5-acetyl-1h-pyrazole-3-carboxylic acid and its preparation method and application

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to 5-acetyl-1H-pyrazole-3-carboxylic acid and a preparation method and application thereof. The preparation method comprises the following steps: firstly, reacting raw material 3,5-pyrazole dicarboxylic acid and tert-butyl alcohol to obtain intermediate a; then, reacting the intermediate a with N,O-dimethylhydroxylamine hydrochloride to obtain intermediate b; then, reacting the intermediate b with methyl magnesium bromide to obtain intermediate c; finally, hydrolyzing the intermediate c by using alkali liquor, and neutralizing the product by using acid to obtain 5-acetyl-1H-pyrazole-3-carboxylic acid. The raw material used in the reaction is easy to obtain, the reaction condition is mild, the operation is simple, the total yield of the product is greater than 70%, the purity of the product reaches more than 99.9%, and the method is suitable for large-scale industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic synthesis, and particularly relates to 5-acetyl-1H-pyrazole-3-carboxylic acid and a preparation method and application thereof. BACKGROUND

[0002] 5-acetyl-1H-pyrazole-3-carboxylic acid is a white, yellow or brown solid, has no irritating odor, is easily soluble in acetone, ethyl acetate, dichloromethane and other organic solvents, and is a key intermediate for synthesizing darolutamide. Darolutamide is an oral non-steroidal androgen receptor inhibitor (ARi) with a unique chemical structure, which binds to the receptor with high affinity and exhibits strong antagonistic activity, thereby inhibiting the function of the receptor and the growth of prostate cancer cells, and is suitable for treating non-metastatic castration-resistant prostate cancer adult patients with high risk of metastasis.

[0003] In the prior art, the synthesis method of 5-acetyl-1H-pyrazole-3-carboxylic acid disclosed in patent US2017101397 is to synthesize 5-acetyl-1H-pyrazole-3-carboxylic acid ethyl ester from ethyl diazoacetate and 3-butyne-2-ketone as raw materials under the action of a catalyst indium chloride, and then base hydrolysis. The ethyl diazoacetate used in the route has the properties of flammability and explosiveness, and the metal catalyst indium chloride is used, and the waste water generated in the post-treatment is difficult to treat. The raw materials used in the process route are not easy to prepare, so the large-scale industrial production of the synthesis method is limited.

[0004]

[0005] Patent WO2004032928 discloses that 3,3-dimethoxy-2-butanone and diethyl oxalate are reacted in ethanol and sodium ethoxide solution to obtain a sodium salt, which is then reacted with hydrazine monohydrochloride to obtain 5-acetyl-1H-pyrazole-3-carboxylic acid ethyl ester crude product, which is purified by liquid phase to obtain a yield of only 26%. Then, according to the general method disclosed in patent WO2004032928, 5-acetyl-1H-pyrazole-3-carboxylic acid ethyl ester (2.56 mmol) is hydrolyzed, acidified with hydrochloric acid, extracted with ethyl acetate (100 vol), and concentrated to obtain 5-acetyl-1H-pyrazole-3-carboxylic acid. The 5-acetyl-1H-pyrazole-3-carboxylic acid ethyl ester crude product prepared by the route has poor purity, is difficult to separate, has low yield, and is not suitable for industrial production.

[0006]

[0007] A document László Poszávácz; Tamás Nagy; Katalin Kátai-Fadgyas, et al. New, Scalable Process for the Preparation of 5-Acetyl-1H-pyrazole-3-carboxylic Acid, a Key Intermediate of Darolutamide [J]. Synthesis, 2023, 55:2061-2069 reports that 3,5-pyrazole carboxylic acid diethyl ester is hydrolyzed under the action of magnesium hydroxide to obtain 3-ethoxycarbonyl-1H-pyrazole-5-carboxylic acid, 3-ethoxycarbonyl-1H-pyrazole-5-carboxylic acid and thionyl chloride are reacted to obtain pyrazole chloride, pyrazole chloride and diethyl malonate are reacted in a sodium hydride solution in tetrahydrofuran, and then acid hydrolysis is carried out to obtain a crude product 5-acetyl-1H-pyrazole-3-carboxylic acid, and the crude product is purified by sodium carbonate aqueous solution and methyl tert-butyl ether. This route has a long step, low yield, uses smelly thionyl chloride, and flammable and explosive sodium hydride, and is not suitable for industrial production.

[0008]

[0009] Therefore, there is an urgent need for a method for synthesizing 5-acetyl-1H-pyrazole-3-carboxylic acid which is simple and economical to operate, easy to obtain raw materials and suitable for industrial production. SUMMARY

[0010] The purpose of the present application is to provide a method for preparing 5-acetyl-1H-pyrazole-3-carboxylic acid which is simple and economical to operate, easy to obtain raw materials and suitable for industrial production, in view of the current synthesis process of 5-acetyl-1H-pyrazole-3-carboxylic acid which has a long route, low yield, complicated processing, and flammable and explosive raw materials, and is not easy to scale up.

[0011] The technical scheme of the present application is a method for preparing 5-acetyl-1H-pyrazole-3-carboxylic acid, comprising the following steps:

[0012] (1) Preparation of intermediate a: raw materials 3,5-pyrazole dicarboxylic acid and tert-butyl alcohol are subjected to esterification reaction under the action of a catalyst and a dehydrating agent to obtain intermediate a. The structural formula of intermediate a is:

[0013] The structural formula of 3,5-pyrazole dicarboxylic acid is:

[0014] The structural formula of tert-butyl alcohol is:

[0015] The specific operation of step (1) is as follows: first, 3,5-pyrazole dicarboxylic acid is added to a solvent at room temperature for dissolution, and tert-butyl alcohol and a catalyst are added under stirring. The solvent can be tetrahydrofuran, dichloromethane, toluene, methyl tert-butyl ether, N,N-dimethylformamide, etc. The stirring speed can be 50-150 r / min.

