Synthesis method of oxazole carboxylic acid
By reacting oxazole with AlCl3, KI, and an auxiliary catalyst in a solvent, and introducing CO2 while controlling the pressure, the problem of requiring anhydrous and oxygen-free conditions for the synthesis of oxazole-2-carboxylic acid was solved, achieving a highly efficient and environmentally friendly synthesis that is suitable for industrial applications.
Patent Information
- Application Number
- CN202511030097.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-25
- Publication Date
- 2025-10-31
- Estimated Expiration
- Not applicable · inactive patent
AI Technical Summary
The existing synthetic route for oxazole-2-carboxylic acid requires anhydrous and oxygen-free conditions, the raw materials are expensive and the post-processing is complicated, making it difficult to achieve industrial application.
Oxazole was reacted with AlCl3, KI and an auxiliary catalyst in a solvent, CO2 was introduced and the pressure was controlled, and oxazole-2-carboxylic acid was obtained through simple post-treatment.
The method achieves efficient synthesis of oxazole-2-carboxylic acid under mild conditions with a yield of 80%, without the need for harsh reaction conditions, is environmentally friendly, and is suitable for kilogram-scale production.
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Figure CN120865115A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to a method for synthesizing oxazole-2-carboxylic acid, belonging to the field of organic synthesis. Background Technology
[0002] Oxazole-2-carboxylic acid (CAS 672948-03-7) is a five-membered aromatic carboxylic acid containing nitrogen and oxygen heteroatoms, exhibiting typical aromatic carboxylic acid chemical activities. Oxazole-2-carboxylic acid and its derivatives are key building blocks in the synthesis of JNK inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, and candidate drugs against hepatitis B virus. Its rigid planar structure facilitates hydrogen bonding and π-π stacking interactions with target proteins, enhancing the binding affinity of drug molecules. Furthermore, as a bioisosteric compound with an amide bond, this compound can replace traditional peptide bonds in the construction of peptide-like drugs, improving metabolic stability and membrane permeability.
[0003] Currently, there are few reported synthetic routes for oxazole-2-carboxylic acid. Existing synthetic routes are as follows: 1) Using oxazole as a starting material, a metallization-carboxylation reaction is carried out under strong base conditions to obtain the target product; this route requires anhydrous and oxygen-free conditions and produces a large amount of inorganic salts as byproducts, making post-processing cumbersome. 2) Using oxazole-2-carboxaldehyde as a starting material, oxidization is carried out with an oxidant (such as potassium permanganate) to obtain oxazole-2-carboxylic acid; however, oxazole-2-carboxaldehyde is expensive and difficult to obtain, making industrial application difficult. To address these issues, developing a synthetic process for oxazole-2-carboxylic acid that is mild, atom-economical, and suitable for kilogram-scale production is of significant practical importance for promoting its large-scale application in innovative drugs, functional materials, and fine chemicals. Summary of the Invention
[0004] The technical problem to be solved by the present invention is to provide a simple, environmentally friendly and efficient method for synthesizing oxazole-2-carboxylic acid that does not require harsh reaction conditions.
[0005] To achieve these objectives and other advantages of the present invention, a method for synthesizing oxazole carboxylic acid is provided, characterized by comprising the following steps: S1, add oxazole, AlCl3, and KI sequentially to the reactor, add solvent, and stir until homogeneous. Then add auxiliary catalyst, purge air with nitrogen, raise the temperature to 140℃~150℃, introduce CO2, maintain the pressure at 0.4~0.6MPa, and maintain the reaction temperature for 6 hours; S2, after the reaction is complete, the reaction solution is cooled to room temperature and filtered. The filtrate is slowly poured into ice water with stirring for 30 minutes, resulting in the precipitation of a solid. The solid is then filtered, and the filter cake is dissolved in water and a saturated sodium hydroxide solution, with the solution adjusted to a final concentration of concentrated hydrochloric acid. P H=2~3, filter, and dry the solid to obtain oxazole-2-carboxylic acid.
[0006] Preferably, the solvent is one or more of N-methylpyrrolidone, sulfolane, and 1,3-dimethyl-2-imidazolinone.
