Composite catalyst and method for preparing chlorantraniliprole important intermediate by using composite catalyst

Abstract

The invention relates to the technical field of chemical intermediate synthesis, and discloses a composite catalyst and a method for preparing an important intermediate of chlorantraniliprole by using the composite catalyst, and the method comprises the following steps: S1, stirring and heating a sodium ethoxide solution, 3-chloro-2-hydrazinopyridine, the composite catalyst and ethanol, dropwise adding diethyl maleate, and carrying out heat preservation reaction; the composite catalyst is a compound system of a phase transfer catalyst, a transition metal catalyst and a ligand; s2, dropwise adding an acidic material to adjust the reaction system to be acidic, neutralizing the incompletely reacted raw material 3-chloro-2-hydrazinopyridine into water-soluble salt, removing the solvent ethanol, and adding process water for crystallization; and S3, filtering the crystallization liquid obtained in the step S2, and pulping, washing and drying a filter cake to obtain a finished product. Compared with a traditional method, the technical scheme has the advantages that the yield and the product content are higher; the post-treatment is simpler, the unreacted raw materials can be purified through crystallization and suction filtration after being neutralized, and the operation complexity is reduced; the ethanol consumption is reduced, and the green process requirements are better met.

Description

Technical Field

[0001] This invention relates to the field of chemical intermediate synthesis technology, specifically to a composite catalyst and a method for preparing an important intermediate of chlorantraniliprole using the composite catalyst. Background Technology

[0002] Chlorantraniliprole (trade name: Conquer) is a novel, highly effective, and low-toxicity ryanodine receptor activator insecticide. It is highly effective against lepidopteran insects, safe for mammals, and exhibits no cross-resistance with existing insecticides. It is a promising insecticide with a broad market prospect and is currently the world's number one insecticide, successfully replacing thiamethoxam as the leading insecticide. Since its launch, chlorantraniliprole sales have consistently increased year by year, with its global production compound annual growth rate reaching 6.24% between 2013 and 2017. Currently, the main producers of chlorantraniliprole are concentrated in the United States and Brazil. Global chlorantraniliprole sales reached US$1.961 billion in 2024, and experts predict that global demand will exceed 60,000 tons by 2027, with a value reaching US$3.3 billion.

[0003] Ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-carboxylate is the lowest-yield step in the synthesis of kilotinib (K acid), a key intermediate for chlorantraniliprole. Its yield directly determines the overall yield of the synthesis of K acid and kilotinib. Therefore, finding a simple, efficient, and economical method to synthesize ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-carboxylate is of great significance. Currently, the most common method used by kilotinib or K acid production companies is to use 3-chloro-2-hydrazinopyridine and diethyl maleate as raw materials, with sodium ethoxide solution as the base, to undergo a Michael addition cyclization reaction in ethanol to synthesize ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-carboxylate. The main drawbacks of this method are low yield and a high proportion of uncyclized byproducts. Furthermore, the current yield of this step is only around 60-70%, leaving room for further optimization. Therefore, developing a synthetic method for ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-carboxylate that can improve reaction selectivity and yield is of great significance. Summary of the Invention

[0004] The present invention aims to provide a composite catalyst and a method for preparing an important intermediate of chlorantraniliprole using the composite catalyst, so as to solve the problems of unsatisfactory selectivity and yield in the preparation process of the prior art.

[0005] To achieve the above objectives, the present invention adopts the following technical solution: a composite catalyst and a method for preparing an important intermediate of chlorantraniliprole using the composite catalyst, wherein the composite catalyst is used to catalyze the reaction, and the composite catalyst is a complex system of phase transfer catalyst, transition metal catalyst and ligand. Preferably, as an improvement, the mass ratio of phase transfer catalyst to transition metal catalyst is 1~20:1.

[0006] Preferably, as an improvement, the phase transfer catalyst is one or more of tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride, triphenylbutylphosphine bromide, benzyltriphenylphosphine chloride, tetramethylammonium bromide, benzyltriethylammonium chloride, benzyltrimethylammonium chloride, tetraethylammonium bromide, tetrabutylammonium acetate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium fluoride, and tetrabutylammonium tetrafluoroborate.

[0007] Preferably, as an improvement, the transition metal catalyst is one or more of the following: bis(acetonitrile)palladium dichloride, bis(dibenzylacetone)palladium, bis(triphenylphosphine)palladium chloride, tri(dibenzylacetone)palladium, tetra(triphenylphosphine)palladium, Pd(X-Phos)2Cl2, Pd(S-Phos)2Cl2, Pd(dppm)Cl2, Pd(dppb)Cl2, Pd(dppf)Cl2, Pd(dppe)Cl2, cuprous chloride, cuprous bromide, cuprous iodide, copper acetylacetonate, bis(hexafluoroacetylacetonate)copper(II), copper hexafluorophosphate tetraacetonitrile(I), bis(benzoyltrifluoroacetone)copper(II), and bis(ethyl acetoacetate)copper(II).

