Green-based 1-(-)-3-[5-(-)-1H-tetrazole-1-yl]-1H-pyrazole-5-carboxylic acid synthesis process
By adopting a green chemical process in the preparation of 1-(3-chloropyridin-2-yl)-3-[5-(trifluoromethyl)-1H-tetrazole-1-yl]-1H-pyrazol-5-carboxylic acid, using ethanol and water as solvents, and optimizing the reaction conditions, the problems of low recrystallization yield and expensive solvents in the prior art were solved, and efficient, economical and environmentally friendly production effects were achieved.
Patent Information
- Application Number
- CN202411994953.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-31
- Publication Date
- 2025-03-28
AI Technical Summary
In the prior art, when preparing 1-(3-chloropyridin-2-yl)-3-[5-(trifluoromethyl)-1H-tetrazole-1-yl]-1H-pyrazol-5-carboxylic acid, the recrystallization yield is low, the gradient cooling is difficult to control, and the solvent used is expensive, resulting in a greater impact on cost and environmental in large-scale production.
The synthesis process based on green chemistry is adopted, and the product yield and purity of the product is improved by selecting non-toxic and renewable raw materials, using ethanol and water to replace traditional toxic solvents, and by precisely combining the ratio of ethanol-water mixed solvents, the reaction selectivity and yield and purity of the product are improved by optimizing reaction conditions such as temperature and time.
It significantly improves the yield and purity of the product, reduces the cost of solvents and the difficulty of subsequent treatment, reduces waste of raw materials and waste generation, realizes efficient utilization of resources, and is economical and environmentally feasible.
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of chemical drug research and development, and specifically to a synthesis process of 1-(3-chloropyridin-2-yl)-3-[5-(trifluoromethyl)-1H-tetrazol-1-yl]-1H-pyrazole-5-carboxylic acid (abbreviated as: 1-(-)-3-[5-(-)-1H-tetrazol-1-yl]-1H-pyrazole-5-carboxylic acid) based on green chemistry. Background Art
[0002] 1-(3-chloropyridin-2-yl)-3-[5-(trifluoromethyl)-1H-tetrazol-1-yl]-1H-pyrazole-5-carboxylic acid is an important pharmaceutical intermediate and is widely used in the preparation of anti-tumor drugs. Its preparation involves the purification step of a trifluoromethyl-containing compound. Usually, a water-soluble solvent such as acetonitrile, tetrahydrofuran, etc. is used, and a gradient cooling method is used in a mixed solvent with water for recrystallization. However, the solubility of the target product in acetonitrile or tetrahydrofuran is very large, so the recrystallization yield is low. Especially in large-scale production, the yield reduction is particularly obvious, and in large-scale production, the gradient cooling is not easy to control. At the same time, acetonitrile and tetrahydrofuran are relatively expensive. Therefore, the development of this project has a demand for technical improvement and has broad market prospects. Summary of the invention
[0003] In view of the deficiencies in the prior art, the present invention provides a synthesis process of 1-(3-chloropyridin-2-yl)-3-[5-(trifluoromethyl)-1H-tetrazolyl-1-yl]-1H-pyrazole-5-carboxylic acid based on green chemistry.
[0004] To achieve the above object, the present invention provides the following technical solution: a synthesis process of 1-(3-chloropyridin-2-yl)-3-[5-(trifluoromethyl)-1H-tetrazolyl-1-yl]-1H-pyrazole-5-carboxylic acid based on green chemistry, Raw material selection: When selecting raw materials such as 3-chloropyridine-2-carboxaldehyde, 5-(trifluoromethyl)-1H-tetrazole, hydrazine hydrate and diethyl malonate, their toxicity and environmental impact are strictly evaluated to ensure that the harm to operators and the environment during the synthesis process is minimized; Green replacement of solvents: Use ethanol and water to replace traditional toxic organic solvents such as dichloromethane and N,N-dimethylformamide. By accurately adjusting the ratio of ethanol-water mixed solvents, the synergistic effect of the two can be fully utilized to improve reaction selectivity and yield, while reducing solvent costs and subsequent processing difficulties; Synthesis of intermediates: In a 250 mL three-necked flask equipped with a magnetic stirrer, a thermometer and a reflux condenser, add 3-chloropyridine-2-carboxaldehyde (10 mmol) and 50 mL of ethanol, and stir to completely dissolve the raw materials to form a uniform solution; Synthesis of the target product: Transfer the crude intermediate to a new 250 mL three-necked flask, add diethyl malonate (12 mmol) and 50 mL of ethanol-water mixed solvent (volume ratio 1:1), stir evenly to fully mix the components; Product purification: The product is purified by filtration, washing, recrystallization and drying.
