A method for synthesizing 3-fluoro-1-methyl-1h-pyrazol-4-amine

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of 3-fluoro-1-methyl-1H-pyrazol-4-amine, which is prepared by taking 3-methyl-4-nitro-1H-pyrazole as raw material. The synthesis method provided by the application solves technical problems of high raw material cost, great safety risk, great purification difficulty and difficult large-scale production, the starting raw material 3-methyl-4-nitro-1H-pyrazole has been industrialized, is cheap and low in cost, nitration reaction does not occur, the synthesis process is safer, the methylation reaction as the first step in the synthesis process can be well crystallized and purified, the cost and process difficulty are reduced, the reduction of the nitro group is carried out by using reduced iron powder, the reaction process is safer, and the cost is lower.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for synthesizing 3-fluoro-1-methyl-1H-pyrazole-4-amine. Background Technology

[0002] Pyrazoles and their derivatives are an important class of structures in the pharmaceutical field. Pyrazole ketone drugs play a crucial role in the field of analgesics and antipyretics, such as aminopyrine, metamizole, phenylbutazone, and hydroxyphenylbutazone. Simultaneously, pyrazole heterocyclic compounds also possess multiple agricultural activities, including insecticidal / acaricidal, fungicidal, and herbicidal activities. There are 26 pyrazole heterocyclic herbicides with ISO generic names, including 25 aromatic pyrazole heterocyclic herbicides and 1 non-aromatic pyrazole heterocyclic herbicide. In conclusion, the synthesis of different pyrazole and its derivative structures is of great significance.

[0003] International application WO2022 / 212538A1 discloses a method for synthesizing 3-fluoro-1-methyl-1H-pyrazole-4-amine, which uses 3-fluoro-1H-pyrazole as a starting material to prepare 3-fluoro-1-methyl-1H-pyrazole-4-amine. The specific reaction process is as follows:

[0004] .

[0005] However, the main raw material 3-fluoro-1H-pyrazole-4-amine used in the above-mentioned synthesis method has not been industrialized. Currently, it is only available in gram-scale quantities, which are expensive and unsuitable for cost control in large-scale production. This method requires nitration synthesis intermediates, which poses high safety risks. Although continuous flow equipment has reduced some safety risks in recent years, safety risks in post-reaction processing and material storage have not been well resolved. The methylation reaction of this method produces isomers, which are difficult and costly to purify, making it unsuitable for industrial production. The method also has significant safety risks in the catalytic hydrogenation process for nitro reduction, and the precious metal catalysts used are expensive. Summary of the Invention

[0006] The purpose of this invention is to provide a method for synthesizing 3-fluoro-1-methyl-1H-pyrazole-4-amine to solve the above-mentioned technical problems.

[0007] To achieve the above-mentioned technical objectives, the technical solution of the present invention is as follows:

[0008] A method for synthesizing 3-fluoro-1-methyl-1H-pyrazole-4-amine, using 3-methyl-4-nitro-1H-pyrazole as a starting material, is provided via the following reaction route:

[0009] .

[0010] As a further improvement, the specific steps are as follows:

[0011] S1. Using 3-methyl-4-nitro-1H-pyrazole and iodomethane as reactants, intermediate 1,3-dimethyl-4-nitro-1H-pyrazole is obtained by methylation reaction.

[0012] S2. Dissolve the intermediate 1,3-dimethyl-4-nitro-1H-pyrazole in glacial acetic acid, add sodium nitrite aqueous solution dropwise at 15-20℃, and react for 3-4 hours. After the reaction is complete, pour the reaction solution into water, extract with methyl tert-butyl ether, wash the organic phase, dry and concentrate to obtain a concentrated solution; add thionyl chloride to the concentrated solution, heat to reflux, and react for 2-3 hours. After the reaction is complete, concentrate, add dichloromethane to dissolve, wash and dry, evaporate to a slurry, then add petroleum ether to disperse, filter, and vacuum dry to obtain the intermediate 1-methyl-4-nitro-1H-pyrazole-3-carboxynitrile.

[0013] S3. Dissolve the intermediate 1-methyl-4-nitro-1H-pyrazole-3-carboxynitrile in ethanol, add sodium hydroxide solution, react at 40~50℃ for 1~2h, after the reaction is completed, cool down, adjust pH to 7~8, concentrate under negative pressure, filter, and dry the solid to obtain the intermediate 1-methyl-4-nitro-1H-pyrazole-3-carboxamide.

[0014] S4. Dissolve the intermediate 1-methyl-4-nitro-1H-pyrazole-3-carboxamide in a mixed solution of methanol and water, adjust the pH to 11-12, add sodium hypochlorite solution dropwise at 0-10℃, and keep the reaction at this temperature for 1-2 hours. After the reaction is complete, add sodium thiosulfate solution, concentrate under reduced pressure, extract with dichloromethane, wash with the organic phase, dry, evaporate to a paste, disperse in petroleum ether, filter, and dry under vacuum to obtain the intermediate 1-methyl-4-nitro-1H-pyrazole-3-amine.