[0008] Preferably, as an improvement, the ligand is one or more of triphenylphosphine, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (X-Phos), dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (S-Phos), bis(diphenylphosphine)methane (dppm), 1,4-bis(diphenylphosphine)butane (dppb), 1,1-bis(diphenylphosphine)ferrocene (dppf), and 1,2-bis(diphenylphosphine)ethane (dppe).

[0009] Preferably, as an improvement, a composite catalyst and a method for preparing an important intermediate of chlorantraniliprole using the composite catalyst include the following steps: S1. Sodium ethoxide solution, 3-chloro-2-hydrazinopyridine, composite catalyst, and ethanol are stirred, heated, and diethyl maleate is added dropwise while maintaining the temperature for reaction. S2. Add acidic substances to adjust the reaction system to acidity, neutralize the unreacted raw material 3-chloro-2-hydrazinopyridine into a water-soluble salt, remove the solvent ethanol, and then add process water to crystallize. S3. Filter the crystallization liquid obtained in step S2, and the filter cake is pulped, washed and dried to obtain the finished product.

[0010] Preferably, as an improvement, in step S1, the stirring time is 15 minutes and the temperature range for heating is room temperature to 70°C.

[0011] Preferably, as an improvement, in step S2, the acidic substance is hydrochloric acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, or phosphoric acid.

[0012] Preferably, as an improvement, in step S2, the pH of the system is adjusted to 2-6.

[0013] The principle and advantages of this scheme are as follows: In practical applications, this technical scheme addresses the problems existing in the synthesis of ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-carboxylate using existing technologies. It comprehensively upgrades the synthesis process and innovatively proposes a new synthetic route: using 3-chloro-2-hydrazinopyridine and diethyl maleate as raw materials, and sodium ethoxide solution as a base, a Michael addition cyclization reaction occurs under the action of a composite catalyst (phase transfer catalyst + transition metal catalyst + ligand). The reaction equation is as follows:

[0014] Phase-transfer catalysts improve the compatibility of reactants, while transition metal catalysts and ligands synergistically promote carbon-nitrogen bond formation, enhancing reaction selectivity. Subsequent purification processes, including acid neutralization, solvent removal and crystallization, and separation, yield a high-purity target intermediate. This approach reduces ethanol usage by introducing a composite system of phase-transfer catalysts and transition metal catalysts. Compared to the traditional 60-70% yield, this approach increases the yield to 72.4% (example data) with a product purity of 99.7%. Post-processing is simpler; purification is achieved through crystallization and filtration after neutralizing unreacted raw materials, reducing operational complexity. The reduced ethanol usage also aligns with green process requirements. Attached Figure Description

[0015] Figure 1 This is the central control liquid phase detection spectrum of Embodiment 1 of the present invention.

[0016] Figure 2 This is the liquid phase detection spectrum of the finished product in Example 1 of the present invention. Detailed Implementation

[0017] The following detailed description provides further details on specific embodiments, but the embodiments of the present invention are not limited thereto. Unless otherwise specified, the technical means used in the following embodiments are conventional means well known to those skilled in the art; the experimental methods used are all conventional methods; and the materials and reagents used are all commercially available.

[0018] Overview of the plan: A composite catalyst and a method for preparing an important intermediate of chlorantraniliprole using the composite catalyst, comprising the following steps: S1. Reaction initiation and execution: Add 20% sodium ethoxide solution, 3-chloro-2-hydrazinopyridine, composite catalyst, and ethanol to a four-necked flask. Stir for 15 minutes, then heat to room temperature to 70°C. Add diethyl maleate dropwise and keep the reaction at this temperature until almost no raw material remains.

[0019] The phase transfer catalyst is one or more of the following: tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride, triphenylbutylphosphine bromide, benzyltriphenylphosphine chloride, tetramethylammonium bromide, benzyltriethylammonium chloride, benzyltrimethylammonium chloride, tetraethylammonium bromide, tetrabutylammonium acetate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium fluoride, and tetrabutylammonium tetrafluoroborate.

[0020] The transition metal catalyst is one or more of the following: bis(acetonitrile)palladium dichloride, bis(dibenzylacetone)palladium, bis(triphenylphosphine)palladium chloride, tri(dibenzylacetone)palladium, tetra(triphenylphosphine)palladium, Pd(X-Phos)2Cl2, Pd(S-Phos)2Cl2, Pd(dppm)Cl2, Pd(dppb)Cl2, Pd(dppf)Cl2, Pd(dppe)Cl2, cuprous chloride, cuprous bromide, cuprous iodide, copper acetylacetonate, bis(hexafluoroacetylacetonate)copper(II), copper hexafluorophosphate tetraacetonitrile(I), bis(benzoyltrifluoroacetone)copper(II), and bis(ethyl acetoacetate)copper(II).

