraction comprises ethyl acetate;

Preferably, the washing detergent includes saturated brine;

Preferably, step (2) specifically includes the following steps:

Disperse the mixture of compounds C-1 and C-2 in water, dropwise add hydrochloric acid with a concentration of 2 to 5 mol/L at a temperature of <10 ° C, stir for 20 to 40 min, then add alkali to adjust the pH to 10 to 11, extract , washed, dried and distilled to obtain compound C-1.

6. The preparation method according to any one of claims 1 to 5, wherein in step (1), the solvent of the reaction comprises N,N-dimethylformamide, N,N-dimethylformamide any one or a combination of at least two of acetamide, N-methylpyrrolidone or dimethyl sulfoxide;

Preferably, in step (1), the reaction is carried out under nitrogen protection;

Preferably, in step (1), the temperature of the reaction is 100-150°C, preferably 125°C;

Preferably, in step (1), the reaction time is 20-25h, preferably 24h;

Preferably, step (1) specifically includes the following steps:

Compound A, compound B and solvent are mixed, heated to 100-150° C. under the protection of nitrogen, and stirred for 20-25 h to obtain a mixture of compounds C-1 and C-2.

7. The preparation method according to any one of claims 1 to 6, wherein in step (3), the solvent of the reaction comprises ethanol, methanol, isopropanol, 1,4-dioxane , any one or a combination of at least two in acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran or n-butanol;

Preferably, in step (3), the temperature of the reaction is 70-90°C, preferably 85°C;

Preferably, in step (3), the reaction time is 4-6h, preferably 5h;

Preferably, step (3) specifically includes the following steps:

Compound C-1, hydrazine hydrate and solvent are mixed, the temperature is raised to 70-90° C., and stirred for 4-6 h to obtain the 3-alkylpyrazole.

8. The preparation method according to any one of claims 1 to 7, wherein the preparation method specifically comprises the following steps:

(1) Mixing compound A, compound B and a solvent, heating to 100-150° C. under the protection of nitrogen, stirring for 20-25 h, to obtain a mixture of compounds C-1 and C-2;

(2) Disperse the mixture of compounds C-1 and C-2 in water, dropwise add hydrochloric acid with a concentration of 2 to 5 mol/L at a temperature of <10°C, stir for 20 to 40 min, and then add an alkali to adjust the pH to 10 to 10 11. Extraction, washing, drying and distillation to obtain compound C-1;

(3) Compound C-1, hydrazine hydrate and solvent are mixed, the temperature is raised to 70-90° C., and stirred for 4-6 h to obtain the 3-alkylpyrazole.

9 . A 3-alkylpyrazole, characterized in that, the 3-alkylpyrazole is prepared by the preparation method according to any one of claims 1 to 8 .

10 . The 3-alkylpyrazole according to claim 9 , wherein the purity of the 3-alkylpyrazole is greater than 95%. 11 .