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-alkylpyrazole-4-carboxylic acid derivative, which comprises the following steps: by taking alpha-halogenated-beta-keto ester as shown in a general formula (I), a hydrazine compound as shown in a general formula (II) and a formaldehyde donor as reaction raw materials, carrying out a reaction under the existence of alkali, so as to obtain the 3-alkylpyrazole-4-carboxylic acid derivative. And carrying out a one-pot reaction in the presence of water and / or an alcohol solvent to generate the 3-alkylpyrazole-4-carboxylic acid derivative as shown in a formula (III). According to the synthesis method disclosed by the invention, a formaldehyde donor, hydrazine (or substituted hydrazine) and alpha-halogenated-beta-keto ester which are low in price and easy to obtain are taken as raw materials, and the target product is efficiently synthesized with high selectivity by a three-component one-pot method through innovative'fast-slow-fast 'reaction process regulation and control; the problems of many steps, poor selectivity and difficult control of direct participation of formaldehyde in the reaction in the traditional method are overcome.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and more specifically, relates to a method for synthesizing a 3-alkylpyrazole-4-carboxylic acid derivative. Background Technology

[0002] Pyrazole rings are an important class of nitrogen-containing five-membered heterocyclic structures, widely found in various biologically active natural products and drug molecules. Among them, 3-alkylpyrazole-4-carboxylic acid derivatives, as a class of highly functionalized pyrazole compounds, are key pharmacophores or core intermediates in 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, developing efficient and green methods to synthesize such structural units has important application value in the fields of medicinal chemistry and agricultural chemistry.

[0003] Taking 3-alkylpyrazole-4-carboxylic acid derivatives, represented by 3-alkyl-4-carboxylic acid ester-substituted pyrazoles, as an example, the traditional methods for synthesizing 3-alkyl-4-carboxylic acid ester-substituted pyrazoles currently mainly rely on multi-step reaction sequences. The most common strategy is as follows: first, a condensation cyclization reaction is performed between a 1,3-dicarbonyl compound and a hydrazine derivative to obtain a 3-substituted pyrazole ring; subsequently, the 4-position of the pyrazole ring is functionalized, for example, by introducing a carboxylic acid ester group through halogenation-carboxylation or metal-catalyzed cross-coupling reactions (Karrouchi, K. et al.). Molecules (2018, 23, 134). However, these methods generally suffer from lengthy steps, low overall yield, difficulty in controlling regioselectivity, and the unavoidable use of precious metal reagents or harsh reaction conditions (e.g., high-temperature activation or introduction of strong acid reagents, where the temperature is often no lower than 120 °C to achieve solvent reflux). Therefore, from the perspective of atom economy and step economy, developing new synthetic methods that can directly construct the target pyrazole ring molecule from simple and readily available raw materials in a one-pot process has significant advantages.

[0004] Theoretically, a one-pot three-component reaction using formaldehyde, hydrazine, and α-halo-β-keto esters is the most direct and ideal route to construct the target molecule. However, implementing this strategy faces significant challenges, primarily due to the precise control of reactant reactivity and selectivity. On one hand, formaldehyde, as a highly reactive C1 electrophile, readily undergoes non-selective addition reactions with other nucleophilic components in the system. On the other hand, α-halo-β-keto esters themselves possess multiple reaction sites, all of which contribute to the complexity of the reaction system. Therefore, guiding these three components with significantly different reactivity along a predetermined pathway within a single reaction system, thereby suppressing the formation of byproducts, is crucial for the success of this three-component reaction and remains a long-standing technical challenge.

[0005] Therefore, developing a method for the efficient one-pot selective synthesis of 3-alkylpyrazole-4-carboxylic acid derivatives from formaldehyde, hydrazine, and α-halo-β-keto esters would not only provide a more competitive process route for the preparation of such high-value chemicals, but also offer a highly attractive technical solution for the high-value transformation of bulk chemical formaldehyde into fine chemicals. Summary of the Invention

[0006] In view of the above-mentioned defects or improvement needs of the existing technology, the purpose of this invention is to provide a method for synthesizing 3-alkylpyrazole-4-carboxylic acid derivatives. Using inexpensive and readily available formaldehyde donor, hydrazine (or substituted hydrazine) and α-halo-β-keto ester as raw materials, the method achieves efficient and highly selective synthesis of the target product in a three-component one-pot process through innovative "fast-slow-fast" reaction process control. This overcomes the problems of traditional methods, such as multiple steps, poor selectivity and difficulty in controlling the direct participation of formaldehyde in the reaction.

