Preparation method and application of indazole carboxylic acid
By using cyanidation and hydrolysis reactions, and replacing highly toxic substances with cuprous cyanide, high-pressure reactions are avoided, enabling the safe and low-cost preparation of indazole carboxylic acid. This solves the safety and economic problems of existing technologies and demonstrates good prospects for industrialization.
Patent Information
- Application Number
- CN202610119719.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-01-28
- Publication Date
- 2026-05-15
AI Technical Summary
Existing methods for preparing indazole carboxylic acid pose safety risks due to the use of highly toxic chemicals and high-pressure reactions, and are also costly and require demanding equipment, making them unsuitable for industrial production.
The process employs cyanidation and hydrolysis reactions, using relatively safe cuprous cyanide as the cyanide source, avoiding high-pressure reactors and highly toxic carbon monoxide, and conducting the reaction under normal pressure conditions, thus simplifying the process steps and reducing catalyst costs.
This method enables the safe, economical, and environmentally friendly preparation of indazole carboxylic acid, avoiding the risks of high-pressure operation, reducing equipment investment and raw material costs, and improving yield and production safety, making it suitable for industrial applications.
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Figure CN122036679A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of pesticide intermediate synthesis technology, and specifically relates to a method for preparing indazole carboxylic acid and its application. Background Technology
[0002] Indazole carboxylic acid (Formula I) is a key intermediate in the synthesis of novel and highly efficient indazapyroxamet insecticides. Therefore, developing a safe, economical, efficient, and industrially viable synthetic route for indazole carboxylic acids has significant commercial value.
[0003] For example, the methods disclosed in patent documents with publication numbers WO2015038503A and WO2016144351A have problems with using highly toxic and explosive sodium azide (NaN3) and highly toxic zinc cyanide (Zn(CN)2), respectively. These reagents pose significant safety hazards in industrial production, require harsh operating conditions, and are not suitable for large-scale promotion and application.
[0004] To address the aforementioned issues, Chinese patent application No. 202211004058.4 (Publication No. CN 115232104 A) discloses a novel preparation method. This method involves a palladium-catalyzed carbonylation reaction of 4-bromo-2-(pyridyl-3-yl)-2H-indazole to directly generate the corresponding methyl ester in a high-pressure reactor under a CO atmosphere, followed by hydrolysis to obtain the target product, indazole carboxylic acid. While this method successfully avoids the use of azides and zinc cyanide, it also introduces new problems:
[0005] 1. High equipment requirements and high operational risks: The carbonylation reaction requires the use of a high-pressure reactor and the introduction of toxic carbon monoxide (CO) gas, which places extremely high demands on the sealing of the equipment, poses safety risks, and increases equipment investment costs.
[0006] 2. High catalyst cost: The reaction relies on expensive organic palladium catalysts (such as [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride) and corresponding ligands, which significantly increases production costs.
[0007] 3. Relatively harsh reaction conditions: The reaction needs to be carried out at high temperatures and pressures, requiring high levels of process control.
[0008] In summary, existing technical routes either have fatal safety hazards (using azides, zinc cyanide) or have industrialization barriers such as high cost and demanding equipment requirements (palladium-catalyzed high-pressure carbonylation).
[0009] Therefore, developing a method for preparing indazole carboxylic acid that avoids the use of highly toxic chemicals, avoids high-pressure reactions and expensive catalysts, and has milder process conditions, lower costs, and is more suitable for industrial production remains a pressing technical challenge in this field. Summary of the Invention
[0010] This invention aims to solve at least one of the technical problems existing in the prior art. To this end, this invention proposes a method for preparing indazole carboxylic acid and its application. The preparation method of this invention features mild conditions, low cost, safe operation, and environmental friendliness, with a high yield of the target product. It avoids the use of highly toxic and expensive chemical raw materials.
[0011] A first aspect of the present invention provides a method for preparing indazole carboxylic acid.
