CN111362874B - Preparation method of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid - Google Patents
Preparation method of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid Download PDFInfo
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Abstract
The invention discloses a preparation method of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, belonging to the technical field of organic synthesis. 2, 2-difluoro acetyl halide is used as a raw material, and is subjected to addition reaction with alpha, beta-unsaturated ester and alkaline hydrolysis to obtain alpha-difluoro acetyl intermediate carboxylic acid; then condensing and cyclizing the product with methyl hydrazine water solution in the presence of a catalyst to obtain a crude product of the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid; recrystallizing to obtain the pure product of the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid. The method has the advantages of simple operation, easily obtained raw materials, high reaction yield, reduction of isomers in the reaction process through various ways, and convenience in product purification.
Description
Technical Field
The invention relates to a preparation method of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, belonging to the technical field of organic synthesis.
Background
3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, CAS: 176969-34-9. The English name 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid. With the development of the pesticide industry and the infinite emergence of compounds thereof, heterocyclic compounds occupy very important positions, wherein the pyrazole derivatives have important positions in the field of new drug development as an important class of heterocyclic compounds, and due to the characteristics of high efficiency, low toxicity and structural diversity presented by the pyrazole derivatives, the pyrazole derivatives attract extensive attention of people, and a plurality of novel, high-efficiency and environment-friendly pesticide products of the pyrazole derivatives are produced.
The 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid is an important medical and fine chemical intermediate, can be used for synthesizing various bactericides and pesticides, and is a key intermediate for synthesizing novel amides bactericides such as fluopyram, bixafen, isopyrazam and the like.
The existing synthesis method is as in patent [ US2011040096a1], and 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid is obtained by adopting a cyclization mode, but the isomer ratio is larger than 89: 10, the chemical purity is more less than 90 percent, the recrystallization times are too many, the operation is relatively complicated, the product with the chemical purity of more than 99.5 percent can be obtained, and the yield is less than 75 percent. Therefore, there is a need to develop a new synthesis method to achieve an efficient preparation method that increases the ratio of the target product while decreasing the ratio of isomers.
Disclosure of Invention
In order to overcome the problem of reducing the content of isomers (impurities) in the reaction process, and a brand new process improvement is carried out on the basis of the original process. 2, 2-difluoro acetyl halide is used as a raw material, and is subjected to addition reaction with alpha, beta-unsaturated ester and alkaline hydrolysis to obtain alpha-difluoro acetyl intermediate carboxylic acid; then condensing and cyclizing the product with methyl hydrazine water solution in the presence of a catalyst to obtain a crude product of the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid; recrystallizing to obtain the pure product of the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid. The method has the advantages of simple operation, easily obtained raw materials, high reaction yield, reduction of isomers in the reaction process through various ways, and convenience in product purification.
The invention relates to a preparation method of (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, which comprises the following steps:
the reaction equation is as follows:
wherein X is F or Cl; r1Is C1-C4 alkyl; r2Is dimethylamino, diethylamino, morpholinyl or 2,2,6, 6-tetramethylpiperidine;
the first step is as follows: substitution/hydrolysis reaction
Dissolving alpha, beta-unsaturated ester 2 and an acid-binding agent in an organic solvent, dropwise adding 2, 2-difluoroacetyl halide 1 at low temperature for reaction, and then adding alkali for hydrolysis to obtain a solution of an alpha-difluoroacetyl intermediate 3;
the second step is that: condensation/cyclization reaction
Adding a catalyst into the solution of the alpha-difluoro acetyl intermediate 3, then carrying out low-temperature condensation reaction with a methylhydrazine aqueous solution, then carrying out reduced pressure and temperature rise reaction for cyclization, acidifying to obtain a crude product of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, and recrystallizing to obtain 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid 4.
Further, in the above technical scheme, the acid scavenger is selected from triethylamine or N, N-diisopropylethylamine.
Further, in the above technical solution, the solvent in the first step is selected from dioxane, tetrahydrofuran, dichloromethane or 1, 2-dichloroethane.
