CN108084093B - Method for synthesizing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid by one-pot method - Google Patents
Method for synthesizing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid by one-pot method Download PDFInfo
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
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Abstract
The invention discloses a method for synthesizing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid by a one-pot method, which comprises the following steps: in xylene, 4, 4-difluoro ethyl acetoacetate and triethyl orthoformate are subjected to condensation reaction under the catalysis of heating and metal carboxylate, after cooling, methyl hydrazine aqueous solution is dropwise added, then the temperature is raised for ring closure reaction, and the obtained ring closure reaction solution is saponified and acidified to obtain the 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid. The method has the advantages of reasonable process design, high yield, simple process operation and low cost, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of compound intermediate synthesis, and particularly relates to a method for synthesizing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid by a one-pot method.
Background
The pyrazole amides are succinate dehydrogenase inhibitor (SDHI) bactericides which are developed in recent years, have novel structures, high activity and broad insecticidal spectrum and have the effect of improving the quality and yield of crops.
3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid of formula: c6H6F2N2O2Molecular weight: 176.12, which is an important intermediate for synthesizing pyrazole amide bactericides, the varieties of the pyrazole amide bactericides synthesized by taking the pyrazole amide bactericides as raw materials are up to 9, and the pyrazole amide bactericides mainly comprise fluxapyroxad, bixafen, epoxiconazole, pyrazolonaphthisim and benzovindiflupyr, so that the synthesis of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid is an important prerequisite for intervention in the pyrazole amide bactericides.
At present, many patents and documents research and report on the synthesis process, wherein currently, the industrially used process route is that 4, 4-difluoroacetoacetic acid ethyl ester is used as a raw material to synthesize 2-ethoxymethylene-4, 4-difluoroacetoacetic acid ethyl ester with trimethyl orthoformate, and then the ethyl ester reacts with methylhydrazine in a water phase or a mixed phase of water and an organic solvent to form 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate, and the target product is obtained through saponification and acidification, such as the reports of patents US5093347, EP1997808, WO2010009990, CN101959840, and the like.
For the synthesis of 2-ethoxymethylene-4, 4-difluoroacetoacetic acid ethyl ester, patents WO/2012/161965A1, WO/2012/025469A1, WO/2009/012482A2 and the like report that 4, 4-difluoroacetoacetic acid ethyl ester and triethyl orthoformate are used as raw materials, the raw materials are synthesized at high temperature under the action of acetic anhydride, and after the reaction is finished, the 2-ethoxymethylene-4, 4-difluoroacetoacetic acid ethyl ester is obtained through post-treatment. This is also a common synthesis method for such reactions, but this reaction must be post-treated to remove acetic acid and excess acetic anhydride, which are by-products of the reaction system, in order to proceed the next reaction.
A method for synthesizing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid from ethyl 2-ethoxymethylene-4, 4-difluoroacetoacetate has been reported. Chinese patent publication No. CN1968934A discloses adding methylhydrazine to an ethanol solution of ethyl 2-ethoxymethylene-4, 4-difluoroacetoacetate, reacting at-40 deg.C, and after the reaction is finished, decompressing, concentrating and recrystallizing to obtain 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate. The method has the disadvantages that the method needs to be carried out at low temperature, and the anhydrous methylhydrazine is used as a raw material, so that the method has high operation risk and harsh reaction conditions. U.S. Pat. No. 4, 20080154045, 1 and European patent EP1854788, 1 report that 2-ethoxymethylidene difluoroacetoacetate and methylhydrazine undergo a ring closure reaction at low temperature, such as cooling in a water bath, to give 3-difluoromethyl-1-methyl-1-hydro-pyrazole-4-carboxylate with high selectivity, but the product still contains the isomer 5-difluoromethyl-1-methyl-1-hydro-4-carboxylate in a molar ratio of 94: 6, which is still high in isomer content and low in product purity. The world patent WO2010009990A1 reports a method for synthesizing high-purity 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid, the GC purity reaches 99.6%, but in the process, the ring closure reaction of raw material 2-ethoxymethine difluoro acetoacetate and methyl hydrazine is carried out under the condition of extremely low temperature of-60 ℃ to-50 ℃. The process has harsh conditions, large difficulty in industrial scale-up production and high cost. In addition to the above problems, these patents all adopt a step-by-step batch reaction, which is long in steps, complicated in post-treatment, and high in cost, and thus is not an ideal industrial production method.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a method for synthesizing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid by a one-pot method, which has the advantages of reasonable process design, high yield, simple process operation and low cost and is suitable for industrialization.
