Method for preparing 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid with high selectivity

Abstract

The invention provides a method for preparing 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid with high selectivity, which comprises the following steps: reacting methylhydrazine with a protective agent in an inert solvent to obtain single-protection methylhydrazine (IV); in the presence of alkali, carrying out condensation reaction on the single protection methylhydrazine (IV) and 2-ethoxymethylene-4, 4-difluoro-3-oxobutyric acid ethyl ester (I) to obtain an intermediate (V); adding acid into the reaction system obtained in the step S2 to synchronously remove the protecting group R and form a pyrazole ring, so as to obtain 1-methyl-3-difluoromethyl-1H-pyrazole-4-ethyl formate (II); alkali is added into the 1-methyl-3-difluoromethyl-1H-pyrazole-4-ethyl formate (II) for hydrolysis, then the hydrolysis product is acidified with acid, and suction filtration is performed to obtain the 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid (III). The content of regioisomers in the prepared product is less than or equal to 1%, the HPLC purity of the product is more than or equal to 98.0%, the content of single impurities is less than or equal to 0.15%, the moisture content is less than or equal to 0.1%, the residual acid content is less than or equal to 50 ppm, and the downstream reaction requirement can be met without secondary refining.

Description

Technical Field

[0001] This invention belongs to the field of preparation technology of fluorinated pyrazole carboxylic acids, specifically relating to a method for highly selective preparation of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid. Background Technology

[0002] In existing technologies, the direct cyclization of β-keto esters with substituted hydrazides often results in poor regioselectivity, leading to numerous isomer impurities, difficult purification, and low yields. Therefore, there is an urgent need to develop a new process that can significantly improve regioselectivity, reduce isomer content, and is suitable for industrial scale-up.

[0003] Difluoropyrazolic acid, also known as 1-methyl-3-difluoromethyl-1H-pyrazol-4-carboxylic acid, can be used to prepare difluoromethylpyrazol carboxamide compounds. These compounds can be used as succinate dehydrogenase inhibitors, a class of fungicides. Succinate dehydrogenase inhibitors are highly effective fungicides, exhibiting high activity against a wide range of plant pathogenic fungi. They can be used for fungal control in various cultivated plants such as cotton, vegetables, barley, corn, rice, soybeans, and wheat, as well as seeds, showing promising prospects. Currently, the main raw materials for preparing 1-methyl-3-(difluoromethyl)-1H-pyrazol-4-carboxylic acid include dichloroacetyl chloride, ethyl difluoroacetate, 1,1,2,2-tetrafluoroethyldimethylamine, propynyl alcohol, and difluoroacetyl chloride, which are used to prepare difluoroacetic acid. However, the inventors discovered that the process of synthesizing difluoropyrazolic acid using the above-mentioned raw materials has the following problems: the raw materials are expensive and difficult to obtain; the reaction conditions are harsh; isomers are generated during the synthesis process and are not easy to separate; the reaction steps are too long; and the yield and purity are low.

[0004] Patents EP1997808 and WO2010009990 report a method for synthesizing a class of 1,3-disubstituted pyrazole carboxylic acids. However, this reaction easily yields a mixture of 1,3-substituted pyridine and 1,5-substituted pyridine isomers, which are difficult to purify and separate, making large-scale production unfavorable and resulting in high industrial production costs.

[0005] Chinese patent CN104945325B discloses a method for preparing pyrazolium carboxylic acid derivatives, which uses 1,1,2,2-tetrafluoroethyl dimethylamine, 3-methoxyacrylate, and methylhydrazine as raw materials for synthesis. The problems with this route are that the raw materials are not easy to obtain, the fluorinating reagents used are relatively dangerous, and isomers are generated, resulting in a low reaction yield.

[0006] Chinese patent CN111362874B discloses a method for preparing 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. The method uses 2,2-difluoroacetyl halide as a raw material, which undergoes addition reaction with an α,β-unsaturated ester, followed by alkaline hydrolysis to obtain the α-difluoroacetyl intermediate carboxylic acid. This is then condensed and cyclized with an aqueous solution of methylhydrazine to obtain crude difluoropyrazole acid, which is then recrystallized to obtain pure difluoropyrazole acid. However, this method has several drawbacks: 2,2-difluoroacetyl halide is difficult to obtain, and the raw material has poor stability; furthermore, the reaction conditions are quite demanding, requiring the dropping temperature to be controlled at -30°C during the cyclization reaction. Summary of the Invention To address the aforementioned technical problems, this invention provides a method for preparing isoxazole-oxadiazole compounds, and a method for preparing 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid with high selectivity and high yield, achieving a regioisomer content ≤1% and a molar yield ≥83%. This method achieves highly selective synthesis of the target compound through an "amino protection-directional condensation-acid deprotection / cyclization" process, while simplifying the operation process to achieve a "one-pot" process, reducing energy consumption and waste. The technical solution of this invention is as follows: .