Further, in the above technical solution, the molar ratio of the 2, 2-difluoroacetic acid halide 1, α, β -unsaturated ester 2 to the acid scavenger in the first step is 1: 0.95-0.98: 1.0-1.5.
Further, in the above technical solution, the alkali for the first hydrolysis is selected from sodium hydroxide and potassium hydroxide.
Further, in the above technical scheme, the low-temperature reaction temperature in the second step is-30 ℃ to 0 ℃; the temperature of the heating reaction is 50-120 ℃.
Further, in the above technical scheme, the methylhydrazine in the second step is a methylhydrazine aqueous solution with a mass concentration of not less than 40%.
Further, in the above technical scheme, the catalyst in the second step is selected from sodium iodide or potassium iodide.
Further, in the above technical scheme, the molar ratio of the α -difluoroacetyl intermediate 3, the catalyst and methylhydrazine in the second step is 1: 0.2-1.0: 1.05-1.15.
Further, in the above technical scheme, the recrystallization solvent in the second step is a mixture of an alcohol solvent and water, and the proportion thereof is selected from 35% to 65%; the alcohol solvent is selected from methanol, ethanol or isopropanol.
Advantageous effects of the invention
The method comprises the steps of taking 2, 2-difluoro acetyl halide as a raw material, carrying out substitution reaction with alpha, beta-unsaturated ester, hydrolyzing under an alkaline condition to change carboxylic ester into carboxylic acid negative ions to form electron-donating groups, and simultaneously carrying out condensation and cyclization with methyl hydrazine aqueous solution in the presence of catalytic amount of iodine negative ions to obtain a crude product of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid;
wherein the ratio of the product to the isomer in the crude product of the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid is 93-96: 4-7:
subsequent recrystallization afforded 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid. The method has the advantages of simple operation, easily obtained raw materials, high reaction yield, obviously reduced reaction isomers and high purity of the obtained product up to more than 99.5 percent.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following specific examples.
These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
Synthesis of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid
Example 1
393g (2.5mol,1eq) of isopropyl N, N-dimethylamino acrylate, 303.6g (3.0mol,1.2eq) of triethylamine and 3000mL of 1, 4-dioxane were charged into a reaction flask under the protection of nitrogen. Controlling the reaction temperature to be-10-5 ℃, slowly dripping 235.3g (2.4mol,0.96eq) of 2, 2-difluoroacetyl fluoride, reacting at-5-5 ℃ for 1 hour after dripping is finished, detecting the raw material by GC (gas chromatography) to be less than 0.5%, adding 500g of water for quenching, standing for layering, cooling the organic phase to-5-5 ℃, dripping 1000g of 10% NaOH aqueous solution, reacting at-5-5 ℃ for 1 hour after dripping is finished, filtering to obtain a 2-difluoroacetyl-3- (dimethylamino) sodium acrylate mixed solution, and storing the mixed solution at 5-5 ℃ in nitrogen for later use.
