Method for synthesizing methyl oxazole-2-formate from triazole and oxalyl chloride monomethyl ester through mixed base mediation

Abstract

The oxazole ring, as a classical nitrogen-containing heteroaromatic ring skeleton, has irreplaceable application value in the frontier fields of pharmaceutical chemistry, functional material creation, bioactive molecule research and development and the like. Wherein the methyl oxazole-2-formate has become a core synthesis precursor of a variety of pharmaceutical molecules and high value-added fine chemicals by virtue of unique structural characteristics and reaction activity. In order to solve the common bottleneck problems of low yield, insufficient product purity, strict reaction conditions and the like in the existing synthesis process, the invention aims at efficient and green synthesis of oxazole-2-methyl formate, and systematically explores the regulation and control effects of key parameters such as reaction solvent, reaction time, reaction temperature, type and dosage of alkali and the like on the synthesis process. Results show that 1.0 equivalent of 1H-1, 2, 3-triazole and 1.2 equivalent of oxalyl chloride monomethyl ester are taken as initial raw materials, 1.0 equivalent of sodium hydride and 1.0 equivalent of potassium carbonate are adopted to construct a mixed base catalysis system, sulfolane is taken as a solvent, reaction is performed for 2 hours at the temperature of 80 DEG C, the oxazole-2-methyl formate can be efficiently prepared through a one-pot method, the product yield reaches up to 92%, and the purity reaches up to 98%. The purity of the product obtained by the process meets the application requirements of subsequent separation and purification of medical intermediates, structural modification and large-scale preparation, a feasible technical path is provided for industrial production of oxazole derivatives, and the method has remarkable application potential and popularization value.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, and specifically relates to a method for synthesizing methyl oxazol-2-carboxylate. Background Technology

[0002] Heterocyclic compounds are a class of cyclic organic compounds whose molecular skeleton contains at least one heteroatom. As core structural units of drugs, functional materials, and bioactive molecules, their research plays a crucial role in advancing pharmaceutical development, new material creation, and life science exploration. Oxazoles are an important class of five-membered heterocyclic compounds, with a molecular structure containing one nitrogen atom and one oxygen atom. This structure is widely found in various natural compounds and forms the core skeleton of many bioactive molecules and drug lead structures, holding significant research value in medicinal chemistry and organic synthesis. Oxazole derivatives exhibit rich biological activities, and their application potential has attracted considerable attention in drug development. For example, Texaline (Formula A), isolated from *Amygdalina*, has been shown to have good anti-tuberculosis activity; 2-methoxybenzoxazole (Formula B) is a benzoxazole derivative with significant biological activity. Studies have shown that this compound exhibits excellent inhibitory activity against various pathogenic fungi, demonstrating good application potential in the field of antifungal drug development; and 2-(3,4-dimethoxyphenyl)-5-methyloxazole (Formula C) shows significant activity against various tumor cell lines. Furthermore, oxazole derivatives have demonstrated significant application value beyond medicinal chemistry. For example, 5-chlorobenzoxazole-2-amine (Formula D), as a structurally stable ligand with excellent coordination ability, has been widely used in the design and development of various metal catalysts, playing a crucial role in organic synthesis and catalytic reactions. 2,5-Diphenyloxazole (Formula E) is an important precursor to fluorescent materials, often used as a key structural unit in the design and synthesis of organic scintillators, and is of great significance for the development of high-performance radiation detection materials. Oxazole pesticides such as quizalofop-p-ethyl (Formula F) play an important role in plant protection. Therefore, how to achieve efficient and convenient synthesis of oxazole compounds has always been a key research focus and hot topic in the field of chemical synthesis.

[0003] Summary of the Invention

[0004] This invention uses 1.0 equivalent of 1H-1,2,3-triazole and 1.2 equivalent of oxaloyl chloride monomethyl ester as starting materials, a mixed alkali system consisting of 1.0 equivalent of sodium hydride and 1.0 equivalent of potassium carbonate, and sulfolane as solvent. The reaction is carried out at 80°C for 2 hours, resulting in a one-pot synthesis of oxazole-2-carboxylate with a yield of 92% and a purity of 98%. This effectively improves upon existing processes for synthesizing oxazole-2-carboxylate, which suffer from low yield, insufficient purity, and stringent reaction conditions. The specific method is as follows:

[0005]

[0006] A method for synthesizing methyl oxazole-2-carboxylate, using 1H-1,2,3-triazole and oxaloyl chloride monomethyl ester as starting materials, sodium hydride and potassium carbonate as a mixed base system, sulfolane as a solvent, and reacting with an organic solvent at 80°C to synthesize methyl oxazole-2-carboxylate as shown in Formula 3.