In order to solve the technical problems, the invention adopts the following technical scheme:
a method for synthesizing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid by a one-pot method comprises the following steps:
in xylene, 4, 4-difluoro ethyl acetoacetate and triethyl orthoformate are subjected to condensation reaction under the catalysis of heating and metal carboxylate, after cooling, methyl hydrazine aqueous solution is dropwise added, then the temperature is raised for ring closure reaction, and the obtained ring closure reaction solution is saponified and acidified to obtain the 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid.
In the above one-pot method for synthesizing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid, preferably, the metal carboxylate is calcium acetate or calcium propionate.
In the above one-pot method for synthesizing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid, the molar ratio of ethyl 4, 4-difluoroacetoacetate, triethyl orthoformate and methylhydrazine is preferably 1.0: 1.05-1.5: 0.9-1.3.
In the above one-pot method for synthesizing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid, the molar ratio of ethyl 4, 4-difluoroacetoacetate to metal carboxylate is preferably 1.0: 0.01-0.5.
In the above one-pot method for synthesizing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid, preferably, the use amount ratio of ethyl 4, 4-difluoroacetoacetate to xylene is 1.0 mol: 500-1500 mL.
In the above one-pot method for synthesizing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid, the condensation reaction is preferably carried out at 90-130 ℃ for 2-5 hours.
In the method for synthesizing the 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid by the one-pot method, preferably, the dropping temperature of the methylhydrazine aqueous solution is-10-20 ℃; the temperature of the ring closing reaction is 0-30 ℃, and the time is 0.5-2 h.
In the above one-pot method for synthesizing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid, preferably, the inorganic alkali solution is added after the temperature is reduced, and then the methylhydrazine aqueous solution is added dropwise.
In the above one-pot method for synthesizing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid, preferably, the inorganic base in the inorganic base solution comprises sodium hydroxide, potassium hydroxide or potassium carbonate.
In the above one-pot method for synthesizing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid, the molar ratio of the inorganic base in the inorganic base solution to methylhydrazine in the aqueous solution of methylhydrazine is preferably 0.2-0.5: 0.9-1.0.
The invention process of the invention is as follows:
the conventional method mostly adopts a batch method, the first step of reaction is generally carried out by adding triethyl orthoformate into excessive acetic anhydride for reaction, purification is carried out after the reaction, the second step of batch method is carried out by adding another solvent again, and then methylhydrazine is added for reaction, and the defects of long steps, complex post-treatment and high cost exist in comparison with a one-pot method. However, the yield of the target product prepared by the one-pot method is low, so that no report related to the synthesis of the 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid by the one-pot method exists at present.
In an attempt to synthesize 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid by a one-pot method, the applicant found that acetic acid is generated by reacting acetic anhydride with ethanol which is a reaction byproduct, and that the existence of acetic acid and acetic anhydride affects the ring-closing reaction due to the fact that the ring-closing reaction is generally carried out in an alkaline environment, so that the yield of the target product is low. Therefore, in the prior art, an intermediate step of removing the impurity acetic acid generated in the system, recovering acetic anhydride and then adding a new solvent to react with methylhydrazine is required. Thereby bringing about the disadvantages of long time consumption of steps, more complex post-treatment, higher cost and the like.
