A kind of synthetic method of 4-fluoro-1H-pyrazole

Abstract

The present invention provides a method for synthesizing 4-fluoro-1H-pyrazoles, wherein the method, under alkaline conditions, methylates 5-fluorouracil in a solvent to obtain 1,3-dimethyl-5-fluorouracil; then, in the presence of a metal reducing agent, the lactam is reduced and ring-opened to generate an intermediate state, and then reacted with hydrazine hydrate to generate 4-fluoro-1H-pyrazoles. This synthetic route does not require highly toxic sodium fluoroacetate, does not require expensive fluorination reagents, and can well control the exothermic reaction. After the raw material 5-fluorouracil is first methylated and protected, the lactam is reduced using a metal reducing agent, and then the one-pot method reacts with hydrazine hydrate to prepare 4-fluoro-1H-pyrazoles. The present invention increases the activity of the reactant by methylating and protecting the lactam, improves the reaction yield, and the intermediate does not need to be separated. The one-pot method synthesizes the product, greatly reduces the cost, simplifies the purification process, and improves the product quality and yield.

Description

Technical Field

[0001] The invention relates to a synthesis method of 4-fluoro-1H-pyrazole, belonging to the technical field of chemical synthesis. Background Art

[0002] Pyrazole and fluorine-containing pyrazole have high potential application value in medicine, dyes and many luminescent materials in terms of biological activity and coordination ability. At the same time, pyrazole compounds have excellent herbicidal, insecticidal and fungicidal activities, and their high efficiency and low toxicity have strong advantages in all aspects. In particular, the different substituents and positions on the pyrazole ring make its varieties increasingly rich in the market. In particular, the introduction of fluorine atoms with strong electronegativity and small atomic radius can improve the lipophilicity and metabolic stability of the compound, and can modify the structure of various drugs, improve the toxicity, efficacy and metabolic process of drug molecules.

[0003] 4-Fluoro-1H-pyrazole is an important intermediate in drug development. Currently, there are several industrial synthesis methods:

[0004]

[0005] Reichardt and Halbritter first used ethyl fluoroacetate as a raw material in 1970, hydrolyzed it with sodium hydroxide to form highly toxic sodium fluoroacetate, then reacted it with oxalyl chloride and DMF to prepare 3-(dimethylamino)-2-fluoroprop-2-enal, which was then reacted with hydrazine hydrochloride to produce the target product. This route involves highly toxic raw materials and highly toxic intermediates, which are highly harmful to humans, and the total yield of 20% is very low and not suitable for industrial production (see Scheme 1 for the reaction formula).

[0006]

[0007] Katherine England, Helen Mason and their colleagues optimized this route in 2010, reducing the four-step process of raw materials to two steps, but the overall yield still did not change significantly, making it unsuitable for industrial production (see Scheme 2 for the reaction formula).

[0008]

[0009] Zhao Qing and others from Nanjing Yaoshi Technology Co., Ltd. used 1,1,3,3-tetramethoxypropane as raw material, hydrolyzed with hydrochloric acid, fluorinated with Selectfluor, and closed the pyrazole ring in one pot to prepare 4-fluoro-1H-pyrazole. The laboratory was scaled up to 500g batches, with a maximum yield of 45.35%. Although the total yield was improved, it still failed to reach the industrial production scale. In addition, the fluorination reagent Selectfluor was expensive, and the reaction released heat significantly, which was not conducive to industrial production control (see Scheme 3 for the reaction formula). Summary of the invention

[0010] The present invention aims to overcome the above-mentioned shortcomings and provide a method for synthesizing 4-fluoro-1H-pyrazole, wherein the raw materials are cheap and readily available, the method improves the product yield and purity, reduces the cost and ensures the route and process of industrial production safety.

[0011] The synthetic route is shown in Scheme 4.

