CN111362948B - Method for synthesizing pyrrole [3,4-c ] pyrazole-4, 6(1H,5H) diketone derivative - Google Patents
Method for synthesizing pyrrole [3,4-c ] pyrazole-4, 6(1H,5H) diketone derivative Download PDFInfo
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Abstract
The invention provides a novel method for synthesizing a 3-bromo-1-methyl-5-arylpyrrole [3,4-c ] pyrazole-4, 6(1H,5H) -diketone derivative, which is characterized in that the 3-bromo-1-methyl-5-arylpyrrole [3,4-c ] pyrazole-4, 6(1H,5H) -diketone derivative is synthesized through bromination, condensation and cyclization reactions in only 3 steps; the synthetic method has the advantages of short steps of the whole synthetic route, less side reactions, high conversion rate and yield, simplified method of sharing intermediates, wide application substrates, mild operation conditions and high safety, and is favorable for large-scale production and industrialized popularization and application.
Description
Technical Field
The invention relates to the technical field of organic compound synthesis, in particular to a novel method for synthesizing pyrrole [3,4-c ] pyrazole-4, 6(1H,5H) diketone derivatives.
Background
The 3-bromo-1-methyl-5-arylpyrrole [3,4-c ] pyrazole-4, 6(1H,5H) -dione derivative is an important intermediate compound, and the structure of the intermediate compound is shown as a formula A:
at present, the synthesis method of 3-bromo-1-alkyl-5-arylpyrrole [3,4-c ] pyrazole-4, 6(1H,5H) -dione derivatives disclosed in the prior art documents is to use arylamine as a starting material to synthesize a parent nucleus fused ring structure of pyrrole [3,4-c ] pyrazole-4, 6(1H,5H) -dione derivatives through ring closure, and then to obtain the product compound, namely 3-bromo-1-alkyl-5-arylpyrrole [3,4-c ] pyrazole-4, 6(1H,5H) -dione derivatives through a series of functional group conversion reactions, wherein the route is shown as follows:
the prior synthesis method has a plurality of defects, the whole synthesis route needs 6 steps to be finished, the steps are long, the side reactions are more, the conversion rate and the yield are low, and the preparation cost is high; each specific compound in the derivative needs to be synthesized from an initial raw material, a common intermediate is not used, the synthesis is simplified, the applicability is low, and the industrial production and application are not facilitated; in the synthesis, expensive rhodium reagent is needed to be used as a catalyst, the cost is high, and the method is not beneficial to scale-up industrialization.
Therefore, those skilled in the art have worked on developing a new method for synthesizing 3-bromo-1-methyl-5-arylpyrrolo [3,4-c ] pyrazole-4, 6(1H,5H) -dione derivatives, aiming at solving the above-mentioned problems of the drawbacks of the methods for synthesizing such compounds in the prior art.
Disclosure of Invention
The invention aims to solve the technical problems that in the prior art, the synthesis method of the 3-bromo-1-methyl-5-arylpyrrole [3,4-c ] pyrazole-4, 6(1H,5H) -diketone derivative has the defects of multiple steps, multiple side reactions, low conversion rate and yield, simplified synthesis without a shared intermediate, poor applicability, expensive reagents, high cost, inconvenience for industrialization and the like.
