A method for preparing 3-chloro-1H-pyrazole-5-amine

Abstract

This invention discloses a method for preparing 3-chloro-1H-pyrazole-5-amine. The target product is prepared via a three-step reaction involving cyclization, chlorination, and decarboxylation, starting with ethyl ethoxymethylene cyanoacetate. Hydrazine hydrate is used for cyclization, dichlorohydantoin for chlorination, and dilute sulfuric acid for decarboxylation. This process is mild, simple to operate, highly safe, and requires minimal equipment, making it suitable for large-scale production. The yield of compound III is up to 61.6%, compound IV to 44.2%, and compound I to 64%. The purity of all products, as determined by HPLC, reaches 99%, effectively improving production efficiency.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemical synthesis technology, specifically to a method for preparing 3-chloro-1H-pyrazole-5-amine. Background Technology

[0002] 3-Chloro-1H-pyrazole-5-amine is a widely used pharmaceutical intermediate. Existing technology WO2018 / 85247,2018, A1 reports its potential use in a class of bifunctional compounds that can inhibit MALT1 and / or promote targeted ubiquitination to degrade MALT1. Specifically, the compounds provided by the prior art can bind to MALT1—a protein that causes constitutive NF-κB signaling in certain cancers (e.g., activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL))—and can promote the ubiquitination of MALT1 by recruiting E3 ubiquitin ligases (e.g., Cereblon, VHL), thereby tagging the protein for proteasome degradation.

[0003] Existing technologies J. [Journal of Medicinal Chemistry, 2012, vol. 55, #7, p.3036-3048] and WO2018 / 85247, 2018, A1 report the following preparation method, and its synthetic route is as follows: .

[0004] However, this route is lengthy, has high raw material costs, and the overall yield of only 13% across the four steps is low, resulting in low economic efficiency. Furthermore, this route involves hazardous reactions such as diazotization and nitration. The operation involves high temperature and pressure, posing a high risk and causing significant environmental pollution. It requires sophisticated equipment and has stringent safety and environmental protection requirements, making it unsuitable for industrial production. Summary of the Invention

[0005] To address the problems of high cost, low yield, and high risk associated with existing routes and preparation methods for 3-chloro-1H-pyrazole-5-amine, which are unsuitable for industrial production, this invention provides a method for preparing 3-chloro-1H-pyrazole-5-amine. This method uses ethyl ethoxymethylene cyanoacetate as a starting material and proceeds through cyclization, chlorination, and decarboxylation steps, thus solving the problems of high cost, low yield, high risk, and unsuitability for industrial production associated with existing technologies.

[0006] This invention proposes a method for preparing 3-chloro-1H-pyrazole-5-amine. The method involves using ethyl ethoxymethylene cyanoacetate as a raw material, followed by cyclization, chlorination, and decarboxylation steps. The synthetic route for 3-chloro-1H-pyrazole-5-amine is as follows: .

[0007] Preferably, the cyclizing agent in the reaction of the compounds of formula II to III is 80% hydrazine hydrate or 85% hydrazine hydrate, wherein the molar ratio of the compound of formula II to hydrazine hydrate is 1:1 to 1.5.

[0008] Preferably, the preparation method of the compound of formula III is as follows: take a dry reaction flask, add anhydrous ethanol and ethyl ethoxymethylene cyanoacetate, stir to dissolve, add hydrazine hydrate dropwise to the reaction flask, heat up, concentrate and crystallize after reaction, cool down, add purified water, slurry and filter, and dry to obtain the compound of formula III.

[0009] Preferably, in the reaction of the compounds of formula III to IV, the chlorination reagent is dichlorohydantoin.

[0010] Preferably, the molar ratio of the compound of formula III to dichlorohydantoin is 1:0.6~0.7.

[0011] Preferably, the preparation method of the compound of formula IV is as follows: Ethyl acetate and the compound of formula III are added to a dry glass reaction flask and stirred and dispersed. Acetic acid and sodium acetate are then added and stirred continuously. Dichlorohydantoin is added and stirred. Sodium sulfite aqueous solution is slowly added and stirred. The mixture is allowed to stand and separated. The organic phase is washed with sodium sulfite aqueous solution and saturated brine. Anhydrous sodium sulfate is added and the mixture is dried and filtered. The filtrate is concentrated to dryness at 45°C. Dichloroethane is added and stirred to form a slurry. The mixture is then filtered and dried to obtain the compound of formula IV.

[0012] Preferably, in the reaction of the compounds of formula IV to I, the decarboxylating agent is dilute sulfuric acid.