Under the protection of nitrogen, 187.4g (1.25mol,0.5eq) of sodium iodide is added into the mixed solution of the sodium 2-difluoroacetyl-3- (dimethylamino) acrylate, the temperature of the reaction liquid is reduced to-30 ℃, 316.7g (2.75mol,1.1eq) of 40% methylhydrazine aqueous solution is dripped, the temperature of the dripping process is controlled to-30 ℃ to-20 ℃, the reaction is carried out for 2 hours after the dripping is finished, HPLC detection raw materials are less than or equal to 0.5% after the reaction is finished, organic phase is distilled under micro negative pressure (50-70 mm water column, temperature is 40-80 ℃), the generated dimethylamine/isopropanol and solvent and a small amount of water are distilled out, dichloromethane 1000mL of extraction impurities are added after the temperature is reduced to room temperature, standing and layering are carried out, and water. Cooling the water phase to 20 ℃, slowly dropwise adding 2mol/L hydrochloric acid to adjust the pH value to be 1-2, separating out solids at the moment, cooling to 10-15 ℃, stirring for 4 hours, filtering, rinsing a filter cake with a small amount of water to obtain a crude product of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, taking a solid sample, and detecting the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid and 5- (difluoromethyl) -1-methyl-1H-pyridine-4-carboxylic acidThe ratio of oxazole-4-carboxylic acid to carboxylic acid is 96: 4. the crude product was recrystallized from 2500mL of a 40% aqueous ethanol solution to give 344.8g of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid in 78.3% yield, HPLC: 99.7 percent.1HNMR(400MHz,DMSO-d6):δ＝12.71(s,1H),8.33(s,1H),7.19(t,1H),3.89(s,3H)。
Example 2
Under nitrogen protection, 428.1g (2.5mol,1eq) of N, N-dimethylamino-acrylic acid tert-butyl ester, 355.4g (2.75mol,1.1eq) of N, N-diisopropylethylamine and 3500mL of methylene chloride were charged into a reaction flask. Controlling the reaction temperature to be-10-5 ℃, slowly dropwise adding 280.5g (2.45mol,0.98eq) of 2, 2-difluoroacetyl chloride, reacting for 1 hour at-5-5 ℃ after dropwise adding, detecting the raw material by GC (gas chromatography) to be less than 0.5%, adding 500g of water, quenching, standing and layering. Cooling the organic phase to-5-5 ℃, dropwise adding 700g of 20% KOH aqueous solution, reacting for 1 hour at-5-5 ℃ after dropwise adding, filtering to obtain a 2-difluoroacetyl-3- (dimethylamino) potassium acrylate mixed solution, and storing the mixed solution at 5-5 ℃ under nitrogen for later use.
Adding 249g (1.5mol,0.6eq) of potassium iodide into the mixed solution of the 2-difluoroacetyl-3- (dimethylamino) potassium acrylate under the protection of nitrogen, cooling the reaction liquid to-30 ℃, dropwise adding 316.7g (2.75mol,1.1eq) of 40% methylhydrazine aqueous solution, controlling the temperature of the dropwise adding process to-30 ℃ to-20 ℃, reacting for 2 hours after dropwise adding, detecting that the raw material is less than or equal to 0.5% by HPLC, distilling an organic phase under slight negative pressure (50-70 mm water column, temperature is 40-85 ℃), distilling generated dimethylamine/tert-butanol and solvent and a small amount of water, cooling to room temperature, adding 1000mL of dichloromethane extraction impurities, standing for layering, and keeping the water phase. Cooling the water phase to 20 ℃, slowly dropwise adding 2mol/L hydrochloric acid to adjust the pH value to be 1-2, separating out solids at the moment, cooling to 10-15 ℃, stirring for 4 hours, filtering, rinsing a filter cake with a small amount of water to obtain a crude product of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, taking a solid sample, and detecting that the proportion of the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid to the 5- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid is 95: 5. the crude product was recrystallized from 2400mL of 40% aqueous ethanol (reflux by heating for 1-2 hours, cooling to 10 ℃ C.) to give 334.2g of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, 75.9% yield, 99.6% HPLC.
Example 3
393g (2.5mol,1eq) of methyl N, N-diethylaminoacrylate, 303.6g (3mol,1.2eq) of triethylamine and 3500mL of tetrahydrofuran were charged into the reaction flask under nitrogen protection. Controlling the reaction temperature to be-10-5 ℃, slowly dripping 235.3g (2.4mol,0.96eq) of 2, 2-difluoroacetyl fluoride, reacting for 1 hour at-5-5 ℃ after dripping is finished, detecting the raw material by GC (gas chromatography) and adding 500g of water for quenching, standing and layering. Cooling the organic phase to-5-5 ℃, dropwise adding 1000g of 10% NaOH aqueous solution, reacting for 1 hour at-5-5 ℃ after dropwise adding, filtering to obtain a 2-difluoroacetyl-3- (diethylamino) sodium acrylate mixed solution, and storing the mixed solution at 5-5 ℃ under nitrogen for later use.