[0012]

[0013] A method for synthesizing 4-fluoro-1H-pyrazole comprises the following steps:

[0014] Step (1): in the presence of an alkaline substance and a methylating agent, methylating 5-fluorouracil in a solvent to obtain 1,3-dimethyl-5-fluorouracil;

[0015] Step (2): the 1,3-dimethyl-5-fluorouracil obtained in step (1) is dissolved in a solvent, and in the presence of a reducing agent, the lactam is reduced and ring-opened to generate an intermediate state, and then the intermediate state is ring-closed with hydrazine hydrate to generate 4-fluoro-1H-pyrazole;

[0016] Step (3): Add the crude 4-fluoro-1H-pyrazole in step (2) into a reactor equipped with a vacuum distillation apparatus, collect the 55-65°C fraction under a vacuum degree of 0.09-0.097 MPa, and obtain a clear colorless liquid, namely 4-fluoro-1H-pyrazole.

[0017] The alkaline substance in step (1) is selected from one or more of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, potassium hydroxide, potassium phosphate, lithium hydroxide, lithium carbonate, cesium carbonate, triethylamine, and diisopropylethylamine, and the molar ratio of the alkaline substance to 5-fluorouracil is (1-20):1, preferably (2-10):1. The purpose is to provide a suitable alkaline reaction environment.

[0018] The methylating agent in step (1) is selected from one or more of dimethyl sulfate, methyl iodide, methyl bromide, methyl chloride, methyl magnesium bromide, methyl magnesium chloride, methyl p-toluenesulfonate, and methyl trifluoromethanesulfonate. The molar ratio of the alkaline substance to 5-fluorouracil is (1-10):1, preferably (2-7):1.

[0019] When step (1) is carried out in a solvent system, the solvent is selected from one or more of the following solvents: organic alcohol solvents, organic amide solvents, organic ether solvents, acetonitrile and water.

[0020] The organic alcohol solvent in step (1) is selected from methanol, ethanol, isopropanol, n-butanol, tert-amyl alcohol or a mixture of several thereof; the organic amide solvent in step (1) is selected from N, N-dimethylacetamide and / or N, N-dimethylformamide; the organic ether solvent is selected from diethyl ether, isopropyl ether or tetrahydrofuran or a mixture of several thereof.

[0021] The reducing agent in step (2) is a metal reducing agent, preferably one or a mixture of the following: DIBAL-H, sodium borohydride, lithium aluminum hydride, lithium borohydride, potassium borohydride, and the molar ratio of the above reducing agent to 1,3-dimethyl-5-fluorouracil is (0.5-5):1.

[0022] The solvent in step (2) is an organic ether, and the organic ether solvent is one or more mixed solvents selected from the following: tetrahydrofuran, diethyl ether, 1,4-dioxane, etc.

[0023] The molar ratio of hydrazine hydrate to 1,3-dimethyl-5-fluorouracil in step (2) is (1-10):1, preferably (2-4):1.

[0024] Compared with the prior art, the present invention has the following notable features:

[0025] (1) This synthetic route first methylates the raw material, uses DIBAL-H to reduce and open the ring, and then closes the ring with hydrazine hydrate to synthesize the product in one pot, which reduces the separation of intermediates, improves production efficiency, reduces three wastes, and is conducive to industrial production;

[0026] (2) No highly toxic raw materials are required in the synthesis steps. The raw materials are cheap and easy to obtain, the reagents are easy to obtain, no expensive reagents are used, and the reaction conditions are not strict;

[0027] (3) Product distillation is avoided, and the product can be obtained by conventional distillation, which is suitable for industrial production;

[0028] (4) The product quality and yield were greatly improved, with the total yield increased from 20% and 45.35% in the literature to 54~57%.

[0029] In summary, the present invention methylates 5-fluorouracil in a solvent under alkaline conditions to obtain 1,3-dimethyl-5-fluorouracil; then, in the presence of a metal reducing agent, the lactam is reduced and ring-opened to generate an intermediate state, and then reacted with hydrazine hydrate to form 4-fluoro-1H-pyrazole. This synthetic route does not use highly toxic sodium fluoroacetate, does not use expensive fluorination reagents, and can well control the exothermic reaction. After the raw material 5-fluorouracil is methylated and protected, the lactam is reduced by a metal reducing agent, and then reacted with hydrazine hydrate in a one-pot method to prepare 4-fluoro-1H-pyrazole. By methylating and protecting the lactam, the activity of the reactant is increased, the reaction yield is improved, the intermediate does not need to be separated, and the product is synthesized in a one-pot method, which greatly reduces the cost, simplifies the purification process, and improves the product quality and yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 The final product of the present invention, 4-fluoro-1H-pyrazole 1 HNMR spectrum. DETAILED DESCRIPTION

[0031] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. Under the premise of not departing from the technical solution of the present invention, any modification of the present invention that is easily implemented by a person of ordinary skill in the art will fall within the scope of the claims of the present invention.