The applicant optimizes the reaction conditions through a large number of experiments, calcium carboxylate is used as a catalyst of the condensation reaction, xylene is used as a solvent of the condensation reaction and the ring closure reaction, and a byproduct ethanol generated by the condensation reaction can not react with the calcium carboxylate and can not influence the subsequent ring closure reaction, so that the intermediate step of removing impurity acetic acid generated by a system and recycling acetic anhydride firstly, and then adding a new solvent to react with methylhydrazine in the prior art is omitted. Moreover, the influence of acetic acid as an impurity is avoided, the catalytic effect of the calcium carboxylate is good, and the yield and the purity of the obtained product are greatly improved; in addition, the existence of calcium carboxylate has no influence on the subsequent reaction and can be removed in saponification and acidification post-treatment. Therefore, the reaction operation of the invention is greatly simplified, and a set of reaction equipment and solvent recovery equipment are reduced in industrial production; the reaction period is greatly shortened, the reaction efficiency is greatly improved, the synthesis cost is greatly reduced, and the reaction yield and the product purity are improved.
Compared with the prior art, the invention has the advantages that:
the method adopts a one-pot method to synthesize the 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid, adopts calcium carboxylate as a catalyst of a condensation reaction, and dimethylbenzene as a solvent of the condensation reaction and a ring closing reaction, and the condensation reaction has no impurity generation and has no influence on the ring closing reaction, so that the yield of the product is greatly improved; in addition, the calcium carboxylate has good catalytic effect, the yield and the purity of the obtained product are further improved, and the technical problem of low yield of the one-pot method is solved. In addition, compared with a batch method, the one-pot synthesis method shortens the reaction time, simplifies the operation steps, reduces a set of reaction equipment and solvent recovery equipment in industrial production, improves the production efficiency, saves the cost and has high industrial application value.
Detailed Description
The invention is further described below with reference to specific preferred embodiments, without thereby limiting the scope of protection of the invention.
Example 1
169.4g (98 percent and 1.0 mol) of ethyl 4, 4-difluoroacetoacetate, 157.0 g (99 percent and 1.05 mol) of triethyl orthoformate, 1000mL of xylene and 1.58g (0.01 mol) of calcium acetate are added into a 2000mL four-mouth bottle provided with a mechanical stirring pipe, a condenser pipe, a constant pressure dropping funnel and a thermometer, stirring is started, and the reaction is carried out for 2 hours at the temperature of 90-100 ℃; then the temperature is reduced to 10 ℃, 26.6g of sodium hydroxide aqueous solution with the mass fraction of 30% (containing 0.2mol of NaOH) is added, after the addition is finished, 103.5g of 40% methylhydrazine aqueous solution (containing 0.9mol of methylhydrazine) is dripped, the temperature is raised to 20 ℃, and the ring forming reaction is carried out for 0.5 hour. After the reaction is finished, the reaction solution is saponified and acidified to obtain a target product, and the target product is filtered and dried to obtain 134.1g of a light yellow solid product, wherein the yield is 75.1%, and the content of the light yellow solid product is 98.5% by liquid chromatography quantitative analysis.
Example 2
169.4g (98 percent, 1.0 mol) of 4, 4-difluoroacetoacetic acid ethyl ester, 171.9 (99 percent, 1.15 mol) of triethyl orthoformate, 1000mL of xylene and 1.58g (0.01 mol) of calcium acetate are added into a 2000mL four-mouth bottle provided with a mechanical stirring pipe, a condensation pipe, a constant pressure dropping funnel and a thermometer, stirring is started, the reaction is carried out for 2 hours at 90-100 ℃, then the temperature is reduced to 10 ℃, 26.6g (containing 0.2mol of NaOH) of sodium hydroxide aqueous solution with the mass fraction of 30 percent is added, and after the addition is finished, 103.5g (containing 0.9mol of methylhydrazine) of 40 percent methylhydrazine aqueous solution is added dropwise and the reaction is carried out for 0.5 hour at 20 ℃. After the reaction is finished, the reaction solution is saponified and acidified to obtain a target product, and 136.1g of a light yellow solid product is obtained by filtering and drying, wherein the yield is 76.2%, and the content is 98.6% by liquid chromatography quantitative analysis.