[0015] S5. The intermediate 1-methyl-4-nitro-1H-pyrazole-3-amine was dissolved in an aqueous solution of tetrafluoroboric acid. An aqueous solution of sodium nitrite was added dropwise at 0~5℃ and kept at this temperature for 1 h. Then the temperature was slowly raised to room temperature and the reaction was carried out for 12 h. After the reaction was completed, the intermediate was extracted with dichloromethane, washed with the organic phase, dried, concentrated by evaporation, dispersed in petroleum ether, filtered, and dried under vacuum to obtain the intermediate 3-fluoro-1-methyl-4-nitro-1H-pyrazole.

[0016] S6. Dissolve the intermediate 3-fluoro-1-methyl-4-nitro-1H-pyrazole in ethanol, add acetic acid and reduced iron powder, heat to reflux, and react for 3-4 hours. After the reaction is completed, cool to room temperature, filter, concentrate, add water and adjust pH to 9-10, extract with dichloromethane, wash with organic phase, decolorize with activated carbon, dry, concentrate under negative pressure, and recrystallize to obtain 3-fluoro-1-methyl-1H-pyrazole-4-amine.

[0017] As a further improvement, in step S1, the molar ratio of 3-methyl-4-nitro-1H-pyrazole to iodomethane is 1:1~3. During the methylation reaction, if the mass fraction of 3-methyl-4-nitro-1H-pyrazole in the reaction solution is <2% by liquid chromatography, the reaction ends.

[0018] As a further improvement, in step S2, the molar ratio of the intermediate 1,3-dimethyl-4-nitro-1H-pyrazole to sodium nitrite is 1:1 to 1.5, and the feed-to-liquid ratio of 1,3-dimethyl-4-nitro-1H-pyrazole to thionyl chloride is 1g:2 to 5mL.

[0019] As a further improvement, in step S3, the mass concentration of the sodium hydroxide solution is 20%, and the molar ratio of the intermediate 1-methyl-4-nitro-1H-pyrazole-3-carboxynitrile to sodium hydroxide in the sodium hydroxide solution is 1:2~5.

[0020] As a further improvement, in step S4, the molar ratio of the intermediate 1-methyl-4-nitro-1H-pyrazole-3-carboxamide to sodium hypochlorite in the sodium hypochlorite solution is 1:1.5~3.

[0021] As a further improvement, in step S5, the mass concentration of the tetrafluoroboric acid aqueous solution is 40%, and the molar ratio of the intermediate 1-methyl-4-nitro-1H-pyrazole-3-amine to sodium nitrite in the sodium nitrite aqueous solution is 1:1.2~2.

[0022] As a further improvement, in step S6, the ratio of intermediate 3-fluoro-1-methyl-4-nitro-1H-pyrazole to acetic acid is 1g:2~5mL, and the molar ratio of intermediate 3-fluoro-1-methyl-4-nitro-1H-pyrazole to the reduced iron powder is 1:2~5.

[0023] Due to the adoption of the above technical solution, the beneficial effects of the present invention are as follows:

[0024] This invention provides a method for synthesizing 3-fluoro-1-methyl-1H-pyrazole-4-amine, which solves the technical problems of high raw material cost, high safety risk, high purification difficulty and difficulty in scale-up production.

[0025] In this invention, the starting material 3-methyl-4-nitro-1H-pyrazole has been industrialized, is inexpensive, and has low cost; no nitration reaction occurs, making the synthesis process safer; the methylation reaction is the first step in the synthesis process, with an isomer ratio of about 9:1, which allows for good separation through crystallization with minimal product loss, reducing cost and process difficulty; and the use of reduced iron powder for nitro reduction makes the reaction process safer and lower in cost. Attached Figure Description

[0026] Figure 1 This is the NMR spectrum of 1,3-dimethyl-4-nitro-1H-pyrazole in Example 1 of this invention;

[0027] Figure 2 This is the NMR spectrum of 1-methyl-4-nitro-1H-pyrazole-3-carboxynitrile in Example 1 of this invention;

[0028] Figure 3 This is the NMR spectrum of 1-methyl-4-nitro-1H-pyrazole-3-carboxamide in Example 1 of this invention;

[0029] Figure 4 This is the NMR spectrum of 1-methyl-4-nitro-1H-pyrazole-3-amine in Example 1 of this invention;

[0030] Figure 5 This is the NMR spectrum of 3-fluoro-1-methyl-1H-pyrazole-4-amine in Example 1 of this invention. Detailed Implementation

[0031] The technical solution of the present invention will be clearly and completely described below with reference to specific embodiments. However, those skilled in the art will understand that the embodiments described below are some embodiments of the present invention, but not all embodiments, and are only used to illustrate the present invention, and should not be regarded as limiting the scope of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Where specific conditions are not specified in the embodiments, conventional conditions are followed. Where the manufacturers of reagents or instruments are not specified, they are all conventional products that can be purchased commercially.