[0021] The ligand is one or more of the following: triphenylphosphine, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (X-Phos), dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (S-Phos), bis(diphenylphosphine)methane (dppm), 1,4-bis(diphenylphosphine)butane (dppb), 1,1-bis(diphenylphosphine)ferrocene (dppf), and 1,2-bis(diphenylphosphine)ethane (dppe).

[0022] S2. Neutralization and Crystallization: An acidic substance is added dropwise to adjust the system to acidic pH, neutralizing the unreacted raw materials as water-soluble salts. After removing 90% of the ethanol from the system, process water is added for crystallization. The aim is to remove unreacted raw materials, reduce the ethanol content in the system, promote the crystallization of the target intermediate, and simplify subsequent separation.

[0023] Acidic substances include hydrochloric acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, or phosphoric acid.

[0024] S3. Separation and purification: The crystallization reaction solution is filtered, and the filter cake is pulped, washed, and dried to obtain the finished product.

[0025] Example 1 A composite catalyst and a method for preparing an important intermediate of chlorantraniliprole using the composite catalyst are disclosed, comprising the following steps: 25g of 3-chloro-2-hydrazinopyridine, 75g of 20% sodium ethoxide solution, 0.5g of benzyltriethylammonium chloride and 0.5g of Pd(X-Phos)2Cl2 composite catalyst, and 20g of ethanol are added to a four-necked flask. The temperature is then raised to about 45°C and 35g of diethyl maleate is added dropwise. After the addition is complete, the reaction is maintained at this temperature. After the reaction is deemed acceptable, the temperature is lowered to below 25°C in an ice bath. Then, 30g of acetic acid is added to adjust the pH to about 3. 90% of the ethanol is then removed. The mixture is then filtered to obtain a crude product. The crude product is slurried with process water to obtain a wet product. Finally, the product is dried to obtain 34g of a pale yellow solid with a purity of 99.7% and a yield of 72.4%.

[0026] Example 2 The difference between this embodiment and Example 1 is that in this embodiment, the composite catalyst is a compound system of triphenylbutylphosphine bromide and tris(dibenzylacetone)dipalladium in a mass ratio of 2:1.

[0027] Example 3 The difference between this embodiment and Example 1 is that in this embodiment, the composite catalyst is a compound system of tetraethylammonium bromide, tetrabutylammonium tetrafluoroborate, Pd(dppm)Cl2 and bis(benzoyltrifluoroacetone)copper(II) in a mass ratio of 2:2:1:1.

[0028] Example 4 The difference between this embodiment and Embodiment 1 is that in this embodiment, the temperature for heating is 70°C.

[0029] Comparative Example 1 A composite catalyst and a method for preparing an important intermediate of chlorantraniliprole using the composite catalyst are disclosed, comprising the following steps: 25g of 3-chloro-2-hydrazinopyridine, 75g of 20% sodium ethoxide solution, and 20g of ethanol are added to a four-necked flask. The temperature is then raised to approximately 45°C, and 35g of diethyl maleate is added dropwise. After the addition is complete, the reaction is maintained at this temperature. Once the reaction is deemed satisfactory, the temperature is lowered to below 25°C in an ice bath. Then, 30g of acetic acid is added to adjust the pH to approximately 3. 90% of the ethanol is then removed, followed by filtration to obtain a crude product. The crude product is then slurried with process water to obtain a wet product, which is finally dried to obtain 31.8g of a pale yellow solid with a purity of 99.1% and a yield of 67.7%.

[0030] Comparative Example 2 The difference between this comparative example and Example 1 is that the catalyst in this comparative example is 0.5g of benzyltriethylammonium chloride.

[0031] Comparative Example 3 The difference between this comparative example and Example 1 is that the catalyst in this comparative example is 0.5g Pd(X-Phos)2Cl2.

[0032] Comparative Example 4 The difference between this comparative example and Example 1 is that the composite catalyst in this comparative example is a compound system of tetrabutylammonium bromide, bis(acetonitrile)palladium dichloride, and 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl in a mass ratio of 2:1:5.

[0033] Comparative Example 5 The difference between this comparative example and Example 1 is that the heating temperature in this comparative example is 78°C.