Under the protection of nitrogen, 187.4g (1.25mol,0.5eq) of sodium iodide is added into the mixed solution of the 2-difluoroacetyl-3- (diethylamino) sodium acrylate, the temperature of the reaction solution is reduced to-30 ℃, 316.7g (2.75mol,1.1eq) of 40% methylhydrazine aqueous solution is dripped, the temperature of the dripping process is controlled to-30 ℃ to-25 ℃, the reaction is carried out for 2 hours after the dripping is finished, HPLC detection raw materials are less than or equal to 0.5% after the reaction is finished, organic phase is distilled under slight negative pressure (50-70 mm water column, temperature is 40-75 ℃), the removed group diethylamine/methanol and solvent and a small amount of water are distilled out, the temperature is reduced to room temperature, 1000mL of dichloromethane extraction impurities are added, the mixture is kept stand for. Cooling the water phase to 20 ℃, slowly dropwise adding 2mol/L hydrochloric acid to adjust the pH value to be 1-2, separating out solids at the moment, cooling to 10-15 ℃, stirring for 4 hours, filtering, rinsing a filter cake with a small amount of water to obtain a crude product of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, taking a solid sample, and detecting that the proportion of the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid to the 5- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid is 94: 6. the crude product was recrystallized from 2400mL of 35% aqueous methanol (reflux at elevated temperature for 1-2 hours, cooled to 10 ℃ C.) to give 339.5g of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, 77.1% yield, 99.6% HPLC.
Example 4
Under the protection of nitrogen, 428.2g (2.5mol,1eq) of N, N-diethylaminoethyl acrylate, 371.6g (2.875mol,1.15eq) of N, N-diisopropylethylamine and 3500mL of dichloroethane were charged into the reaction flask. Controlling the reaction temperature to be-10-5 ℃, slowly dripping 283.9g (2.45mol,0.98eq) of 2, 2-difluoroacetyl chloride, reacting for 1 hour at-5-5 ℃ after dripping is finished, detecting the raw material by GC (gas chromatography) to be less than 0.5%, adding 500g of water for quenching, standing for layering, cooling the organic phase to-5-5 ℃, dripping 700g of 20% KOH aqueous solution, reacting for 1 hour at-5-5 ℃ after dripping is finished, filtering to obtain a 2-difluoroacetyl-3- (diethylamino) potassium acrylate mixed solution, and storing the mixed solution at 5-5 ℃ in nitrogen for later use.
Adding 249g (1.5mol,0.6eq) of potassium iodide into the mixed solution of the 2-difluoroacetyl-3- (diethylamino) potassium acrylate under the protection of nitrogen, cooling the reaction liquid to-30 ℃, dropwise adding 316.7g (2.75mol,1.1eq) of 40% methylhydrazine aqueous solution, controlling the temperature of the dropwise adding process to-30 ℃ to-20 ℃, reacting for 2 hours after dropwise adding, detecting that the raw material is less than or equal to 0.5% by HPLC, distilling an organic phase under slight negative pressure (50-70 mm water column, temperature of 40-85 ℃), distilling generated diethylamine/ethanol and solvent and a small amount of water, cooling to room temperature, adding 1000mL of dichloromethane extraction impurities, standing for layering, and keeping a water phase. Cooling the water phase to 20 ℃, slowly dropwise adding 2mol/L hydrochloric acid to adjust the pH value to be 1-2, separating out solids at the moment, cooling to 10-15 ℃, stirring for 4 hours, filtering, rinsing a filter cake with a small amount of water to obtain a crude product of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, taking a solid sample, and detecting that the proportion of the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid to the 5- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid is 96: 4. the crude product was recrystallized from 2400mL of 35% aqueous methanol (reflux by heating for 1-2 hours, cooling to 5-10 ℃ C.) to give 350.5g of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, yield 79.6%, HPLC 99.3%.