[0032] Example 1: A method for synthesizing 3-fluoro-1-methyl-1H-pyrazole-4-amine, prepared via the following reaction route:

[0033] .

[0034] Specifically, the following steps are included:

[0035] Synthesis of S1 and intermediate 1,3-dimethyl-4-nitro-1H-pyrazole;

[0036] 127 g (1 mol) of 3-methyl-4-nitro-1H-pyrazole was dissolved in 1270 mL of acetonitrile, and 213 g (1.5 mol) of iodomethane was added. The mixture was heated to reflux and stirred for 3 h. During the reaction, the mass fraction of 3-methyl-4-nitro-1H-pyrazole was monitored by liquid chromatography and found to be <2%, indicating the reaction was complete. The mixture was cooled to 20 °C, and the reaction solution was filtered to remove solids. The solution was concentrated at 45 °C and -0.085 MPa to remove acetonitrile, yielding 126 g of crude product. The crude product was refluxed in 630 mL of 95% ethanol and slowly cooled to 0 °C for 0.5 h to crystallize. The crystals were filtered, and the filter cake was washed with 95% ethanol and dried under vacuum at 65 °C to obtain 105 g of pure 1,3-dimethyl-4-nitro-1H-pyrazole, with a yield of 75%. The NMR spectrum of 1,3-dimethyl-4-nitro-1H-pyrazole is shown below. Figure 1 As shown;

[0037] Synthesis of S2 and intermediate 1-methyl-4-nitro-1H-pyrazole-3-carboxynitrile;

[0038] Dissolve 61.6 g (0.89 mol) of sodium nitrite in 185 mL of water to obtain an aqueous solution of sodium nitrite;

[0039] 105 g (0.74 mol) of intermediate 1,3-dimethyl-4-nitro-1H-pyrazole was dissolved in 1050 mL of glacial acetic acid, cooled to 15 °C in an ice-water bath, and sodium nitrite aqueous solution was added dropwise. The reaction was carried out at 15 °C for 3 h. The reaction was considered complete when the mass concentration of 1,3-dimethyl-4-nitro-1H-pyrazole was <1% by liquid chromatography.

[0040] After the reaction was complete, the reaction solution was poured into 3L of water and extracted three times with 1L of methyl tert-butyl ether. The organic phases were combined, washed with 1L of saturated sodium bicarbonate solution, then washed with 500mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. 525mL of thionyl chloride was added, and the mixture was refluxed for 2 hours. The mass fraction of the intermediate 1-methyl-4-nitro-1H-pyrazole-3-hydroxyoxime was monitored by liquid chromatography as <1%. After the reaction was complete, the thionyl chloride was concentrated to remove it, dissolved in 1L of dichloromethane, and then washed successively with 1L of saturated sodium bicarbonate solution and 200mL of saturated brine. The mixture was dried over anhydrous sodium sulfate, evaporated to a slurry, dispersed in 300mL of petroleum ether, filtered to obtain a filter cake, and dried under vacuum at 35℃ to obtain 92.8g of pure 1-methyl-4-nitro-1H-pyrazole-3-carboxynitrile, with a yield of 82%. The NMR spectrum of 1-methyl-4-nitro-1H-pyrazole-3-carboxynitrile is shown below. Figure 2 As shown;

[0041] Synthesis of S3 and intermediate 1-methyl-4-nitro-1H-pyrazole-3-carboxamide;

[0042] 92.8 g (0.62 mol) of the intermediate 1-methyl-4-nitro-1H-pyrazole-3-carboxynitrile was dissolved in 500 mL of 95% ethanol, and 248 g of 20% sodium hydroxide solution was added. The mixture was heated to 40 °C and reacted for 2 h. During the reaction, the mass fraction of 1-methyl-4-nitro-1H-pyrazole-3-carboxynitrile was monitored by liquid chromatography and found to be <1%, indicating the reaction was complete. After the reaction, the temperature was lowered to 10 °C, the pH was adjusted to 7 with 6 mol / L hydrochloric acid, and the mixture was concentrated at 45 °C under negative pressure to remove ethanol. The product precipitated, cooled to 5 °C, filtered, and dried in a forced-air environment at 75 °C to obtain 98.5 g of 1-methyl-4-nitro-1H-pyrazole-3-carboxamide, with a yield of 95%. The NMR spectrum of 1-methyl-4-nitro-1H-pyrazole-3-carboxamide is shown below. Figure 3 As shown;

[0043] Synthesis of S4, intermediate 1-methyl-4-nitro-1H-pyrazole-3-amine;

[0044] Mix 985 mL of methanol and 985 mL of water to obtain a mixed solution of methanol and water;