Example 3
169.4g (98 percent, 1.0 mol) of ethyl 4, 4-difluoroacetoacetate, 194.3 (99 percent, 1.3 mol) of triethyl orthoformate, 1000mL of xylene and 1.58g (0.01 mol) of calcium acetate are added into a 2000mL three-necked flask equipped with a mechanical stirring pipe, a condenser pipe, a constant pressure dropping funnel and a thermometer, stirring is started, the mixture reacts at 90-100 ℃ for 2 hours, then the temperature is reduced to 10 ℃, 26.6g (containing 0.2mol of NaOH) of sodium hydroxide aqueous solution with the mass fraction of 30 percent is added, and after the addition is finished, 103.5g (containing 0.9mol of methylhydrazine) of 40 percent methylhydrazine aqueous solution is dropwise added, and the temperature is raised to 20 ℃ for 0.5 hour. After the reaction is finished, the reaction solution is saponified and acidified to obtain a target product, and the target product is filtered and dried to obtain 136.4g of a light yellow solid product, wherein the yield is 76.3%, and the content of the light yellow solid product is 98.4% by liquid chromatography quantitative analysis.
Example 4
169.4g (98 percent, 1.0 mol) of ethyl 4, 4-difluoroacetoacetate, 171.9 (99 percent, 1.15 mol) of triethyl orthoformate, 1000mL of xylene and 7.9g (0.05 mol) of calcium acetate are added into a 2000mL three-necked flask equipped with a mechanical stirring pipe, a condenser pipe, a constant pressure dropping funnel and a thermometer, stirring is started, the mixture reacts at 90-100 ℃ for 2 hours, then the temperature is reduced to 10 ℃, 26.6g (containing 0.2mol of NaOH) of sodium hydroxide aqueous solution with the mass fraction of 30 percent is added, and after the addition is finished, 103.5g (containing 0.9mol of methylhydrazine) of 40 percent aqueous solution of methylhydrazine is added dropwise and the mixture is heated to 20 ℃ for 0.5 hour. After the reaction is finished, the reaction solution is saponified and acidified to obtain a target product, and the target product is filtered and dried to obtain 140.5g of a light yellow solid product, wherein the yield is 78.7%, and the content of the light yellow solid product is 98.5% by liquid chromatography quantitative analysis.
Example 5
169.4g (98 percent, 1.0 mol) of ethyl 4, 4-difluoroacetoacetate, 171.9 (99 percent, 1.15 mol) of triethyl orthoformate, 1000mL of xylene and 15.8g (0.1 mol) of calcium acetate are added into a 2000mL three-necked flask equipped with a mechanical stirring pipe, a condenser pipe, a constant pressure dropping funnel and a thermometer, stirring is started, the mixture reacts at 90-100 ℃ for 2 hours, then the temperature is reduced to 10 ℃, 26.6g (containing 0.2mol of NaOH) of sodium hydroxide aqueous solution with the mass fraction of 30 percent is added, and after the addition is finished, 103.5g (containing 0.9mol of methylhydrazine) of 40 percent methylhydrazine aqueous solution is dropwise added, and the temperature is raised to 20 ℃ for 0.5 hour. After the reaction is finished, the reaction solution is saponified and acidified to obtain a target product, and the target product is filtered and dried to obtain 143.9g of a light yellow solid product, wherein the yield is 80.7%, and the content of the light yellow solid product is 98.7% by liquid chromatography quantitative analysis.