Example 5:
under the protection of nitrogen, 342.4g (2.0mol,1eq), 303.6g (3mol,1.2eq) of methyl 3-morpholin-4-ylacrylate and 4000mL of dichloromethane were put into a reaction flask. Controlling the reaction temperature to be-15-0 ℃, slowly dripping 226.7g (1.98mol,0.99eq) of 2, 2-difluoroacetyl chloride, reacting for 1 hour at-5-0 ℃ after dripping is finished, detecting the raw material by HPLC (high performance liquid chromatography) to be less than 0.5 percent, adding 700g of water to quench, standing and layering. Cooling the organic phase to-5-5 ℃, dropwise adding 1000g of 10% NaOH aqueous solution, reacting for 1 hour at-5-5 ℃ after dropwise adding, filtering to obtain a 2-difluoroacetyl-3- (morpholinyl) sodium acrylate mixed solution, and storing in nitrogen at 5-5 ℃ for later use.
Under the protection of nitrogen, 187.4g (1.25mol,0.5eq) of sodium iodide is added into the mixed solution of the sodium 2-difluoroacetyl-3- (morpholinyl) acrylate, the temperature of the reaction liquid is reduced to-30 ℃, 316.7g (2.75mol,1.1eq) of 40% methylhydrazine aqueous solution is dripped, the temperature of the dripping process is controlled to-30 ℃ to-20 ℃, the reaction is carried out for 2 hours after the dripping is finished, HPLC detection raw materials are less than or equal to 0.5% of the reaction is finished, organic phase is distilled under slight negative pressure (50-70 mm water column, temperature is 40-105 ℃), the generated morpholine/methanol and solvent and a little water are distilled out, dichloromethane 1000mL of extraction impurities are added after the temperature is reduced to room temperature, standing and layering are carried out, and. Cooling the water phase to 20 ℃, slowly dropwise adding 2mol/L hydrochloric acid to adjust the pH value to be 1-2, separating out solids at the moment, cooling to 10-15 ℃, stirring for 4 hours, filtering, rinsing a filter cake with a small amount of water to obtain a crude product of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, taking a solid sample, and detecting that the proportion of the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid to the 5- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid is 93: 7. the crude product was recrystallized from 2500mL of 45% isopropanol water solution (heated under reflux for 1-2H, cooled to 0-5 ℃ and rinsed with cold 45% isopropanol water solution) to give 328.9g of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, 74.7% yield, 99.6% HPLC.
Example 6:
under the protection of nitrogen, 370.5g (2.0mol,1eq), 371.6g (2.875mol,1.15eq) of N, N-diisopropylethylamine and 3500mL of dichloroethane were charged into a reaction flask. Controlling the reaction temperature to be-15-5 ℃, slowly dropwise adding 194.1g (1.98mol,0.99eq) of 2, 2-difluoroacetyl fluoride, reacting for 1 hour at-5-0 ℃ after dropwise adding, detecting by HPLC that the raw material is less than 0.5 percent and the product purity is more than or equal to 93 percent, adding 1000g of water, quenching, standing and layering. Cooling the organic phase to-5-5 ℃, dropwise adding 700g of 20% KOH aqueous solution, reacting for 1 hour at-5-5 ℃ after dropwise adding, filtering to obtain a 2-difluoroacetyl-3- (morpholinyl) potassium acrylate mixed solution, and storing the mixed solution at 5-5 ℃ under nitrogen for later use.
Under the protection of nitrogen, 332g (2.0mol,0.8eq) of potassium iodide is added into the mixed solution of the 2-difluoroacetyl-3- (morpholinyl) potassium acrylate, the temperature of the reaction liquid is reduced to-30 ℃, 316.7g (2.75mol,1.1eq) of 40% methylhydrazine aqueous solution is dripped, the temperature of the dripping process is controlled to-30 ℃ to-20 ℃, the reaction is carried out for 2 hours after the dripping is finished, HPLC detection raw materials are less than or equal to 0.5% after the reaction is finished, organic phase is distilled under slight negative pressure (50-70 mm water column, temperature is 40-105 ℃), the generated morpholine/ethanol and solvent and a little water are distilled out, the temperature is reduced to room temperature, 1000mL of dichloromethane is added for extracting impurities, the mixture is kept stand for delamination. Cooling the water phase to 20 ℃, slowly dropwise adding 2mol/L hydrochloric acid to adjust the pH value to be 1-2, separating out solids at the moment, cooling to 10-15 ℃, stirring for 4 hours, filtering, rinsing a filter cake with a small amount of water to obtain a crude product of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, taking a solid sample, and detecting that the chemical purity ratio of the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid to the 5- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid is 94: 6. the crude product was recrystallized from 2500mL of 45% isopropanol water solution (reflux for 1-2H, cooling to 0-5 ℃ and rinsing with cold 45% isopropanol water solution) to give 331.1g of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, 75.2% yield, HPLC: 99.6 percent.