[0012] A method for preparing indazole carboxylic acid includes the following steps:
[0013] (1) Cyanidation reaction: Under a protective gas atmosphere, the bromoindazole compound is reacted with cuprous cyanide (CuCN) in an organic solvent to obtain the cyanoindazole compound;
[0014] (2) Hydrolysis reaction: The cyanoindazole compound obtained in step (1) is hydrolyzed to obtain the indazole carboxylic acid.
[0015] Preferably, in step (1), the structural formula of the bromoindazole compound is shown in formula (A):
[0016] The substance corresponding to formula (A) is 4-bromo-2-(pyridin-3-yl)-2H-indazole.
[0017] Preferably, in step (1), the molar ratio of the bromoindazole compound represented by formula (A) to cuprous cyanide is 0.1:(0.1-0.3).
[0018] Preferably, in step (1), the protective gas includes nitrogen or a rare gas.
[0019] Preferably, in step (1), the reaction temperature is 100-120℃ and the reaction time is 4-8 hours.
[0020] Preferably, in step (1), the ratio of the bromoindazole compound represented by formula (A) to the organic solvent is 0.1 mol: (100-180) mL. For example, it is 0.1 mol: 150 mL.
[0021] Preferably, in step (1), the organic solvent includes at least one of N,N-dimethylformamide (DMF), toluene, acetone, and ethyl acetate. For example, N,N-dimethylformamide (DMF).
[0022] Preferably, in step (1), after the reaction is completed, a separation process is also included.
[0023] Preferably, the separation process includes monitoring the reaction proceeds until the starting material spot disappears by thin-layer chromatography (TLC), cooling the reaction liquid to room temperature, adding ethyl acetate and saturated sodium chloride, washing with water multiple times, filtering, drying the organic phase with anhydrous sodium sulfate, filtering, removing the solvent by rotary evaporation under reduced pressure, purifying the crude product by silica gel column chromatography, and finally obtaining the cyanoindazole compound.
[0024] Preferably, in step (1), the structural formula of the cyanoindazole compound is shown in formula (B):
[0025] .
[0026] Preferably, in step (2), the hydrolysis is carried out under acidic or alkaline conditions.
[0027] Preferably, the hydrolysis temperature is 100-120℃ and the hydrolysis time is 4-6 hours.
[0028] Preferably, the acidic conditions consist of glacial acetic acid and sulfuric acid.
[0029] Preferably, the alkaline conditions consist of a sodium hydroxide or potassium hydroxide solution.
[0030] Preferably, after the hydrolysis is completed, the process further includes cooling, extraction and drying.
[0031] Preferably, the structural formula of the indazole carboxylic acid is shown in formula (I):
[0032] .
[0033] The synthetic route for the above-mentioned indazole carboxylic acid is as follows:
[0034] .
[0035] A second aspect of the present invention provides an application of a method for preparing indazole carboxylic acid.
[0036] The application of the above preparation method in the preparation of pesticides.
[0037] Preferably, the pesticide includes indazole amide insecticides.
[0038] Compared with the prior art, the beneficial effects of the present invention are as follows:
[0039] (1) The preparation method of the present invention utilizes specific raw materials and cyanation and hydrolysis reactions to obtain indazole carboxylic acid. The preparation method is mild, low-cost, safe to operate, and environmentally friendly. It avoids the use of highly toxic and expensive chemical raw materials.
[0040] (2) High safety: The present invention uses cuprous cyanide (CuCN), which has relatively low toxicity and more stable properties, as the cyanide source, replacing the highly toxic zinc cyanide. More importantly, the method of the present invention completely avoids the use of high-pressure reactors and highly toxic carbon monoxide (CO) gas, fundamentally eliminating the risks of physical explosion and chemical poisoning caused by high-pressure operation, and greatly improving the inherent safety of the production process.
[0041] (3) Significant economic benefits: Cuprous cyanide, as a basic chemical raw material, is priced much lower than the precious metal organopalladium catalyst and ligands used in CN115232104A. This invention effectively avoids dependence on expensive catalysts, thereby significantly reducing raw material costs and improving the market competitiveness of the product.