[0013] Preferably, the molar ratio of the compound of formula IV to dilute sulfuric acid is 1:2~3.

[0014] Preferably, the preparation method of the compound of formula I is as follows: dilute sulfuric acid is added to a glass reaction flask, compound of formula IV is added, the temperature is raised and stirred to react, sodium hydroxide solution is added dropwise to the reaction solution while controlling the temperature at 5~20℃, the pH value is adjusted, methyl tert-butyl ether is added, the mixture is stirred and filtered, the filtrate is collected and allowed to stand to separate into layers, the organic phase is collected, anhydrous sodium sulfate is dried and filtered, the filtrate is concentrated until a solid is precipitated, solvent is added to purify, the filter cake is collected and dried to obtain compound of formula I.

[0015] Preferably, the solvent used to purify compound I in the reaction of compounds of formula IV to formula I is any one of dichloromethane or 1,2-dichloroethane.

[0016] The beneficial effects of the embodiments of the present invention are as follows: The preparation route and method of 3-chloro-1H-pyrazole-5-amine of the present invention are ingeniously designed. Starting from ethyl ethoxymethylene cyanoacetate, the process involves cyclization, chlorination, and decarboxylation steps. The raw materials are inexpensive and readily available, the conditions are mild and the operation is simple with low equipment requirements, and the process is highly safe. The yield of compound III is up to 61.6%, the yield of compound IV is 44.2%, and the yield of compound I is 64%. The purity of the products is 99% as determined by HPLC. This method can effectively improve production efficiency and fill the gap in the existing technology. Attached Figure Description

[0017] Figure 1 This is a flowchart illustrating the preparation route of compound III in Example 1 of the present invention.

[0018] Figure 2 This is a flowchart illustrating the preparation route of compound IV in Example 4 of the present invention.

[0019] Figure 3 This is a flowchart illustrating the preparation route of compound I in Example 5 of the present invention. Detailed Implementation

[0020] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0021] In the following examples of the present invention, ethyl ethoxymethylene cyanoacetate and hydrazine hydrate were purchased from Sinopharm Group; all other reagents not specifically mentioned were obtained commercially available.

[0022] Example 1

[0023] Preparation of Compound III Route: The preparation route of compound III is as follows Figure 1 As shown; method: 1) Feeding and dissolving: Take a dry 5L reaction flask and fix it in a fume hood. Place a magnetic stir bar in the flask and slowly add 2L of anhydrous ethanol. Adjust the stirring speed to 250rpm and stir until uniform. Then add 200g of ethyl ethoxymethylene cyanoacetate (Formula ⅠⅠ) in batches to avoid local clumping caused by adding it all at once. Continue stirring for 15min until completely dissolved and clear and transparent.

[0024] 2) Add hydrazine hydrate dropwise: Add 80% hydrazine hydrate (88.8g) to a constant pressure dropping funnel and add it dropwise to the reaction flask at room temperature with continuous stirring. Keep the temperature of the reaction solution from rising significantly. After the addition is complete, keep stirring the reaction solution until the temperature stabilizes.

[0025] 3) Concentration: Slowly heat the reaction solution to 80℃ and maintain the temperature at 80℃ for 2 hours. After the reaction is complete, stop heating and allow the system to cool naturally to below 50℃. Take a sample for HPLC detection to confirm the completion of the reaction. Transfer the reaction solution to a rotary evaporator flask and concentrate it to 1 / 3 to 1 / 4 of the original reaction solution volume under reduced pressure, with the vacuum degree controlled at -0.08 to -0.09 MPa and the water bath temperature set to 55℃. Stop the concentration and place the concentrated semi-solid solution in a 0℃ water bath for 1 hour to allow the product to precipitate crystals.

[0026] 4) Pulping and filtration: Add 500 mL of purified water, adjust the stirring speed to 200 rpm, and continue stirring and pulverizing for 30 min to form a slurry mixture. Filter and collect the filter cake. Rinse the filter cake with a small amount of purified water and collect the filter cake. Dry the filter cake at 45°C with forced air to obtain a white solid, namely compound III, with a mass of 113 g, HPLC 99%, and yield of 61.6%.

