CN112745265A - 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. N-methyl-3-aminopyrazole is used as a raw material, reacts with bromine/iodine to substitute pyrazole 4 position, is diazotized and coupled with potassium difluoromethyl trifluoroborate to obtain 4-bromo-3- (difluoromethyl) -1-methyl-1H-pyrazole, is subjected to Grignard exchange by isopropyl magnesium chloride and the like, and reacts with carbon dioxide to obtain the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid. The method is simple and convenient to operate, the total yield of the three steps is up to 64%, the product purity can reach more than 99.5%, the condition that isomers exist in the traditional process is avoided, and the method has a potential process amplification prospect.
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, english name: 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, CAS: 176969-34-9. 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 particularly is a key intermediate for synthesizing novel amides bactericides such as fluopyram, bixafen and isopyrazam.
At present, the compound has more and more application values, the synthesis reports of the compound are more, and hydrazine or methylhydrazine is mostly used for cyclization, hydrolysis or oxidation and the like in the synthesis method. However, isomers are inevitably produced during the cyclization, and a great deal of effort is required for subsequent purification.
It is therefore necessary to develop more synthetic routes to avoid the isomers of the above products, with relative ease of operation, to meet the ever-increasing market demand.
Disclosure of Invention
In order to overcome the technical defects, the invention provides a preparation method of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid. N-methyl-3-aminopyrazole is used as a raw material, reacts with bromine/iodine to substitute pyrazole 4-position, is diazotized and coupled with potassium difluoromethyl trifluoroborate to obtain 4-bromo-3- (difluoromethyl) -1-methyl-1H-pyrazole, is subjected to Grignard exchange by isopropyl magnesium chloride, and reacts with carbon dioxide to obtain 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid. The method is simple and convenient to operate, the total yield of the three steps is up to 64%, the product purity can reach more than 99.5%, the condition that isomers exist in the traditional process is avoided, and the method has a potential process amplification prospect.
A method for preparing 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, comprising the steps of:
the first step is as follows: dissolving N-methyl-3-aminopyrazole in water, and reacting with halogen to obtain 4-halogen-1-methyl-1H-pyrazole-3-amine;
the second step is that: reacting 4-halo-1-methyl-1H-pyrazole-3-amine with a sodium nitrite aqueous solution to obtain diazonium salt, and then reacting with potassium difluoromethyl trifluoroborate in the presence of cuprous oxide to obtain 4-halo-3- (difluoromethyl) -1-methyl-1H-pyrazole;
the third step: exchanging 4-halogen-3- (difluoromethyl) -1-methyl-1H-pyrazole by adopting a Grignard reagent, then cooling, reacting with carbon dioxide, quenching and recrystallizing to obtain the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid.
Further, in the above technical solution, in the first step, the halogen is selected from bromine and iodine. When iodine is adopted, hydrogen peroxide is added for reaction.
Further, in the above technical solution, the molar ratio of N-methyl-3-aminopyrazole to halogen in the first step is 1: 0.5-1.05. Wherein, the iodine simple substance is needed to be approximately 0.5 equivalent, and the bromine is used for approximately equivalent reaction.
Further, in the above technical scheme, the molar ratio of the addition of the oxidized imino ketone and the addition of the 4-halogen-1-methyl-1H-pyrazol-3-amine in the second step is 0.05-0.10: 1.
furthermore, in the technical scheme, the molar ratio of the 4-halogen-1-methyl-1H-pyrazole-3-amine, the potassium difluoromethyl trifluoroborate and the sodium nitrite in the second step is 1:0.98-1.3: 2.0-2.5.
Further, in the above technical solution, in the third step, the grignard reagent is selected from isopropyl magnesium chloride, isopropyl magnesium chloride-lithium chloride or sec-butyl magnesium chloride-lithium chloride.
Further, in the above technical scheme, in the third step, the reaction with carbon dioxide is performed by introducing carbon dioxide gas or a saturated solution of carbon dioxide under the condition of a catalytic amount of DBU. The addition of DBU can reduce the consumption of carbon dioxide, accelerate the reaction speed and enhance the process stability.