[0045] 98.5 g (0.58 mol) of the intermediate 1-methyl-4-nitro-1H-pyrazole-3-carboxamide was dissolved in a mixed solution of methanol and water. Sodium hydroxide was added to adjust the pH to 11, and the solution was cooled to 0°C in an ice-salt bath. 1078 g of a 12% sodium hypochlorite solution was added dropwise, and the reaction was maintained at 0°C for 2 hours. During the reaction, the mass fraction of 1-methyl-4-nitro-1H-pyrazole-3-carboxamide was monitored by liquid chromatography; if it was less than 1%, the reaction was considered complete. 1 The oxidizing agent was removed by 1000 mL of 15% sodium thiosulfate solution, and the mixture was concentrated under reduced pressure at 45 °C to remove methanol. The mixture was extracted four times with 500 mL of dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to a paste state. 200 mL of petroleum ether was added for dispersion, and the mixture was filtered. The filter cake was dried under vacuum at 35 °C to obtain 66.5 g of 1-methyl-4-nitro-1H-pyrazole-3-amine, with a yield of 81%. The NMR spectrum of 1-methyl-4-nitro-1H-pyrazole-3-amine is shown below. Figure 4 As shown;

[0046] Synthesis of S5 and intermediate 3-fluoro-1-methyl-4-nitro-1H-pyrazole;

[0047] Dissolve 38.8 g (0.56 mol) of sodium nitrite in 133 mL of water to obtain an aqueous solution of sodium nitrite;

[0048] 66.5 g (0.47 mol) of the intermediate 1-methyl-4-nitro-1H-pyrazole-3-amine was dissolved in 333 mL of 40% tetrafluoroboric acid aqueous solution. The solution was cooled to 0 °C in an ice-salt bath, and sodium nitrite aqueous solution was added dropwise. After the addition was complete, the solution was kept at 0 °C for 1 h, and then slowly heated to room temperature for 12 h. During the reaction, the mass fraction of 1-methyl-4-nitro-1H-pyrazole-3-amine was monitored by liquid chromatography and found to be <1%. The reaction was considered complete when the mass fraction was <1%. After the reaction was complete, the solution was extracted three times with 300 mL of dichloromethane. The organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, and evaporated until a large amount of product precipitated. The product was dispersed in 200 mL of petroleum ether, filtered, and the filter cake was dried under vacuum at 35 °C to obtain 51 g of 3-fluoro-1-methyl-4-nitro-1H-pyrazole.

[0049] S6. Synthesis of the product 3-fluoro-1-methyl-1H-pyrazole-4-amine;

[0050] 51 g (0.35 mol) of the intermediate 3-fluoro-1-methyl-4-nitro-1H-pyrazole was dissolved in 510 mL of ethanol. 102 mL of acetic acid and 59 g of reduced iron powder were added, and the mixture was refluxed for 3 h. During the reaction, the mass fraction of 3-fluoro-1-methyl-4-nitro-1H-pyrazole was monitored by liquid chromatography and found to be <1%, indicating the reaction was complete. After the reaction, the mixture was cooled to room temperature, filtered through a diatomaceous earth filter, concentrated to remove ethanol, and 200 mL of water was added. The pH was adjusted to 9 with 10% sodium hydroxide solution, and then extracted three times with 200 mL of dichloromethane. The organic phases were combined, washed with saturated brine, decolorized with 10 g of activated carbon, dried over anhydrous sodium sulfate, concentrated under negative pressure at 45 °C, and recrystallized with 80 mL of 50% ethanol to obtain 34.2 g of the product 3-fluoro-1-methyl-1H-pyrazole-4-amine, with a yield of 85.5%. The NMR spectrum of 3-fluoro-1-methyl-1H-pyrazole-4-amine is shown below. Figure 5 As shown.

[0051] Example 2 A method for synthesizing 3-fluoro-1-methyl-1H-pyrazole-4-amine, specifically including the following steps:

[0052] Synthesis of S1 and intermediate 1,3-dimethyl-4-nitro-1H-pyrazole;

[0053] 127g of 3-methyl-4-nitro-1H-pyrazole was dissolved in 1270mL of acetonitrile, and 142g of iodomethane was added. The mixture was heated to reflux and stirred for 5h. During the reaction, the mass fraction of 3-methyl-4-nitro-1H-pyrazole was monitored by liquid chromatography and found to be <2%, indicating the end of the reaction. The mixture was cooled to 30℃, and the reaction solution was filtered to remove solids. The solution was concentrated under negative pressure at 50℃ to remove acetonitrile, yielding a crude product. The crude product was placed in 630mL of 95% ethanol and refluxed until dissolved. The solution was slowly cooled to 5℃ and kept at that temperature for 0.5h to crystallize. The crystals were filtered, and the filter cake was washed with 95% ethanol and dried under vacuum at 65℃ to obtain pure 1,3-dimethyl-4-nitro-1H-pyrazole.