[0027] 5) The synthesized compound of formula III was subjected to... 1 ¹H NMR detection: Detection conditions: 400 MHz, CDCl₃; Detection data: δ (ppm): 1.23 (t, 3H), 4.15 (q, 2H), 5.98 (bs, 2H), 7.45 (bs, 1H), 12.04 (bs, 1H); It should be explained that: δ 1.23 (t, 3H) corresponds to the terminal methyl hydrogen, δ 4.15 (q, 2H) corresponds to the methylene hydrogen, δ 5.98 (bs, 2H) corresponds to the two hydrogens in the acylhydrazine group (-NH₂), δ 7.45 (bs, 1H) corresponds to the amide hydrogen (-NH⁻) in the acylhydrazine group, and δ 12.04 (bs, 1H) corresponds to the amide hydrogen (-C(=O)-NH⁻) that forms a hydrogen bond in the acylhydrazine group. These peak shapes, chemical shifts, and integral values ​​are completely consistent with the structure of the compound of formula III.

[0028] Example 2

[0029] Preparation of Compound III 1) Feeding and dissolving: Take a dry 5L reaction flask and fix it in a fume hood. Place a magnetic stir bar in the flask and slowly add 2L of anhydrous ethanol. Adjust the stirring speed to 250rpm and stir until uniform. Then add 200g of ethyl ethoxymethylene cyanoacetate in batches to avoid local clumping caused by adding it all at once. Continue stirring for 15min until completely dissolved and clear and transparent.

[0030] 2) Add hydrazine hydrate dropwise: Add 85% hydrazine hydrate (88.8g) to a constant pressure dropping funnel and add it dropwise to the reaction flask at room temperature with continuous stirring. Keep the temperature of the reaction solution from rising significantly. After the addition is complete, keep stirring the reaction solution until the temperature stabilizes.

[0031] 3) Concentration: Slowly heat the reaction solution to 75℃ and maintain the temperature at 75℃ for 2 hours. After the reaction is complete, stop heating and allow the system to cool naturally to below 50℃. Take a sample for HPLC detection to confirm the completion of the reaction. Transfer the reaction solution to a rotary evaporator flask and concentrate it to 1 / 3 to 1 / 4 of the original reaction solution volume under reduced pressure, with the vacuum degree controlled at -0.08 to -0.09 MPa and the water bath temperature set to 55℃. Stop the concentration and place the concentrated semi-solid solution in a 0℃ water bath for 1 hour to allow the product to precipitate crystals.

[0032] 4) Pulping and filtration: Add 500 mL of purified water, adjust the stirring speed to 200 rpm, and continue stirring and pulverizing for 30 min to form a slurry mixture. Filter and collect the filter cake. Rinse the filter cake with a small amount of purified water and collect the filter cake. Dry the filter cake at 40°C with forced air to obtain a white solid, namely compound III.

[0033] Example 3

[0034] Preparation of Compound III 1) Feeding and dissolving: Take a dry 5L reaction flask and fix it in a fume hood. Place a magnetic stir bar in the flask and slowly add 2L of anhydrous ethanol. Adjust the stirring speed to 250rpm and stir until uniform. Then add 200g of ethyl ethoxymethylene cyanoacetate in batches to avoid local clumping caused by adding it all at once. Continue stirring for 15min until completely dissolved and clear and transparent.

[0035] 2) Add hydrazine hydrate dropwise: Add 80% hydrazine hydrate (88.8g) to a constant pressure dropping funnel and add it dropwise to the reaction flask at room temperature with continuous stirring. Keep the temperature of the reaction solution from rising significantly. After the addition is complete, keep stirring the reaction solution until the temperature stabilizes.

[0036] 3) Concentration: Slowly heat the reaction solution to 85℃ and maintain the temperature at 85℃ for 2 hours. After the reaction is complete, stop heating and allow the system to cool naturally to below 50℃. Take a sample for HPLC detection to confirm the completion of the reaction. Transfer the reaction solution to a rotary evaporator flask and concentrate it to 1 / 3 to 1 / 4 of the original reaction solution volume under reduced pressure, with the vacuum degree controlled at -0.08 to -0.09 MPa and the water bath temperature set to 55℃. Stop the concentration and place the concentrated semi-solid solution in a 0℃ water bath for 1 hour to allow the product to precipitate crystals.

[0037] 4) Pulping and filtration: Add 500 mL of purified water, adjust the stirring speed to 200 rpm, and continue stirring and pulverizing for 30 min to form a slurry mixture. Filter and collect the filter cake. Rinse the filter cake with a small amount of purified water and collect the filter cake. Dry the filter cake at 50°C with forced air to obtain a white solid, namely compound III.