[0005] 2. The green chemistry-based 1-(3-chloropyridin-2-yl)-3-[5-(trifluoromethyl)-1H-tetrazolyl-1-yl]-1H-pyrazole-5-carboxylic acid synthesis process according to claim 1, characterized in that: the specific process of the intermediate synthesis is: add 5-(trifluoromethyl)-1H-tetrazolyl (10mmol) and an appropriate amount of bio-enzyme catalyst to the solution, slowly heat up to 40-50°C, and continue stirring at this temperature for 6-8 hours. Monitor the reaction progress by thin layer chromatography (TLC), using ethanol: water = 4:1 as the developing solvent. When the raw material spot basically disappears, it indicates that the intermediate reaction is basically completed; After the reaction was completed, the reaction solution was cooled to room temperature, and the ethanol solvent was removed by a reduced pressure distillation apparatus to obtain a pale yellow crude intermediate.
[0006] Preferably, the specific process of synthesizing the target product is as follows: adding an appropriate amount of solid acid catalyst to the mixed solution, heating to 70-80°C, and performing reflux reaction for 10-12 hours. During the reaction, the reaction progress is tracked by monitoring the physical properties of the reaction system (such as color, odor, temperature change, etc.) and chemical analysis methods to ensure that the reaction is fully carried out and the target product is generated; After the reaction is completed, the reaction solution is cooled to room temperature, and the pH value is slowly adjusted to 6-7 with an appropriate amount of sodium bicarbonate solution. At this time, a white solid will gradually precipitate out of the solution, which is the crude product of the target product.
[0007] Preferably, the specific process of the product purification is: Filtration and washing: Collect the precipitated solid by suction filtration or filtration under normal pressure, and wash the solid surface with a small amount of cold deionized water to remove adsorbed impurities and unreacted raw materials to obtain a preliminarily purified target product. Recrystallization: Dissolve the crude product in an appropriate amount of preheated ethanol-water mixed solvent, heat until the solution is completely clear and transparent, then slowly cool to room temperature, and let the solution cool and crystallize naturally. Then put it in the refrigerator (0-5°C) for further cooling to allow the crystals to grow and precipitate fully, thereby improving the purity of the product. Drying: Filter and collect the recrystallized crystals, place them in a vacuum drying oven, and dry them at 50-60°C for 6-8 hours to remove the residual solvent to obtain a high-purity 1-(3-chloropyridin-2-yl)-3-[5-(trifluoromethyl)-1H-tetrazol-1-yl]-1H-pyrazole-5-carboxylic acid product.
[0008] Preferably, the reaction temperature is optimized during the reaction process: by designing a temperature gradient experiment, the effects of different temperatures on the reaction rate, yield and purity of intermediate synthesis and target product synthesis are investigated. The results show that the optimal temperature for intermediate synthesis is 45°C, at which the reaction rate is moderate, side reactions are few, and the yield is high; the optimal temperature for target product synthesis is 75°C, at which the reaction can proceed fully and the yield and purity of the product reach an optimal balance.
[0009] Preferably, the reaction time is optimized during the reaction process: a comparative test of different reaction times is carried out to determine that the suitable time for the synthesis of the intermediate is 7 hours, at which time the reaction is basically completed and no obvious side reactions occur; the optimal time for the synthesis of the target product is 11 hours, and too long or too short reaction time will lead to a decrease in yield or purity.