[0042] (4) Low equipment requirements and low investment costs: The cyanation reaction of this invention can be carried out smoothly under normal pressure, without the need for special equipment such as high-pressure reactors. Conventional reactors can meet the production needs. This greatly reduces the investment in production equipment and the subsequent maintenance costs.
[0043] (5) The reaction route is simple and efficient: the present invention can efficiently obtain the target product in two steps of "cyano-hydrolysis". The reaction conditions are mild, the operation is simple, the post-processing is simple, and the overall yield (more than 70%, or even more than 75%) is high, showing excellent prospects for industrial application. Attached Figure Description
[0044] Figure 1 The image shows the 1H NMR spectrum of the indazole carboxylic acid prepared in Example 1. Detailed Implementation
[0045] To enable those skilled in the art to more clearly understand the technical solutions described in this invention, the following embodiments are provided for illustration. It should be noted that the following embodiments do not constitute a limitation on the scope of protection claimed by this invention.
[0046] Unless otherwise specified, the raw materials, reagents or devices used in the following examples are available from conventional commercial sources or can be obtained by existing known methods.
[0047] The synthetic route of indazole carboxylic acid in the following examples is as follows:
[0048] .
[0049] Example 1
[0050] A method for preparing indazole carboxylic acid includes the following steps:
[0051] (1) Cyanidation reaction: In a 500 mL three-necked flask, 0.1 mol of 4-bromo-2-(pyridin-3-yl)-2H-indazole was added and dissolved in N,N-dimethylformamide (DMF, 150 mL). 0.15 mol of cuprous cyanide was added. The reaction system was heated to 120 °C under nitrogen protection and stirred for 8 hours. The reaction was monitored by thin-layer chromatography (TLC) until the starting material spot disappeared. The reaction solution was cooled to room temperature, and 500 mL of ethyl acetate and 200 mL of saturated sodium chloride were added. The mixture was washed three times with water, filtered, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether to ethyl acetate volume ratio = 2:1) to obtain 18.5 g of a pale yellow solid product (cyanoindazole compound shown in formula B), with a yield of 84.1%.
[0052] (2) Hydrolysis reaction: The pale yellow solid product (50 mmol) from step (1) was completely dissolved in 50 mL of glacial acetic acid, and 200 mL of 80% volume fraction concentrated sulfuric acid aqueous solution was added. The temperature was raised to 120 °C and the reaction was carried out for 6 hours. The reaction mixture was monitored by TLC until the starting material disappeared. The reaction solution was cooled to room temperature and added to 100 mL of ice water. The mixture was extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate. After removing the solvent, 10.8 g of pale yellow solid (indazole carboxylic acid as shown in Formula I) was obtained, with a yield of 90.3%.
[0053] The total yield of steps (1) and (2) is approximately 75.9%.
[0054] Figure 1 The image shows the 1H NMR spectrum of the indazole carboxylic acid prepared in Example 1. "f1 (ppm)" indicates the chemical shift.
[0055] Example 2
[0056] Except for replacing the solvent DMF with toluene and setting the reaction temperature to 110°C (the reflux temperature of toluene), the other operating steps and feed amounts were the same as in Example 1. Example 2 yielded 9.9 g of a pale yellow solid product (substance shown in Formula B), with a yield of 45.0%, and 9.57 g of the corresponding indazole carboxylic acid (shown in Formula I), with a yield of 89.0%.
[0057] The total yield of steps (1) and (2) is approximately 40.1%.
[0058] Comparative Example 1: Cyanolation-hydrolysis route using Zn(CN)2
[0059] The synthetic route for the comparative example is as follows:
[0060] .
[0061] In a reaction flask, 4-bromo-2-(pyridin-3-yl)-2H-indazole (5 mmol), tetrakis(triphenylphosphine)palladium(O) (Pd(PPh3)4, 0.5 mmol), zinc cyanide (3 mmol), and N,N-dimethylformamide (DMF, 13 mL) were added. Under nitrogen protection, the reaction system was heated to 110 °C and stirred for 12 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, washed with saturated NaCl aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by column chromatography to give intermediate B 886 mg (80.5% yield). Intermediate B was then subjected to KOH (90 mmol) V EtOH V H2O Hydrolysis was carried out at 120°C with a ratio of 4:1 (50 mL). After 6 h of reaction, the solution was acidified to pH 4 with 2 M dilute hydrochloric acid aqueous solution to finally obtain 770 mg of the target product indazole carboxylic acid (Formula I) with a yield of 80.0% and an overall yield of 64.4% for the two steps.