[0016] Then, a dehydrating agent is added for reaction. The dehydrating agent can be added in batches, 3-5 times.

[0017] Finally, after the reaction is completed, filtration is performed, the obtained filtrate is concentrated to a viscous state to obtain a concentrated solution; the concentrated solution is added to an organic solvent for dissolution, water is added, and the organic phase is washed with water; the phases are separated, and the obtained organic phase is concentrated to obtain the intermediate a.

[0018] The filtration concentration can be performed by using the existing concentration method such as a rotary evaporator. The concentration is performed until no solvent flows out, and at this time, the concentrated solution is in a viscous state. Generally, the mass of the obtained concentrated solution is 1.2-1.4 times the mass of the raw material.

[0019] The organic solvent used for dissolving the concentrated solution can be dichloromethane, ethyl acetate, methyl tert-butyl ether, or trichloromethane. Preferably, the organic solvent is dichloromethane or ethyl acetate. The organic phase obtained by concentrating the phases is also concentrated until no solvent flows out.

[0020] (2) Preparation of intermediate b: the intermediate a prepared in step (1) is subjected to a condensation reaction with N,O-dimethylhydroxylamine hydrochloride in the presence of a condensing agent and an acid-binding agent to obtain the intermediate b. The structural formula of the intermediate b is

[0021] The structural formula of the N,O-dimethylhydroxylamine hydrochloride is:

[0022] The specific operation of step (2) is as follows: first, the intermediate a is added to an organic solvent for dissolution, and then the condensing agent and the N,O-dimethylhydroxylamine hydrochloride are added. The organic solvent can be tetrahydrofuran, dichloromethane, or trichloromethane, etc.

[0023] Then, the acid-binding agent is added dropwise for reaction.

[0024] Finally, after the reaction is completed, the organic phase is washed with water, and the phases are separated; the obtained organic phase is concentrated to a viscous state to obtain the intermediate b. Generally, the mass of the obtained concentrated solution is 1.2-1.4 times the mass of the raw material.

[0025] (3) Preparation of intermediate c: the intermediate b prepared in step (2) is subjected to a nucleophilic substitution reaction with methyl magnesium bromide to obtain the intermediate c. The structural formula of the intermediate c is

[0026] The specific operation of the above step (3) is as follows: first, the intermediate b is added to a solvent for dissolution, cooling, and dropwise addition of methyl magnesium bromide for reaction. The solvent can be tetrahydrofuran or methyl tert-butyl ether, etc.

[0027] Then, after the reaction is completed, water is first added, and then an organic solvent is added for extraction, and the phases are separated; the organic phase obtained by the phase separation is washed with water, and then the phases are separated. The organic phase obtained by the phase separation is concentrated, and intermediate c is obtained. The organic solvent can be methyl tert-butyl ether, dichloromethane or trichloromethane, etc. Preferably, the organic solvent is dichloromethane. The amount of water added after the reaction is completed can be a molar ratio of water: intermediate b of 20-40:1.

[0028] (4) Preparation of 5-acetyl-1H-pyrazole-3-carboxylic acid: the intermediate c obtained in step (3) is first placed in a lye for hydrolysis reaction; after the reaction is completed, an organic solvent is added for extraction, and the phases are separated; the pH value of the obtained aqueous phase is first adjusted to 2-4 by adding an acid; then, the crystal is precipitated by cooling, and filtered, dried to obtain 5-acetyl-1H-pyrazole-3-carboxylic acid with a purity of >99.9%. The crystal can be precipitated by cooling to 5-10℃. The drying temperature can be 50-80℃. The lye can be NaOH aqueous solution or KOH aqueous solution, etc. The acid is selected from hydrochloric acid, sulfuric acid, acetic acid or citric acid, etc., and the preferred one is hydrochloric acid. The organic solvent can be dichloromethane, trichloromethane, toluene or methyl tert-butyl ether, etc. The preferred one is dichloromethane.

[0029] The synthesis route of the above reaction steps is as follows:

[0030] (1)

[0031] (2)

[0032] (3)

[0033] (4)

[0034] In the present application, the reaction temperature of the esterification reaction in step (1) of the preparation method of 5-acetyl-1H-pyrazole-3-carboxylic acid is 30-60℃; and the reaction time is 2-4h.

[0035] The reaction temperature of the condensation reaction in step (2) is 0-20℃; and the reaction time is 3-7h.

[0036] The reaction temperature of the nucleophilic substitution reaction in step (3) is -10-20℃, and the reaction time is 2-4h.

[0037] The reaction temperature of the hydrolysis reaction in the step (4) is 20-60℃, and the reaction time of the hydrolysis is 1-3h.

[0038] In the application, the catalyst in the step (1) of the preparation method of 5-acetyl-1H-pyrazole-3-carboxylic acid is 4-dimethylaminopyridine; and the dehydrating agent is N,N'-dicyclohexyl carbodiimide or 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI).

[0039] 4-dimethylaminopyridine: N,N'-dicyclohexyl carbodiimide:

[0040] In the application, the molar ratio of 3,5-pyrazole dicarboxylic acid, tert-butyl alcohol, catalyst and dehydrating agent in the step (1) of the preparation method of 5-acetyl-1H-pyrazole-3-carboxylic acid is 1:1-1.5:0.1-0.5:1-1.5.

[0041] In the application, the condensing agent in the step (2) of the preparation method of 5-acetyl-1H-pyrazole-3-carboxylic acid is one or more of N,N'-carbonyldiimidazole, 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride and dicyclohexyl carbodiimide (DCC).

[0042] The acid binding agent is one or more of triethylamine, N,N-diisopropyl ethylamine, diazabicyclo (DBU) and pyridine.

[0043] In the application, the molar ratio of intermediate a, condensing agent, N,O-dimethyl hydroxylamine hydrochloride and acid binding agent in the step (2) of the preparation method of 5-acetyl-1H-pyrazole-3-carboxylic acid is 1:1-1.3:1-1.3:0.5-1.3.