To achieve the above objects, the present invention provides a novel method for synthesizing 3-bromo-1-methyl-5-arylpyrrolo [3,4-c ] pyrazole-4, 6(1H,5H) -dione derivatives,
the structure of the 3-bromo-1-methyl-5-arylpyrrole [3,4-c ] pyrazole-4, 6(1H,5H) -diketone derivative is shown as the following formula A,
wherein R is1、R2Each independently selected from hydrogen, halogen, C1-C10 alkyl, aryl;
the synthetic method route of the 3-bromo-1-methyl-5-arylpyrrole [3,4-c ] pyrazole-4, 6(1H,5H) -dione derivative is shown as the following route I:
route I:
wherein R is1、R2As defined above;
the specific operation steps are as follows:
step 1, cooling a raw material compound A-1 and organic sodium in the presence of a mixed solvent and bromine for bromination reaction, and performing post-treatment to obtain a compound A-2;
step 2, intermediate Compounds A-2 and R1R2Heating a substituted arylamine compound A-3 in the presence of an organic solvent and trimethylaluminum to perform condensation reaction, and performing post-treatment to obtain a compound A-4;
step 3, intermediate compound A-4, NaNO2Carrying out cyclization reaction with cuprous cyanide under acidic condition, and carrying out post-treatment to obtain the target product 3-bromo-1-methyl-5-arylpyrrole [3,4-c]Pyrazole-4, 6(1H,5H) -dione derivatives (formula a);
further, the C1-C10 alkyl is C1-C10 straight chain or branched chain alkyl;
further, the halogen is fluorine, chlorine, bromine, iodine;
further, the aryl group is an aryl group including or not including heteroatoms of C5-C10;
in a preferred embodiment of the present application, said R1、R2Each independently selected from hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl;
further, in the step 1, the mixed solvent is a mixed solvent of alcohol and water;
further, the alcohol is one of methanol, ethanol, isopropanol and tert-butanol;
further, in the step 1, the weight-to-volume ratio (g: mL) of the compound A-1 to the mixed solvent is 1: 50-1: 60;
further, in the mixed solvent, the volume ratio (mL: mL) of the alcohol solvent to the water is 1: 1-1: 2;
further, in the step 1, the weight ratio (g: g) of the compound A-1 to the bromine is 1: 4-1: 5;
further, in the step 1, the weight ratio (g: g) of the compound A-1 to the sodium organic acid is 1: 4-1: 5;
further, in the step 2, the organic solvent is one or more of benzene, toluene, DMF and DMSO;
further, in the step 2, the weight-to-volume ratio (g: mL) of the compound A-2 to the organic solvent is 1: 20-1: 30;
further, in the step 2, the compounds A-2 and R1R2The weight ratio (g: g) of the substituted arylamine compound A-3 is 1: 0.5-1: 1;
further, in the step 2, the trimethylaluminum is a 2N toluene solution of trimethylaluminum;
further, in the step 2, the weight-to-volume ratio (g: mL) of the compound A-2 to the toluene solution of 2N trimethylaluminum is 1: 5-1: 10;
further, in the step 3, the acid is one or more of hydrochloric acid, sulfuric acid and nitric acid;
further, in the step 3, the compound A-4 and NaNO are2The weight ratio of the copper cyanide to the cuprous cyanide (g: g: g) is 1:0.4: 0.3-1: 0.5: 0.4;
further, in the step 3, the weight-to-volume ratio (g: mL) of the compound A-4 to the acid is 1: 10-1: 15;
further, the novel method for preparing the 3-bromo-1-methyl-5-arylpyrrole [3,4-c ] pyrazole-4, 6(1H,5H) -diketone derivative comprises the following specific operations in the step 1: adding a raw material compound A-1 into an alcohol solvent, adding organic sodium into water, dissolving and mixing, cooling to 0-10 ℃, adding bromine, stirring for 2-5 hours, and performing post-treatment to obtain an intermediate compound A-2;
further, the 3-bromo-1-methyl-5-arylpyrrole [3,4-c]The novel method for preparing pyrazole-4, 6(1H,5H) -diketone derivatives comprises the following specific operations in step 2: r1R2Adding a toluene solvent into a substituted arylamine compound A-3, cooling to 0-10 ℃, adding a 2N toluene solution of trimethylaluminum, stirring for 20-30 minutes, adding an intermediate compound A-2, heating a reaction solution to 80-100 ℃, stirring for 5-12 hours, and carrying out aftertreatment to obtain an intermediate compound A-4;
further, the 3-bromo-1-methyl-5-arylpyrrole [3,4-c]The novel method for preparing pyrazole-4, 6(1H,5H) -diketone derivatives comprises the following specific operations in step 3: adding the intermediate compound A-4 into concentrated hydrochloric acid, cooling to 0-10 ℃, and adding NaNO2Stirring the aqueous solution for 20 to 30 minutes, adding cuprous cyanide, continuously stirring for 2 to 3 hours, and carrying out aftertreatment to obtain a target product 3-bromo-1-methyl-5-arylpyrrole [3,4-c ]]Pyrazole-4, 6(1H,5H) -dione derivatives (formula a);
in a preferred embodiment of the present invention, in the step 1, the mixed solvent is a mixed solvent of ethanol and water; wherein the volume ratio (mL: mL) of the ethanol to the water is 1: 1.4;
in a preferred embodiment of the present invention, in the step 1, the sodium organic acid is sodium acetate;
in a preferred embodiment of the present invention, in the step 1, the weight to volume ratio (g: mL) of the compound a-1 to the mixed solvent is 1: 60;