[0007] To achieve the above objectives, according to the present invention, a method for synthesizing a 3-alkylpyrazole-4-carboxylic acid derivative is provided, characterized in that an α-halo-β-keto ester of general formula (I), a hydrazine compound of general formula (II), and a formaldehyde donor are used as reactants, and a one-pot reaction is carried out in the presence of a base and with the participation of water and / or an alcohol solvent to generate a 3-alkylpyrazole-4-carboxylic acid derivative as shown in formula (III):

[0008] In general formula (I), X represents halogen, and R 1 It is an alkyl group from C1 to C10, R 2 It is an alkyl group from C1 to C10; In general formula (II), R 3 It is aryl; The formaldehyde donor is a formaldehyde solution, paraformaldehyde, or triformaldehyde.

[0009] As a further preferred embodiment of the present invention, the base is an inorganic base or an organic base, wherein the inorganic base is sodium carbonate, sodium acetate, or sodium bicarbonate; and the organic base is triethylamine. Preferably, the base is sodium acetate.

[0010] As a further preferred embodiment of the present invention, the molar ratio of the α-halo-β-keto ester to the base is 1:1 to 1:3.

[0011] As a further preferred embodiment of the present invention, the alcohol solvent is a C1-C4 alcohol, preferably ethanol or methanol, and more preferably ethanol.

[0012] As a further preferred embodiment of the present invention, the molar ratio of the α-halo-β-keto ester to the hydrazine compound is 1:1 to 1:1.5; The molar ratio of the α-halo-β-keto ester to the formaldehyde contained in the formaldehyde donor is 1:1 to 1:2.5.

[0013] As a further preferred embodiment of the present invention, the temperature of the one-pot reaction is 60 ℃ to 80 ℃, and the reaction time is 2 to 6 hours.

[0014] As a further preferred embodiment of the present invention, the hydrazine compound is a phenylhydrazine compound with the structural formula shown in Formula 2b or its hydrochloride salt form:

[0015] Wherein, the substituent R is in the form of a monosubstituted or polysubstituted group, specifically any one or more of CH3, OMe, F, Cl, and Br.

[0016] As a further preferred embodiment of the present invention, the hydrazine compound is phenylhydrazine or phenylhydrazine hydrochloride.

[0017] Compared with the prior art, the synthesis method of this invention, through the above-conceived technical solution, involves a one-pot reaction of formaldehyde donor, hydrazine (or substituted hydrazine), and α-halo-β-keto ester in a "fast-slow-fast" cascade process. Taking formaldehyde solution as the formaldehyde donor as an example: Fast step one: Highly reactive formaldehyde rapidly undergoes hydroxymethylation with α-halo-β-keto ester to generate a relatively stable α-halo-β-hydroxy-β-keto ester intermediate (M-1), thereby rapidly converting formaldehyde; Slow step two: Under alkaline conditions, intermediate M-1 slowly undergoes intramolecular nucleophilic substitution cyclization to generate a highly reactive 2,2-diacyl ethylene oxide intermediate (M-2) and is slowly released; Fast step three: Intermediate M-2 is rapidly captured by hydrazine or substituted hydrazine in the system and sequentially undergoes nucleophilic ring opening, intramolecular cyclization, and dehydration processes, irreversibly generating the final product (III). The method of the present invention can in particular use an aqueous formaldehyde solution as a formaldehyde donor, in which case the synthesis reaction can be carried out without introducing additional solvents (as in Example 8 below), and generally a better yield can be obtained.

[0018]

[0019] This invention successfully develops a one-pot three-component reaction with a simplified route and high atom economy, directly constructing complex pyrazole rings from simple raw materials, in accordance with the principles of green synthesis. Its unique "fast-slow-fast" kinetic control strategy, like a "precision valve," effectively controls the release and consumption of highly reactive formaldehyde, fundamentally solving the core bottleneck of poor selectivity when formaldehyde participates in multi-component reactions. The reaction conditions are mild, and it can be carried out under normal atmospheric pressure, without the need for anhydrous and oxygen-free conditions or precious metal catalysts, as well as high temperature conditions and strong acid reagents. The operation and post-processing are simple, with good process operability and industrial application potential. This method can effectively suppress side reactions and obtain structurally singular target products with good to excellent yields and high selectivity.