[0007] A method for highly selectively preparing 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid, the method comprising the following steps: S1 amino protection: Methylhydrazine is reacted with a protecting agent in an inert solvent to obtain monoprotected methylhydrazine (IV); S2 Directional Condensation: In the presence of a base, the monoprotected methylhydrazine (Ⅳ) is subjected to a condensation reaction with ethyl 2-ethoxymethylene-4,4-difluoro-3-oxobutyrate (Ⅰ) to obtain intermediate (V); S3 Acid Deprotection-Cycloning: Add acid to the reaction system obtained in step S2 to simultaneously remove the protecting group R and form a pyrazole ring, to obtain ethyl 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylate (II); S4 Carboxylic Acid Ester Hydrolysis: The ethyl 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid (II) obtained in step S3 is hydrolyzed with alkali, then acidified and filtered to obtain 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid (III).

[0008] Preferably, in step S1, the protective agent is benzyloxycarbonyl chloride (Cbz-Cl), di-tert-butyl dicarbonate (Boc2O), fluorenemethyloxycarbonyl succinimide (Fmoc-OSu), phthalic anhydride (Pht), p-toluenesulfonyl chloride (TsCl), trifluoroacetyl chloride (Tfa-Cl), allyloxycarbonyl chloride (Alloc-Cl), or methyl chloroformate (MeOCOCl). More preferably, it is di-tert-butyl dicarbonate (Boc2O) or phthalic anhydride (Pht); most preferably, it is di-tert-butyl dicarbonate (Boc2O). Preferably, in step S1, the inert solvent is dichloromethane, acetonitrile, 1,2-dichloroethane, or a mixture thereof; more preferably, dichloromethane; the acid-binding agent is triethylamine, N,N-diisopropylethylamine, or pyridine; more preferably, triethylamine. In step S1, the reaction temperature is -10℃ to 30℃; more preferably 0℃ to 10℃. The molar ratio of feed ingredients to protective agent to methylhydrazine is 1.0~1.2:1; a further preferred ratio is 1.05:1. Preferably, in step S2, the catalyst used for the condensation reaction is an organic base selected from triethylamine, N,N-diisopropylethylamine or pyridine; more preferably triethylamine; the catalyst dosage is 0.1~0.4 eq; more preferably 0.15 eq.

[0009] Preferably, in step S2, the directional condensation reaction temperature is 0~60℃ and the reaction time is 2~8 h; more preferably, it is 20~30℃ and 4~6 h.

[0010] Preferably, in step S3, the acid is hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, or sulfuric acid; more preferably, 3-6N hydrochloric acid; Acid dosage: Acid: Intermediate (Ⅳ) = 2-3.5 eq; more preferably 3 eq; Preferably, in step S3, the reaction temperature is 0-70°C under reflux; more preferably 20-60°C; and the reaction time is 1-6 h; more preferably 3-5 h.

[0011] Preferably, in step S4, the alkali is a lithium hydroxide, sodium hydroxide, or potassium hydroxide aqueous-alcohol solution; more preferably, it is a 1–2 N sodium hydroxide aqueous solution.

[0012] Preferably, in step S4, the solvent for hydrolyzing the carboxylic acid ester is water, water / methanol, or water / ethanol, with a volume ratio of water:ethanol = 1:0-1:1; more preferably, pure water. Hydrolysis temperature: 0℃ - reflux; further preferred 20-60℃.

[0013] Hydrolysis time: 0.5-8 h; further preferred 1-3 h.

[0014] Acidification: After hydrolysis, adjust the pH to ≤2 with hydrochloric acid or sulfuric acid to precipitate carboxylic acid (III); Post-treatment: Filtration or extraction, recrystallization (water / ethanol), drying to obtain white crystals; Steps S1 to S4 can be performed continuously in a single batch.