Further, in the technical scheme, the molar ratio of the 4-halogen-3- (difluoromethyl) -1-methyl-1H-pyrazole, the Grignard reagent and the carbon dioxide in the third step is 1:1.01-1.15: 1-2.5.
Further, in the above technical solution, when the crystallization is performed in the third step, the solvent is selected from a mixture of an alcohol solvent and water used for the crystallization in the third step. The alcohol solvent is methanol, ethanol or isopropanol.
Further, in the above-mentioned embodiment, it is preferable that the crystallization in the third step is performed using 40% (v/v) ethanol aqueous solution.
Advantageous effects of the invention
The method takes N-methyl-3-aminopyrazole as a raw material, and comprises three steps of halogenation, diazo coupling, Grignard exchange/carbon dioxide and the like in sequence, and the product is finally purified after recrystallization. The method is simple and convenient to operate, the total reaction yield is up to 64%, the purity of the obtained product can reach more than 99.5%, and a new process approach is provided for the synthesis of the compounds.
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.
CF2HBF3K, preparation:
under the protection of nitrogen, 26.2g of bromodifluoromethane (0.2mol), 43.3g of triisopropyl borate (0.23mol) and 240mL of 2-MeTHF are sequentially added into a reaction bottle cooled to-78 ℃, after uniform stirring, 84mL of 2.5M n-butyllithium solution is dropwise added at the temperature of-78 ℃ to-65 ℃ and the dropwise addition is finished within about 40 minutes; after the dropwise addition, the mixture was kept at a temperature for 2 hours, and then naturally warmed to room temperature and stirred overnight. Controlling the temperature to be less than or equal to 0 ℃, dropwise adding 10% hydrochloric acid aqueous solution into the reaction bottle to adjust the pH value to be 2-3, continuously stirring for 1 hour, standing to separate an organic layer, extracting an aqueous layer twice by using 110mL of 2-MeTHF, combining the organic layers, adding 39g of KHF2The reaction was stirred at room temperature for 3 hours with 55mL of water. Evaporating the reaction solution to dryness to obtain a viscous solid, adding 440mL of acetone for refluxing, cooling, filtering by using kieselguhr, performing rotary evaporation to dryness, adding 440mL of acetone again, filtering to remove a small amount of insoluble substances, adding 130mL of methyl tert-butyl ether for pulping, filtering, and drying to obtain 16.4g of white powdery solid with the yield of 52%.1HNMR(Acetone-d6,400MHz):4.33ppm.11FNMR(Acetone-d6,376MHz):-72.2ppm,-151.8ppm.
Example 1
97.1g (1mol,1.0eq) of N-methyl-3-aminopyrazole and 800mL of water and 500mL of ethanol are put into a three-port reaction flask, and 129.5g (0.51mol,0.51 eq) of iodine is added in portions at a controlled temperature of 15-25 DEG C) 72.9g (0.6mol,0.6eq) of 28% hydrogen peroxide was added dropwise at 15-25 ℃. Heating to 30-35 ℃, reacting for 6 hours, taking a sample with GC raw material less than 1%, cooling to 10 ℃, adding 80mL of saturated sodium thiosulfate aqueous solution, stirring for 5-6 hours, distilling ethanol under reduced pressure, separating out a large amount of yellow-brown solid, filtering to obtain 207.6g of 4-iodine-1-methyl-1H-pyrazole-3-amine, wherein GC content is 95.6%, and yield is 93.1%.1HNMR(400MHz,CDCl3):7.40(s,1H),5.81(s,2H),3.80(s,3H).
4-iodine-1-methyl-1H-pyrazole-3-amine (100g,0.45mol) and 6mol/L hydrochloric acid aqueous solution are put into a reaction bottle, the pH value is regulated to be less than 1, the temperature is reduced to minus 5 ℃, 78.1g of 40 percent sodium nitrite aqueous solution is slowly dripped, the reaction is carried out for 1 hour at minus 5 to 5 ℃ after the dripping is finished, and the mixture is transferred into a dropping funnel under the protection of nitrogen.