[0020] It is worth noting that the recognition of the "fast-slow-fast" mechanism in multi-component reactions led this invention to use formaldehyde donors (e.g., aqueous formaldehyde solution, alcoholic formaldehyde solution) as key compounds to construct this typical "fast-slow-fast" reaction process. Specifically, the combination of formaldehyde and carbonyl compounds forms a stable hydrogen bond system in aqueous (or alcoholic) solutions, promoting the stable formation of intermediates. This allows the third component to bind orderly with the generated intermediates, thereby achieving highly selective acquisition of the target product.

[0021] In addition, this invention uses formaldehyde, a bulk chemical, as the C1 source to efficiently convert it into a high-value-added pyrazole pharmaceutical intermediate skeleton. Not only are the raw materials cheap and readily available, but the product value is also significantly improved, opening up a new technical path for the downstream high-value utilization of formaldehyde. The synthesized 3-alkylpyrazole-4-carboxylic acid derivative is an important advantageous heterocyclic skeleton. The method of this invention provides an efficient platform for its rapid construction and diverse derivation, with broad application prospects. Detailed Implementation

[0022] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention. Furthermore, the technical features involved in the various embodiments of this invention described below can be combined with each other as long as they do not conflict with each other.

[0023] All reaction materials used in the following examples were commercially available, and the one-pot reactions were all carried out under normal atmospheric pressure and air conditions.

[0024] Example 1: Synthesis of ethyl 3-methyl-1-phenyl-1H-pyrazole-4-carboxylate (5a, R=H)

[0025] In a 20 mL reaction tube equipped with a magnetic stirrer, ethyl 2-chloroacetoacetate (1a, 16.5 mg, 0.1 mmol), phenylhydrazine hydrochloride (2b, 21.7 mg, 0.15 mmol), and 37... wt.A 16.2 μL (0.2 mmol) aqueous solution of formaldehyde and 24.6 mg (0.3 mmol) of anhydrous sodium acetate were prepared. 1 mL of anhydrous ethanol was added as a solvent. The reaction mixture was stirred in an oil bath at 80 °C for 6 hours (monitored by TLC). After the reaction was complete, the mixture was cooled to room temperature, quenched with 5 mL of water, and extracted with ethyl acetate (3 × 5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, v / v) to give a white solid product 5a, in 68% yield. ¹H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.55–7.38 (m, 5H), 4.33 (q, J = 7.1 Hz, 2H), 2.57 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl3) δ 163.87,143.55, 141.91, 138.86, 129.26, 128.65, 125.52, 112.98, 59.99, 14.45, 11.96ppm. Similar to existing technology reports, the ethyl 3-methyl-1-phenyl-1H-pyrazole-4-carboxylate synthesized in this embodiment can serve as a potential non-steroidal anti-inflammatory molecular structure.

[0026] Examples 2-9 Following the general procedure of Example 1, the reaction conditions were systematically changed, including the type and amount of base (Na₂CO₃, NaHCO₃, NEt₃), solvent (methanol, no additional solvent introduced), and reaction temperature. The reaction results are shown in the table below. The results show that good yields can be obtained by reacting with 3 equivalents of sodium acetate in ethanol at 80 °C (corresponding to Example 1), or by reacting at 80 °C without using ethanol solvent (corresponding to Example 8).

[0027]

[0028] Examples 10-16: Substrate-based synthesis of various 3-alkylpyrazole-4-carboxylic acid derivatives Under conditions of methanol solvent, ethyl 2-chloroacetoacetate (1a) and formaldehyde were fixed, and the hydrazine composition was changed. The hydrazine was reacted with various substituted phenylhydrazines (the equivalent of different substituted phenylhydrazines was the same as that of phenylhydrazine hydrochloride in Example 1, all of which were kept at 1.5 equivalents). A series of ethyl 3-methyl-1-aryl-1H-pyrazole-4-carboxylic acid derivatives (5b-5h) were successfully synthesized in moderate to good yields.