[0038] Example 4

[0039] Preparation of Compound IV (1) Route: The preparation route of compound IV is as follows Figure 2 As shown; (2) Method: 1) Feeding and dissolving: Take a dry 2L glass reaction flask, add 1L of ethyl acetate and 100g of the compound of formula III prepared in Example 1, put it into a magnetic stir bar, adjust the speed to 250rpm and stir until dispersed, add 7.7g of acetic acid and 42.3g of sodium acetate and continue stirring, control the temperature at 5~15℃, and slowly add dichlorohydantoin (83.8g) in batches. 2) Reaction: After the addition of materials, the temperature is controlled at 5~15℃ and the mixture is stirred for 1 hour. After the reaction is completed, a sample is taken for HPLC detection to confirm that the reaction is complete. Then, 500 mL of 20% sodium sulfite aqueous solution is slowly added, stirred for 10 min, and then allowed to stand and separate. 3) Concentration and filtration: The upper organic phase was collected and washed once with 500 mL of 20% sodium sulfite aqueous solution; the organic phase was washed twice with 500 mL of saturated brine, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated at 45 °C to a dark brown viscous solid, and then dispersed by stirring with 250 mL of dichloromethane and filtered. After drying at 50 °C, compound IV was obtained with a mass of 54 g, HPLC yield of 99%, and a yield of 44.2%.

[0040] 4) The synthesized compound of formula IV was subjected to... 1 ¹H NMR detection: Detection conditions: 400MHz, DMSO-d6; Detection data: δ (ppm): 12.04 (s, 1H), 6.28 (s, 2H), 4.17-4.42 (m, 2H), 1.25-1.29 (t, 3H); The structure is completely consistent with that of compound IV.

[0041] Example 5

[0042] Preparation of Compound I (1) Route: The preparation route of compound I is as follows Figure 3 As shown; (2) Method: 1) Feeding reaction: Add 70mL of purified water to a dry 250mL glass reaction flask, turn on the stirrer and slowly add 45.3g of 98% concentrated sulfuric acid under an ice-water bath. After cooling, add 35g of compound IV. After the addition is complete, raise the internal temperature to 100℃ and stir for 22h.

[0043] 2) Filtration: After sampling and HPLC detection to confirm the completion of the reaction, the reaction solution was cooled to 5~10℃. 37g of sodium hydroxide was dissolved in 150mL of purified water. After cooling, the solution was added dropwise to the reaction solution at a controlled temperature of 5~20℃. The pH value was adjusted to 7~8, and a large amount of solid, which is an inorganic salt, was precipitated. 100mL of methyl tert-butyl ether was added to the reaction solution. After stirring and dispersing, the solution was filtered through a filter cloth. The filtrate was collected and allowed to stand for separation.

[0044] 3) Collect the upper organic phase, extract the aqueous phase three times with eluted methyl tert-butyl ether, combine the organic phases, dry with anhydrous sodium sulfate and filter, concentrate the filtrate by rotary evaporation in a water bath at 45°C until a solid is precipitated, add a small amount of dichloromethane to the solid and slurry, filter, collect the filter cake; dry at 50°C to obtain a yellow solid, namely compound I, with a mass of 14 g, HPLC 99%, yield 64%.

[0045] 4) Concentration and precipitation: The synthesized compound of formula I is subjected to... 1 ¹H NMR detection: Detection conditions: 400MHz, DMSO-d6; Detection data: δ 11.55 (bs, 1H), 5.26 (s, 2H), 5.21 (s, 1H); The structure is completely consistent with that of the compound of formula I.

[0046] Example 6

[0047] Preparation of Compound I 1) Feeding reaction: Add 70mL of purified water to a dry 250mL glass reaction flask, turn on the stirrer and slowly add 45.3g of 98% concentrated sulfuric acid under an ice-water bath. After cooling, add 35g of compound IV. After the addition is complete, raise the internal temperature to 120℃ and stir for 22h.

[0048] 2) Filtration: After sampling and HPLC detection to confirm the completion of the reaction, the reaction solution was cooled to 5~10℃. 37g of sodium hydroxide was dissolved in 150mL of purified water. After cooling, the solution was added dropwise to the reaction solution at a controlled temperature of 5~20℃. The pH value was adjusted to 7~8, and a large amount of solid, which is an inorganic salt, was precipitated. 100mL of methyl tert-butyl ether was added to the reaction solution. After stirring and dispersing, the solution was filtered through a filter cloth. The filtrate was collected and allowed to stand for separation.

[0049] 3) Concentration and precipitation: Collect the upper organic phase, extract the aqueous phase three times with eluted methyl tert-butyl ether, combine the organic phases, dry with anhydrous sodium sulfate and filter, concentrate the filtrate by rotary evaporation in a water bath at 45°C until a solid is precipitated, add a small amount of dichloromethane to the solid and slurry, filter, collect the filter cake; dry at 50°C with forced air to obtain a yellow solid, namely compound I.