Under the protection of nitrogen, adding 73.3g (470.8mmol,1.05eq) of potassium difluoromethyl trifluoroborate, 4.5g (31.4mmol,0.07eq) of cuprous oxide and 500mL of tetrahydrofuran into a reaction bottle, cooling to 0 ℃, starting to dropwise add the prepared diazonium salt solution, slowly heating to 35-50 ℃, sampling HPLC raw materials, cooling to 0-10 ℃, adding saturated sodium carbonate aqueous solution for quenching, extracting by ethyl acetate, washing an organic phase by water, concentrating, adding n-heptane for pulping, filtering to obtain 98.7g of 4-iodine-3- (difluoromethyl) -1-methyl-1H-pyrazole, and carrying out HPLC: 98.7% and yield 85.3%.1HNMR(400MHz,CDCl3):7.80(s,1H),6.02(s,1H),3.95(s,3H).
Under the protection of nitrogen, 95g (0.368mol,1eq) of 4-iodo-3-difluoromethyl-1-methylpyrazole and 500mL of tetrahydrofuran were put into a reaction flask, stirred uniformly, and then cooled to-5 ℃. 202mL of i-PrMgCl (2.0M,1.1eq) tetrahydrofuran solution was slowly added dropwise, and the mixture was stirred for 2 hours while maintaining the temperature after the addition of the solution, thereby obtaining a Grignard exchange solution. Sampling quenching GC detects that the raw material is less than 0.5 percent. Drop wise addition preparation500mL of tetrahydrofuran solution containing 5.6g (0.037mol,0.1eq) of DBU and 21.6g (0.49mol,1.25eq) of carbon dioxide at-25 ℃, slowly raising the temperature to 0 ℃, stirring at the temperature for 5 hours, reducing the temperature to-10 ℃, adding 4mol/L hydrochloric acid for quenching, extracting by using aqueous phase ethyl acetate, washing an organic phase by using water, concentrating an enriched organic phase, concentrating to obtain a constant solution, distilling again to dryness after replacing ethanol, finally adding 330mL of 40% (v/v) ethanol aqueous solution for recrystallization to obtain 53.9g of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, wherein the GC purity is 99.5%, and the yield is 83.2%.1HNMR(400MHz,DMSO-d6):12.71(s,1H),8.33(s,1H),7.19(t,1H),3.89(s,3H)。
Example 2:
adding 97.1g (1mol,1eq) of 1, 3-dimethylpyrazole and 700mL of ethanol into a reaction bottle, slowly dropwise adding 158.4g (0.99mol,0.99eq) of bromine at 0-5 ℃ under stirring, dropwise adding for reaction at 0-15 ℃ for 1 hour, sampling GC raw materials, reducing the temperature to 10 ℃, adding 500mL of water, dropwise adding 30% sodium hydroxide aqueous solution for quenching reaction, adjusting the pH to 9-10, adding 80mL of saturated sodium thiosulfate aqueous solution, concentrating an organic phase under reduced pressure, removing ethanol, reducing the temperature to 15-20 ℃, pulping for 3 hours, and filtering to obtain 157.4g of 4-bromo-1-methyl-1H-pyrazol-3-amine, wherein the GC yield is 89.4%.1HNMR(400MHz,CDCl3):7.41(s,1H),5.90(s,2H),3.82(s,3H).
Under the protection of nitrogen, 100g (568.1mmol) of 4-bromo-1-methyl-1H-pyrazol-3-amine and 6mol/L of hydrochloric acid aqueous solution are put into a reaction bottle, and the pH value is adjusted<1, cooling to-5 ℃, slowly dropwise adding 87.8g of 45% sodium nitrite aqueous solution, and reacting for 1 hour at-5-5 ℃ after dropwise adding. 89.7g (568.1mmol,1.0eq), 4.1g (28.4mmol,0.05eq) of cuprous oxide and 500mL of acetonitrile are added into another reaction flask under the protection of nitrogen, the temperature is reduced to 0 ℃, and the prepared mixture is added dropwiseAfter the dropwise addition of the diazonium salt solution, slowly heating to 35-50 ℃, sampling HPLC raw materials, reducing the temperature to 0-10 ℃, adding saturated sodium carbonate aqueous solution for quenching, extracting by ethyl acetate, washing an organic phase by water, concentrating, and distilling under reduced pressure to obtain 105.7g of 4-bromo-3- (difluoromethyl) -1-methyl-1H-pyrazole, wherein the weight ratio of the diazonium salt solution to the saturated sodium carbonate aqueous solution is HPLC: 98.5% and a yield of 88.2%.1HNMR(400MHz,CDCl3):7.93(s,1H),6.05(s,1H),3.95(s,3H).