[0007] The method of this invention can achieve one-pot production of methyl oxazol-2-carboxylate, reducing reaction steps and thus improving product yield; the raw materials used in the synthesis method are obtained through diverse means and have high economic benefits.

[0008] Preferably, the mixed alkali is NaH and K2CO3.

[0009] Preferably, the ratio of the mixed alkali NaH to K2CO3 is 1:1.

[0010] Preferably, the organic solvent is sulfolane.

[0011] Preferably, the molar ratio of 1H-1,2,3-triazole (1) as shown in Formula 1, oxaloyl chloride monomethyl ester (2) as shown in Formula 2, and the mixed base in the reaction is 1:1.2:2.

[0012] Preferably, the reaction temperature of the synthesis method is 80°C.

[0013] Preferably, the method of the present invention can generate compounds with the following structures:

[0014]

[0015] The technical solution of the present invention can achieve at least one of the following beneficial effects:

[0016] The synthesis method of this invention uses inexpensive raw materials that are available through diverse means, resulting in high economic benefits.

[0017] This invention employs a one-pot synthesis method, which reduces the loss of raw materials and saves reaction time due to fewer reaction steps, thereby improving product yield and reaction efficiency.

[0018] The operation steps required by this invention are relatively simple, without the need for extreme heating or cooling, and the reaction can be carried out under normal pressure. It is safe, convenient and energy-efficient. Attached Figure Description

[0019] The attached figures show the proton and carbon NMR spectra of the products from each embodiment. The figure numbers correspond to the embodiment numbers. Figure A is the proton NMR spectrum, and Figure B is the carbon NMR spectrum. Figure 1A The above is the proton NMR spectrum of the product obtained in Example 1. Figure 1B The image shows the carbon NMR spectrum of the product obtained in Example 1. Specific Implementation

[0020] To facilitate understanding by those skilled in the art, the concept of the present invention will be further explained below with reference to embodiments. The specific descriptions of the following embodiments are not intended to limit the present invention, but are merely for the convenience of those skilled in the art to understand the technical solution. All raw materials mentioned in the specification were purchased from the market or synthesized through simple methods. Other pharmaceuticals were purchased from Amex, Bide, Sigma-Aldrich, Acros, Alfa Aesar, Adamas-beta, or J&K. The nuclear magnetic resonance spectrometer was a JEOL 400M.

[0021] Example

[0022] To a dry, round-bottom flask equipped with a magnetic stirrup, NaH (24.0 mg, 1.0 mmol), K₂CO₃ (138.0 mg, 1.0 mmol), 1H₂,2,3-triazole (58 μL, 1.0 mmol), oxaloyl chloride monomethyl ester (110 μL, 1.2 mmol), and sulfolane (0.5 mL) were added sequentially. The mixture was reacted at 80 °C for 2 hours. After cooling to room temperature, the reaction was complete. The crude product was purified by rapid silica gel column chromatography, yielding a product with a purity of 98% and a yield of 92%. 1 H NMR (400MHz, Chloroform-d) δ: 7.88 (d, J=0.8Hz, 1H), 7.38 (q, J=1.4Hz, 1H), 4.03 (s, 3H); 13 C NMR (101MHz, Chloroform-d) δ: 155.88, 152.38, 141.71, 129.30, 53.16ppm.

Claims

1. A method for synthesizing methyl oxazol-2-carboxylate mediated by a mixed base from 1H-1,2,3-triazole and oxaloyl chloride monomethyl ester, characterized in that: Using 1H-1,2,3-triazole as shown in Formula 1 and oxaloyl chloride monomethyl ester as shown in Formula 2, methyl oxazol-2-carboxylate as shown in Formula 3 was synthesized in the presence of a mixed base and an organic solvent.

2. The synthesis method according to claim 1, characterized in that, The mixed alkali is NaH and K2CO3.

3. The synthesis method according to claim 2, characterized in that, The ratio of the mixed alkali NaH to K2CO3 is 1:

1.

4. The synthesis method according to claim 1, characterized in that, The organic solvent is sulfolane.

5. The synthesis method according to claim 1, characterized in that, In the reaction, the molar ratio of 1H-1,2,3-triazole (1) shown in Formula 1, oxaloyl chloride monomethyl ester (2) shown in Formula 2, and the mixed base is 1:1.2:

2.

6. The synthesis method according to claim 1, characterized in that, The reaction temperature of the synthesis method is 80℃.

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