Process for preparation of pyrazole carboxylic acids

Abstract

The invention relates to the field of organic synthesis, and discloses a method for preparing pyrazole carboxylic acid, which comprises the following steps: (1) in the presence of a first solvent, contacting (3-methylbutane-2-yl) hydrazine or a salt thereof with a compound III for reaction to obtain a compound II; (2) contacting the compound II with an alkaline substance for saponification, and then mixing a saponification product with acid for acidification; in the formula (I), R1 and R2 are respectively and independently alkyl groups with 1-4 carbon atoms. The preparation method disclosed by the invention has the characteristics of simplicity in operation, mild reaction conditions, greenness, no pollution and high yield.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic synthesis, in particular to a method for preparing pyrazole carboxylic acid. BACKGROUND

[0002] 5-methyl-1-(3-methylbutan-2-yl)-1H-pyrazole-4-carboxylic acid is an important intermediate of the pesticide zaname dam, and the preparation method of the compound is disclosed and protected in patent CN106573893B: 2-methyl butanone is used as the starting material, 2-methyl butanone is first dehydrated into hydrazone with hydrazine hydrate, then reacts with 2-ethoxymethyl acetoacetate in the presence of a reducing agent to generate ethyl 5-methyl-1-(3-methylbutan-2-yl)-1H-pyrazole carboxylate, and finally generates 5-methyl-1-(3-methylbutan-2-yl)-1H-pyrazole-4-carboxylic acid through saponification reaction. In the process, sodium cyanoborohydride is used for asymmetric reduction reaction in the reduction reaction, and toxic hydrogen cyanide gas is easily generated in the reaction process, which brings certain danger to the operation, and sodium cyanoborohydride is high in price, which is not conducive to scale-up production. Patent CN108699003B discloses and protects a method for preparing pyrazole compounds or salts thereof by catalytic hydrogenation reaction, which avoids the use of sodium cyanoborohydride. However, the dehydration of 2-methyl butanone into hydrazone with hydrazine hydrate is a reversible reaction, and the residual hydrazine hydrate in the hydrazone reacts with 2-ethoxymethyl acetoacetate to generate impurity 5-methyl-1H-pyrazole-4-carboxylic acid ester. Therefore, the above existing technologies for synthesizing 5-methyl-1-(3-methylbutan-2-yl)-1H-pyrazole-4-carboxylic acid all have the problem of low yield.

[0003] Based on the above, it is urgent to propose a method for preparing 5-methyl-1-(3-methylbutan-2-yl)-1H-pyrazole-4-carboxylic acid with high yield, simple operation, low cost and environmental friendliness. SUMMARY

[0004] The purpose of the present application is to overcome the problems existing in the prior art, and to provide a method for preparing pyrazole carboxylic acid.

[0005] In order to achieve the above-mentioned purpose, the present application provides a method for preparing pyrazole carboxylic acid, which comprises the following steps:

[0006] (1) contacting (3-methylbutan-2-yl)hydrazine or a salt thereof with compound III in the presence of a first solvent to obtain compound II;

[0007] (2) contacting compound II with a basic substance to perform saponification, and then mixing the saponification product with an acid to perform acidification;

[0008]

[0009] wherein R1 and R2 are each independently a C1-C4 alkyl group.

[0010] By the above technical solution, the method for preparing pyrazole carboxylic acid has the characteristics of simple operation, mild reaction condition, green pollution-free and high yield. DETAILED DESCRIPTION

[0011] The endpoints of the ranges and any values claimed herein are not to be construed as strictly limiting the exact range or value. Ranges involving endpoints are to be construed as having been modified to include the endpoints themselves. Ranges involving endpoints and individual points are to be construed as having been modified to include the endpoints and the individual points themselves. Ranges involving endpoints and individual points are to be construed as having been modified to include the endpoints and the individual points themselves.

[0012] The present application provides a method for preparing pyrazole carboxylic acid, characterized in that the method comprises the following steps:

[0013] (1) contacting (3-methylbutan-2-yl)hydrazine or a salt thereof with compound III in the presence of a first solvent to obtain compound II;

[0014] (2) contacting compound II with a basic substance to perform saponification, and then mixing the saponification product with an acid to perform acidification;

[0015]

[0016] wherein R1 and R2 are each independently a C1-C4 alkyl group.

[0017] In the present application, R1 can be methyl, ethyl or isopropyl, and is preferably ethyl.