[0044] In the application, the molar ratio of intermediate b and methyl magnesium bromide in the step (3) of the preparation method of 5-acetyl-1H-pyrazole-3-carboxylic acid is 1:1-1.5.

[0045] The concentration of the lye in the step (4) is 8-20wt%.

[0046] 5-acetyl-1H-pyrazole-3-carboxylic acid prepared by the above preparation method.

[0047] The application of 5-acetyl-1H-pyrazole-3-carboxylic acid prepared by the above preparation method in the drug darolutamide.

[0048] An anticancer drug darolutamide, and the intermediate for synthesizing darolutamide includes 5-acetyl-1H-pyrazole-3-carboxylic acid prepared by the above preparation method.

[0049] The process route for preparing Darolutamide with 5-acetyl-1H-pyrazole-3-carboxylic acid as intermediate is shown as follows:

[0050]

[0051] In the formula, HOBt represents 1-hydroxybenzotriazole, and EDC represents 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0052] The present application has the following beneficial effects: the present application provides a new method for preparing 5-acetyl-1H-pyrazole-3-carboxylic acid, which first reacts raw material 3,5-pyrazole dicarboxylic acid with tert-butyl alcohol to obtain intermediate a; then reacts intermediate a with dimethylhydroxylamine hydrochloride to obtain intermediate b; further reacts intermediate b with methyl magnesium bromide to obtain intermediate c; finally, hydrolyzes intermediate c with lye and neutralizes with acid to obtain 5-acetyl-1H-pyrazole-3-carboxylic acid. The process does not need to use flammable and explosive diazoacetic acid ethyl ester and sodium hydride, effectively improving the production safety factor; the raw material used in the reaction is easy to obtain, the reaction condition is mild, the operation is simple, the total yield of the product is > 70%, the purity of the product reaches more than 99.9%, and the process is suitable for large-scale industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0053] Figure 1 It is a liquid chromatogram of the product 5-acetyl-1H-pyrazole-3-carboxylic acid obtained in Example 1.

[0054] Figure 2 It is a nuclear magnetic hydrogen spectrum diagram of the product 5-acetyl-1H-pyrazole-3-carboxylic acid obtained in Example 1.

[0055] Figure 3 It is a liquid chromatogram of the product 5-acetyl-1H-pyrazole-3-carboxylic acid obtained in Example 2.

[0056] Figure 4 It is a nuclear magnetic hydrogen spectrum diagram of the product 5-acetyl-1H-pyrazole-3-carboxylic acid obtained in Example 2.

[0057] Figure 5 It is a liquid chromatogram of the product 5-acetyl-1H-pyrazole-3-carboxylic acid obtained in Example 3.

[0058] Figure 6 It is a nuclear magnetic hydrogen spectrum diagram of the product 5-acetyl-1H-pyrazole-3-carboxylic acid obtained in Example 3.

[0059] Figure 7 It is a liquid chromatogram of the product 5-acetyl-1H-pyrazole-3-carboxylic acid obtained in Example 4.

[0060] Figure 8 NMR hydrogen spectrum of the product obtained in Example 4, 5-acetyl-1H-pyrazole-3-carboxylic acid.

[0061] Figure 9 Liquid chromatogram of the product obtained in Example 5, 5-acetyl-1H-pyrazole-3-carboxylic acid.

[0062] Figure 10 NMR hydrogen spectrum of the product obtained in Example 5, 5-acetyl-1H-pyrazole-3-carboxylic acid.

[0063] Figure 11 Liquid chromatogram of the product obtained in Example 6, 5-acetyl-1H-pyrazole-3-carboxylic acid.

[0064] Figure 12 NMR hydrogen spectrum of the product obtained in Example 6, 5-acetyl-1H-pyrazole-3-carboxylic acid. DETAILED DESCRIPTION

[0065] The product obtained in the following examples was characterized by liquid chromatography by an Agilent Technologies 1260 Infinity II model liquid chromatograph, and by NMR hydrogen spectrum by a Magnet System 400'54 Ascend NMR instrument produced by Bruker, Switzerland.

[0066] Example 1

[0067] The preparation method of the 5-acetyl-1H-pyrazole-3-carboxylic acid, the specific steps are as follows:

[0068] (1) Preparation of intermediate a:

[0069] At room temperature, 1.0 mol of 3,5-pyrazole dicarboxylic acid was added to the reactor, and tetrahydrofuran was added, and the amount of tetrahydrofuran added was 5 times the mass of 3,5-pyrazole dicarboxylic acid.

[0070] Under stirring conditions, 1 mol of tert-butyl alcohol and 0.2 mol of catalyst 4-dimethylaminopyridine were first added to the tetrahydrofuran solution of the above 3,5-pyrazole dicarboxylic acid, and then 1.0 mol of dehydrating agent N,N'-dicyclohexyl carbodiimide was added, and the temperature was controlled at 30°C, and the reaction was carried out for 3 hours.

[0071] After the reaction was completed, filtration was carried out, and the obtained filtrate was concentrated to obtain a concentrated solution.

[0072] Dichloromethane was added to the concentrated solution, and the amount of dichloromethane added was 3 times the mass of the obtained concentrated solution; water was then added, and the amount of water added was 3 times the mass of the obtained concentrated solution, and the phases were separated; the organic phase obtained by concentrating the separated phases was concentrated to obtain intermediate a.

[0073] (2) Preparation of intermediate b:

[0074] The obtained intermediate a was added into dichloromethane, the mass ratio of intermediate a:dichloromethane was 1:5; 1.0 mol of condensing agent N,N'-carbonyldiimidazole, 1.2 mol of N,O-dimethylhydroxylamine hydrochloride and 0.5 mol of acid binding agent triethylamine were added; the temperature was controlled at 10°C, and the reaction was carried out for 4 hours.

[0075] After the reaction was completed, water was added into the obtained reaction solution, the amount of water was 2 times of the mass of the reaction solution; phase separation was carried out; the obtained organic phase after phase separation was concentrated to a viscous state, and intermediate b was obtained.