in a preferred embodiment of the present invention, in step 1, the weight ratio (g: g) of compound a-1 to bromine is 1: 4.8;
in a preferred embodiment of the present invention, in the step 1, the weight ratio (g: g) of the compound a-1 to the sodium organic acid is 1: 4.4;
in a preferred embodiment of the present invention, in the step 2, the weight to volume ratio (g: mL) of the compound a-2 to the organic solvent is 1: 22;
in a preferred embodiment of the present invention, in step 2, the compounds A-2 and R1R2The weight ratio (g: g) of the substituted arylamine compound A-3 was 1: 0.75;
in a preferred embodiment of the present invention, in the step 2, the weight to volume ratio (g: mL) of the compound a-2 to the toluene solution of 2N trimethylaluminum is 1: 6;
in a preferred embodiment of the present invention, in the step 3, the compound A-4, NaNO2The weight ratio of the copper cyanide to the cuprous cyanide (g: g: g) is 1:0.46: 0.38;
in a preferred embodiment of the present invention, in the step 3, the weight to volume ratio (g: mL) of the compound A-4 to the acid is 1: 11;
in a preferred embodiment of the present invention, in the step 3, the NaNO is2Aqueous solution of (1), NaNO2The weight-to-volume ratio (g: mL) to water is 1: 8;
the technical parameter characteristics in the above methods of the present invention can be combined at will.
In the above-mentioned operations, the post-treatment includes, but is not limited to, quenching with a quenching agent, stirring, extraction, liquid or solid transfer, water washing, alkali washing, acid washing, filtration, ultrafiltration, cyclic ultrafiltration, dilution, concentration, drying, purification, lyophilization, etc., or one or more of water quenching, stirring, extraction, liquid or solid transfer, water washing, alkali washing, acid washing, filtration, ultrafiltration, cyclic ultrafiltration, dilution, concentration, drying, purification, lyophilization, etc.
In a preferred embodiment of the present invention, the quenching with a quencher refers to a process in which a quencher is added to a reaction solution to stop the reaction from proceeding to the right;
the quenching agent is one or more of water, ice water and hydrochloric acid aqueous solution;
in a preferred embodiment of the present invention, the extraction solvent is dichloromethane or ethyl acetate;
in a preferred embodiment of the present invention, the filtration refers to a process of separating solids and liquids in a reaction solution, or a process of separating solids and liquids in a post-treatment operation; the filtration comprises common filtration and separation and centrifugal separation; wherein, the common filtration separation includes but is not limited to filtration using filter cloth, membrane filtration, and diatomite filtration;
in a preferred embodiment of the present invention, the water washing, alkali washing and acid washing include, but are not limited to, the use of saturated sodium bicarbonate solution, 5% potassium carbonate aqueous solution, saturated brine;
in a preferred embodiment of the present invention, the drying comprises anhydrous sodium sulfate drying of the filtrate, vacuum drying;
in a preferred embodiment of the present invention, the concentration refers to a process of removing a liquid solvent, including concentration under reduced pressure, concentration under normal pressure, low-temperature spin-drying, etc.;
the steps, solvents, reagents, filtration, drying, concentration, extraction, separation and the like in the synthetic method of the 3-bromo-1-methyl-5-arylpyrrole [3,4-c ] pyrazole-4, 6(1H,5H) -dione derivative can be combined/separated at will, and the purpose of the invention can be achieved.
Compared with the prior art, the novel method for synthesizing the 3-bromo-1-methyl-5-arylpyrrole [3,4-c ] pyrazole-4, 6(1H,5H) -dione derivative only needs 3 steps of reaction to obtain a target product, and has the advantages of short steps, few side reactions, high conversion rate and yield, single-step yield of more than 80 percent, total yield of more than 60 percent and total yield far higher than that of the prior disclosed method; the intermediate compound A-2 which can be shared in the synthesis method can react with various arylamine compounds (A-3), so that the synthesis method is simplified, and the intermediate compound is applied to synthesis of different derivative structures and has good applicability; the whole method has the advantages of simple and easily obtained reagent raw materials, avoidance of expensive reagent application, cost reduction, mild reaction conditions, good operability and high safety; the operation repeatability is good, and the method is suitable for production in an enlarged workshop; the post-treatment energy consumption is low, a large amount of toxic wastewater is not generated, the environment is protected, the environment is not polluted, the safety level and the production cost of production are reduced, the application of green and environment-friendly industrial production is facilitated, and the method has a wide application prospect.