[0062] Comparative Example 2: Palladium-catalyzed carbonylation route (data cited in CN 115232104 A)
[0063] The cyanoindazole compound (50 mmol) obtained in Example 1 was placed in a 250 mL reaction flask, and 100 mL of ethanol and 50 mL of 20% sodium hydroxide aqueous solution were added. The mixture was heated under reflux for 10 hours, and TLC monitoring was performed until the starting material disappeared. According to Examples 6 and 7 of Chinese Patent Application CN 115232104 A, 4-bromo-2-(pyridin-3-yl)-2H-indazole was used as a starting material, and the reaction was carried out under the catalysis of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride at a CO pressure of 0.8 MPa and a temperature of 100 °C for 12 hours to obtain methyl indazole carboxylate with a yield of 85%. The methyl ester was then hydrolyzed with sodium hydroxide to obtain the target product, indazole carboxylate, with a yield of 90%. The overall yield of this two-step route was 76.5%.
[0064] Product effectiveness test
[0065] The yields of indazole carboxylic acid corresponding to the above examples and comparative examples are shown in Table 1 below.
[0066]
[0067] As shown in the table above, Example 1 of the present invention achieved a total yield of 75.9% under normal pressure conditions, completely avoiding the use of high-pressure equipment and highly toxic CO gas. This yield is essentially the same as the yield (76.5%) of the palladium-catalyzed carbonylation route (Comparative Example 2), which requires high pressure and high cost. The yield of the target product corresponding to Example 1 of the present invention is significantly better than the yield (64.4%) of Comparative Example 1, which also uses cyanide but requires a palladium catalyst.
[0068] In summary, this invention successfully solves the major safety hazards and high costs of existing technologies while ensuring high yield. The process conditions are mild and the operation is simple, making it highly valuable for industrial applications.
Claims
1. A method for preparing indazole carboxylic acid, characterized in that, Includes the following steps: (1) Cyanidation reaction: Under a protective gas atmosphere, the bromoindazole compound is reacted with cuprous cyanide in an organic solvent to obtain the cyanoindazole compound; (2) Hydrolysis reaction: The cyanoindazole compound obtained in step (1) is hydrolyzed to obtain the indazole carboxylic acid.
2. The preparation method according to claim 1, characterized in that, In step (1), the structural formula of the bromoindazole compound is shown in formula (A): 。 3. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of the bromoindazole compound to cuprous cyanide is 0.1:(0.1-0.3).
4. The preparation method according to claim 1, characterized in that, In step (1), the protective gas includes nitrogen or a rare gas; and / or, the reaction temperature is 100-120°C and the reaction time is 4-8 hours.
5. The preparation method according to claim 1, characterized in that, In step (1), the ratio of the amount of the bromoindazole compound to the organic solvent is 0.1 mol: (100-180) mL.
6. The preparation method according to claim 1, characterized in that, In step (1), the organic solvent includes at least one of N,N-dimethylformamide, toluene, acetone, and ethyl acetate; and / or, in step (1), after the reaction is completed, a separation process is also included.
7. The preparation method according to claim 1, characterized in that, In step (1), the structural formula of the cyanoindazole compound is shown in formula (B): 。 8. The preparation method according to claim 1, characterized in that, In step (2), the hydrolysis is carried out under acidic or alkaline conditions.
9. The preparation method according to claim 1, characterized in that, The hydrolysis temperature is 100-120℃, and the hydrolysis time is 4-6 hours; and / or, the structural formula of the indazole carboxylic acid is shown in formula (I): 。 10. The application of the preparation method according to any one of claims 1-9 in the preparation of pesticides.