[0054] Synthesis of S2 and intermediate 1-methyl-4-nitro-1H-pyrazole-3-carboxynitrile;

[0055] Dissolve 34.5 g (0.5 mol) of sodium nitrite in 185 mL of water to obtain an aqueous solution of sodium nitrite;

[0056] Dissolve 70 g (0.5 mol) of the intermediate 1,3-dimethyl-4-nitro-1H-pyrazole in 1050 mL of glacial acetic acid, cool to 20 °C in an ice-water bath, add sodium nitrite aqueous solution dropwise, and react at 20 °C for 4 h. The reaction ends when the mass concentration of 1,3-dimethyl-4-nitro-1H-pyrazole is <1% by liquid chromatography.

[0057] After the reaction was completed, the reaction solution was poured into 3L of water and extracted three times with 1L of methyl tert-butyl ether. The organic phases were combined, washed with 1L of saturated sodium bicarbonate solution, washed with 500mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. Then, 140mL of thionyl chloride was added, and the mixture was heated to reflux for 3 hours. The intermediate was monitored by liquid chromatography and found to be <1%. After the reaction was completed, the thionyl chloride was concentrated to remove it, dissolved in 1L of dichloromethane, and then washed successively with 1L of saturated sodium bicarbonate solution and 200mL of saturated brine. The mixture was dried over anhydrous sodium sulfate, evaporated to a slurry, and then dispersed in 300mL of petroleum ether. The filter cake was obtained by vacuum drying at 35℃ to obtain pure 1-methyl-4-nitro-1H-pyrazole-3-carboxynitrile.

[0058] Synthesis of S3 and intermediate 1-methyl-4-nitro-1H-pyrazole-3-carboxamide;

[0059] 92.8 g (0.62 mol) of the intermediate 1-methyl-4-nitro-1H-pyrazole-3-carboxynitrile was dissolved in 500 mL of 95% ethanol, and 620 g of 20% sodium hydroxide solution was added. The mixture was heated to 50 °C and reacted for 1 h. During the reaction, the mass fraction of 1-methyl-4-nitro-1H-pyrazole-3-carboxynitrile was monitored by liquid chromatography and found to be <1%. The reaction was considered complete when the mass fraction was <1%. After the reaction was completed, the mixture was cooled to 15 °C, the pH was adjusted to 8 with 6 mol / L hydrochloric acid, and the mixture was concentrated at 50 °C under negative pressure to remove ethanol. The product precipitated, cooled to 10 °C, filtered, and dried at 75 °C to obtain 1-methyl-4-nitro-1H-pyrazole-3-carboxamide.

[0060] Synthesis of S4, intermediate 1-methyl-4-nitro-1H-pyrazole-3-amine;

[0061] Mix 985 mL of methanol and 985 mL of water to obtain a mixed solution of methanol and water;

[0062] 98.5 g (0.58 mol) of the intermediate 1-methyl-4-nitro-1H-pyrazole-3-carboxamide was dissolved in a mixed solution of methanol and water. Sodium hydroxide was added to adjust the pH to 12, and the solution was cooled to 10°C in an ice-salt bath. 539.7 g of 12% sodium hypochlorite solution was added dropwise, and the reaction was maintained at 10°C for 1 h. During the reaction, the mass fraction of 1-methyl-4-nitro-1H-pyrazole-3-carboxamide was monitored by liquid chromatography and the reaction was considered complete when it was less than 1%. 1000 mL of 15% sodium thiosulfate solution was added to remove oxidizing properties. The solution was concentrated under reduced pressure at 50°C to remove methanol. The solution was extracted four times with 500 mL of dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to a paste state. 200 mL of petroleum ether was added to disperse the solution. The solution was filtered, and the filter cake was dried under vacuum at 35°C to obtain 1-methyl-4-nitro-1H-pyrazole-3-amine.

[0063] Synthesis of S5 and intermediate 3-fluoro-1-methyl-4-nitro-1H-pyrazole;

[0064] Dissolve 64.86 g (0.94 mol) of sodium nitrite in 133 mL of water to obtain an aqueous solution of sodium nitrite;

[0065] 66.5 g (0.47 mol) of the intermediate 1-methyl-4-nitro-1H-pyrazole-3-amine was dissolved in 333 mL of 40% tetrafluoroboric acid aqueous solution. The solution was cooled to 5 °C in an ice-salt bath, and sodium nitrite aqueous solution was added dropwise. After the addition was complete, the solution was kept at 5 °C for 1 h, and then the temperature was slowly raised to room temperature for 12 h. During the reaction, the mass fraction of 1-methyl-4-nitro-1H-pyrazole-3-amine was monitored by liquid chromatography and found to be <1%. The reaction was considered complete when the mass fraction was <1%. After the reaction was complete, the solution was extracted three times with 300 mL of dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated until a large amount of product precipitated. The product was dispersed in 200 mL of petroleum ether, filtered, and the filter cake was dried under vacuum at 35 °C to obtain 3-fluoro-1-methyl-4-nitro-1H-pyrazole.