Example 6
169.4g (98 percent, 1.0 mol) of ethyl 4, 4-difluoroacetoacetate, 171.9 (99 percent, 1.15 mol) of triethyl orthoformate, 1000mL of xylene and 79g (0.5 mol) of calcium acetate are added into a 2000mL three-necked flask equipped with a mechanical stirring pipe, a condenser pipe, a constant pressure dropping funnel and a thermometer, stirring is started, the mixture reacts at 90-100 ℃ for 2 hours, then the temperature is reduced to 10 ℃, 26.6g (containing 0.2mol of NaOH) of sodium hydroxide aqueous solution with the mass fraction of 30 percent is added, and after the addition, 103.5g (containing 0.9mol of methylhydrazine) of 40 percent aqueous solution is dropwise added, and the temperature is raised to 20 ℃ for reaction for 0.5 hour. After the reaction is finished, the reaction solution is saponified and acidified to obtain a target product, and 138.8g of a light yellow solid product is obtained by filtering and drying, wherein the yield is 80.1%, and the content is 98.5% by liquid chromatography quantitative analysis.
Example 7
169.4g (98 percent, 1.0 mol) of ethyl 4, 4-difluoroacetoacetate, 171.9 (99 percent, 1.15 mol) of triethyl orthoformate, 1000mL of xylene and 15.8g (0.1 mol) of calcium acetate are added into a 2000mL three-necked flask equipped with a mechanical stirring pipe, a condenser pipe, a constant pressure dropping funnel and a thermometer, stirring is started, the mixture reacts at 100-110 ℃ for 2 hours, then the temperature is reduced to 10 ℃, 26.6g (containing 0.2mol of NaOH) of sodium hydroxide aqueous solution with the mass fraction of 30 percent is added, and after the addition is finished, 103.5g (containing 0.9mol of methylhydrazine) of 40 percent methylhydrazine aqueous solution is dropwise added, and the temperature is raised to 20 ℃ for 0.5 hour. After the reaction is finished, the reaction solution is saponified and acidified to obtain a target product, and the target product is filtered and dried to obtain 144.4g of a light yellow solid product, wherein the yield is 81.0%, and the content of the light yellow solid product is 98.7% by liquid chromatography quantitative analysis.
Example 8
169.4g (98 percent, 1.0 mol) of ethyl 4, 4-difluoroacetoacetate, 171.9 (99 percent, 1.15 mol) of triethyl orthoformate, 1000mL of xylene and 15.8g (0.1 mol) of calcium acetate are added into a 2000mL three-necked flask equipped with a mechanical stirring pipe, a condenser pipe, a constant pressure dropping funnel and a thermometer, stirring is started, the mixture reacts at 120-130 ℃ for 2 hours, then the temperature is reduced to 10 ℃, 26.6g (containing 0.2mol of NaOH) of sodium hydroxide aqueous solution with the mass fraction of 30 percent is added, and after the addition is finished, 103.5g (containing 0.9mol of methylhydrazine) of 40 percent methylhydrazine aqueous solution is dropwise added, and the temperature is raised to 20 ℃ for 0.5 hour. After the reaction is finished, the reaction solution is saponified and acidified to obtain a target product, and the target product is filtered and dried to obtain 141.8g of a light yellow solid product, wherein the yield is 79.2%, and the content of the light yellow solid product is 98.3% by liquid chromatography quantitative analysis.
Example 9
169.4g (98 percent, 1.0 mol) of ethyl 4, 4-difluoroacetoacetate, 171.9 (99 percent, 1.15 mol) of triethyl orthoformate, 1000mL of xylene and 15.8g (0.1 mol) of calcium acetate are added into a 2000mL three-necked flask equipped with a mechanical stirring pipe, a condenser pipe, a constant pressure dropping funnel and a thermometer, stirring is started, the mixture reacts at 100-110 ℃ for 2 hours, then the temperature is reduced to 10 ℃, 26.6g (containing 0.2mol of NaOH) of sodium hydroxide aqueous solution with the mass fraction of 30 percent is added, and after the addition is finished, 115.0g (containing 1.0mol of methylhydrazine) of 40 percent methylhydrazine aqueous solution is dropwise added, and the temperature is raised to 20 ℃ for 0.5 hour. After the reaction is finished, the reaction solution is saponified and acidified to obtain a target product, and 147.1g of a light yellow solid product is obtained by filtering and drying, wherein the yield is 82.5%, and the content is 98.7% by liquid chromatography quantitative analysis.