[0032] The present invention achieves the technical purpose through the following process.

[0033] According to a specific embodiment of the present invention, a method for preparing 4-fluoro-1H-pyrazole is provided, and the reaction is carried out according to the reaction formula:

[0034]

[0035] Example 1

[0036] Step (1), preparation of compound 3: 5-fluorouracil (50 kg, 0.384 kmol, 1.0 eq.) was dispersed and dissolved in a 13 wt% sodium hydroxide (115.3 kg, 2.88 kmol, 7.5 eq.) aqueous solution at room temperature, nitrogen was replaced, stirred for 10 min and then cooled to 0-5°C. Dimethyl sulfate (242 kg, 1.92 kmol, 5.0 eq.) was added dropwise at 0-5°C, stirred at 0-5°C for 30 min, heated to 20-25°C and stirred for 30 min, then heated to 95-100°C and refluxed and stirred for 16 hours. HPLC showed that the raw material 5-fluorouracil disappeared. The reaction mixture was cooled to 20-25°C, and DCM (10V*2) was added for extraction twice. The organic phases were combined and washed once with a half-saturated sodium bicarbonate aqueous solution (5V), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness in a water bath at 40°C to obtain 57.8 kg of compound 3 as a white solid with an HPLC purity of 100% and a molar yield of 95 mol%.

[0037] Step (2), preparation of compound 1: Add compound 3 (55 kg, 0.348 kmol, 1.0 eq.) to the reactor, replace nitrogen, add dry tetrahydrofuran (275 L, 5 V), stir to dissolve, and replace nitrogen. Under nitrogen protection, cool to -5~0°C, control the temperature to -5~5°C, and slowly drop 1.0M DIBAL-H toluene solution (418 L, 0.418 kmol, 1.2 eq.). After the dropwise addition is completed, stir at 0~5°C for 2 hours, and monitor the reaction by HPLC until compound 3 disappears. Under nitrogen protection, slowly drop 50wt% hydrazine hydrate (44.5 kg, 0.696 kmol, 2.0 eq.) at 0~5°C. After the dropwise addition is completed, keep warm and stir for 30 minutes, then heat to 20~25°C, stir for 10~12 hours, and monitor the reaction by HPLC until the product in the reaction solution no longer increases. After the reaction is completed, cool to 0~5°C and heat at T 内 At ≤20°C, process water was added dropwise, methyl tert-butyl ether was added, stirred, filtered, the filter cake was washed with methyl tert-butyl ether, the filtrate was combined, the layers were separated, the aqueous phase was extracted three times with methyl tert-butyl ether, the organic layers were combined, and washed twice with 10wt% sodium chloride aqueous solution. After the organic phase was concentrated, 42kg of brown oil was obtained, that is, the crude 4-fluoro-1H-pyrazole was obtained. After weight content conversion, the net weight of 4-fluoro-1H-pyrazole in the crude product was 30kg, and its molar yield was 62mol%.

[0038] Step (3), distillation of compound 1: The crude product of 4-fluoro-1H-pyrazole in step (2) (40 kg, weight content of 71.4%, net weight of 28.6 kg) was added to a reactor equipped with a vacuum distillation apparatus, and the 55-65°C fraction was collected under a vacuum degree of 0.09-0.097 MPa to obtain 26.3 kg of a clear colorless liquid, namely 4-fluoro-1H-pyrazole, with a distillation yield of 92% and a total yield of 54.2% in three steps.