Under the protection of nitrogen, 95g (0.368mol,1eq) of 4-iodo-3-difluoromethyl-1-methylpyrazole and 500mL of 2-methyltetrahydrofuran were put into a reaction flask, stirred uniformly, and then cooled to-5 ℃. 311mL of a 2-methyltetrahydrofuran solution of i-PrMgCl-LiCl (1.3M,1.1eq) was slowly added dropwise, and the mixture was stirred for 2 hours while maintaining the temperature, thereby obtaining a Grignard exchange solution. Sampling quenching GC detects that the raw material is less than 0.5 percent. 500mL of a pre-prepared 2-methyltetrahydrofuran solution containing 5.6g (0.037mol,0.1eq) of DBU5 and 21.6g (0.49mol,1.25eq) of carbon dioxide at-25 ℃ is added dropwise, the temperature is slowly raised to 0 ℃, the mixture is stirred for 5 hours at the temperature, the temperature is reduced to-10 ℃, 4mol/L hydrochloric acid is added for quenching, the water phase is extracted by ethyl acetate, the organic phase is washed by water, the organic phase is enriched and concentrated to a non-flowing liquid, the ethanol is replaced and distilled again to be dry, and finally, 340mL of 40% (v/v) ethanol aqueous solution is added for recrystallization to obtain 54.8g of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, the GC purity is 99.7%, and the yield is 84.6%.1HNMR(400MHz,DMSO-d6):12.71(s,1H),8.33(s,1H),7.19(t,1H),3.89(s,3H)。
Example 3:
adding 97.1g (1mol,1eq) of 1, 3-dimethylpyrazole and 700mL of ethanol into a reaction bottle, slowly dropwise adding 158.4g (0.99mol,0.99eq) of bromine at 0-5 ℃ under stirring, dropwise adding the mixture at 0-15 ℃ for reacting for 1 hour, sampling GC raw materials, reducing the temperature to 10 ℃, adding 500mL of water, dropwise adding 30% sodium hydroxide aqueous solution to quench the reactionAnd adjusting the pH to 9-10, adding 80mL of saturated sodium thiosulfate aqueous solution, concentrating the organic phase under reduced pressure to remove ethanol, cooling to 15-20 ℃, pulping for 3 hours, and filtering to obtain 157.4g of 4-bromo-1-methyl-1H-pyrazol-3-amine, wherein the GC content is 97.6%, and the yield is 89.4%.1HNMR(400MHz,CDCl3):7.41(s,1H),5.90(s,2H),3.82(s,3H).
Under the protection of nitrogen, 100g (568.1mmol) of 4-bromo-1-methyl-1H-pyrazol-3-amine and 6mol/L of hydrochloric acid aqueous solution are put into a reaction bottle, and the pH value is adjusted<1, cooling to-5 ℃, slowly dropwise adding 87.8g of 45% sodium nitrite aqueous solution, and reacting for 1 hour at-5-5 ℃ after dropwise adding. Adding 89.7g (568.1mmol,1.0eq) of potassium difluoromethyl trifluoroborate, 4.1g (28.4mmol,0.05eq) of cuprous oxide and 500mL of acetonitrile into another reaction bottle under the protection of nitrogen, cooling to 0 ℃, dropwise adding the prepared diazonium salt solution, slowly heating to 35-50 ℃, sampling HPLC raw materials, cooling to 0-10 ℃, adding saturated sodium carbonate aqueous solution for quenching, extracting by ethyl acetate, washing an organic phase by water, concentrating, distilling under reduced pressure to obtain 105.7g of 4-bromo-3- (difluoromethyl) -1-methyl-1H-pyrazole, and carrying out HPLC: 98.5% and a yield of 88.2%.1HNMR(400MHz,CDCl3):7.93(s,1H),6.05(s,1H),3.95(s,3H).