[0010] Preferably, the amount of the reaction catalyst is optimized during the reaction process: the effects of different amounts of bio-enzyme catalysts and solid acid catalysts on the reaction are studied, and it is found that the appropriate amount of catalyst can significantly improve the reaction rate and yield, but when the amount of catalyst exceeds a certain threshold, the reaction effect is no longer improved, but the cost and subsequent processing difficulty are increased. Therefore, the optimal dosage range of the two catalysts is determined to achieve cost control while ensuring the reaction effect.
[0011] Compared with the prior art, the present invention provides a synthesis process of 1-(3-chloropyridin-2-yl)-3-[5-(trifluoromethyl)-1H-tetrazolyl-1-yl]-1H-pyrazole-5-carboxylic acid based on green chemistry, which has the following beneficial effects: 1. This green chemistry-based synthesis process of 1-(3-chloropyridin-2-yl)-3-[5-(trifluoromethyl)-1H-tetrazol-1-yl]-1H-pyrazole-5-carboxylic acid is the result of the development of the entire synthesis process, emphasizing its significance in theory and practical application. At the same time, it puts forward prospects for the future development of green chemistry in this field, such as exploring new synthesis routes and promoting industrial production, pointing out the direction for subsequent research and industrial development, sublimating the integrity of the article, and providing readers with thoughts on the future development of this field.
[0012] 2. The green chemistry-based 1-(3-chloropyridin-2-yl)-3-[5-(trifluoromethyl)-1H-tetrazolyl-1-yl]-1H-pyrazole-5-carboxylic acid synthesis process calculates the atomic utilization rate according to the chemical reaction equation. Compared with the traditional synthesis process, the atomic utilization rate of this green synthesis process is significantly improved. This means that more raw material atoms are effectively converted into target products, reducing the waste of raw materials and the generation of waste, which is in line with the atomic economy principle of green chemistry and realizes efficient utilization of resources at the atomic level.
[0013] 3. The green chemistry-based 1-(3-chloropyridin-2-yl)-3-[5-(trifluoromethyl)-1H-tetrazolyl-1-yl]-1H-pyrazole-5-carboxylic acid synthesis process comprehensively considers factors such as raw material cost, solvent cost, catalyst cost, energy consumption, equipment depreciation, and product yield and purity, and conducts a cost-benefit analysis of the green synthesis process. Although the initial purchase cost of green raw materials and catalysts may be slightly higher than that of traditional reagents, the yield and purity of the product are improved by optimizing the reaction conditions, reducing the waste of raw materials and waste disposal costs. Considering the long-term environmental benefits and potential market advantages, this process is economically feasible and competitive.
[0014] 4. This green chemistry-based synthesis process of 1-(3-chloropyridin-2-yl)-3-[5-(trifluoromethyl)-1H-tetrazolyl-1-yl]-1H-pyrazole-5-carboxylic acid elaborates on how to implement the concept of green chemistry from three key aspects: raw materials, solvents, and catalysts. In the raw materials section, the importance of selecting non-toxic, harmless, and renewable raw materials and the specific operations are emphasized; in terms of solvents, the types and advantages of replacing toxic solvents with green solvents, as well as the principles of mixed solvent optimization, are explained in detail; in the catalyst section, the green characteristics of bio-enzymes and solid acid catalysts and their mechanisms of action in the process are explained, and specific measures to achieve green synthesis processes from multiple angles are demonstrated.
[0015] 5. This green chemistry-based 1-(3-chloropyridin-2-yl)-3-[5-(trifluoromethyl)-1H-tetrazolyl-1-yl]-1H-pyrazole-5-carboxylic acid synthesis process elaborates on how to implement the green chemistry concept from three key aspects: raw materials, solvents, and catalysts. In the raw material part, the importance of selecting non-toxic, harmless, and renewable raw materials and the specific operations are emphasized; in the solvent part, the types and advantages of replacing toxic solvents with green solvents, as well as the principles of mixed solvent optimization, are explained in detail; in the catalyst part, the green characteristics of bio-enzymes and solid acid catalysts and their mechanisms of action in the process are explained, and specific measures to achieve green synthesis processes from multiple angles are demonstrated.