[0015] The beneficial effects of this invention are as follows: 1. Regioisomer content ≤1%, determined by HPLC area normalization method.

[0016] 2. Molar yield ≥ 83%, based on methylhydrazine.

[0017] 3. The product has an HPLC purity of ≥98.0%, with a single impurity of ≤0.15%, moisture content of ≤0.1%, and residual acid of ≤50 ppm. It can meet the requirements of downstream reactions without secondary purification. Attached Figure Description Figure 1 Liquid chromatography spectrum of crude 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid in Example 1 (product peak: 6.566; isomer: 7.900); Figure 2 Liquid chromatography pattern of crude 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid in Example 2; Figure 3 Liquid chromatography pattern of crude 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid in Example 3; Figure 4 Liquid chromatography pattern of crude 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid in Example 4; Figure 5 The 1H NMR spectrum of ethyl 2-ethoxymethylene-4,4-difluoro-3-oxobutyrate (Structural Formula I). Figure 6 The 1H NMR spectrum of ethyl 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylate (II); Figure 7 The 1H NMR spectrum of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid (III); Figure 8 The liquid phase diagram of the crude 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid is shown below; Figure 9 The liquid phase diagram of the crude 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid in aqueous phase is shown as a comparative example. Detailed Implementation

[0018] The technical solution of the present invention will be further explained and described below with reference to specific embodiments. It is worth noting that the following embodiments are only preferred embodiments of the present invention and should not be construed as limiting the present invention. The scope of protection of the present invention should be determined by the contents of the claims. Modifications and substitutions made by those skilled in the art to the technical solution of the present invention without creative effort all fall within the scope of protection of the present invention. Example 1 Under nitrogen protection at 0°C, methylhydrazine (15.0 g, 0.325 mol) was dissolved in dichloromethane (500 mL), and a mixture of Boc₂O (74.8 g, 0.343 mol) and triethylamine (36.2 g, 0.358 mol) was slowly added dropwise. The reaction was maintained at 0°C for 2 hours. After the reaction was complete, the reaction solution was used directly for the next reaction without post-treatment. Ethyl 2-ethoxymethylene-4,4-difluoro-3-oxobutyrate (76.4 g, 0.325 mol) was added, and the mixture was stirred at 25°C for 6 hours. 6 N hydrochloric acid (163 mL) was added dropwise at 0°C, and the temperature was raised to 40°C for 3 hours to remove the protection. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed successively with water, saturated NaHCO₃, and saturated brine, and dried over anhydrous Na₂SO₄. After concentration, recrystallization from ethyl acetate / n-hexane (1:3) yielded white crystalline ethyl 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylate (75.1 g, 92% yield). This ester (40.0 g, 0.170 mol) was dissolved in 1 N NaOH (480 mL), stirred at 25°C for 2 hours, and then adjusted to pH ≈ 1 with 6 N hydrochloric acid. The mixture was filtered, the filter cake was washed with water, and dried to give the target carboxylic acid (34.4 g, 97% yield). Figure 1 ).

[0019] Example 2 Under nitrogen protection at 0°C, methylhydrazine (15.0 g, 0.325 mol) was dissolved in dichloromethane (400 mL), and Cbz-Cl (55.7 g, 0.325 mol) and triethylamine (36.2 g, 0.358 mol) were added dropwise. The reaction mixture was reacted at 0°C for 2 hours. The reaction solution was washed with water (200 mL), and the organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude N-Cbz-N'-methylhydrazine, which was used directly in the next step. Ethyl 2-ethoxymethylene-4,4-difluoro-3-oxobutyrate (76.4 g, 0.325 mol) was added, and the mixture was stirred at 25°C for 6 hours. 10% Pd / C (2.0 g) was added to the reaction solution, and the mixture was reacted at room temperature under a hydrogen atmosphere (1 atm) for 4 hours to remove the protection. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate (3 × 200 mL), and the organic phase was washed successively with water and saturated brine, and dried over anhydrous Na₂SO₄. After concentration, recrystallization from ethyl acetate / n-hexane (1:3) yielded ethyl 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylate (73.6 g, yield 90.2%). This ester (40.0 g, 0.170 mol) was dissolved in 1 N NaOH (480 mL), stirred at 25 °C for 2 hours, and then adjusted to pH ≈ 1 with 6 N hydrochloric acid. The mixture was filtered, the filter cake was washed with water, and dried to give the target carboxylic acid (34.1 g, yield 96%). Figure 2 ).

