CN-121974853-A - Synthesis method of 3-alkylpyrazole-4-carboxylic acid derivative

Abstract

The invention belongs to the technical field of organic synthesis, and discloses a synthesis method of a 3-alkyl pyrazole-4-carboxylic acid derivative, which is characterized in that alpha-halogenated-beta-keto ester shown in a general formula (I), hydrazine compounds shown in a general formula (II) and a formaldehyde donor are used as reaction raw materials, and the 3-alkyl pyrazole-4-carboxylic acid derivative shown in a general formula (III) is generated by performing one-pot reaction in the presence of alkali and in the presence of water and/or an alcohol solvent. The synthesis method of the invention takes formaldehyde donor, hydrazine (or substituted hydrazine) and alpha-halogenated-beta-keto ester which are cheap and easy to obtain as raw materials, realizes the high-efficiency and high-selectivity synthesis of target products by a three-component one-pot method through the innovative regulation and control of the reaction process of fast-slow-fast, and solves the problems of more steps, poor selectivity and difficult control of direct participation of formaldehyde in the reaction in the traditional method.

Inventors

• GU YANLONG
• BAI YUHAN
• Mohammed Norman Haider Tariq

Assignees

• 华中科技大学

Dates

Publication Date

20260505

Application Date

20260313

Claims (8)

1. 1. A synthesis method of 3-alkylpyrazole-4-carboxylic acid derivative is characterized in that alpha-halogenated-beta-ketoester shown in a general formula (I), hydrazine compound shown in a general formula (II) and formaldehyde donor are used as reaction raw materials, and one-pot reaction is carried out in the presence of alkali and in the presence of water and/or alcohol solvent to generate the 3-alkylpyrazole-4-carboxylic acid derivative shown in a general formula (III): Wherein X in the general formula (I) represents halogen, R 1 is C1-C10 alkyl, and R 2 is C1-C10 alkyl; In the general formula (II), R 3 is aryl; The formaldehyde donor is formaldehyde solution, paraformaldehyde or trioxymethylene.
2. 2. The method of synthesis according to claim 1, wherein the base is an inorganic base or an organic base, wherein the inorganic base is sodium carbonate, sodium acetate or sodium bicarbonate; Preferably, the base is sodium acetate.
3. 3. The synthetic method of claim 1, wherein the molar ratio of the α -halo- β -keto ester to the base is 1:1 to 1:3.
4. 4. The method of claim 1, wherein the alcoholic solvent is a C1-C4 alcohol, preferably ethanol or methanol, more preferably ethanol.
5. 5. The synthesis method according to claim 1, wherein the molar ratio of the alpha-halo-beta-keto ester to the hydrazine compound is 1:1 to 1:1.5; the molar ratio of the alpha-halogenated-beta-keto ester to formaldehyde contained in the formaldehyde donor is 1:1-1:2.5.
6. 6. The synthetic method of claim 1 wherein the one-pot reaction is at a temperature of from 60 ℃ to 80 ℃ and a reaction time of from 2 to 6 hours.
7. 7. The synthesis method according to claim 1, wherein the hydrazine compound is phenylhydrazine compound represented by the structural formula 2b or hydrochloride form thereof: Wherein the substituent R is in a form of single substituent or multiple substituents, in particular any one or more of CH 3 and OMe, F, cl, br.
8. 8. The method of claim 1, wherein the hydrazine compound is phenylhydrazine or phenylhydrazine hydrochloride.

Description

Synthesis method of 3-alkylpyrazole-4-carboxylic acid derivative Technical Field The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of a 3-alkyl pyrazole-4-carboxylic acid derivative. Background Pyrazole rings are an important class of nitrogen-containing five-membered heterocyclic structures, which are widely found in a variety of biologically active natural products and drug molecules. Among them, 3-alkylpyrazole-4-carboxylic acid derivatives, a class of highly functionalized pyrazole compounds, are key pharmacophores or core intermediates for the construction of nonsteroidal anti-inflammatory drugs (such as celecoxib), hypoglycemic agents, and various kinase inhibitors due to their unique structure (Fustero, s. Et al chem. Rev.2011, 111, 6984-7034). Therefore, the method for synthesizing the structural unit by developing an efficient and green method has important application value in the fields of pharmaceutical chemistry and agricultural chemistry. Taking 3-alkylpyrazole-4-carboxylic acid derivatives as represented by 3-alkyl-4-carboxylate substituted pyrazoles as an example, currently, conventional methods for synthesizing 3-alkyl-4-carboxylate substituted pyrazoles mainly rely on multi-step reaction sequences. The most common strategy is to first obtain a 3-substituted pyrazole ring by condensation cyclisation of the 1, 3-dicarbonyl compound with a hydrazine derivative, and then to functionalize the 4-position of the pyrazole ring, for example by introducing carboxylate groups by halo-carboxylation or metal-catalyzed cross-coupling reactions (Karrouchi, k. Et al. Molecular 2018, 23, 134). However, these methods generally suffer from problems of lengthy steps, low overall yields, difficult control of regioselectivity, and difficulty in avoiding the use of noble metal reagents or harsh reaction conditions (e.g., high temperature activation or introduction of strong acid reagents, where high temperatures are often not lower than 120 ℃ to achieve solvent reflux). Therefore, from the viewpoints of atom economy and step economy, it is of significant advantage to develop a novel synthetic method capable of directly constructing a target pyrazole ring molecule by a one-pot method, starting from a simple and readily available raw material. In theory, the one-pot three-component reaction of formaldehyde, hydrazine and alpha-halogenated-beta-keto ester is the most direct and ideal way for constructing target molecules. However, the implementation of the strategy faces great challenges, and the core is precise regulation and control of the activity and selectivity of reactants, namely, formaldehyde is used as a high-activity C1 electrophile, so that non-selective addition reaction is very easy to occur with other nucleophilic components in a system, and on the other hand, the alpha-halogenated-beta-keto ester also has a plurality of reaction sites, so that the reaction system is complicated due to the factors. Therefore, how to guide the three components with obvious reactivity difference to orderly react according to a preset path in one reaction system, so that the generation of byproducts is inhibited, which is a key for realizing the success of the three-component reaction and is a technical problem which cannot be solved for a long time. Therefore, a method capable of efficiently synthesizing 3-alkylpyrazole-4-carboxylic acid derivatives from formaldehyde, hydrazine and alpha-halogenated-beta-keto ester by a one-pot method is developed, a more competitive process route for preparing high-value chemicals is provided, and a very attractive technical scheme is provided for high-value conversion of bulk chemicals-formaldehyde into fine chemicals. Disclosure of Invention Aiming at the defects or improvement demands of the prior art, the invention aims to provide a synthesis method of 3-alkyl pyrazole-4-carboxylic acid derivatives, which takes cheap and easily available formaldehyde donors, hydrazine (or substituted hydrazine) and alpha-halogenated-beta-keto ester as raw materials, realizes high-efficiency and high-selectivity synthesis of target products by a three-component one-pot method through the regulation and control of an innovative 'fast-slow-fast' reaction process, and solves the problems of more steps, poor selectivity and difficult control of direct participation of formaldehyde in the reaction in the traditional method. In order to achieve the above object, according to the present invention, there is provided a method for synthesizing a 3-alkylpyrazole-4-carboxylic acid derivative, characterized in that an α -halo- β -ketoester represented by general formula (I), a hydrazine compound represented by general formula (II), and a formaldehyde donor are used as reaction raw materials, and in the presence of a base, a one-pot reaction is performed in the presence of water and/or an alcoholic solvent to produce a 3-alkylpyrazole-4-carboxylic a