[0016] 6. The synthesis process of 1-(3-chloropyridin-2-yl)-3-[5-(trifluoromethyl)-1H-tetrazolyl-1-yl]-1H-pyrazole-5-carboxylic acid based on green chemistry elaborates on how to implement the concept of green chemistry from three key aspects: raw materials, solvents and catalysts. In the raw materials part, the importance and specific operations of selecting non-toxic and harmless and renewable raw materials are emphasized; in terms of solvents, the types and advantages of replacing toxic solvents with green solvents are explained in detail, as well as the principles of mixed solvent optimization; in the catalyst part, the green characteristics of bio-enzymes and solid acid catalysts and their mechanism of action in the process are explained, and specific measures to achieve green synthesis processes from multiple angles are demonstrated. DETAILED DESCRIPTION
[0017] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.
[0018] Green chemistry-based synthesis process of 1-(3-chloropyridin-2-yl)-3-[5-(trifluoromethyl)-1H-tetrazolyl-1-yl]-1H-pyrazole-5-carboxylic acid. Raw material selection: Screen 3-chloropyridine-2-carboxaldehyde, 5-(trifluoromethyl)-1H-tetrazole, hydrazine hydrate and diethyl malonate, and strictly evaluate their toxicity and environmental impact to ensure that the harm to operators and the environment is minimized during the synthesis process; Green replacement of solvents: Use ethanol and water to replace traditional dichloromethane and N,N-dimethylformamide. By accurately adjusting the ratio of ethanol-water mixed solvents, the synergistic effect of the two can be fully utilized to improve the reaction selectivity and yield, while reducing solvent costs and subsequent processing difficulties; Synthesis of intermediates: In a 250 mL three-necked flask equipped with a magnetic stirrer, a thermometer and a reflux condenser, add 3-chloropyridine-2-carboxaldehyde (10 mmol) and 50 mL of ethanol, and stir to completely dissolve the raw materials to form a uniform solution; Synthesis of the target product: Transfer the crude intermediate to a new 250 mL three-necked flask, add diethyl malonate (12 mmol) and 50 mL of ethanol-water mixed solvent (volume ratio 1:1), stir evenly to fully mix the components; Product purification: The product is purified by filtration, washing, recrystallization and drying.
[0019] The specific process of the intermediate synthesis is: add 5-(trifluoromethyl)-1H-tetrazole (10mmol) and an appropriate amount of enzyme catalyst to the solution, slowly raise the temperature to 40-50°C, and continue stirring at this temperature for 6-8 hours. Monitor the reaction progress by thin layer chromatography (TLC), using ethanol: water = 4:1 as the developing solvent. When the raw material spot basically disappears, it indicates that the intermediate reaction is basically completed; After the reaction was completed, the reaction solution was cooled to room temperature, and the ethanol solvent was removed by a reduced pressure distillation apparatus to obtain a pale yellow crude intermediate.
[0020] The specific process of synthesizing the target product is as follows: adding an appropriate amount of solid acid catalyst to the mixed solution, heating to 70-80°C, and performing reflux reaction for 10-12 hours. During the reaction, the physical properties of the reaction system (such as color, odor, temperature change, etc.) and chemical analysis methods are monitored to track the reaction progress to ensure that the reaction is fully carried out and the target product is generated; After the reaction is completed, the reaction solution is cooled to room temperature, and the pH value is slowly adjusted to 6-7 with an appropriate amount of sodium bicarbonate solution. At this time, a white solid will gradually precipitate out of the solution, which is the crude product of the target product.