[0076] (3) Preparation of intermediate c:

[0077] First, intermediate b was added into tetrahydrofuran, the mass ratio of intermediate b:tetrahydrofuran was 1:5. Then 1.2 mol of methyl magnesium bromide reagent was added dropwise, and the temperature was controlled at 5°C, and the reaction was carried out for 3 hours.

[0078] After the reaction was completed, 20 mol of water was added into the obtained reaction solution, and methyl tert-butyl ether was added, the amount of methyl tert-butyl ether was 3 times of the mass of the reaction solution; phase separation was carried out; 20 mol of water was further added into the obtained organic phase after phase separation, and the phase separation was carried out under stirring; the obtained organic phase after this phase separation was concentrated, and intermediate c was obtained.

[0079] (4) Preparation of 5-acetyl-1H-pyrazole-3-carboxylic acid:

[0080] Intermediate c was added into 10 wt% NaOH aqueous solution, the mass ratio of intermediate c:NaOH aqueous solution was 1:5. The temperature was controlled at 35°C, and the reaction was carried out for 3 hours.

[0081] After the reaction was completed, dichloromethane was added into the obtained reaction solution, the amount of dichloromethane was 2 times of the mass of the reaction solution; phase separation was carried out; hydrochloric acid was added into the obtained aqueous phase after phase separation to adjust pH to 3.0, and the temperature was lowered to 10°C for crystallization; and then filtration and drying were carried out, and 111.3 g of solid was obtained, the total yield of the product was 72.2%, and the purity of the product was 99.995%.

[0082] Figure 1 The specific parameters of the liquid chromatography characterization are shown in Table 1.

[0083] Table 1

[0084]

[0085] By area normalization method, the purity of the product was 99.995%.

[0086] Figure 2The NMR data of the intermediate a: 1H NMR (400 MHz, Acetone-d6) δH: 12.601 (br s, 1H), 7.272 (s, 1H), 2.558 (s, 3H). The above characterization results fully prove that the 5-acetyl-1H-pyrazole-3-carboxylic acid is successfully synthesized in this example.

[0087] Example 2

[0088] The preparation method of the 5-acetyl-1H-pyrazole-3-carboxylic acid, and the specific steps are as follows:

[0089] (1) Preparation of the intermediate a:

[0090] At room temperature, 1.0 mol of 3,5-pyrazole dicarboxylic acid is added into a reactor, and tetrahydrofuran is added, and the amount of tetrahydrofuran added is 5 times the mass of 3,5-pyrazole dicarboxylic acid.

[0091] Under stirring conditions, 1.2 mol of tert-butyl alcohol and 0.2 mol of catalyst 4-dimethylaminopyridine are first added into the tetrahydrofuran solution of 3,5-pyrazole dicarboxylic acid, and then 1.1 mol of dehydrating agent N,N'-dicyclohexyl carbodiimide is added, and the temperature is controlled at 30°C, and the reaction is carried out for 3 hours.

[0092] After the reaction is completed, filtration is performed, and the obtained filtrate is concentrated to obtain a concentrated solution.

[0093] Dichloromethane is added into the concentrated solution, and the amount of dichloromethane added is 3 times the mass of the obtained concentrated solution; water is further added, and the amount of water added is 3 times the mass of the obtained concentrated solution, and phase separation is performed; the obtained organic phase after phase separation is concentrated to obtain the intermediate a.

[0094] (2) Preparation of the intermediate b:

[0095] The obtained intermediate a is added into dichloromethane, and the mass ratio of intermediate a to dichloromethane is 1:5; 1.0 mol of condensing agent N,N'-carbonyldiimidazole, 1.1 mol of N,O-dimethylhydroxylamine hydrochloride and 0.5 mol of acid-binding agent triethylamine are further added, and the temperature is controlled at 10°C, and the reaction is carried out for 3 hours.

[0096] After the reaction is completed, water is added into the obtained reaction solution, and the amount of water added is 2 times the mass of the reaction solution; phase separation is performed; and the obtained organic phase after phase separation is concentrated to a viscous state to obtain the intermediate b.

[0097] (3) Preparation of the intermediate c:

[0098] Firstly, the intermediate b is added into tetrahydrofuran, and the mass ratio of intermediate b to tetrahydrofuran is 1:5; and then 1.3 mol of methyl magnesium bromide reagent is added dropwise, and the temperature is controlled at 10°C, and the reaction is carried out for 3 hours.

[0099] After the reaction is completed, 30 mol of water is added to the obtained reaction solution, and methyl tert-butyl ether is further added, and the amount of methyl tert-butyl ether added is 3 times the mass of the reaction solution; phase separation is performed; 30 mol of water is further added to the obtained organic phase after phase separation, and phase separation is performed by stirring; and the obtained organic phase after phase separation is concentrated to obtain intermediate c.

[0100] (4) Preparation of 5-acetyl-1H-pyrazole-3-carboxylic acid:

[0101] Intermediate c is added to an aqueous NaOH solution with a concentration of 8 wt%, and the mass ratio of intermediate c to the aqueous NaOH solution is 1:5. The temperature is controlled at 50°C, and the reaction is performed for 2 hours.

[0102] After the reaction is completed, 30 mol of water is added to the obtained reaction solution, and methyl tert-butyl ether is further added, and the amount of methyl tert-butyl ether added is 3 times the mass of the reaction solution; phase separation is performed; 30 mol of water is further added to the obtained organic phase after phase separation, and phase separation is performed by stirring; and the obtained organic phase after phase separation is concentrated to obtain intermediate c.

[0103] Figure 3 The specific parameters of the HPLC characterization are shown in Table 2.

[0104] Table 2

[0105]

[0106] By area normalization method, the purity of the product is 99.993%.

[0107] Figure 4 The HPLC data of the compound are as follows: 1H NMR (400 MHz, Acetone-d6) δH: 12.595 (brs, 1H), 7.272 (s, 1H), 2.558 (s, 3H). The above characterization results fully prove that the 5-acetyl-1H-pyrazole-3-carboxylic acid is successfully synthesized.