Under the protection of nitrogen, 95g (0.368mol,1eq) of 4-iodo-3-difluoromethyl-1-methylpyrazole and 500mL of tetrahydrofuran were put into a reaction flask, stirred uniformly, and then cooled to-5 ℃. S-BuMgCl-LiCl (1.2M,1.1eq) solution in tetrahydrofuran 337mL is slowly added dropwise, and stirring is carried out for 2 hours while maintaining the temperature after the addition is finished, thus obtaining the Grignard exchange solution. Sampling quenching GC detects that the raw material is less than 0.5 percent. 500mL of a previously prepared 2-methyltetrahydrofuran solution containing 5.6g (0.037mol,0.1eq) of DBU and 21.6g (0.49mol,1.25eq) of carbon dioxide at-25 ℃ was added dropwise, the temperature was slowly raised to 0 ℃ and the mixture was stirred at that temperature for 5 hours, then the temperature was lowered to-10 DEG CAdding 4M/L hydrochloric acid for quenching, extracting water phase ethyl acetate, washing an organic phase with water, concentrating an enriched organic phase, concentrating to obtain a non-flowing liquid, replacing ethanol, distilling again to dryness, and finally adding 320mL of 40% (v/v) ethanol aqueous solution for recrystallization to obtain 54.5g of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, wherein the GC purity is 99.6%, and the yield is 84.1%.1HNMR(400MHz,DMSO-d6):12.71(s,1H),8.33(s,1H),7.19(t,1H),3.89(s,3H)。
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 (10)
1. A method for preparing 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, which is characterized by comprising the following steps:
the first step is as follows: dissolving N-methyl-3-aminopyrazole in water, and reacting with halogen to obtain 4-halogen-1-methyl-1H-pyrazole-3-amine;
the second step is that: reacting 4-halo-1-methyl-1H-pyrazole-3-amine with a sodium nitrite aqueous solution to obtain diazonium salt, and then reacting with potassium difluoromethyl trifluoroborate in the presence of cuprous oxide to obtain 4-halo-3- (difluoromethyl) -1-methyl-1H-pyrazole;
the third step: exchanging 4-halogen-3- (difluoromethyl) -1-methyl-1H-pyrazole by adopting a Grignard reagent, then cooling, reacting with carbon dioxide, quenching and recrystallizing to obtain the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid.
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 halogen is selected from bromine and iodine elementary substance, wherein when the iodine elementary substance is adopted, hydrogen peroxide is added for reaction.
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 molar ratio of the N-methyl-3-aminopyrazole to the halogen is 1: 0.5-1.05; wherein, the iodine simple substance adopts nearly 0.5 equivalent, and the bromine is adopted for nearly equivalent reaction.
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 second step, the molar ratio of the addition of the oxidized imino ketone to the 4-halo-1-methyl-1H-pyrazol-3-amine is 0.05-0.10: 1.
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 second step, the molar ratio of the 4-halogen-1-methyl-1H-pyrazole-3-amine, the potassium difluoromethyl trifluoroborate and the sodium nitrite is 1:0.98-1.3: 2.0-2.5.
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 third step, the grignard reagent is selected from isopropyl magnesium chloride, isopropyl magnesium chloride-lithium chloride or sec-butyl magnesium chloride-lithium chloride.
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 third step, the reaction with carbon dioxide is carried out by introducing carbon dioxide gas or carbon dioxide saturated solution and under the condition of catalytic amount of DBU.
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 third step, the molar ratio of the 4-halo-3- (difluoromethyl) -1-methyl-1H-pyrazole, the Grignard reagent and the carbon dioxide is 1:1.01-1.15: 1-2.5.
9. The process for the preparation of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid according to any of claims 1 to 8, characterized in that: in the third step, a mixture of an alcohol solvent and water is used for crystallization.
10. The process for the preparation of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid according to claim 9, wherein: in the third step, 40% ethanol water solution is adopted for recrystallization.
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