Example 9
169.4g (98 percent, 1.0 mol) of 4, 4-difluoroacetoacetic acid ethyl ester, 171.9 (99 percent, 1.15 mol) of triethyl orthoformate, 1000mL of xylene and 15.8g (0.1 mol) of calcium acetate are added into a 2000mL three-necked flask equipped with a mechanical stirring pipe, a condenser pipe, a constant pressure dropping funnel and a thermometer, stirring is started, the mixture reacts at 100-110 ℃ for 2 hours, then the temperature is reduced to 10 ℃, 40.0g (containing 0.3mol of NaOH) of sodium hydroxide aqueous solution with the mass fraction of 30 percent is added, and after the addition is finished, 115.0g (containing 1.0mol of methylhydrazine) of 40 percent methylhydrazine aqueous solution is added dropwise and the temperature is increased to 20 ℃ for reaction for 0.5 hour. After the reaction is finished, the reaction solution is saponified and acidified to obtain a target product, and the target product is filtered and dried to obtain 148.6g of a light yellow solid product, wherein the yield is 83.3%, and the content of the light yellow solid product is 98.6% by liquid chromatography quantitative analysis.
Example 10
169.4g (98 percent, 1.0 mol) of ethyl 4, 4-difluoroacetoacetate, 171.9 (99 percent, 1.15 mol) of triethyl orthoformate, 1000mL of xylene and 15.8g (0.1 mol) of calcium acetate are added into a 2000mL three-necked flask equipped with a mechanical stirring pipe, a condenser pipe, a constant pressure dropping funnel and a thermometer, stirring is started, the mixture reacts at 100-110 ℃ for 2 hours, then the temperature is reduced to 10 ℃, 66.6g (containing 0.5mol of NaOH) of sodium hydroxide aqueous solution with the mass fraction of 30 percent is added, and after the addition is finished, 115.0g (containing 1.0mol of methylhydrazine) of 40 percent methylhydrazine aqueous solution is dropwise added, and the temperature is raised to 20 ℃ for 0.5 hour. After the reaction is finished, the reaction solution is saponified and acidified to obtain a target product, and the target product is filtered and dried to obtain 146.8g of a light yellow solid product, wherein the yield is 82.1%, and the content of the light yellow solid product is 98.4% by liquid chromatography quantitative analysis.
Example 11
169.4g (98 percent, 1.0 mol) of 4, 4-difluoroacetoacetic acid ethyl ester, 171.9 (99 percent, 1.15 mol) of triethyl orthoformate, 1000mL of xylene and 18.6g (0.1 mol) of calcium propionate are added into a 2000mL three-necked flask equipped with a mechanical stirring pipe, a condenser pipe, a constant pressure dropping funnel and a thermometer, stirring is started, the mixture reacts at 100-110 ℃ for 2 hours, then the temperature is reduced to 10 ℃, 66.6g (containing 0.5mol of NaOH) of sodium hydroxide aqueous solution with the mass fraction of 30 percent is added, and after the addition, 115.0g (containing 1.0mol of methylhydrazine) of 40 percent methylhydrazine aqueous solution is added dropwise and the temperature is increased to 20 ℃ for 0.5 hour. After the reaction is finished, the reaction solution is saponified and acidified to obtain a target product, and the target product is filtered and dried to obtain 144.3g of a light yellow solid product, wherein the yield is 80.8%, and the content of the light yellow solid product is 98.5% by liquid chromatography quantitative analysis.