[0020] Example 3 Methylhydrazine (15.0 g, 0.325 mol) was dissolved in dichloromethane (400 mL), and Fmoc-OSu (115.8 g, 0.343 mol) and triethylamine (36.2 g, 0.358 mol) were added. The reaction mixture was reacted at 0 °C for 4 hours. The reaction solution was washed with water (200 mL), and the organic phase was dried over anhydrous Na₂SO₄. The solution was concentrated under reduced pressure to obtain crude N-Fmoc-N'-methylhydrazine, which was used directly in the next step. Ethyl 2-ethoxymethylene-4,4-difluoro-3-oxobutyrate (76.4 g, 0.325 mol) was added, and the mixture was stirred at 25 °C for 8 hours. The reaction solution was then deprotected by adding 20% ​​piperidine / DMF solution (200 mL) and stirring at room temperature for 1 hour. The solution was concentrated under reduced pressure to remove most of the solvent. The residue was extracted with water (200 mL) and ethyl acetate (3 × 200 mL). The combined organic phases were washed successively with water and saturated brine, and dried over anhydrous Na₂SO₄. After concentration, recrystallization from ethyl acetate / n-hexane (1:3) yielded ethyl 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylate (72.2 g, yield 88.4%). This ester (40.0 g, 0.170 mol) was dissolved in 1 N NaOH (480 mL), stirred at 25 °C for 2 hours, and then adjusted to pH ≈ 1 with 6 N hydrochloric acid. The mixture was filtered, the filter cake was washed with water, and dried to obtain the target carboxylic acid (33.8 g, yield 95%). Figure 3 ).

[0021] Example 4 Methylhydrazine (15.0 g, 0.325 mol) and phthalic anhydride (50.8 g, 0.343 mol) were refluxed in dichloromethane (500 mL) at 80 °C for 2 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with cold dichloromethane and dried to obtain N-phthaloyl-N'-methylhydrazine, a white solid, which was used directly in the next step. This solid was reacted with ethyl 2-ethoxymethylene-4,4-difluoro-3-oxobutyrate (76.4 g, 0.325 mol) in dichloromethane (500 mL) and stirred at 25 °C for 6 hours. 6N hydrochloric acid (272 mL) was added dropwise at 0 °C, and the mixture was refluxed for 4 hours to remove protection. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with water and dried to obtain the crude product. The crude product was extracted with ethyl acetate (3 × 200 mL), and the combined organic phases were washed successively with water, saturated NaHCO3, and saturated brine, and dried over anhydrous Na2SO4. After concentration, recrystallization from ethyl acetate / n-hexane (1:3) yielded ethyl 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylate (68.6 g, yield 83.9%). This ester (40.0 g, 0.170 mol) was dissolved in 1 N NaOH (480 mL), stirred at 25°C for 2 hours, and then adjusted to pH ≈ 1 with 6 N hydrochloric acid. The mixture was filtered, the filter cake was washed with water, and dried to give the target carboxylic acid (33.5 g, yield 94%). Figure 4 ). Table 1

[0022] Table 1 shows that the "amino protection-directional condensation" method can achieve highly selective synthesis of the target compound and significantly reduce the formation of isomers. Depending on the amino protecting reagent used in the examples, the yield is ≥83%, and the isomer content is ≤0.55%. The Boc protecting group showed the best effect, with a quantitative yield of 92%, a product peak area of ​​96.8%, and an isomer peak area of ​​0.09%, fully demonstrating the feasibility and advancement of this technology.

[0023] Comparative Example 1 Under nitrogen protection, methylhydrazine (11.4 g, 0.248 mol) was dissolved in dichloromethane (50 mL), and ethyl 2-ethoxymethylene-4,4-difluoro-3-oxobutyrate (50.0 g, 0.225 mol) was slowly added dropwise at 5 °C. Figure 5 The mixture was stirred at 25°C for 1 hour. The solvent was removed by concentration under reduced pressure, and the residue was extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed successively with water, saturated NaHCO3, and saturated brine, and dried over anhydrous Na2SO4 to give 26.2 g of a white solid product. Figure 8 ), evaporated in aqueous phase to give 10.7 g of red solid ( Figure 9 ), liquid phase detection Figure 8 The peak area of ​​ethyl 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylate was 93.8%, while the peak area of ​​the isomer was 2.4%. Figure 9 The peak area of ​​ethyl 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylate was 32.6%, while the peak area of ​​the isomer was 36.7%. The liquid phase results indicate that a large number of isomers were produced, meaning that the reaction conditions could not yield the target compound with high selectivity.