[0108] Example 3

[0109] The preparation method of the 5-acetyl-1H-pyrazole-3-carboxylic acid comprises the following specific steps:

[0110] (1) Preparation of intermediate a:

[0111] At room temperature, 1.0 mol of 3,5-pyrazole dicarboxylic acid is added to a reactor, and tetrahydrofuran is further added, and the amount of tetrahydrofuran added is 5 times the mass of 3,5-pyrazole dicarboxylic acid.

[0112] Under stirring, 1.3 mol of tert-butyl alcohol and 0.3 mol of catalyst 4-dimethylaminopyridine were added into the above-mentioned tetrahydrofuran solution of 3,5-pyrazole dicarboxylic acid, and then 1.0 mol of dehydrating agent N,N'-dicyclohexyl carbodiimide was added, and the temperature was controlled at 40°C, and the reaction was carried out for 2 hours.

[0113] After the reaction was completed, filtration was carried out, and the obtained filtrate was concentrated to obtain a concentrated solution.

[0114] Dichloromethane was added into the concentrated solution, and the amount of dichloromethane was 3 times the mass of the obtained concentrated solution; then water was added, and the amount of water was 3 times the mass of the obtained concentrated solution, and phase separation was carried out; the obtained organic phase after phase separation was concentrated to obtain intermediate a.

[0115] (2) Preparation of intermediate b:

[0116] The obtained intermediate a was added into dichloromethane, and the mass ratio of intermediate a to dichloromethane was 1:5; then 1.0 mol of condensing agent N,N'-carbonyldiimidazole, 1.3 mol of N,O-dimethylhydroxylamine hydrochloride and 0.7 mol of acid-binding agent triethylamine were added, and the temperature was controlled at 15°C, and the reaction was carried out for 3 hours.

[0117] After the reaction was completed, water was added into the obtained reaction solution, and the amount of water was 2 times the mass of the reaction solution; phase separation was carried out; and the obtained organic phase after phase separation was concentrated to a viscous state to obtain intermediate b.

[0118] (3) Preparation of intermediate c:

[0119] First, intermediate b was added into tetrahydrofuran, and the mass ratio of intermediate b to tetrahydrofuran was 1:5; then 1.3 mol of methyl magnesium bromide reagent was added dropwise, and the temperature was controlled at 0°C, and the reaction was carried out for 4 hours.

[0120] After the reaction was completed, 30 mol of water was added into the obtained reaction solution, and then methyl tert-butyl ether was added, and the amount of methyl tert-butyl ether was 3 times the mass of the reaction solution; phase separation was carried out; and then 40 mol of water was added into the obtained organic phase after phase separation, and phase separation was carried out under stirring, and the obtained organic phase after this phase separation was concentrated to obtain intermediate c.

[0121] (4) Preparation of 5-acetyl-1H-pyrazole-3-carboxylic acid:

[0122] Intermediate c was added into a 15wt% NaOH aqueous solution, and the mass ratio of intermediate c to the NaOH aqueous solution was 1:5; the temperature was controlled at 45°C, and the reaction was carried out for 1 hour.

[0123] After the reaction is completed, dichloromethane is added to the obtained reaction solution, the amount of dichloromethane added is 2 times the mass of the reaction solution; phase separation is performed; hydrochloric acid is added to the water phase obtained after phase separation to adjust the pH to 3.3, and the temperature is reduced to 5°C for crystallization; and then filtration and drying are performed to obtain 111.9 g of a solid, the total yield of the product is 72.6%, and the purity of the product is 99.984%.

[0124] Figure 5 The specific parameters of the liquid chromatography characterization are shown in Table 3.

[0125] Table 3

[0126]

[0127]

[0128] By area normalization method, the purity of the product is 99.993%.

[0129] Figure 6 The nuclear magnetic resonance data of the compound are as follows: 1H NMR (400 MHz, Acetone-d6) δH: 12.620 (brs, 1H), 7.272 (s, 1H), 2.559 (s, 3H). The above characterization results fully prove that the 5-acetyl-1H-pyrazole-3-carboxylic acid is successfully synthesized.

[0130] Example 4

[0131] The preparation method of the 5-acetyl-1H-pyrazole-3-carboxylic acid comprises the following specific steps:

[0132] (1) Preparation of intermediate a:

[0133] At room temperature, 1.0 mol of 3,5-pyrazole dicarboxylic acid is added to a reactor, and tetrahydrofuran is added, the amount of tetrahydrofuran added is 5 times the mass of 3,5-pyrazole dicarboxylic acid.

[0134] Under stirring conditions, 1.0 mol of tert-butyl alcohol and 0.2 mol of catalyst 4-dimethylaminopyridine are first added to the tetrahydrofuran solution of 3,5-pyrazole dicarboxylic acid, and then 1.0 mol of dehydrating agent N,N'-dicyclohexyl carbodiimide is added, the temperature is controlled at 50°C, and the reaction is performed for 2 hours.

[0135] After the reaction is completed, the obtained filtrate is concentrated to obtain a concentrated solution.

[0136] Dichloromethane is added to the concentrated solution, the amount of dichloromethane added is 3 times the mass of the obtained concentrated solution; water is then added, the amount of water added is 3 times the mass of the obtained concentrated solution, phase separation is performed; and the organic phase obtained after phase separation is concentrated to obtain intermediate a.

[0137] (2) Preparation of intermediate b:

[0138] The obtained intermediate a was added into dichloromethane, the mass ratio of intermediate a to dichloromethane was 1:5; 1.0 mol of condensing agent N,N'-carbonyldiimidazole, 1.0 mol of N,O-dimethylhydroxylamine hydrochloride and 1.0 mol of acid binding agent triethylamine were added, the temperature was controlled at 2°C, and the reaction was carried out for 6 hours.

[0139] After the reaction was completed, water was added into the obtained reaction solution, the amount of water was 2 times of the mass of the reaction solution; phase separation was carried out; the obtained organic phase after phase separation was concentrated to a viscous state, and intermediate b was obtained.