[0029]

[0030] All products were confirmed by proton NMR, carbon NMR, and high-resolution mass spectrometry, as shown in the following data: Ethyl 3-methyl-1-(p-tolyl)-1H-pyrazole-4-carboxylate(5b): 1 H NMR (400MHz, CDCl3) δ 8.01 (s, 1H), 7.29 (s, 4H), 4.32 (q, J = 7.1 Hz, 2H), 2.54 (s,3H), 2.43 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 163.92,143.52, 141.75, 141.72, 138.71, 136.40, 129.80, 125.35, 112.77, 59.93, 21.18,14.46, 11.91 ppm. IR (KBr) n = 2931, 1712, 1562, 1517, 1400, 1274, 1240, 1186,1097, 1010, 941, 821, 777, 505 cm 1 ; HRMS (ESI, TOF) m / z: calcd for C 14 H 16 N₂O₂[M + H] + : 245.1285, found: 245.1282. Ethyl 1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carboxylate(5c): 1 HNMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.35 – 7.29 (m, 2H), 7.02 – 6.97 (m,2H), 4.32 (q, J = 7.1 Hz, 2H), 3.87 (s, 3H), 2.52 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 163.93, 159.67, 143.64, 141.63, 131.87, 126.92,114.37, 59.93, 55.60, 14.46, 11.84 ppm. Ethyl 1-(4-fluorophenyl)-3-methyl-1H-pyrazole-4-carboxylate (5d): 1 HNMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.37 – 7.27 (m, 2H), 7.17 – 7.09 (m,2H), 4.26 (q, J = 7.1 Hz, 2H), 2.47 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). 13 C NMR (101MHz, CDCl3) δ 162.72, 162.57, 160.10, 142.61, 140.93, 133.95, 126.45, 126.36(d, J = 8.9 Hz)., 115.35, 115.12, 112.02, 59.01, 13.41, 10.83. 19 F NMR (376 MHz,CDCl3) δ -112.12 ppm. Ethyl 1-(4-chlorophenyl)-3-methyl-1H-pyrazole-4-carboxylate (5e): 1 HNMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.52 – 7.45 (m, 2H), 7.42 – 7.34 (m,2H), 4.33 (q, J = 7.1 Hz, 2H), 2.57 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). 13 C NMR (101MHz, CDCl3) δ 162.66, 142.53, 141.14, 133.51, 128.45, 125.66, 112.28, 59.04,13.41, 10.92 ppm. IR (KBr) n= 2925, 1716, 1558, 1502, 1411, 1396, 1245, 1184,1097, 1012, 941, 912, 837, 777, 746, 534, 497 cm 1 ; HRMS (ESI, TOF) m / z:calcd for C 13 H 13 ClN2O2[M + H] + : 265.0738, found: 265.0734. Ethyl 1-(4-bromophenyl)-3-methyl-1H-pyrazole-4-carboxylate (5f): 1 HNMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.66 – 7.62 (m, 2H), 7.33 – 7.30 (m,2H), 4.33 (q, J = 7.1 Hz, 2H), 2.57 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). 13 C NMR (101MHz, CDCl3) δ 163.69, 143.55, 142.20, 137.85, 132.47, 126.96, 122.52, 117.26,114.33, 113.35, 60.10, 14.44, 11.96 ppm. IR (KBr) n = 2931,1735, 1540, 1515,14116, 1396, 1235, 1175, 1085, 1011, 935, 912, 837, 772, 744, 534, 485 cm 1 ;HRMS (ESI, TOF) m / z: calcd for C 13 H 13 BrN2O2[M + H] + : 309.0233, found: 309.0228. Ethyl 3-methyl-1-(m-tolyl)-1H-pyrazole-4-carboxylate (5g): 1H NMR (400MHz, CDCl3) δ 8.02 (s, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.25 (s, 2H), 7.19 (d, J =7.9 Hz, 1H), 2.56 (s, 3H), 2.43 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). 13 C NMR (101MHz, CDCl3) δ 163.91, 143.52, 141.80, 139.50, 138.78, 129.41, 128.95, 126.21,122.48, 112.85, 59.96, 21.32, 14.45, 11.96 ppm. IR (KBr) n = 2928, 1712, 1570,1525, 1405, 1271, 1240, 1190, 1089, 1015, 941, 825, 765, 505 cm 1 ; HRMS (ESI,TOF) m / z: calcd for C 14 H 16 N2O2[M + H] + : 245.1285, found: 245.1279. Ethyl 1-(3,5-dimethylphenyl)-3-methyl-1H-pyrazole-4-carboxylate (5h): 1 H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.07 (s, 1H), 7.02 (s, 2H), 4.32 (q, J = 7.1 Hz, 2H), 2.55 (s, 3H), 2.38 (s, 6H), 1.38 (t, J = 7.1 Hz, 3H). 13 C NMR (101MHz, CDCl3) δ 163.93, 143.47, 141.68, 139.11, 138.70, 130.28, 123.23, 112.72,59.92, 21.23, 14.45, 11.97 ppm. IR (KBr) n= 2939, 1712, 1575, 1517, 1409,1274, 1240, 1191, 1097, 1018, 955, 821, 745, 625, 515 cm 1 ; HRMS (ESI, TOF)m / z: calcd for C 15 H 18 N₂O₂[M + H] + : 259.1441, found: 259.1439. In addition to the products 5b-5h mentioned above, the substitution position of the R substituent (i.e., meta, para, or ortho), the number of substitutions, and the type of group can all be flexibly adjusted. Only compound 2b needs to be adjusted accordingly.