[0018] In the present application, R2 can be methyl or ethyl, and is preferably ethyl.

[0019] In the present application, in step (1), the salt of (3-methylbutan-2-yl)hydrazine can be a common salt form, for example, can be selected from at least one of hydrochloride, sulfate, phosphate and acetate, and is preferably hydrochloride.

[0020] In the present application, in step (1), the molar ratio of (3-methylbutan-2-yl)hydrazine or a salt thereof to compound III can be (0.8-1.2):1, preferably (0.9-1.1):1, and more preferably (1.02-1.07):1.

[0021] When the reactant molar ratio is 1:1, theoretically the reactants can react completely. However, as the reaction nears its end, the concentrations of the two reactants are too low, and according to the reaction equilibrium conditions, the reactants cannot be completely consumed. However, if one reactant is present in greater quantity than the other, i.e., the reactant molar ratio is not 1:1, the reactant with the lower concentration can be consumed to the maximum extent, promoting the reaction towards the target direction and promoting product formation. If one reactant is in significant excess, the yield is expected to increase. However, to reduce costs, a reactant molar ratio around 1:1 is suitable for industrial production. Furthermore, in this invention, the content of (3-methylbutane-2-yl)hydrazine or its salt can be greater than that of compound III, or the content of compound III can be greater than that of (3-methylbutane-2-yl)hydrazine and its salt. Therefore, to reduce costs, facilitate post-treatment, and improve wastewater treatment efficiency, in some preferred embodiments of this invention, the amount of (3-methylbutane-2-yl)hydrazine or its salt is greater than that of compound III, and the molar ratio is (1.02-1.07):1.

[0022] In this invention, in step (1), the compound III can be added to the reaction vessel in one go, in multiple parts, or by dripping at a specific rate. In order to accelerate the reaction rate and make the reaction occur uniformly and prevent local over-addition, dripping is preferred. The dripping rate is not limited and can be adjusted according to the production scale.

[0023] In this invention, in step (1), the rate at which compound III is added to the reactor relative to each mole of compound III can be 0.05-0.2 mol / h, preferably 0.08-0.12 mol / h.

[0024] In this invention, in step (1), the amount of the first solvent used can be 500-1000g relative to each mole of compound III.

[0025] In this invention, there are no special requirements for the first solvent. It is usually selected as a substance that is liquid under reaction conditions, and can be selected from at least one of C1-C6 alcohols, C5-C16 alkanes, C1-C16 halogenated hydrocarbons, C1-C16 nitriles, C1-C12 benzene series compounds and C1-C16 acids.

[0026] In a preferred embodiment of the present invention, the first solvent may be at least one selected from methanol, ethanol, propanol, butanol, cyclohexane, n-hexane, dichloromethane, dichloroethane, chloroform, acetonitrile, benzene, toluene, xylene, formic acid, and acetic acid, more preferably ethanol and / or dichloromethane.

[0027] In this invention, in step (1), the reaction temperature can be 0-80℃, preferably 10-30℃.

[0028] In this invention, the reaction time in step (1) is not strictly limited; it can be suitable for production scale and ensure that the reaction is completed. In this invention, for a 500ml reaction vessel, the reaction time can be 1-6 hours, preferably 1.5-2.5 hours.

[0029] In order to obtain compound II for step (2) in this invention, the method further includes: in step (1), after the reaction is completed, desolvation under negative pressure.

[0030] In this invention, in step (1), in order to further ensure the yield and productivity, a sample can be taken for control before the negative pressure desolventizing to ensure that the reaction time is sufficient to make the content of methyl 2-ethoxymethylene acetoacetate in the reaction system less than 0.5 wt%.

[0031] In this invention, steps (1) and (2) can be carried out in laboratory and industrial synthesis reaction vessels. The reaction vessel can be any suitable container such as test tube, beaker and reaction vessel. In the field of large-scale industrial synthesis, in order to obtain more stable reaction conditions and thus further ensure yield and production rate, it is preferred to carry out the reaction in a reaction vessel.

[0032] In this invention, in steps (1) and (2), the reaction system needs to be stirred to ensure sufficient dissolution of the reactants and / or better contact between the reactants. The stirring speed can be 100-200 rpm, preferably 120-180 rpm.

[0033] In this invention, in step (2), the saponification can be carried out in the presence of a second solvent.

[0034] In this invention, in step (2), the amount of the second solvent used can be 20-100g relative to each mole of compound III.