[0140] (3) Preparation of intermediate c:

[0141] First, intermediate b was added into tetrahydrofuran, the mass ratio of intermediate b to tetrahydrofuran was 1:5. Then 1.1 mol of methyl magnesium bromide reagent was added dropwise, the temperature was controlled at 5°C, and the reaction was carried out for 4 hours.

[0142] After the reaction was completed, 40 mol of water was added into the obtained reaction solution, and methyl tert-butyl ether was further added, the amount of methyl tert-butyl ether was 3 times of the mass of the reaction solution; phase separation was carried out; 20 mol of water was further added into the obtained organic phase after phase separation, the phase separation was stirred, and the obtained organic phase after this phase separation was concentrated, and intermediate c was obtained.

[0143] (4) Preparation of 5-acetyl-1H-pyrazole-3-carboxylic acid:

[0144] Intermediate c was added into a 14 wt% NaOH aqueous solution, the mass ratio of intermediate c to the NaOH aqueous solution was 1:5. The temperature was controlled at 35°C, and the reaction was carried out for 3 hours.

[0145] After the reaction was completed, dichloromethane was added into the obtained reaction solution, the amount of dichloromethane was 2 times of the mass of the reaction solution; phase separation was carried out; hydrochloric acid was added into the obtained aqueous phase after phase separation to adjust the pH to 4.0, the temperature was lowered to 5°C for crystallization; and filtration and drying were carried out, and 112.7 g of solid was obtained, the total yield of the product was 73.1%, and the purity of the product was 99.993%.

[0146] Figure 7 The specific parameters of the liquid chromatography were shown in Table 4.

[0147] Table 4

[0148]

[0149] By area normalization method, the purity of the product was 99.993%.

[0150] Figure 8The intermediate a was prepared by the following steps.

[0151] Example 5

[0152] The preparation method of the 5-acetyl-lH-pyrazole-3-carboxylic acid is specifically as follows:

[0153] (1) Preparation of the intermediate a:

[0154] At room temperature, 1.0 mol of 3,5-pyrazole dicarboxylic acid was added into a reactor, and tetrahydrofuran was added, and the amount of tetrahydrofuran added was 5 times the mass of 3,5-pyrazole dicarboxylic acid.

[0155] Under stirring, 1.1 mol of tert-butyl alcohol and 0.4 mol of the catalyst 4-dimethylaminopyridine were first added into the tetrahydrofuran solution of 3,5-pyrazole dicarboxylic acid, and then 1.0 mol of the dehydrating agent N,N'-dicyclohexyl carbodiimide was added, and the temperature was controlled at 40°C, and the reaction was performed for 2 hours.

[0156] After the reaction was completed, the obtained filtrate was concentrated to obtain a concentrated solution.

[0157] Dichloromethane was added into the concentrated solution, and the amount of dichloromethane added was 3 times the mass of the obtained concentrated solution; water was further added, and the amount of water added was 3 times the mass of the obtained concentrated solution, and the phases were separated; the obtained organic phase after the phase separation was concentrated to obtain the intermediate a.

[0158] (2) Preparation of the intermediate b:

[0159] The obtained intermediate a was added into dichloromethane, and the mass ratio of the intermediate a to dichloromethane was 1:5; 1.0 mol of the condensing agent N,N'-carbonyldiimidazole, 1.3 mol of N,O-dimethylhydroxylamine hydrochloride and 0.6 mol of the acid-binding agent triethylamine were further added, the temperature was controlled at 20°C, and the reaction was performed for 3 hours.

[0160] After the reaction was completed, water was added into the obtained reaction solution, and the amount of water added was 2 times the mass of the reaction solution; the phases were separated; and the obtained organic phase after the phase separation was concentrated to a viscous state to obtain the intermediate b.

[0161] (3) Preparation of the intermediate c:

[0162] The intermediate b was first added into tetrahydrofuran, and the mass ratio of the intermediate b to tetrahydrofuran was 1:5; and then 1.5 mol of the methyl magnesium bromide reagent was added dropwise, the temperature was controlled at 5°C, and the reaction was performed for 3 hours.

[0163] After the reaction is completed, 30 moles of water is added to the obtained reaction solution, and methyl tert-butyl ether is further added, the amount of methyl tert-butyl ether added is 3 times the mass of the reaction solution; phase separation is performed; 40 moles of water is further added to the obtained organic phase after phase separation, and phase separation is performed by stirring, and the obtained organic phase after phase separation is concentrated to obtain intermediate c.

[0164] (4) Preparation of 5-acetyl-1H-pyrazole-3-carboxylic acid:

[0165] Intermediate c is added to a 10 wt% NaOH aqueous solution, and the mass ratio of intermediate c to the NaOH aqueous solution is 1:5. The temperature is controlled at 60°C, and the reaction is performed for 1 hour.

[0166] After the reaction is completed, dichloromethane is added to the obtained reaction solution, the amount of dichloromethane added is 2 times the mass of the reaction solution; phase separation is performed; hydrochloric acid is added to the obtained aqueous phase after phase separation to adjust the pH to 2.6, and the temperature is lowered to 10°C for crystallization; and filtration and drying are performed to obtain 115.7 g of a solid, the total yield of the product is 75.1%, and the purity of the product is 99.996%.

[0167] Figure 9 The specific parameters of the HPLC characterization are shown in Table 5.

[0168] Table 5

[0169]

[0170] By area normalization method, the purity of the product is 99.979%.

[0171] Figure 10 The HPLC data of the compound are as follows: 1H NMR (400 MHz, Acetone-d6) δH: 12.598 (brs, 1H), 7.272 (s, 1H), 2.559 (s, 3H). The above characterization results fully prove that the 5-acetyl-1H-pyrazole-3-carboxylic acid is successfully synthesized.