[0007] Preferably, the auxiliary catalyst is one or more of the following: 1,3-bis(diphenylphosphine propane) nickel chloride, (1,1'-bis(diphenylphosphine)ferrocene) nickel chloride, bis(triphenylphosphine) nickel chloride, 1,10-o-phenanthroline nickel chloride, 2,2'-bipyridine nickel chloride, [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine] nickel chloride (II), 3,4,7,8-tetramethyl-1,10-phenanthroline nickel chloride, 2,6-bis(N-pyrazolyl)pyridine nickel chloride (II), and 1,2-bis(diphenylphosphine)ethane nickel chloride.
[0008] Preferably, the molar ratio of AlCl3 to oxazole is 1.3:1 to 1.8:1, more preferably 1.5:1.
[0009] Preferably, the molar ratio of the auxiliary catalyst to the oxazole is 0.005:1 to 0.01:1, and more preferably 0.007:1.
[0010] The present invention has the following technical effects: 1. The raw materials used in this invention are readily available, the reaction process does not require strict anhydrous and oxygen-free conditions, the post-processing is simple, and it is environmentally friendly.
[0011] 2. Through the exploration of various reaction conditions, this invention enables the synthesis of the target oxazole-2-carboxylic acid to achieve a high yield, up to 80%. Attached Figure Description
[0012] Figure 1 The synthetic route diagram of oxazole-2-carboxylic acid provided in the embodiments of the present invention. Specific Implementation
[0013] The preparation method of the present invention will be further illustrated by specific embodiments below, but the present invention is not limited to these embodiments.
[0014] Example 1 0.69 g (1 eq) of oxazole, 2.13 g (1.6 eq) of AlCl3, and 0.05 g of KI (catalytic amount) were added sequentially to a reaction vessel. 10 ml of N-methylpyrrolidone was added, and the mixture was stirred until homogeneous. 0.04 g (0.007 eq) of 1,3-bis(diphenylphosphine propane) nickel chloride was added. After purging with nitrogen to remove air, the reaction vessel was heated to 140℃~150℃, and CO2 was introduced. The pressure was maintained at 0.4~0.6 MPa, and the reaction was continued for 6 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filter cake was collected and recovered. The filtrate was slowly poured into 20 ml of ice water with stirring for 30 minutes, resulting in the precipitation of a solid. The solid was filtered, and 10 ml of water was added to the filter cake. A saturated aqueous solution of sodium hydroxide was added dropwise with stirring until completely dissolved. The solution was adjusted with concentrated hydrochloric acid. P H=2~3, filtered, and dried to obtain 0.88g of oxazole-2-carboxylic acid, yield 78%, purity 98.3%.
[0015] Example 2 0.69 g (1 eq) of oxazole, 2.13 g (1.6 eq) of AlCl3, and 0.05 g of KI (catalytic amount) were added sequentially to a reaction vessel. 10 ml of 1,3-dimethyl-2-imidazolinone was added, and the mixture was stirred thoroughly. 0.05 g (0.007 eq) of (1,1'-bis(diphenylphosphine)ferrocene)dichloride was added. After purging with nitrogen to remove air, the reaction vessel was heated to 140℃~150℃, CO2 was introduced, and the pressure was maintained at 0.4~0.6 MPa for 6 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filter cake was collected and recovered. The filtrate was slowly poured into 20 ml of ice water with stirring for 30 minutes, resulting in the precipitation of a solid. The solid was filtered, and 10 ml of water was added to the filter cake. A saturated sodium hydroxide solution was added dropwise with stirring until completely dissolved. The solution was adjusted with concentrated hydrochloric acid. P H=2~3, filtered, and dried to obtain 0.85g of oxazole-2-carboxylic acid, yield 75%, purity 98.6%.
[0016] Example 3 0.69 g (1 eq) of oxazole, 2.40 g (1.8 eq) of AlCl3, and 0.05 g of KI (catalytic amount) were added sequentially to a reaction vessel. 10 ml of N-methylpyrrolidone was added, and the mixture was stirred until homogeneous. 0.05 g (0.007 eq) of bis(triphenylphosphine) nickel chloride was added. After purging with nitrogen to remove air, the reaction vessel was heated to 140℃~150℃, and CO2 was introduced. The pressure was maintained at 0.4~0.6 MPa, and the reaction was continued for 6 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filter cake was collected and recovered. The filtrate was slowly poured into 20 ml of ice water with stirring for 30 minutes, resulting in the precipitation of a solid. The solid was then filtered, and 10 ml of water was added to the filter cake. A saturated sodium hydroxide solution was added dropwise with stirring until completely dissolved. The solution was adjusted with concentrated hydrochloric acid. PH=2~3, filtered, and dried to obtain 0.78g of oxazole-2-carboxylic acid, yield 69%, purity 99.0%.