[0035] In this invention, in step (2), the second solvent can be a C1-C6 alcohol, more preferably selected from at least one of methanol, ethanol and isopropanol, and most preferably ethanol.

[0036] In this invention, in step (2), the alkaline substance is used to convert -COOR1 into -COOM (M represents the metal element in the alkaline substance). Those skilled in the art can determine the amount of the alkaline substance based on the raw materials. Generally, to maximize the product yield, the molar ratio of the alkaline substance to compound III is ≥1, preferably (1-4):1. When (1) the salt of (3-methylbutane-2-yl)hydrazine is used to contact compound III, the molar ratio of the alkaline substance to compound III is ≥2, preferably (2.5-4):1.

[0037] In this invention, in step (2), the alkaline substance is an inorganic alkaline substance, preferably an alkali metal hydroxide and / or an alkali metal carbonate, more preferably selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

[0038] In this invention, in step (2), the saponification temperature is 20-80℃, preferably 40-60℃.

[0039] In this invention, the reaction time for saponification in step (2) is not strictly limited; it can be suitable for production scale and ensure complete reaction. For example, for a 500ml reactor, the reaction time for saponification can be 2-25 hours.

[0040] In this invention, in step (2), during the saponification process, sampling is performed using HPLC control. By controlling the saponification conditions within the above-mentioned preferred range, the content of the intermediate methyl 5-methyl-1-(3-methylbutane-2-yl)-1H-pyrazole-4-carboxylate in the reaction system can be less than 0.5 wt%.

[0041] In this invention, in step (2), the amount of acid used is such that the pH of the reaction system is 2-3.

[0042] In this invention, in step (2), the acid can be a common inorganic acid, preferably hydrochloric acid.

[0043] In this invention, in step (2), the concentration of hydrochloric acid can be the concentration commonly used in industrial production, preferably 10-50 wt%, more preferably 25-35 wt%.

[0044] In this invention, the method may further include: in step (2), cooling the acidified system, preferably, the temperature after cooling is below 10°C, more preferably 0-5°C.

[0045] In this invention, the method may further include: in step (2), the cooled mixture needs to be subjected to solid-liquid separation (such as vacuum filtration) and drying to finally obtain compound I.

[0046] The present invention will be described in detail below through examples. In the following examples, compound III was purchased from Bidex Pharmaceuticals, and (3-methylbutane-2-yl)hydrazine and its salt were prepared in-house. The contents of intermediate product compound II and final product compound I were measured by HPLC analysis and obtained by further calculations.

[0047] Preparation Example

[0048] Preparation method of (3-methylbutane-2-yl)hydrazine (CAS: 30924-08-4):

[0049] 2.1 mol of hydrochloric acid was added to a 2L reactor, and the temperature was controlled at 25±5℃. 2.1 mol of hydrazine hydrate was then added dropwise. After the addition was complete, 2 mol of methyl isopropyl ketone was added dropwise over 1 hour, forming a mixture. This mixture was transferred to a hydrogenation reactor, and 8 g of 5 wt% Pt / C was added as a catalyst. Hydrogenation was carried out at 25±5℃ and 10 bar. Hydrogenation continued until the intermediate product conversion was complete. The catalyst was separated by filtration, and the mixture was distilled under reduced pressure until crystals precipitated. 276 g of 32 wt% sodium hydroxide solution was added dropwise with stirring to neutralize the crystals. Dichloromethane was added for extraction, and after the dichloromethane layer was desolventized, further distillation under reduced pressure yielded 172.4 g of (3-methylbutane-2-yl)hydrazine, with a purity of 98%.

[0050] Preparation method of (3-methylbutane-2-yl)hydrazine hydrochloride:

[0051] (3-Methylbutane-2-yl)hydrazine is mixed with hydrochloric acid in a 1:1 molar ratio and the hydrochloric acid is neutralized to obtain the hydrochloride salt of (3-methylbutane-2-yl)hydrazine.

[0052] Example 1

[0053] 100 g of ethanol, 50 g of acetic acid, and 0.22 mol of (3-methylbutane-2-yl)hydrazine were added to a 500 ml reactor. The mixture was stirred, and then 0.2 mol of methyl 2-ethoxymethylene acetoacetate was added dropwise over 2 hours. After the addition was complete, the reaction was continued for another 3 hours. A sample was taken for HPLC control; the content of methyl 2-ethoxymethylene acetoacetate was less than 0.5 wt%. The reaction was then terminated, and compound II was obtained by desolvation under negative pressure. Throughout the process, the temperature was controlled at 2 ± 2 °C.