Detailed Description
The following describes preferred embodiments of the present invention to make the technical contents thereof clearer and easier to understand. The invention may be embodied in many different forms of embodiments, which are intended to be illustrative only, and the scope of the invention is not intended to be limited to the embodiments shown herein.
If there is an experimental method not specified specific conditions, it is usually carried out according to conventional conditions, such as the relevant instructions or manuals.
Example 1 Synthesis of 3-bromo-1-methyl-5-phenylpyrrolo [3,4-c ] pyrazole-4, 6(1H,5H) -dione (formula A-a)
Step 1, adding a sodium formate aqueous solution (4.4g of sodium formate dissolved in 25mL of purified water) into an ethanol (25mL) solution of a raw material compound A-1(1.0g), then cooling to 0 ℃ in an ice bath, dropwise adding bromine (4.8g), and stirring a reaction solution for 3 hours; after the reaction is finished, adding water (30mL) into the reaction system for extraction and extinguishment, extracting with ethyl acetate, collecting organic phase saturated saline solution for washing, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to remove the solvent, and carrying out column chromatography separation and purification on residues to obtain a yellow solid compound A-2(1.2g, yield 81%);
step 2, adding a toluene (20mL) solvent into aniline (compound A-3a) (0.9g), cooling to 0 ℃ in an ice bath, adding a 2N toluene solution of trimethylaluminum (7.2mL), stirring for 30 minutes, adding an intermediate compound A-2(1.2g), heating the reaction solution to 80 ℃, and stirring for 8 hours; after the reaction is finished, cooling the reaction system in an ice bath, quenching the reaction system by using 1N HCl, filtering, extracting filtrate by using ethyl acetate, collecting an organic phase, washing the organic phase by using saturated saline solution, drying the organic phase by using anhydrous sodium sulfate, filtering, concentrating the filtrate to remove a solvent, and separating and purifying residues by using column chromatography to obtain a light yellow solid compound A-4a (1.3g, the yield is 95%);
step 3, dissolving the intermediate compound A-4a (1.3g) in concentrated hydrochloric acid (15mL), cooling to 0 ℃ in ice bath, and dropwise adding NaNO2After stirring for 30 minutes for an aqueous solution of (0.6 g) NaNO2 dissolved in 5mL purified water, cuprous cyanide (0.5g) was added and the temperature was maintained<Continuously stirring and reacting for 2 hours at 10 ℃; after the reaction is finished, pouring the reaction system into ice water for quenching, extracting by ethyl acetate, collecting an organic phase, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate to remove the solvent, and separating and purifying the residue by using column chromatography to obtain a white solid target product compound 3-bromo-1-methyl-5-phenylpyrrole [3,4-c ] -c]Pyrazole-4, 6(1H,5H) -dione (formula a-a) (1.34g, yield 80%);
the 3-bromo-1-methyl-5-phenylpyrrolo [3,4-c ] pyrazole-4, 6(1H,5H) -dione (formula A-a) obtained above was subjected to structural NMR detection, and the detection results were as follows:
1HNMR(400MHz,d6-DMSO)：δppm 7.59-7.56(m,5H),4.19(s,3H)。
the detection result shows that the synthesized compound 3-bromo-1-methyl-5-phenylpyrrolo [3,4-c ] pyrazole-4, 6(1H,5H) -diketone (A-a) has a correct structure.