[0066] S6. Synthesis of the product 3-fluoro-1-methyl-1H-pyrazole-4-amine;

[0067] 51 g (0.35 mol) of the intermediate 3-fluoro-1-methyl-4-nitro-1H-pyrazole was dissolved in 510 mL of ethanol, 255 mL of acetic acid and 39 g of reduced iron powder were added, and the mixture was refluxed for 4 h. During the reaction, the mass fraction of 3-fluoro-1-methyl-4-nitro-1H-pyrazole was monitored by liquid chromatography and found to be <1%, indicating the end of the reaction. After the reaction, the mixture was cooled to room temperature, filtered through diatomaceous earth, concentrated to remove ethanol, and 200 mL of water was added. The pH was adjusted to 10 with 10% sodium hydroxide solution, and then extracted three times with 200 mL of dichloromethane. The organic phases were combined, washed with saturated brine, decolorized with 10 g of activated carbon, dried with anhydrous sodium sulfate, concentrated under negative pressure at 50 °C, and recrystallized with 80 mL of 50% ethanol to obtain the product 3-fluoro-1-methyl-1H-pyrazole-4-amine.

[0068] Example 3 A method for synthesizing 3-fluoro-1-methyl-1H-pyrazole-4-amine, specifically including the following steps:

[0069] Synthesis of S1 and intermediate 1,3-dimethyl-4-nitro-1H-pyrazole;

[0070] 127 g (1 mol) of 3-methyl-4-nitro-1H-pyrazole was dissolved in 1270 mL of acetonitrile, and 426 g of iodomethane was added. The mixture was heated to reflux and stirred for 4 h. During the reaction, the mass fraction of 3-methyl-4-nitro-1H-pyrazole was monitored by liquid chromatography and found to be <2%. The reaction was then considered complete. The mixture was cooled to 25 °C, and the reaction solution was filtered to remove solids. The mixture was concentrated under negative pressure at 48 °C to remove acetonitrile and obtain crude product. The crude product was placed in 630 mL of 95% ethanol and refluxed to dissolve it. The mixture was slowly cooled to 3 °C and kept at that temperature for 0.5 h to crystallize. The crystals were filtered, and the filter cake was washed with 95% ethanol and dried under vacuum at 65 °C to obtain pure 1,3-dimethyl-4-nitro-1H-pyrazole.

[0071] Synthesis of S2 and intermediate 1-methyl-4-nitro-1H-pyrazole-3-carboxynitrile;

[0072] Dissolve 76.6 g (1.11 mol) of sodium nitrite in 185 mL of water to obtain an aqueous solution of sodium nitrite;

[0073] 105 g (0.74 mol) of the intermediate 1,3-dimethyl-4-nitro-1H-pyrazole was dissolved in 1050 mL of glacial acetic acid, cooled to 18 °C in an ice-water bath, and sodium nitrite aqueous solution was added dropwise. The reaction was carried out at 18 °C for 3.5 h. The reaction was considered complete when the mass concentration of 1,3-dimethyl-4-nitro-1H-pyrazole was <1% by liquid chromatography.

[0074] After the reaction was completed, the reaction solution was poured into 3L of water and extracted three times with 1L of methyl tert-butyl ether. The organic phases were combined, washed with 1L of saturated sodium bicarbonate solution, washed with 500mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. 368mL of thionyl chloride was added, and the mixture was heated to reflux for 2.5h. The intermediate was monitored by liquid chromatography and found to be <1%. After the reaction was completed, the thionyl chloride was concentrated to remove the thionyl chloride. 1L of dichloromethane was added to dissolve the thionyl chloride. The mixture was then washed successively with 1L of saturated sodium bicarbonate solution and 200mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated to a slurry. 300mL of petroleum ether was added to disperse the slurry. The filter cake was obtained by vacuum drying at 35℃ to obtain pure 1-methyl-4-nitro-1H-pyrazole-3-carboxynitrile.

[0075] Synthesis of S3 and intermediate 1-methyl-4-nitro-1H-pyrazole-3-carboxamide;

[0076] 92.8 g (0.62 mol) of the intermediate 1-methyl-4-nitro-1H-pyrazole-3-carboxynitrile was dissolved in 500 mL of 95% ethanol, and 434 g of 20% sodium hydroxide solution was added. The mixture was heated to 45 °C and reacted for 1.5 h. During the reaction, the mass fraction of 1-methyl-4-nitro-1H-pyrazole-3-carboxynitrile was monitored by liquid chromatography and found to be <1%. The reaction was considered complete when the mass fraction was <1%. After the reaction was complete, the mixture was cooled to 12 °C, the pH was adjusted to 8 with 6 mol / L hydrochloric acid, and the ethanol was removed by concentration at 48 °C under negative pressure. The product precipitated, cooled to 8 °C, filtered, and dried by forced air at 75 °C to obtain 1-methyl-4-nitro-1H-pyrazole-3-carboxamide.