[0054] Add 30g of methanol to the reactor, stir, and add 0.3mol of liquid alkali dropwise. After the addition is complete, heat to 30-40℃ and maintain the temperature for saponification reaction for 24h. Take a sample for HPLC control. The content of the intermediate methyl 5-methyl-1-(3-methylbutane-2-yl)-1H-pyrazole-4-carboxylate is less than 0.5wt%. After the reaction is complete, add 30wt% hydrochloric acid dropwise to the reactor to adjust the pH to 2-3. A solid product precipitates during the dropwise addition. After the dropwise addition is complete, cool to 2±2℃, filter, and dry to obtain the solid product.

[0055] Example 2

[0056] 120 g of acetic acid and 0.2 mol of (3-methylbutane-2-yl)hydrazine were added to a 500 ml reactor and stirred. Then, 0.2 mol of ethyl 2-methoxymethylene acetoacetate was added dropwise over 1.5 h. After the addition was completed, the reaction was continued for another 5 h. HPLC analysis showed that the content of ethyl 2-methoxymethylene acetoacetate was less than 0.5 wt%. The reaction was then terminated, and compound II was obtained by desolvation under negative pressure. The temperature was maintained at 25 ± 5 °C throughout the entire process.

[0057] Add 30g of ethanol to the reactor, stir, and add 0.4mol of liquid alkali dropwise. After the addition is complete, heat to 52±2℃ and maintain the temperature for saponification reaction for 6h. Take a sample for HPLC control. The content of the intermediate ethyl 5-methyl-1-(3-methylbutane-2-yl)-1H-pyrazole-4-carboxylate is less than 0.5wt%. After the reaction is complete, add 30wt% hydrochloric acid dropwise to the reactor to adjust the pH to 2-3. A solid product precipitates during the dropwise addition. After the dropwise addition is complete, cool to 2±2℃, filter, and dry to obtain the solid product.

[0058] Example 3

[0059] 120 g of toluene and 0.21 mol of (3-methylbutane-2-yl)hydrazine hydrochloride were added to a 500 ml reactor and stirred. Then, 0.2 mol of ethyl 2-ethoxymethylene acetoacetate was added dropwise over 1.5 h. After the addition was complete, the reaction continued for another 2 h. HPLC analysis showed that the content of ethyl 2-ethoxymethylene acetoacetate was less than 0.5 wt%. The reaction was then terminated, and compound II was obtained by desolvation under negative pressure. The temperature was maintained at 75 ± 5 °C throughout the entire process.

[0060] Add 50g of isopropanol to the reactor, stir, and add 0.61mol of liquid alkali dropwise. After the addition is complete, heat to 75±5℃ and maintain the temperature for saponification reaction for 3h. Take a sample for HPLC control. The content of the intermediate ethyl 5-methyl-1-(3-methylbutane-2-yl)-1H-pyrazole-4-carboxylate is less than 0.5wt%. After the reaction is complete, add 30wt% hydrochloric acid dropwise to the reactor to adjust the pH to 2-3. A solid product precipitates during the dropwise addition. After the dropwise addition is complete, cool to 2±2℃, filter, and dry to obtain the solid product.

[0061] Example 4

[0062] 120 g of ethanol and 0.21 mol of (3-methylbutane-2-yl)hydrazine hydrochloride were added to a 500 ml reactor and stirred. Then, 0.2 mol of ethyl 2-ethoxymethylene acetoacetate was added dropwise over 2 hours. After the addition was complete, the reaction was continued for another 2 hours. HPLC analysis showed that the content of ethyl 2-ethoxymethylene acetoacetate was less than 0.5 wt%. The reaction was then considered complete, and the solvent was removed to obtain compound II. The temperature was maintained at 20 ± 5 °C throughout the entire process.

[0063] Add 30g of ethanol to the reactor, stir, and add 0.61mol of liquid alkali dropwise. After the addition is complete, heat to 50±5℃ and maintain the temperature for saponification reaction for 8h. Take a sample for HPLC control. The content of the intermediate ethyl 5-methyl-1-(3-methylbutane-2-yl)-1H-pyrazole-4-carboxylate is less than 0.5wt%. After the reaction is complete, add 30% hydrochloric acid dropwise to the reactor to adjust the pH to 2-3. A solid product precipitates during the dropwise addition. After the dropwise addition is complete, cool to 2±2℃, filter, and dry to obtain the solid product.