Example 12
169.4g (98 percent, 1.0 mol) of 4, 4-difluoroacetoacetic acid ethyl ester, 171.9 (99 percent, 1.15 mol) of triethyl orthoformate, 1000mL of xylene and 18.6g (0.1 mol) of calcium propionate are added into a 2000mL three-necked flask equipped with a mechanical stirring pipe, a condensation pipe, a constant pressure dropping funnel and a thermometer, stirring is started, the mixture reacts at 100-110 ℃ for 2 hours, then the temperature is reduced to 10 ℃, 56.1g (0.3 mol) of potassium hydroxide aqueous solution with the mass fraction of 30 percent is added, and after the addition, 115.0g (1.0 mol) of 40 percent methylhydrazine aqueous solution is dropwise added, and the temperature is raised to 20 ℃ for reaction for 0.5 hour. After the reaction is finished, the reaction solution is saponified and acidified to obtain a target product, and the target product is filtered and dried to obtain 146.1g of a light yellow solid product, wherein the yield is 81.9%, and the content of the light yellow solid product is 98.7% by liquid chromatography quantitative analysis.
Example 13
169.4g (98 percent, 1.0 mol) of 4, 4-difluoroacetoacetic acid ethyl ester, 171.9 (99 percent, 1.15 mol) of triethyl orthoformate, 1000mL of xylene and 18.6g (0.1 mol) of calcium propionate are added into a 2000mL three-necked flask equipped with a mechanical stirring pipe, a condensation pipe, a constant pressure dropping funnel and a thermometer, stirring is started, the mixture reacts at 100-110 ℃ for 2 hours, then the temperature is reduced to 10 ℃, 138g (0.3 mol) of potassium hydroxide aqueous solution with the mass fraction of 30 percent is added, and after the addition is finished, 115.0g (1.0 mol) of 40 percent methylhydrazine aqueous solution is dropwise added, and the temperature is raised to 20 ℃ for reaction for 0.5 hour. After the reaction is finished, the reaction solution is saponified and acidified to obtain a target product, and the target product is filtered and dried to obtain 143.1g of a light yellow solid product, wherein the yield is 79.9%, and the content of the light yellow solid product is 98.3% by liquid chromatography quantitative analysis.
Example 14
169.4g (98 percent, 1.0 mol) of 4, 4-difluoroacetoacetic acid ethyl ester, 171.9 (99 percent, 1.15 mol) of triethyl orthoformate, 1000mL of xylene and 18.6g (0.1 mol) of calcium propionate are added into a 2000mL three-necked flask equipped with a mechanical stirring pipe, a condensation pipe, a constant pressure dropping funnel and a thermometer, stirring is started, the mixture reacts at 100-110 ℃ for 2 hours, then the temperature is reduced to 20 ℃, 138g (0.3 mol) of potassium hydroxide aqueous solution with the mass fraction of 30 percent is added, and after the addition is finished, 115.0g (1.0 mol) of 40 percent methylhydrazine aqueous solution is dropwise added, and the temperature is raised to 30 ℃ for reaction for 0.5 hour. After the reaction is finished, the reaction solution is saponified and acidified to obtain a target product, and the target product is filtered and dried to obtain 139.9g of a light yellow solid product, wherein the yield is 78.1%, and the content is 98.2% by liquid chromatography quantitative analysis.
Example 15
169.4g (98 percent, 1.0 mol) of 4, 4-difluoroacetoacetic acid ethyl ester, 171.9 (99 percent, 1.15 mol) of triethyl orthoformate, 1500mL of xylene and 55.8g (0.3 mol) of calcium propionate are added into a 3000mL three-neck flask provided with a mechanical stirring pipe, a condenser pipe, a constant pressure dropping funnel and a thermometer, stirring is started, the mixture reacts at 100-110 ℃ for 2 hours, then the temperature is reduced to 10 ℃, 66.6g (containing 0.5mol of NaOH) of sodium hydroxide aqueous solution with the mass fraction of 30 percent is added, and after the addition is finished, 115.0g (containing 1.0mol of methylhydrazine) of 40 percent methylhydrazine aqueous solution is added dropwise and the temperature is raised to 20 ℃ for reaction for 1 hour. After the reaction is finished, the reaction solution is saponified and acidified to obtain a target product, and the target product is filtered and dried to obtain 145.8g of a light yellow solid product, wherein the yield is 81.8%, and the content is 98.7% by liquid chromatography quantitative analysis.