Example 7:
under the protection of nitrogen, 450.7g (2.0mol,1eq) of methyl 2,2,6, 6-tetramethylpiperidylacrylate, 232.8g (2.3mol,1.15eq) and 3000mL of dichloromethane were put into a reaction flask. Controlling the reaction temperature to be-10-5 ℃, slowly dropwise adding 224.4g (1.96mol,0.98eq) of 2, 2-difluoroacetyl chloride, reacting for 1 hour at-5 ℃ after dropwise adding, detecting the raw material by HPLC (high performance liquid chromatography) to be less than 0.5%, adding 700g of water, quenching, standing and layering. Cooling the organic phase to-5-5 ℃, dropwise adding 700g of 20% KOH aqueous solution, reacting for 1 hour at-5-5 ℃ after dropwise adding, filtering to obtain a 2-difluoroacetyl-3- (2,2,6, 6-tetramethylpiperidyl) potassium acrylate mixed solution, and storing the mixed solution at 5-5 ℃ under nitrogen for later use.
Under the protection of nitrogen, 332g (2.0mol,0.8eq) of potassium iodide is added into the mixed solution of the 2-difluoroacetyl-3- (2,2,6, 6-tetramethylpiperidyl) potassium acrylate, the temperature of the reaction liquid is reduced to-30 ℃, 316.7g (2.75mol,1.1eq) of 40% methylhydrazine aqueous solution is dripped, the temperature of the dripping process is controlled to-30 ℃ to-20 ℃, the reaction is carried out for 2 hours after the dripping is finished, HPLC detection raw materials are less than or equal to 0.5%, the reaction is finished, the organic phase is distilled under slight negative pressure (50-70 mm water column, temperature is 40-120 ℃), the generated 2,2,6, 6-tetramethylpiperidine/methanol, solvent and water are distilled out, 500-800mL of water is added in the distillation process, 1000mL of dichloromethane is added when the temperature is reduced to room temperature, the impurities are extracted, the mixture is kept stand and. Cooling the water phase to 20 ℃, slowly dropwise adding 2mol/L hydrochloric acid to adjust the pH value to be 1-2, separating out solids at the moment, cooling to 10-15 ℃, stirring for 4 hours, filtering, rinsing a filter cake with a small amount of water to obtain a crude product of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, taking a solid sample, and detecting that the chemical purity ratio of the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid to the 5- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid is 94: 6. the crude product was recrystallized from 2500mL of 40% ethanol aqueous solution (heating reflux for 1-2 hours, cooling to 0-5 ℃ C.) to give 331.1g of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, yield 75.2%, HPLC 99.6%.
Example 8:
under the protection of nitrogen, 478.7g (2.0mol,1eq), 284.4g (2.2mol, 1.1eq) of N, N-diisopropylethylamine and 3500mL of 1, 4-dioxane were charged into a reaction flask. Controlling the reaction temperature to be-10-5 ℃, slowly dropwise adding 188.2g (1.92mol,0.96eq) of 2, 2-difluoroacetyl fluoride, reacting at-5-5 ℃ for 1 hour after dropwise adding, detecting the raw material by GC (gas chromatography) until the raw material is less than 0.5%, adding 500g of water for quenching, standing for layering, cooling the organic phase to-5-5 ℃, dropwise adding 1000g of 10% NaOH aqueous solution, reacting at-5-5 ℃ for 1 hour after dropwise adding, filtering to obtain a 2-difluoroacetyl-3- (2,2,6, 6-tetramethylpiperidyl) sodium acrylate mixed solution, and storing the mixed solution at 5-5 ℃ under nitrogen for later use.