[0031] The above embodiments are merely illustrative. Those skilled in the art can modify the substituents (i.e., R in general formula I) in the substrate according to actual needs. 1 ,R 2 R in general formula II 3 The type and amount of alkali, solvent, reaction temperature, and time can be adjusted appropriately (of course, the solvent needs to be water or an alcohol, which can be introduced in the form of formaldehyde solution). In addition, the halogen in α-halo-β-keto esters can be other halogens besides Cl (such as F, Br, I); the formaldehyde donor can be paraformaldehyde or trioxyformaldehyde in addition to formaldehyde solution.

[0032] Those skilled in the art will readily understand that the above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for synthesizing a 3-alkylpyrazole-4-carboxylic acid derivative, characterized in that, Using α-halo-β-keto esters of general formula (I), hydrazine compounds of general formula (II), and formaldehyde donors as reactants, a one-pot reaction is carried out in the presence of a base and with the participation of water and / or alcohol solvents to generate 3-alkylpyrazole-4-carboxylic acid derivatives as shown in formula (III): In general formula (I), X represents halogen, and R 1 It is an alkyl group from C1 to C10, R 2 It is an alkyl group from C1 to C10; In general formula (II), R 3 It is aryl; The formaldehyde donor is a formaldehyde solution, paraformaldehyde, or triformaldehyde.

2. The synthesis method as described in claim 1, characterized in that, The base is an inorganic base or an organic base, wherein the inorganic base is sodium carbonate, sodium acetate, or sodium bicarbonate; and the organic base is triethylamine. Preferably, the base is sodium acetate.

3. The synthesis method as described in claim 1, characterized in that, The molar ratio of the α-halo-β-keto ester to the base is 1:1 to 1:

3.

4. The synthesis method as described in claim 1, characterized in that, The alcohol solvent is a C1-C4 alcohol, preferably ethanol or methanol, and more preferably ethanol.

5. The synthesis method as described in claim 1, characterized in that, The molar ratio of the α-halo-β-keto ester to the hydrazine compound is 1:1 to 1:1.5; The molar ratio of the α-halo-β-keto ester to the formaldehyde contained in the formaldehyde donor is 1:1 to 1:2.

5.

6. The synthesis method according to claim 1, characterized in that, The one-pot reaction is carried out at a temperature of 60°C to 80°C for a reaction time of 2 to 6 hours.

7. The synthesis method according to claim 1, characterized in that, The hydrazine compound is a phenylhydrazine compound with the structural formula shown in Formula 2b, or its hydrochloride salt form: Wherein, the substituent R is in the form of a monosubstituted or polysubstituted group, specifically any one or more of CH3, OMe, F, Cl, and Br.

8. The synthesis method according to claim 1, characterized in that, The hydrazine compound is phenylhydrazine or phenylhydrazine hydrochloride.

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