[0050] In summary, the method for preparing 3-chloro-1H-pyrazole-5-amine provided by this invention uses ethyl ethoxymethylene cyanoacetate as the starting material and completes the synthesis of the target product through three core reactions: cyclization, chlorination, and decarboxylation. This reduces safety risks and environmental pollution. The process has low equipment requirements, and the product yields in each step are stable. The yield of compound III is as high as 61.6%, the yield of compound IV is 44.2%, and the yield of compound I is 64%. The purity of the products is 99% as determined by HPLC, which can effectively improve the economic benefits of production.

[0051] Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention. All equivalent changes and improvements made within the scope of the present invention should still fall within the patent coverage of the present invention.

Claims

1. A method for preparing 3-chloro-1H-pyrazole-5-amine, characterized in that, The preparation method of the 3-chloro-1H-pyrazole-5-amine is as follows: using ethyl ethoxymethylene cyanoacetate as a raw material, it is obtained through cyclization, chlorination, and decarboxylation steps. The synthetic route of 3-chloro-1H-pyrazole-5-amine is as follows: 。 2. The method for preparing 3-chloro-1H-pyrazole-5-amine as described in claim 1, characterized in that, In the reaction of the compounds of formulas II to III, the cyclizing agent is 80% hydrazine hydrate or 85% hydrazine hydrate, wherein the molar ratio of the compound of formula II to hydrazine hydrate is 1:1-1.

5.

3. The method for preparing 3-chloro-1H-pyrazole-5-amine as described in claim 1, characterized in that, The preparation method of the compound of formula III is as follows: take a dry reaction flask, add anhydrous ethanol and ethyl ethoxymethylene cyanoacetate, stir to dissolve, add hydrazine hydrate dropwise to the reaction flask, heat up, concentrate and crystallize after reaction, cool down, add purified water, slurry, filter, and dry to obtain compound of formula III.

4. The method for preparing 3-chloro-1H-pyrazole-5-amine as described in claim 1, characterized in that, In the reactions of the compounds of formulas III to IV, the chlorination reagent is dichlorohydantoin.

5. The method for preparing 3-chloro-1H-pyrazole-5-amine as described in claim 4, characterized in that, The molar ratio of the compound of formula III to dichlorohydantoin is 1:0.6-0.

7.

6. The method for preparing 3-chloro-1H-pyrazole-5-amine as described in claim 1, characterized in that, The The preparation method of compound IV is as follows: Ethyl acetate and compound III are added to a dry glass reaction flask and stirred to disperse. Acetic acid and sodium acetate are then added and stirred continuously. Dichlorohydantoin is added and stirred. Sodium sulfite aqueous solution is slowly added and stirred. The mixture is allowed to stand and separated. The organic phase is washed with sodium sulfite aqueous solution and saturated brine. Anhydrous sodium sulfate is added and the mixture is dried and filtered. The filtrate is concentrated to dryness at 45°C. Dichloroethane is added and stirred to form a slurry. The mixture is then filtered and dried to obtain compound IV.

7. The method for preparing 3-chloro-1H-pyrazole-5-amine as described in claim 1, characterized in that, The In the reactions of compounds of formulas IV to I, the decarboxylating agent is dilute sulfuric acid.

8. The method for preparing 3-chloro-1H-pyrazole-5-amine as described in claim 7, characterized in that, The The molar ratio of compound IV to dilute sulfuric acid is 1:2-3.

9. The method for preparing 3-chloro-1H-pyrazole-5-amine as described in claim 1, characterized in that, The preparation method of the compound of formula I is as follows: dilute sulfuric acid is added to a glass reaction flask, compound of formula IV is added, the temperature is raised and stirred to react, sodium hydroxide solution is added dropwise to the reaction solution while controlling the temperature at 5-20℃, the pH value is adjusted, methyl tert-butyl ether is added, the mixture is stirred and filtered, the filtrate is collected and allowed to stand to separate into layers, the organic phase is collected, anhydrous sodium sulfate is dried and filtered, the filtrate is concentrated until a solid is precipitated, solvent is added to purify, the filter cake is collected and dried to obtain compound of formula I.

10. The method for preparing 3-chloro-1H-pyrazole-5-amine according to claim 1, characterized in that, The solvent used to purify compound I in the reactions of compounds of formulas IV to I is either dichloromethane or 1,2-dichloroethane.

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