Under the protection of nitrogen, 374.7g (2.5mol,1eq) of sodium iodide is added into the mixed solution of the sodium 2-difluoroacetyl-3- (2,2,6, 6-tetramethylpiperidyl) acrylate, the temperature of the reaction liquid is reduced to-30 ℃, 316.7g (2.75mol,1.1eq) of 40% methylhydrazine aqueous solution is dripped, the temperature of the dripping process is controlled to-30 ℃ to-20 ℃, the reaction is carried out for 2 hours after the dripping is finished, HPLC detection raw materials are less than or equal to 0.5%, the reaction is finished, the organic phase is distilled under slight negative pressure (50-70 mm water column, temperature is 40-120 ℃), the generated 2,2,6, 6-tetramethylpiperidine/ethanol, solvent and water are distilled out, 1000-1200mL of water is added in the distillation process, dichloromethane is added when the temperature is reduced to room temperature, extraction impurities are added, the mixture is kept stand and layered. Cooling the water phase to 20 ℃, slowly dropwise adding 2mol/L hydrochloric acid to adjust the pH value to be 1-2, separating out solids at the moment, cooling to 10-15 ℃, stirring for 4 hours, filtering, rinsing a filter cake with a small amount of water to obtain a crude product of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, taking a solid sample, and detecting that the proportion of the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid to the 5- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid is 95: 5. the crude product was recrystallized from 2500mL of 40% ethanol aqueous solution (heating reflux for 1-2 hours, cooling to 0-5 ℃ C.) to give 333.7g of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, yield 75.8%, HPLC 99.6%.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.
Claims (8)
1. A method for preparing 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, which is characterized by comprising the following steps:
wherein X is F or Cl; r1Is C1-C4 alkyl; r2Is dimethylamino, diethylamino, morpholinyl or 2,2,6, 6-tetramethylpiperidine;
the first step is as follows: substitution/hydrolysis reaction
Dissolving alpha, beta-unsaturated ester 2 and an acid-binding agent in an organic solvent, dropwise adding 2, 2-difluoroacetyl halide 1 at low temperature for reaction, and then adding alkali for hydrolysis to obtain a solution of an alpha-difluoroacetyl intermediate 3;
the second step is that: condensation/cyclization reaction
Adding a catalyst into the solution of the alpha-difluoro acetyl intermediate 3, then carrying out low-temperature condensation reaction with a methylhydrazine aqueous solution, then carrying out reduced pressure and temperature rise reaction for cyclization, acidifying to obtain a crude product of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, and recrystallizing to obtain 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid 4; the catalyst is selected from sodium iodide or potassium iodide; the recrystallization solvent is a mixture of alcohol solvent and water, and the proportion of the recrystallization solvent is 35-65%; the alcohol solvent is selected from methanol, ethanol or isopropanol.
2. The process for the preparation of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: in the first step, the acid-binding agent is selected from triethylamine or N, N-diisopropylethylamine.
3. The process for the preparation of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: in the first step, the solvent is selected from dioxane, tetrahydrofuran, dichloromethane or 1, 2-dichloroethane.
4. The process for the preparation of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: in the first step, the mol ratio of the 2, 2-difluoroacetyl halide 1, the alpha, beta-unsaturated ester 2 and the acid-binding agent is 1: 0.95-0.98: 1.0-1.5.
5. The process for the preparation of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: in the first step, the hydrolyzed alkali is selected from sodium hydroxide and potassium hydroxide.
6. The process for the preparation of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: in the second step, the low-temperature reaction temperature is-30 ℃ to 0 ℃; the temperature of the heating reaction is 50-120 ℃.
7. The process for the preparation of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: in the second step, the methylhydrazine is an aqueous solution of methylhydrazine with a mass concentration of not less than 40%.
8. The process for the preparation of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: in the second step, the molar ratio of the alpha-difluoroacetyl intermediate 3, the catalyst and the methylnitrile is 1: 0.2-1.0: 1.05-1.15.
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