[0039] Example 2

[0040] Step (1), preparation of compound 3: 5-fluorouracil (100 kg, 0.769 kmol, 1.0 eq.) was dispersed and dissolved in a 13 wt% sodium hydroxide (230.6 kg, 5.77 kmol, 7.5 eq.) aqueous solution at room temperature, nitrogen was replaced, stirred for 10 min and then cooled to 0-5°C. Dimethyl sulfate (485 kg, 3.85 kmol, 5.0 eq.) was added dropwise at 0-5°C, stirred at 0-5°C for 30 min, heated to 20-25°C and stirred for 30 min, then heated to 95-100°C and refluxed and stirred for 16 hours. HPLC showed that the raw material 5-fluorouracil disappeared. The reaction mixture was cooled to 20-25°C, and DCM (10V*2) was added for extraction twice. The organic phases were combined and washed once with a half-saturated aqueous sodium bicarbonate solution (5V), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness in a water bath at 40°C to obtain 116.7 kg of compound 3 as a white solid with an HPLC purity of 100% and a molar yield of 96 mol%.

[0041] Step (2), preparation of compound 1: Compound 3 (115 kg, 0.727 kmol, 1.0 eq.) was added to a reaction kettle, nitrogen was replaced, dry tetrahydrofuran (575 L, 5 V) was added, stirred to dissolve, and nitrogen was replaced. Under nitrogen protection, the mixture was cooled to -5~0°C, the temperature was controlled at -5~5°C, and a 1.0 M DIBAL-H toluene solution (872 L, 0.872 kmol, 1.2 eq.) was slowly added dropwise. After the addition was completed, the mixture was stirred at 0~5°C for 2 hours, and the reaction was monitored by HPLC until compound 3 disappeared. Under nitrogen protection, 50 wt% hydrazine hydrate (93.1 kg, 1.454 kmol, 2.0 eq.) was slowly added dropwise at 0~5°C, and the mixture was stirred for 30 minutes. The mixture was heated to 20~25°C, stirred for 10~12 hours, and the reaction was monitored by HPLC until the product in the reaction solution no longer increased. After the reaction is complete, cool to 0~5℃ and 内At ≤20°C, process water was added dropwise, methyl tert-butyl ether was added, stirred, filtered, the filter cake was washed with methyl tert-butyl ether, the filtrate was combined, the layers were separated, the aqueous phase was extracted three times with methyl tert-butyl ether, the organic layers were combined, and washed twice with 10wt% sodium chloride aqueous solution. After the organic phase was concentrated, 84.4kg of brown oil was obtained, namely, the crude 4-fluoro-1H-pyrazole. After weight content conversion, the net weight of 4-fluoro-1H-pyrazole in the crude product was 62.6kg, and its molar yield was 64mol%.

[0042] Step (3), distillation of compound 1: The crude product of 4-fluoro-1H-pyrazole in step (2) (84 kg, weight content of 74.2%, net weight of 62.3 kg) was added to a reactor equipped with a vacuum distillation apparatus, and the fraction of 55-65° C. was collected under a vacuum degree of 0.09-0.097 MPa to obtain 58.6 kg of clear colorless liquid, namely 4-fluoro-1H-pyrazole, with a distillation yield of 94%. The total yield of the three steps was 57.8%.

[0043] Example 3

[0044] Step (1), preparation of compound 3: 5-fluorouracil (200 kg, 1.538 kmol, 1.0 eq.) was dispersed and dissolved in a 13 wt% sodium hydroxide (461 kg, 11.54 kmol, 7.5 eq.) aqueous solution at room temperature, nitrogen was replaced, stirred for 10 min and then cooled to 0-5°C. Dimethyl sulfate (970 kg, 7.7 kmol, 5.0 eq.) was added dropwise at 0-5°C, stirred at 0-5°C for 30 min, heated to 20-25°C and stirred for 30 min, then heated to 95-100°C and refluxed and stirred for 16 hours. HPLC showed that the raw material 5-fluorouracil disappeared. The reaction mixture was cooled to 20-25°C, and DCM (10V*2) was added for extraction twice. The organic phases were combined and washed once with a half-saturated sodium bicarbonate aqueous solution (5V), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness in a water bath at 40°C to obtain 235 kg of compound 3 as a white solid with an HPLC purity of 100% and a molar yield of 96.7 mol%.