[0172] Example 6

[0173] The preparation method of the 5-acetyl-1H-pyrazole-3-carboxylic acid, and the specific steps are as follows:

[0174] (1) Preparation of intermediate a:

[0175] At room temperature, 1.0 moles of 3,5-pyrazole dicarboxylic acid is added to a reactor, and tetrahydrofuran is further added, the amount of tetrahydrofuran added is 5 times the mass of the 3,5-pyrazole dicarboxylic acid.

[0176] Under stirring, 1.1 mol of tert-butyl alcohol, 0.5 mol of catalyst 4-dimethylaminopyridine and 1.1 mol of dehydrating agent N,N'-dicyclohexyl carbodiimide were added into the above-mentioned tetrahydrofuran solution of 3,5-pyrazole dicarboxylic acid, and the temperature was controlled at 60°C, and the reaction was carried out for 2 hours.

[0177] After the reaction was completed, the reaction solution was filtered, and the obtained filtrate was concentrated to obtain a concentrated solution.

[0178] Dichloromethane was added into the concentrated solution, and the amount of dichloromethane was 3 times the mass of the obtained concentrated solution; then water was added, and the amount of water was 3 times the mass of the obtained concentrated solution, and the phases were separated; the obtained organic phase after the phase separation was concentrated to obtain intermediate a.

[0179] (2) Preparation of intermediate b:

[0180] The obtained intermediate a was added into dichloromethane, and the mass ratio of intermediate a to dichloromethane was 1:5; then 1.0 mol of condensing agent N,N'-carbonyldiimidazole, 1.0 mol of N,O-dimethylhydroxylamine hydrochloride and 1.0 mol of acid-binding agent triethylamine were added, and the temperature was controlled at 15°C, and the reaction was carried out for 4 hours.

[0181] After the reaction was completed, water was added into the obtained reaction solution, and the amount of water was 2 times the mass of the reaction solution; the phases were separated; and the obtained organic phase after the phase separation was concentrated to a viscous state to obtain intermediate b.

[0182] (3) Preparation of intermediate c:

[0183] First, intermediate b was added into tetrahydrofuran, and the mass ratio of intermediate b to tetrahydrofuran was 1:5; then 1.2 mol of methyl magnesium bromide reagent was added dropwise, and the temperature was controlled at 10°C, and the reaction was carried out for 3 hours.

[0184] After the reaction was completed, 20 mol of water was added into the obtained reaction solution, and methyl tert-butyl ether was further added, and the amount of methyl tert-butyl ether was 3 times the mass of the reaction solution; the phases were separated; 30 mol of water was further added into the obtained organic phase after the phase separation, and the phases were stirred and separated, and the obtained organic phase after the phase separation was concentrated to obtain intermediate c.

[0185] (4) Preparation of 5-acetyl-1H-pyrazole-3-carboxylic acid:

[0186] Intermediate c was added into a 10wt% NaOH aqueous solution, and the mass ratio of intermediate c to the NaOH aqueous solution was 1:5; the temperature was controlled at 45°C, and the reaction was carried out for 3 hours.

[0187] After the reaction is completed, dichloromethane is added to the obtained reaction solution, the amount of dichloromethane added is 2 times the mass of the reaction solution; phase separation is performed; hydrochloric acid is added to the water phase obtained after phase separation to adjust the pH to 3.5, and the temperature is reduced to 10°C for crystallization; and then filtration and drying are performed to obtain 112.3 g of solid, the total yield of the product is 72.9%, and the purity of the product is 99.966%.

[0188] Figure 11 The specific parameters of the liquid chromatography characterization are shown in Table 6.

[0189] Table 6

[0190]

[0191] By area normalization method, the purity of the product is 99.979%.

[0192] Figure 12 The nuclear magnetic resonance data of the compound are as follows: 1H NMR (400 MHz, Acetone-d6) δH: 12.599 (brs, 1H), 7.272 (s, 1H), 2.559 (s, 3H). The above characterization results fully prove that the 5-acetyl-1H-pyrazole-3-carboxylic acid is successfully synthesized.

[0193] Example 7

[0194] The difference from Example 1 is that the molar ratio of 3,5-pyrazole dicarboxylic acid: tert-butyl alcohol in step (1) is 1:1.5.

[0195] The rest is the same as Example 1.

[0196] In this example, 112.2 g of solid is finally obtained, the total yield of the product is 72.8%, and the purity of the product is 99.962%.

[0197] Example 8

[0198] The difference from Example 1 is that the temperature control in step (3) is at 20°C.

[0199] The rest is the same as Example 1.

[0200] In this example, 112.3 g of solid is finally obtained, the total yield of the product is 72.9%, and the purity of the product is 99.952%.

[0201] Example 9

[0202] The difference from Example 1 is that the temperature control in step (3) is at -10°C.

[0203] The rest is the same as Example 1.

[0204] The example finally obtained solid 110.2 g, the total yield of product was 71.5%, and the purity of product was 99.971%.

[0205] Example 10

[0206] The difference from Example 1 is that the concentration of the aqueous sodium hydroxide solution in step (4) is 20 wt%.

[0207] The rest is the same as Example 1.

[0208] The example finally obtained solid 110.2 g, the total yield of product was 71.5%, and the purity of product was 99.971%.

[0209] Example 11

[0210] The difference from Example 5 is that the amount of the condensing agent N,N'-carbonyldiimidazole added in step (2) is 1.3 mol.

[0211] The rest is the same as Example 5.

[0212] The example finally obtained solid 113.4 g, the total yield of product was 73.6%, and the purity of product was 99.965%.

[0213] Example 12

[0214] The difference from Example 3 is that the amount of the dehydrating agent N,N'-dicyclohexyl carbodiimide added in step (1) is 1.5 mol.

[0215] The rest is the same as Example 3.

[0216] The example finally obtained solid 111.6 g, the total yield of product was 72.4%, and the purity of product was 99.934%.

[0217] Comparative Example 1

[0218] The difference from Example 1 is that the molar ratio of 3,5-pyrazole dicarboxylic acid:tert-butyl alcohol in step (1) is 1:0.5.