Example 16
169.4g (98 percent, 1.0 mol) of 4, 4-difluoroacetoacetic acid ethyl ester, 171.9 (99 percent, 1.15 mol) of triethyl orthoformate, 1500mL of xylene and 55.8g (0.3 mol) of calcium propionate are added into a 3000mL three-necked flask equipped with a mechanical stirring pipe, a condensation pipe, a constant pressure dropping funnel and a thermometer, stirring is started, the mixture reacts at 100-110 ℃ for 2 hours, then the temperature is reduced to 10 ℃, 230g (0.5 mol) of potassium carbonate aqueous solution with the mass fraction of 30 percent is added, after the addition is finished, 115.0g (1.0 mol) of 40 percent methylhydrazine aqueous solution is added dropwise, and the temperature is raised to 20 ℃ for reaction for 1 hour. After the reaction is finished, the reaction solution is saponified and acidified to obtain a target product, and the target product is filtered and dried to obtain 143.3g of a light yellow solid product, wherein the yield is 79.1%, and the content of the light yellow solid product is 97.1% by liquid chromatography quantitative analysis.
The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above-described embodiments. All technical schemes belonging to the idea of the invention belong to the protection scope of the invention. It should be noted that modifications and embellishments within the scope of the invention may be made by those skilled in the art without departing from the principle of the invention, and such modifications and embellishments should also be considered as within the scope of the invention.
Claims (8)
1. A method for synthesizing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid by a one-pot method comprises the following steps:
in xylene, 4, 4-difluoro ethyl acetoacetate and triethyl orthoformate are subjected to condensation reaction under the catalysis of heating and metal carboxylate, an inorganic alkali solution is added after the temperature is reduced, then a methylhydrazine aqueous solution is added dropwise, the temperature is raised to carry out a ring closing reaction, and the obtained ring closing reaction liquid is saponified and acidified to obtain 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid; the metal carboxylate is calcium acetate or calcium propionate.
2. The method for synthesizing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid according to claim 1, wherein the molar ratio of ethyl 4, 4-difluoroacetoacetate, triethyl orthoformate and methylhydrazine is 1.0: 1.05-1.5: 0.9-1.3.
3. The one-pot synthesis method of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid according to claim 2, wherein the molar ratio of ethyl 4, 4-difluoroacetoacetate to metal carboxylate is 1.0: 0.01-0.5.
4. The method for synthesizing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid according to claim 3, wherein the using amount ratio of ethyl 4, 4-difluoroacetoacetate to xylene is 1.0 mol: 500-1500 mL.
5. The method for synthesizing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid according to claim 4, wherein the condensation reaction is carried out at 90-130 ℃ for 2-5H.
6. The one-pot method for synthesizing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid according to claim 5, wherein the dropping temperature of the methylhydrazine aqueous solution is-10 to 20 ℃; the temperature of the ring closing reaction is 0-30 ℃, and the time is 0.5-2 h.
7. The one-pot synthesis method of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid according to any one of claims 1 to 6, wherein the inorganic base in the inorganic base solution is sodium hydroxide, potassium hydroxide or potassium carbonate.
8. The one-pot synthesis method of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid according to claim 7, wherein the molar ratio of the inorganic base in the inorganic alkali solution to methylhydrazine in the aqueous solution of methylhydrazine is 0.2-0.5: 0.9-1.0.
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| US4808747A (en) * | 1984-06-23 | 1989-02-28 | Huls Ag | Process for producing alkylidene compounds and arylidene compounds |
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