[0064] Example 5

[0065] 150 g of dichloromethane and 0.21 mol of (3-methylbutane-2-yl)hydrazine hydrochloride were added to a 500 ml reactor and stirred. Then, 0.2 mol of ethyl 2-ethoxymethylene acetoacetate was added dropwise over 2 hours. After the addition was complete, the reaction was continued for another 2 hours. HPLC analysis showed that the content of ethyl 2-ethoxymethylene acetoacetate was less than 0.5 wt%. The reaction was then considered complete, and the solvent was removed to obtain compound II. The temperature was maintained at 20 ± 5 °C throughout the entire process.

[0066] Add 30g of ethanol to the reactor, stir, and add 0.61mol of liquid alkali dropwise. After the addition is complete, heat to 50±5℃ and maintain the temperature for saponification reaction for 8h. Take a sample for HPLC control. The content of the intermediate ethyl 5-methyl-1-(3-methylbutane-2-yl)-1H-pyrazole-4-carboxylate is less than 0.5wt%. After the reaction is complete, add 30% hydrochloric acid dropwise to the reactor to adjust the pH to 2-3. A solid product precipitates during the dropwise addition. After the dropwise addition is complete, cool to 2±2℃, filter, and dry to obtain the solid product.

[0067] Table 1 shows the content and yield of compound I.

[0068] No. Content, % Yield, % Example 1 95.10 90.10 Example 2 95.20 91.20 Example 3 95.10 90.10 Example 4 97.30 95.20 Example 5 96.50 96.60

[0069] As can be seen from the results in Table 1, the yields prepared by the method proposed in this invention are all above 90%, with the yields of Examples 4 and 5 both reaching above 95%.

[0070] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A process for the preparation of a pyrazole carboxylic acid, characterized in that, The method comprises the following steps: (1) reacting (3-methylbutan-2-yl)hydrazine or a salt thereof with compound III in the presence of a first solvent to obtain compound II; (2) saponifying compound II with a basic substance, and then acidifying the saponification product with an acid; wherein R1 and R2 are each independently a C1-C4 alkyl.

2. The method of claim 1, wherein, R1 is a methyl group, an ethyl group or an isopropyl group, preferably an ethyl group; and / or R2 is a methyl group or an ethyl group, preferably an ethyl group.

3. The method of claim 1, wherein, In step (1), the salt of (3-methylbutan-2-yl)hydrazine is selected from at least one of hydrochloride, sulfate, phosphate and acetate, preferably hydrochloride.

4. The method of claim 1, wherein, In step (1), the molar ratio of (3-methylbutan-2-yl)hydrazine or a salt thereof to compound III is (0.8-1.2):1, preferably (0.9-1.1):1, and more preferably (1.02-1.07):

1.

5. The method of claim 1, wherein the first solvent is selected from a substance that is in a liquid state under reaction conditions, including at least one of a C1-C6 alcohol, a C5-C16 alkane, a C1-C16 halogenated hydrocarbon, a C1-C16 nitrile, a C1-C12 benzene series and a C1-C16 acid.

6. The method of claim 5, wherein, The first solvent is selected from at least one of methanol, ethanol, propanol, butanol, cyclohexane, n-hexane, dichloromethane, dichloroethane, chloroform, acetonitrile, benzene, toluene, xylene, formic acid and acetic acid.

7. The method of claim 1, wherein, In step (1), the temperature of the reaction is 0-80°C, preferably 10-30°C.

8. The method of claim 1, wherein, In step (2), the saponification is carried out in the presence of a second solvent; Preferably, the second solvent is a C1-C6 alcohol, more preferably selected from at least one of methanol, ethanol and isopropanol, and most preferably ethanol.

9. The method of claim 1, wherein, The molar ratio of the basic substance to compound III is (1-4):1; and / or, in step (2), the basic substance is an inorganic basic substance, preferably an alkali metal hydroxide and / or an alkali metal carbonate, more preferably selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

10. The method of claim 1, wherein, The conditions of the saponification include a temperature of 20-80°C, preferably 40-60°C; and / or, the amount of the acid is such that the end-point pH of the reaction system is 2-3; and / or, the acid is hydrochloric acid.

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