[0021] The specific process of product purification is: Filtration and washing: Collect the precipitated solid by suction filtration or filtration under normal pressure, and wash the solid surface with a small amount of cold deionized water to remove adsorbed impurities and unreacted raw materials to obtain a preliminarily purified target product. Recrystallization: Dissolve the crude product in an appropriate amount of preheated ethanol-water mixed solvent, heat until the solution is completely clear and transparent, then slowly cool to room temperature, and let the solution cool and crystallize naturally. Then put it in the refrigerator (0-5°C) for further cooling to allow the crystals to grow and precipitate fully, thereby improving the purity of the product. Drying: Filter and collect the recrystallized crystals, place them in a vacuum drying oven, and dry them at 50-60°C for 6-8 hours to remove the residual solvent to obtain a high-purity 1-(3-chloropyridin-2-yl)-3-[5-(trifluoromethyl)-1H-tetrazol-1-yl]-1H-pyrazole-5-carboxylic acid product.
[0022] The reaction temperature was optimized during the reaction process: by designing a temperature gradient experiment, the effects of different temperatures on the reaction rate, yield and purity of intermediate synthesis and target product synthesis were investigated. The results showed that the optimal temperature for intermediate synthesis was 45°C, at which the reaction rate was moderate, side reactions were few, and the yield was high; the optimal temperature for target product synthesis was 75°C, at which the reaction could proceed fully and the yield and purity of the product reached an optimal balance.
[0023] The reaction time was optimized during the reaction process: comparative tests of different reaction times were carried out to determine that the appropriate time for the synthesis of the intermediate was 7 hours, at which time the reaction was basically completed and no obvious side reactions occurred; the optimal time for the synthesis of the target product was 11 hours, and too long or too short a reaction time would result in a decrease in yield or purity.
[0024] Optimize the amount of reaction catalyst during the reaction process: Study the effects of different amounts of bio-enzyme catalysts and solid acid catalysts on the reaction, and find that the appropriate amount of catalyst can significantly increase the reaction rate and yield, but when the amount of catalyst exceeds a certain threshold, the reaction effect is no longer improved, but the cost and subsequent processing difficulty are increased. Therefore, the optimal dosage range of the two catalysts is determined to achieve cost control while ensuring the reaction effect.
[0025] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.
Claims
1. A green 1-(-)-3-[5-(-)-1H-tetrazolyl-1-yl]-1H-pyrazole-5-carboxylic acid synthesis process, characterized in that: Raw material selection: When selecting raw materials such as 3-chloropyridine-2-carboxaldehyde, 5-(trifluoromethyl)-1H-tetrazole, hydrazine hydrate and diethyl malonate, their toxicity and environmental impact are strictly evaluated to ensure that the harm to operators and the environment during the synthesis process is minimized; Green replacement of solvents: Use ethanol and water to replace traditional toxic organic solvents such as dichloromethane and N,N-dimethylformamide. By accurately adjusting the ratio of ethanol-water mixed solvents, the synergistic effect of the two can be fully utilized to improve reaction selectivity and yield, while reducing solvent costs and subsequent processing difficulties; Synthesis of intermediates: In a 250 mL three-necked flask equipped with a magnetic stirrer, a thermometer and a reflux condenser, add 3-chloropyridine-2-carboxaldehyde (10 mmol) and 50 mL of ethanol, and stir to completely dissolve the raw materials to form a uniform solution; Synthesis of the target product: Transfer the crude intermediate to a new 250 mL three-necked flask, add diethyl malonate (12 mmol) and 50 mL of ethanol-water mixed solvent, stir evenly to fully mix the components; Product purification: The product is purified by filtration, washing, recrystallization and drying.
2. The green 1-(-)-3-[5-(-)-1H-tetrazolyl-1-yl]-1H-pyrazole-5-carboxylic acid synthesis process according to claim 1, characterized in that: The specific process of the intermediate synthesis is: add 5-(trifluoromethyl)-1H-tetrazole (10 mmol) and an appropriate amount of bio-enzyme catalyst to the solution, slowly heat up to 40-50°C, continue stirring at this temperature for 6-8 hours, monitor the reaction progress by thin layer chromatography, use ethanol: water = 4:1 as the developing solvent, and when the raw material spot basically disappears, it indicates that the intermediate reaction is basically completed; After the reaction was completed, the reaction solution was cooled to room temperature, and the ethanol solvent was removed by a reduced pressure distillation apparatus to obtain a pale yellow crude intermediate.