[0045] Step (2), preparation of compound 1: Add compound 3 (230 kg, 1.45 kmol, 1.0 eq.) to the reactor, replace nitrogen, add dry tetrahydrofuran (1150 L, 5 V), stir to dissolve, and replace nitrogen. Under nitrogen protection, cool to -5~0 ° C, control the temperature to -5~5 ° C, and slowly drop 1.0M DIBAL-H toluene solution (1740 L, 1.74 kmol, 1.2 eq.). After the dropwise addition is completed, stir at 0~5 ° C for 2 hours, and monitor the reaction by HPLC until compound 3 disappears. Under nitrogen protection, slowly drop 50wt% hydrazine hydrate (186 kg, 2.90 kmol, 2.0 eq.) at 0~5 ° C. After the dropwise addition is completed, keep warm and stir for 30 minutes, then heat to 20~25 ° C, stir for 10~12 hours, and monitor the reaction by HPLC until the product in the reaction solution no longer increases. After the reaction is completed, cool to 0~5 ° C, and at T 内 At ≤20°C, process water was added dropwise, methyl tert-butyl ether was added, stirred, filtered, the filter cake was washed with methyl tert-butyl ether, the filtrate was combined, the layers were separated, the aqueous phase was extracted three times with methyl tert-butyl ether, the organic layers were combined, and washed twice with 10wt% sodium chloride aqueous solution. After the organic phase was concentrated, 116.6kg of brown oil was obtained, i.e., crude 4-fluoro-1H-pyrazole. After weight content conversion, the net weight of 4-fluoro-1H-pyrazole in the crude product was 80.8kg, and its molar yield was 64.5mol%.

[0046] Step (3), distillation of compound 1: The crude product of 4-fluoro-1H-pyrazole in step (2) (115 kg, weight content of 69.3%, net weight of 79.7 kg) was added to a reactor equipped with a vacuum distillation apparatus, and the fraction at 55-65° C. was collected under a vacuum degree of 0.09-0.097 MPa to obtain 76 kg of clear colorless liquid, namely 4-fluoro-1H-pyrazole, with a distillation yield of 95.3%. The total yield of the three steps was 57.4%.

[0047] Example 4

[0048] Step (1), preparation of compound 3: 5-fluorouracil (200 kg, 1.538 kmol, 1.0 eq.) was dispersed and dissolved in a 13 wt% sodium hydroxide (461 kg, 11.54 kmol, 7.5 eq.) aqueous solution at room temperature, nitrogen was replaced, stirred for 10 min and then cooled to 0-5°C. Dimethyl sulfate (970 kg, 7.7 kmol, 5.0 eq.) was added dropwise at 0-5°C, stirred at 0-5°C for 30 min, heated to 20-25°C and stirred for 30 min, then heated to 95-100°C and refluxed and stirred for 16 hours. HPLC showed that the raw material 5-fluorouracil disappeared. The reaction mixture was cooled to 20-25°C, and DCM (10V*2) was added for extraction twice. The organic phases were combined and washed once with a half-saturated sodium bicarbonate aqueous solution (5V), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness in a water bath at 40°C to obtain 233 kg of compound 3 as a white solid with an HPLC purity of 100% and a molar yield of 95.8 mol%.

[0049] Step (2), preparation of compound 1: Add compound 3 (235kg, 1.49kmol, 1.0eq.) to the reactor, replace nitrogen, add dry tetrahydrofuran (1175L, 5V), stir to dissolve, and replace nitrogen. Under nitrogen protection, cool to -5~0℃, control the temperature to -5~5℃, and slowly drop 1.0M DIBAL-H toluene solution (1790L, 1.79kmol, 1.2eq.). After the dropwise addition is completed, stir at 0~5℃ for 2 hours, and monitor the reaction by HPLC until compound 3 disappears. Under nitrogen protection, slowly drop 50wt% hydrazine hydrate (191kg, 2.98kmol, 2.0eq.) at 0~5℃, after the dropwise addition is completed, keep warm and stir for 30min, then heat to 20~25℃, stir for 10~12 hours, and monitor the reaction by HPLC until the product in the reaction solution no longer increases. After the reaction is completed, cool to 0~5℃, and at T 内 At ≤20°C, process water was added dropwise, methyl tert-butyl ether was added, stirred, filtered, the filter cake was washed with methyl tert-butyl ether, the filtrate was combined, the layers were separated, the aqueous phase was extracted three times with methyl tert-butyl ether, the organic layers were combined, and washed twice with 10wt% sodium chloride aqueous solution. After the organic phase was concentrated, 115kg of brown oil was obtained, that is, the crude 4-fluoro-1H-pyrazole. After weight content conversion, the net weight of 4-fluoro-1H-pyrazole in the crude product was 82.9kg, and its molar yield was 64.8mol%.