[0219] The rest is the same as Example 1.

[0220] The comparative example finally obtained solid 46.5 g, the total yield was 30.2%, and the purity was 99.125%.

[0221] Comparative Example 2

[0222] The difference from Example 1 is that the molar ratio of 3,5-pyrazole dicarboxylic acid:tert-butyl alcohol in step (1) is 1:2.

[0223] The rest is the same as Example 1.

[0224] The comparative example finally obtained solid 44.1 g, the total yield of product was 28.6%, and the purity of product was 95.456%.

[0225] Comparative Example 3

[0226] The difference from Example 1 was that the temperature control in step (1) was at 65℃.

[0227] The rest was the same as Example 1.

[0228] The comparative example finally obtained solid 71.5 g, the total yield of product was 46.4%, and the purity of product was 96.785%.

[0229] Comparative Example 4

[0230] The difference from Example 1 was that the temperature control in step (2) was at 25℃.

[0231] The rest was the same as Example 1.

[0232] The comparative example finally obtained solid 100.0 g, the total yield of product was 64.9%, and the purity of product was 98.675%.

[0233] Comparative Example 5

[0234] The difference from Example 1 was that the temperature control in step (3) was at 30℃.

[0235] The rest was the same as Example 1.

[0236] The comparative example finally obtained solid 87.7 g, the total yield of product was 56.9%, and the purity of product was 94.654%.

[0237] Comparative Example 6

[0238] The difference from Example 1 was that the temperature control in step (3) was at -15℃.

[0239] The rest was the same as Example 1.

[0240] The comparative example finally obtained solid 98.0 g, the total yield of product was 63.6%, and the purity of product was 98.765%.

[0241] Comparative Example 7

[0242] The difference from Example 1 was that the concentration of sodium hydroxide aqueous solution in step (4) was 30 wt%.

[0243] The rest was the same as Example 1.

[0244] The comparative example finally obtained solid 96.8 g, the total yield of product was 62.8%, and the purity of product was 98.987%.

[0245] Comparative Example 8

[0246] The difference from Example 1 is that the temperature control in step (4) is at 15°C.

[0247] The rest is the same as Example 1.

[0248] This comparative example finally obtained solid 80.6 g, the total yield of the product was 52.3%, and the purity of the product was 98.675%.

[0249] Comparative Example 9

[0250] The difference from Example 1 is that the temperature control in step (4) is at 70°C.

[0251] The rest is the same as Example 1.

[0252] This comparative example finally obtained solid 100.8 g, the total yield of the product was 65.4%, and the purity of the product was 97.563%.

[0253] Comparative Example 10

[0254] The difference from Example 3 is that the amount of dehydrating agent N,N'-dicyclohexyl carbodiimide added in step (1) is 2.0 mol.

[0255] The rest is the same as Example 3.

[0256] This example finally obtained solid 104.0 g, the total yield of the product was 67.5%, and the purity of the product was 98.745%.

[0257] The weight, total yield and purity data of the products obtained in each of the above examples and comparative examples are summarized in Table 7 below.

[0258] Table 7

[0259]

[0260]

Claims

1. A process for the preparation of 5-acetyl-lH-pyrazole-3-carboxylic acid, characterized in that, The method comprises the following steps: (1) preparing intermediate a: raw material 3,5-pyrazole dicarboxylic acid, t-butyl alcohol is subjected to esterification reaction under the action of a catalyst and a dehydrating agent to prepare intermediate a; the esterification reaction is carried out at a temperature of 30-60°C for 2-4 hours; The structural formula of the intermediate a is: ; The molar ratio of 3,5-pyrazole dicarboxylic acid, t-butyl alcohol, catalyst and dehydrating agent is 1:1-1.5:0.1-0.5:1-1.5; The catalyst in step (1) is 4-dimethylaminopyridine; the dehydrating agent is N,N'-dicyclohexyl carbodiimide; (2) preparing intermediate b: intermediate a prepared in step (1) is subjected to condensation reaction with N,O-dimethylhydroxylamine hydrochloride under the action of a condensing agent and an acid-binding agent to prepare intermediate b; the condensation reaction is carried out at a temperature of 0-20°C for 3-7 hours; the condensing agent is N,N'-carbonyldiimidazole; The structural formula of the intermediate b is ; (3) preparing intermediate c: intermediate b prepared in step (2) is subjected to nucleophilic substitution reaction with methyl magnesium bromide to prepare intermediate c; the nucleophilic substitution reaction is carried out at a temperature of -10-20°C for 2-4 hours; The structural formula of the intermediate c is ; (4) preparing 5-acetyl-1H-pyrazole-3-carboxylic acid: intermediate c obtained in step (3) is first subjected to hydrolysis reaction in a lye; the hydrolysis reaction is carried out at a temperature of 20-60°C for 1-3 hours; The concentration of the lye is 8-20 wt%; After the reaction is completed, an organic solvent is added for extraction, and the phases are separated; The pH value of the obtained aqueous phase is first adjusted to 2-4 by adding an acid; Then, the temperature is lowered for crystallization, and filtration and drying are performed to obtain 5-acetyl-1H-pyrazole-3-carboxylic acid with a purity of >99.9%.

2. The process for the preparation of 5-acetyl-lH-pyrazole-3-carboxylic acid according to claim 1, characterized in that, The acid-binding agent in step (2) is one or more of triethylamine, N,N-diisopropyl ethylamine, diazabicyclo or pyridine.

3. The process for the preparation of 5-acetyl-lH-pyrazole-3-carboxylic acid according to claim 1, characterized in that, The molar ratio of intermediate a, condensing agent, N,O-dimethylhydroxylamine hydrochloride and acid-binding agent in step (2) is 1:1-1.3:1-1.3:0.5-1.

3.

4. The process for the preparation of 5-acetyl-lH-pyrazole-3-carboxylic acid according to claim 1, characterized in that, The molar ratio of intermediate b and methyl magnesium bromide in step (3) is 1:1-1.5.

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