[0017] Example 4 0.69 g (1 eq) of oxazole, 2.00 g (1.5 eq) of AlCl3, and 0.05 g of KI (catalytic amount) were added sequentially to a reaction vessel. 10 ml of 1,3-dimethyl-2-imidazolinone was added, and the mixture was stirred until homogeneous. 0.02 g (0.007 eq) of 1,10-o-phenanthroline nickel dichloride was added. After purging with nitrogen to remove air, the reaction vessel was heated to 140℃~150℃, CO2 was introduced, and the pressure was maintained at 0.4~0.6 MPa for 6 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filter cake was collected and recovered. The filtrate was slowly poured into 20 ml of ice water with stirring for 30 minutes, resulting in the precipitation of a solid. The solid was filtered, and 10 ml of water was added to the filter cake. A saturated sodium hydroxide solution was added dropwise with stirring until completely dissolved. The solution was adjusted with concentrated hydrochloric acid. P H=2~3, filtered, and dried to obtain 0.90 g of oxazole-2-carboxylic acid, yield 80%, purity 98.8%.
[0018] Example 5 Add 0.69 g (1 eq) of oxazole, 2.40 g (1.8 eq) of AlCl3, and 0.05 g of KI (catalytic amount) sequentially to a reaction vessel. Add 10 ml of 1,3-dimethyl-2-imidazolinone and stir until homogeneous. Add 0.02 g (0.007 eq) of 2,2'-bipyridine nickel chloride. After purging the air with nitrogen, heat the reaction vessel to 140℃~150℃, introduce CO2, maintain the pressure at 0.4~0.6 MPa, and maintain the reaction temperature for 6 h. After the reaction is complete, cool the reaction solution to room temperature, filter, and collect the filter cake. Slowly pour the filtrate into 20 ml of ice water while stirring, and stir for 30 min to precipitate a solid. Filter by suction, add 10 ml of water to the filter cake, and add saturated sodium hydroxide solution dropwise while stirring until completely dissolved. Adjust the temperature with concentrated hydrochloric acid. P H=2~3, filtered, and dried to obtain 0.87g of oxazole-2-carboxylic acid, yield 77%, purity 98.1%.
[0019] Example 6 0.69 g (1 eq) of oxazole, 2.00 g (1.5 eq) of AlCl3, and 0.05 g of KI (catalytic amount) were added sequentially to the reaction vessel, followed by 10 ml of N-methylpyrrolidone, and stirred until homogeneous. 0.02 g (0.005 eq) of [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel(II) chloride was added. After purging with nitrogen to remove air, the reaction vessel was heated to 140℃~150℃, CO2 was introduced, and the pressure was maintained at 0.4~0.6 MPa for 6 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filter cake was collected and recovered. The filtrate was slowly poured into 20 ml of ice water with stirring for 30 minutes, resulting in the precipitation of a solid. The solid was then filtered, and 10 ml of water was added to the filter cake. A saturated sodium hydroxide solution was added dropwise with stirring until completely dissolved, and the solution was adjusted with concentrated hydrochloric acid. P H=2~3, filtered, and dried to obtain 0.88g of oxazole-2-carboxylic acid, yield 78%, purity 98.9%.
[0020] Example 7 0.69 g (1 eq) of oxazole, 1.73 g (1.3 eq) of AlCl3, and 0.05 g of KI (catalytic amount) were added sequentially to a reaction vessel, followed by 10 ml of sulfolane and stirred until homogeneous. 0.02 g (0.005 eq) of 3,4,7,8-tetramethyl-1,10-phenanthroline nickel dichloride was added. After purging with nitrogen to remove air, the reaction vessel was heated to 140℃~150℃, CO2 was introduced, and the pressure was maintained at 0.4~0.6 MPa for 6 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filter cake was collected and recovered. The filtrate was slowly poured into 20 ml of ice water with stirring for 30 minutes, resulting in the precipitation of a solid. The solid was filtered, and 10 ml of water was added to the filter cake. A saturated aqueous solution of sodium hydroxide was added dropwise with stirring until completely dissolved. The solution was adjusted with concentrated hydrochloric acid. P H=2~3, filtered, and dried to obtain 0.80 g of oxazole-2-carboxylic acid, yield 71%, purity 98.8%.