[0077] Synthesis of S4, intermediate 1-methyl-4-nitro-1H-pyrazole-3-amine;

[0078] Mix 985 mL of methanol and 985 mL of water to obtain a mixed solution of methanol and water;

[0079] 98.5 g (0.58 mol) of the intermediate 1-methyl-4-nitro-1H-pyrazole-3-carboxamide was dissolved in a mixed solution of methanol and water. Sodium hydroxide was added to adjust the pH to 11.5, and the solution was cooled to 5°C in an ice-salt bath. 720 g of 12% sodium hypochlorite solution was added dropwise, and the reaction was maintained at 5°C for 1.5 h. During the reaction, the mass fraction of 1-methyl-4-nitro-1H-pyrazole-3-carboxamide was monitored by liquid chromatography and the reaction was considered complete when it was less than 1%. 1000 mL of 15% sodium thiosulfate solution was added to remove oxidizing properties. The solution was concentrated under reduced pressure at 48°C to remove methanol. The solution was extracted four times with 500 mL of dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to a paste state. 200 mL of petroleum ether was added to disperse the solution. The solution was filtered, and the filter cake was dried under vacuum at 35°C to obtain 1-methyl-4-nitro-1H-pyrazole-3-amine.

[0080] Synthesis of S5 and intermediate 3-fluoro-1-methyl-4-nitro-1H-pyrazole;

[0081] Dissolve 49g (0.71mol) of sodium nitrite in 133mL of water to obtain an aqueous solution of sodium nitrite;

[0082] 66.5 g (0.47 mol) of the intermediate 1-methyl-4-nitro-1H-pyrazole-3-amine was dissolved in 333 mL of 40% tetrafluoroboric acid aqueous solution. The solution was cooled to 3 °C in an ice-salt bath, and sodium nitrite aqueous solution was added dropwise. After the addition was complete, the solution was kept at 0 °C for 1 h, and then slowly heated to room temperature for 12 h. During the reaction, the mass fraction of 1-methyl-4-nitro-1H-pyrazole-3-amine was monitored by liquid chromatography and found to be <1%. The reaction was considered complete when the mass fraction was <1%. After the reaction was complete, the solution was extracted three times with 300 mL of dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated until a large amount of product precipitated. The product was dispersed in 200 mL of petroleum ether, filtered, and the filter cake was dried under vacuum at 35 °C to obtain 3-fluoro-1-methyl-4-nitro-1H-pyrazole.

[0083] S6. Synthesis of the product 3-fluoro-1-methyl-1H-pyrazole-4-amine;

[0084] 51 g (0.35 mol) of the intermediate 3-fluoro-1-methyl-4-nitro-1H-pyrazole was dissolved in 510 mL of ethanol, 178 mL of acetic acid and 97.7 g of reduced iron powder were added, and the mixture was refluxed for 3.5 h. During the reaction, the mass fraction of 3-fluoro-1-methyl-4-nitro-1H-pyrazole was monitored by liquid chromatography and found to be <1%, indicating the end of the reaction. After the reaction, the mixture was cooled to room temperature, filtered through diatomaceous earth, concentrated to remove ethanol, and 200 mL of water was added. The pH was adjusted to 9.5 with 10% sodium hydroxide solution, and then extracted three times with 200 mL of dichloromethane. The organic phases were combined, washed with saturated brine, decolorized with 10 g of activated carbon, dried over anhydrous sodium sulfate, concentrated under negative pressure at 48 °C, and recrystallized with 80 mL of 50% ethanol to obtain the product 3-fluoro-1-methyl-1H-pyrazole-4-amine.