[0024] Based on the preferred embodiments of the present invention described above, those skilled in the art can make various changes and modifications without departing from the inventive concept. The technical scope of this invention is not limited to the contents of the specification, but must be determined according to the scope of the claims.

Claims

1. A method for highly selectively preparing 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid, characterized in that: The method includes the following steps: S1 amino protection: Methylhydrazine is reacted with a protecting agent in an inert solvent to obtain monoprotected methylhydrazine (IV); S2 Directional Condensation: In the presence of a base, the monoprotected methylhydrazine (Ⅳ) is subjected to a condensation reaction with ethyl 2-ethoxymethylene-4,4-difluoro-3-oxobutyrate (Ⅰ) to obtain intermediate (V); S3 Acid Deprotection-Cycloning: Add acid to the reaction system obtained in step S2 to simultaneously remove the protecting group R and form a pyrazole ring, to obtain ethyl 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylate (II); S4 Carboxylic Acid Ester Hydrolysis: The ethyl 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid (II) obtained in step S3 is hydrolyzed with alkali, then acidified and filtered to obtain 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid (III).

2. The method for highly selectively preparing 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: In step S1, the protective agent is benzyloxycarbonyl chloride, di-tert-butyl dicarbonate, fluorenemethyloxycarbonyl succinimide, phthalic anhydride, p-toluenesulfonyl chloride, trifluoroacetyl chloride, allyloxycarbonyl chloride, or methyl chloroformate. More preferably, it is di-tert-butyl dicarbonate or phthalic anhydride; most preferably, it is di-tert-butyl dicarbonate.

3. The method for highly selectively preparing 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: In step S1, the inert solvent is dichloromethane, acetonitrile, 1,2-dichloroethane, or a mixture thereof; dichloromethane is more preferred; the acid-binding agent is triethylamine, N,N-diisopropylethylamine, or pyridine; triethylamine is more preferred. In step S1, the reaction temperature is -10℃ to 30℃; more preferably 0℃ to 10℃. The molar ratio of feed ingredients to protective agent to methylhydrazine is 1.0~1.2:1; a further preferred ratio is 1.05:

1.

4. The method for highly selectively preparing 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: In step S2, the catalyst used for the condensation reaction is an organic base, selected from triethylamine, N,N-diisopropylethylamine or pyridine; triethylamine is more preferred; the catalyst dosage is 0.1~0.4 eq; 0.15 eq is more preferred.

5. The method for highly selectively preparing 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: In step S2, the directional condensation reaction temperature is 0~60℃ and the reaction time is 2~8 h; more preferably 20~30℃ and 4~6 h.

6. The method for highly selectively preparing 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: In step S3, the acid is hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, or sulfuric acid; more preferably, 3-6 N hydrochloric acid. Acid dosage: Acid: Intermediate (Ⅳ) = 2-3.5 eq; more preferably 3 eq.

7. The method for highly selectively preparing 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: In step S3, the reaction temperature is 0-70℃ reflux; more preferably 20-60℃; the reaction time is 1-6 h; more preferably 3-5 h.

8. The method for highly selectively preparing 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: In step S4, the alkali is a lithium hydroxide, sodium hydroxide, or potassium hydroxide aqueous-alcohol solution; more preferably, it is a 1–2N sodium hydroxide aqueous solution.

9. The method for highly selectively preparing 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: In step S4, the solvent for hydrolyzing the carboxylic acid ester is water, water / methanol, or water / ethanol, with a volume ratio of water:ethanol = 1:0-1:1; pure water is preferred. Hydrolysis temperature: 0℃ - reflux; further preferred 20-60℃; Hydrolysis time: 0.5-8 h; further optimized 1-3 h; Acidification: After hydrolysis, adjust the pH to ≤2 with hydrochloric acid or sulfuric acid to precipitate carboxylic acid (III); Post-processing: Filtration or extraction, recrystallization (water / ethanol), and drying to obtain white crystals.

10. The method for highly selectively preparing 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: Steps S1 to S4 are performed continuously using the "one-pot method".

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