[0021] Example 8 0.69 g (1 eq) of oxazole, 1.73 g (1.3 eq) of AlCl3, and 0.05 g of KI (catalytic amount) were added sequentially to a reaction vessel, followed by 10 ml of sulfolane and stirred until homogeneous. 0.03 g (0.01 eq) of 2,6-bis(N-pyrazolyl)pyridine nickel(II) chloride was added, and after purging with nitrogen to remove air, the reaction vessel was heated to 140℃~150℃, CO2 was introduced, and the pressure was maintained at 0.4~0.6 MPa for 6 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filter cake was collected and recovered. The filtrate was slowly poured into 20 ml of ice water with stirring for 30 minutes, resulting in the precipitation of a solid. The solid was then filtered, and 10 ml of water was added to the filter cake. A saturated sodium hydroxide solution was added dropwise with stirring until completely dissolved, and the solution was adjusted with concentrated hydrochloric acid.P H=2~3, filtered, and dried to obtain 0.88g of oxazole-2-carboxylic acid, yield 78%, purity 98.3%.
[0022] Example 9 0.69 g (1 eq) of oxazole, 2.00 g (1.5 eq) of AlCl3, and 0.05 g of KI (catalytic amount) were added sequentially to a reaction vessel, followed by 10 ml of sulfolane and stirred until homogeneous. 0.05 g (0.01 eq) of 1,2-bis(diphenylphosphine)ethane nickel chloride was added, and after purging with nitrogen to remove air, the reaction vessel was heated to 140℃~150℃, CO2 was introduced, and the pressure was maintained at 0.4~0.6 MPa for 6 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filter cake was collected and recovered. The filtrate was slowly poured into 20 ml of ice water with stirring for 30 minutes, resulting in the precipitation of a solid. The solid was then filtered, and 10 ml of water was added to the filter cake. A saturated sodium hydroxide solution was added dropwise with stirring until completely dissolved, and the solution was adjusted with concentrated hydrochloric acid. P H=2~3, filtered, and dried to obtain 0.81g of oxazole-2-carboxylic acid, yield 72%, purity 98.5%.
Claims
1. A method for synthesizing oxazole carboxylic acid, characterized in that, Includes the following steps: S1, add oxazole, AlCl3, and KI sequentially to the reactor, add solvent, and stir until homogeneous. Then add auxiliary catalyst, purge air with nitrogen, raise the temperature to 140℃~150℃, introduce CO2, maintain the pressure at 0.4~0.6MPa, and maintain the reaction temperature for 6 hours; S2, after the reaction is complete, the reaction solution is cooled to room temperature and filtered. The filtrate is slowly poured into ice water with stirring for 30 minutes, resulting in the precipitation of a solid. The solid is then filtered, and the filter cake is dissolved in water and a saturated sodium hydroxide solution, with the solution adjusted to a final concentration of concentrated hydrochloric acid. P H=2~3, filter, and dry the solid to obtain oxazole-2-carboxylic acid.
2. The synthesis method according to claim 1, characterized in that, The solvent is one or more of N-methylpyrrolidone, sulfolane, and 1,3-dimethyl-2-imidazolinone.
3. The synthesis method according to claim 1, characterized in that, The auxiliary catalyst is one or more of the following: 1,3-bis(diphenylphosphine propane) nickel chloride, (1,1'-bis(diphenylphosphine)ferrocene) nickel chloride, bis(triphenylphosphine) nickel chloride, 1,10-o-phenanthroline nickel chloride, 2,2'-bipyridine nickel chloride, [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine] nickel chloride (II), 3,4,7,8-tetramethyl-1,10-phenanthroline nickel chloride, 2,6-bis(N-pyrazolyl)pyridine nickel chloride (II), and 1,2-bis(diphenylphosphine) ethane nickel chloride.
4. The synthesis method according to claim 1, characterized in that, The molar ratio of AlCl3 to oxazole is 1.3:1 to 1.8:1, preferably 1.5:
1.
5. The synthesis method according to claim 1, characterized in that, The molar ratio of the auxiliary catalyst to the oxazole is from 0.005:1 to 0.01:1, preferably 0.007:1.