3. The green 1-(-)-3-[5-(-)-1H-tetrazolyl-1-yl]-1H-pyrazole-5-carboxylic acid synthesis process according to claim 1, characterized in that: The specific process of synthesizing the target product is as follows: adding an appropriate amount of solid acid catalyst to the mixed solution, heating to 70-80°C, and performing reflux reaction for 10-12 hours. During the reaction, the physical properties of the reaction system and chemical analysis methods are monitored to track the reaction progress to ensure that the reaction is fully carried out and the target product is generated; After the reaction is completed, the reaction solution is cooled to room temperature, and the pH value is slowly adjusted to 6-7 with an appropriate amount of sodium bicarbonate solution. At this time, a white solid will gradually precipitate out of the solution, which is the crude product of the target product.
4. The green 1-(-)-3-[5-(-)-1H-tetrazolyl-1-yl]-1H-pyrazole-5-carboxylic acid synthesis process according to claim 1, characterized in that: The specific process of product purification is: Filtration and washing: The precipitated solid is collected by suction filtration or atmospheric filtration, and the solid surface is washed with a small amount of cold deionized water to remove adsorbed impurities and unreacted raw materials to obtain a preliminarily purified target product; Recrystallization: Dissolve the crude product in an appropriate amount of preheated ethanol-water mixed solvent, heat until the solution is completely clear and transparent, then slowly cool it to room temperature, let the solution cool and crystallize naturally, and then put it in the refrigerator to further cool it, so that the crystals can fully grow and precipitate, thereby improving the purity of the product; Drying: Collect the recrystallized crystals by filtration, place in a vacuum drying oven, and dry at 50-60° C. for 6-8 hours to remove the residual solvent to obtain a high-purity 1-(3-chloropyridin-2-yl)-3-[5-(trifluoromethyl)-1H-tetrazol-1-yl]-1H-pyrazole-5-carboxylic acid product.
5. The green 1-(-)-3-[5-(-)-1H-tetrazolyl-1-yl]-1H-pyrazole-5-carboxylic acid synthesis process according to claim 1, characterized in that: The reaction temperature was optimized during the reaction process: by designing a temperature gradient experiment, the effects of different temperatures on the reaction rate, yield and purity of intermediate synthesis and target product synthesis were investigated. The results showed that the optimal temperature for intermediate synthesis was 45°C, at which the reaction rate was moderate, side reactions were few, and the yield was high; the optimal temperature for target product synthesis was 75°C, at which the reaction could proceed fully and the yield and purity of the product reached an optimal balance.
6. The green 1-(-)-3-[5-(-)-1H-tetrazolyl-1-yl]-1H-pyrazole-5-carboxylic acid synthesis process according to claim 1, characterized in that: The reaction time was optimized during the reaction process: comparative tests of different reaction times were carried out to determine that the appropriate time for the synthesis of the intermediate was 7 hours, at which time the reaction was basically completed and no obvious side reactions occurred; the optimal time for the synthesis of the target product was 11 hours, and too long or too short a reaction time would result in a decrease in yield or purity.
7. The green 1-(-)-3-[5-(-)-1H-tetrazolyl-1-yl]-1H-pyrazole-5-carboxylic acid synthesis process according to claim 1, characterized in that: Optimize the amount of reaction catalyst during the reaction process: Study the effects of different amounts of bio-enzyme catalysts and solid acid catalysts on the reaction, and find that an appropriate amount of catalyst can significantly increase the reaction rate and yield. However, when the amount of catalyst exceeds a certain threshold, the reaction effect is no longer improved, but the cost and subsequent processing difficulty are increased. Determine the optimal dosage range of the two catalysts to achieve cost control while ensuring the reaction effect.