[0050] Step (3), distillation of compound 1: The crude product of 4-fluoro-1H-pyrazole in step (2) (113 kg, weight content of 72%, net weight of 81.4 kg) was added to a reactor equipped with a vacuum distillation apparatus, and the fraction at 55-65° C. was collected under a vacuum degree of 0.09-0.097 MPa to obtain 76.8 kg of clear colorless liquid, namely 4-fluoro-1H-pyrazole, with a distillation yield of 94.3%. The total yield of the three steps was 58.0%.

[0051] The method for preparing 4-fluoro-1H-pyrazole of the present invention has a simple process, low requirements on production conditions, easy product purification and high yield, lower cost than known methods, and significantly improves the production efficiency and product quality of 4-fluoro-1H-pyrazole.

[0052] The method for preparing 4-fluoro-1H-pyrazole of the present invention has a simple process, low requirements on production conditions, low cost, readily available raw materials, and easy product purification. A total of four batches are scaled up, and the total yields of each batch are 54.2%, 57.8%, 57.4% and 58.0%, respectively, which are significantly higher than the yields of 20% and 45.35% in the literature, and have been scaled up to 100 kilograms, which significantly improves the production efficiency of 4-fluoro-1H-pyrazole.

Claims

1. A method for synthesizing 4-fluoro-1H-pyrazole, characterized in that: The method comprises the following steps: Step (1): in the presence of an alkaline substance and a methylating agent, methylating 5-fluorouracil in a solvent to obtain 1,3-dimethyl-5-fluorouracil; Step (2): the 1,3-dimethyl-5-fluorouracil obtained in step (1) is dissolved in a solvent, and in the presence of a reducing agent DIBAL-H, the lactam is reduced and ring-opened to generate an intermediate state, and then the intermediate state is reacted with hydrazine hydrate to generate a crude 4-fluoro-1H-pyrazole product; Step (3): distill the crude 4-fluoro-1H-pyrazole in step (2) under reduced pressure to obtain 4-fluoro-1H-pyrazole.

2. A method for synthesizing 4-fluoro-1H-pyrazole according to claim 1, characterized in that: The methylating agent in step (1) is selected from one or more of dimethyl sulfate, methyl iodide, methyl bromide, methyl chloride, methyl magnesium bromide, methyl magnesium chloride, methyl p-toluenesulfonate, and methyl trifluoromethanesulfonate.

3. A method for synthesizing 4-fluoro-1H-pyrazole according to claim 1, characterized in that: The alkaline substance in step (1) is selected from one or more of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, potassium hydroxide, potassium phosphate, lithium hydroxide, lithium carbonate, cesium carbonate, triethylamine, and diisopropylethylamine.

4. A method for synthesizing 4-fluoro-1H-pyrazole according to claim 1, characterized in that: When the step (1) is carried out in a solvent system, the solvent is selected from one or a mixture of the following solvents: organic alcohol solvents, organic amide solvents, organic ether solvents, acetonitrile and water.

5. A method for synthesizing 4-fluoro-1H-pyrazole according to claim 4, characterized in that: The organic alcohol solvent in step (1) is one or a mixture of methanol, ethanol, isopropanol, n-butanol, and tert-amyl alcohol; the organic amide solvent in step (1) is one or a mixture of N,N-dimethylacetamide and N,N-dimethylformamide; the organic ether solvent is one or a mixture of diethyl ether, isopropyl ether, and tetrahydrofuran.

6. The method for synthesizing 4-fluoro-1H-pyrazole according to claim 1, characterized in that: The solvent in step (2) is an organic ether.

7. The method for synthesizing 4-fluoro-1H-pyrazole according to claim 6, characterized in that: The organic ether solvent is tetrahydrofuran, diethyl ether, 1,4-dioxane or a mixture of the above.

8. The method for synthesizing 4-fluoro-1H-pyrazole according to claim 1, characterized in that: The molar ratio of hydrazine hydrate to 1,3-dimethyl-5-fluorouracil in step (2) is (1-10):1.

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