[0034] Experimental Example 1 The purity, conversion rate, and selectivity of the target products prepared in the above embodiments and comparative examples were tested. The conversion rate, as referred to in this invention, is the proportion of raw material reduced during liquid chromatography detection of the intermediate control solution; the yield rate is the ratio of the actual mass of the product to the theoretical mass. The test results are shown in Table 1. The liquid chromatograms of the intermediate control solution and the finished product of Example 1 are shown in Table 1. Figure 1 , Figure 2 As shown: Table 1

[0035] As shown in Table 1, the experimental data indicate that Example 2 of this invention represents the optimal process parameters. Compared to other examples, the compound system of triphenylbutylphosphine bromide and tris(dibenzylacetone)dipalladium at a mass ratio of 2:1 is currently the optimal system. Adjustments to the catalyst type in Comparative Examples 2-4 failed to achieve the same effect as the embodiments of this invention, and the heating temperature also has a certain impact on the catalyst performance, especially on the yield; excessively high heating temperatures lead to a significant decrease in yield.

[0036] The above descriptions are merely embodiments of the present invention, and common knowledge such as specific technical solutions and / or characteristics are not described in detail here. It should be noted that those skilled in the art can make various modifications and improvements without departing from the technical solutions of the present invention, and these should also be considered within the scope of protection of the present invention. These modifications and improvements will not affect the effectiveness of the implementation of the present invention or the practicality of the patent. The scope of protection claimed in this application should be determined by the content of its claims, and the specific embodiments described in the specification can be used to interpret the content of the claims.

Claims

1. A composite catalyst and a method for preparing an important intermediate of chlorantraniliprole using the composite catalyst, characterized in that: The reaction is catalyzed by a composite catalyst, which is a complex system of phase transfer catalyst, transition metal catalyst and ligand.

2. The composite catalyst according to claim 1 and the method for preparing an important intermediate of chlorantraniliprole using the composite catalyst, characterized in that: The mass ratio of the phase transfer catalyst to the transition metal catalyst is 1~20:

1.

3. The composite catalyst according to claim 2 and the method for preparing an important intermediate of chlorantraniliprole using the composite catalyst, characterized in that: The phase transfer catalyst is one or more of the following: tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride, triphenylbutylphosphine bromide, benzyltriphenylphosphine chloride, tetramethylammonium bromide, benzyltriethylammonium chloride, benzyltrimethylammonium chloride, tetraethylammonium bromide, tetrabutylammonium acetate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium fluoride, and tetrabutylammonium tetrafluoroborate.

4. The composite catalyst according to claim 3 and the method for preparing an important intermediate of chlorantraniliprole using the composite catalyst, characterized in that: The transition metal catalyst is one or more of the following: bis(acetonitrile)palladium dichloride, bis(dibenzylacetone)palladium, bis(triphenylphosphine)palladium chloride, tri(dibenzylacetone)palladium, tetra(triphenylphosphine)palladium, Pd(X-Phos)2Cl2, Pd(S-Phos)2Cl2, Pd(dppm)Cl2, Pd(dppb)Cl2, Pd(dppf)Cl2, Pd(dppe)Cl2, cuprous chloride, cuprous bromide, cuprous iodide, copper acetylacetonate, bis(hexafluoroacetylacetonate)copper(II), copper hexafluorophosphate tetraacetonitrile(I), bis(benzoyltrifluoroacetone)copper(II), and bis(ethyl acetoacetate)copper(II).

5. The composite catalyst according to claim 4 and the method for preparing an important intermediate of chlorantraniliprole using the composite catalyst, characterized in that: The ligand is one or more of the following: triphenylphosphine, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (X-Phos), dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (S-Phos), bis(diphenylphosphine)methane (dppm), 1,4-bis(diphenylphosphine)butane (dppb), 1,1-bis(diphenylphosphine)ferrocene (dppf), and 1,2-bis(diphenylphosphine)ethane (dppe).

6. A composite catalyst according to any one of claims 1 to 5 and a method for preparing an important intermediate of chlorantraniliprole using the composite catalyst, characterized in that, Includes the following steps: S1. Sodium ethoxide solution, 3-chloro-2-hydrazinopyridine, composite catalyst, and ethanol are stirred, heated, and diethyl maleate is added dropwise while maintaining the temperature for reaction. S2. Add an acidic substance to adjust the reaction system to acidity, neutralize the unreacted raw material 3-chloro-2-hydrazinopyridine into a water-soluble salt, remove the solvent ethanol, and then add process water to crystallize. S3. Filter the crystallization liquid obtained in step S2, and the filter cake is pulped, washed and dried to obtain the finished product.

7. The composite catalyst according to claim 6 and the method for preparing an important intermediate of chlorantraniliprole using the composite catalyst, characterized in that: In step S1, the stirring time is 15 minutes, and the temperature range for heating is room temperature to 70°C.

8. The composite catalyst according to claim 7 and the method for preparing an important intermediate of chlorantraniliprole using the composite catalyst, characterized in that: In step S2, the acidic substance is hydrochloric acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, or phosphoric acid.

9. The composite catalyst according to claim 8 and the method for preparing an important intermediate of chlorantraniliprole using the composite catalyst, characterized in that: In step S2, the pH of the system is adjusted to 2-6.

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