[0085] The specific embodiments of the present invention described above do not constitute a limitation on the scope of protection of the present invention. Any other corresponding changes and modifications made in accordance with the technical concept of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A process for the synthesis of 3-fluoro-1-methyl-1 H-pyrazol-4-amine, characterized in that, 3-methyl-4-nitro-1H-pyrazole as raw material, prepared by the following reaction scheme: 。 2. The process for the synthesis of 3-fluoro-1-methyl-1 H-pyrazol-4-amine according to claim 1, characterized in that, The specific steps are: S1, 3-methyl-4-nitro-1H-pyrazole and methyl iodide as the reactants, by methylation reaction to get intermediate 1,3-dimethyl-4-nitro-1H-pyrazole; S2, the intermediate 1,3-dimethyl-4-nitro-1H-pyrazole is dissolved in glacial acetic acid, 15~20℃ dropwise added sodium nitrite aqueous solution, reaction 3~4h, after the reaction is completed, the reaction liquid is poured into water, methyl tert-butyl ether extraction, the organic phase is washed, dried, concentrated to get concentrated liquid; to the concentrated liquid, add thionyl chloride, heating to reflux, reaction 2~3h, after the reaction is completed, concentrated, added to dichloromethane, washed, dried, evaporated to paste, then add petroleum ether dispersion, suction filtration, vacuum drying to get intermediate 1-methyl-4-nitro-1H-pyrazole-3-carbonitrile; S3, the intermediate 1-methyl-4-nitro-1H-pyrazole-3-carbonitrile is dissolved in ethanol, add sodium hydroxide solution, 40~50℃ reaction 1~2h, after the reaction is completed, cooling, adjust the pH to 7~8, negative pressure concentration, filtration, solid drying to get intermediate 1-methyl-4-nitro-1H-pyrazole-3-carboxamide; S4, the intermediate 1-methyl-4-nitro-1H-pyrazole-3-carboxamide is dissolved in a mixture of methanol and water, adjust the pH to 11~12, 0~10℃ dropwise added sodium hypochlorite solution, incubation reaction 1~2h, after the reaction is completed, add sodium thiosulfate solution, reduced pressure concentration, dichloromethane extraction, organic phase washing, drying, evaporated to paste, petroleum ether dispersion, suction filtration, vacuum drying to get intermediate 1-methyl-4-nitro-1H-pyrazole-3-amine; S5, the intermediate 1-methyl-4-nitro-1H-pyrazole-3-amine is dissolved in aqueous solution of tetrafluoroboric acid, 0~5℃ dropwise added sodium nitrite aqueous solution, incubation 1h, then slowly rise to room temperature reaction 12h, after the reaction is completed, dichloromethane extraction, organic phase washing, drying, evaporation concentration, petroleum ether dispersion, suction filtration, vacuum drying to get intermediate 3-fluoro-1-methyl-4-nitro-1H-pyrazole; S6, the intermediate 3-fluoro-1-methyl-4-nitro-1H-pyrazole is dissolved in ethanol, add acetic acid, iron powder, heating to reflux, reaction 3~4h, after the reaction is completed, cooling to room temperature, filtration, concentration, add water and adjust the pH to 9~10, dichloromethane extraction, organic phase washing, activated carbon decolorization, drying, negative pressure concentration, recrystallization to get 3-fluoro-1-methyl-1H-pyrazole-4-amine.

3. The method of synthesis of 3-fluoro-1-methyl-1 H-pyrazol-4-amine according to claim 2, characterized in that, In step S1, the molar ratio of 3-methyl-4-nitro-1H-pyrazole and methyl iodide is 1:1~3, during the methylation reaction, the mass fraction of 3-methyl-4-nitro-1H-pyrazole in the reaction liquid is monitored by liquid chromatography, which is less than 2%, then the reaction is completed.

4. The method of synthesis of 3-fluoro-1-methyl-1 H-pyrazol-4-amine according to claim 2, characterized by, In step S2, the molar ratio of the intermediate 1,3-dimethyl-4-nitro-1H-pyrazole and sodium nitrite is 1:1-1.5, and the feed ratio of the 1,3-dimethyl-4-nitro-1H-pyrazole and thionyl chloride is 1g:2-5mL.

5. The method of synthesis of 3-fluoro-1-methyl-1 H-pyrazol-4-amine according to claim 2, characterized by, In step S3, the mass concentration of the sodium hydroxide solution is 20%, and the molar ratio of the intermediate 1-methyl-4-nitro-1H-pyrazole-3-carbonitrile and sodium hydroxide in the sodium hydroxide solution is 1:2-5.

6. The method of synthesis of 3-fluoro-1-methyl-1 H-pyrazol-4-amine according to claim 2, characterized by, In step S4, the molar ratio of the intermediate 1-methyl-4-nitro-1H-pyrazole-3-carboxamide and sodium hypochlorite in the sodium hypochlorite solution is 1:1.5-3.

7. The method for synthesizing 3-fluoro-1-methyl-1H-pyrazole-4-amine according to claim 2, characterized in that, In step S5, the mass concentration of the aqueous tetrafluoroboric acid solution is 40%, and the molar ratio of the intermediate 1-methyl-4-nitro-1H-pyrazole-3-carbonitrile and sodium nitrite in the aqueous sodium nitrite solution is 1:1.2-2.

8. The method for synthesizing 3-fluoro-1-methyl-1H-pyrazole-4-amine according to claim 2, characterized in that, In step S6, the feed ratio of the intermediate 3-fluoro-1-methyl-4-nitro-1H-pyrazole and acetic acid is 1g:2-5mL, and the molar ratio of the intermediate 3-fluoro-1-methyl-4-nitro-1H-pyrazole and the reduced iron powder is 1:2-5.

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