Example 2 Synthesis of 3-bromo-5- (3-chloro-4-fluorophenyl) -1-methylpyrrole [3,4-c ] pyrazole-4, 6(1H,5H) -dione (formula A-b)
Step 1, adding an aqueous solution of sodium acetate (4g of sodium acetate dissolved in 35mL of purified water) into an ethanol (25mL) solution of a raw material compound A-1(1.0g), then cooling to 0 ℃ in an ice bath, dropwise adding bromine (4g), and stirring a reaction solution for 5 hours; after the reaction is finished, adding water (30mL) into the reaction system for extraction and extinguishment, extracting with ethyl acetate, collecting organic phase saturated saline solution for washing, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to remove the solvent, and carrying out column chromatography separation and purification on residues to obtain a yellow solid compound A-2(1.3g, yield 85%);
step 2, adding a benzene (29mL) solvent into 3-chloro-4-fluoroaniline (a compound A-3b) (1.2g), cooling to 0 ℃ in an ice bath, adding a 2N toluene solution of trimethylaluminum (12mL), stirring for 20 minutes, adding an intermediate compound A-2(1.2g), heating the reaction solution to 100 ℃, and stirring for 10 hours; after the reaction is finished, cooling the reaction system in an ice bath, quenching the reaction system by using 1N HCl, filtering, extracting filtrate by using ethyl acetate, collecting an organic phase, washing the organic phase by using saturated saline solution, drying the organic phase by using anhydrous sodium sulfate, filtering, concentrating the filtrate to remove a solvent, and separating and purifying residues by using column chromatography to obtain a light yellow solid compound A-4b (1.2g, the yield is 91%);
step 3, dissolving the intermediate compound A-4b (1.2g) in concentrated sulfuric acid (18mL), cooling to 0 ℃ in ice bath, and dropwise adding NaNO2After stirring for 20 minutes, cuprous cyanide (0.5g) was added to the aqueous solution of (1) (0.6g NaNO2 in 5mL purified water), and the temperature was maintained<Continuously stirring and reacting for 3 hours at 10 ℃; after the reaction is finished, pouring the reaction system into ice water for quenching, extracting by ethyl acetate, collecting an organic phase, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate to remove the solvent, and separating and purifying the residue by using column chromatography to obtain a white solid target product compound 3-bromo-5- (3-chloro-4-fluorophenyl) -1-methylpyrrole [3,4-c ]]Pyrazole-4, 6(1H,5H) -dione (formula a-b) (1.34g, yield 86%);
the 3-bromo-5- (3-chloro-4-fluorophenyl) -1-methylpyrrole [3,4-c ] pyrazole-4, 6(1H,5H) -dione (formula a-b) obtained above was subjected to structural NMR detection, and the detection results were as follows:
1HNMR(400MHz,d6-DMSO)：δppm 7.94-7.92(m,1H),7.68-7.65(m,2 H),4.20(s,3H)。
the detection result shows that the synthesized compound 3-bromo-5- (3-chloro-4-fluorophenyl) -1-methylpyrrole [3,4-c ] pyrazole-4, 6(1H,5H) -diketone (A-b) has a correct structure.
Example 3 Synthesis of 3-bromo-5- (4-tolyl) -1-methylpyrrole [3,4-c ] pyrazole-4, 6(1H,5H) -dione (formula A-c)
The synthesis was carried out in a similar manner to example 1 to obtain the target compound 3-bromo-5- (4-tolyl) -1-methylpyrrole [3,4-c ] pyrazole-4, 6(1H,5H) -dione (formula a-c).
Example 4 Synthesis of 3-bromo-5-biphenyl-1-methylpyrrole [3,4-c ] pyrazole-4, 6(1H,5H) -dione (formula A-d)
The target compound, 3-bromo-5-biphenyl-1-methylpyrrole [3,4-c ] pyrazole-4, 6(1H,5H) -dione (formula a-d), was synthesized in a similar manner to example 2.
Purity detection is carried out on the product compound 3-bromo-1-methyl-5-arylpyrrole [3,4-c ] pyrazole-4, 6(1H,5H) -diketone derivative (formula A) obtained in the embodiments 1-4, and the detection result shows that the purity of the homotopic hydroxyl and the methylsulfonylmethyl compound (formula A) of the product compound obtained in the embodiments 1-2 is more than 95%;
in conclusion, the 3-bromo-1-methyl-5-arylpyrrole [3,4-c ] pyrazole-4, 6(1H,5H) -dione derivative (formula A) obtained in the embodiment of the invention has the advantages of correct structure, high purity, low impurity content and excellent quality.
The 3-bromo-1-methyl-5-arylpyrrole [3,4-c ] pyrazole-4, 6(1H,5H) -dione derivative (formula A) obtained by the method of other embodiments and technical schemes of the invention has similar beneficial effects as described above.
The invention is not limited to the foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification and any novel method or process steps or any novel combination of features disclosed.
Claims (6)
1. A method for synthesizing 3-bromo-1-methyl-5-arylpyrrole [3,4-c ] pyrazole-4, 6(1H,5H) -dione derivatives is characterized in that the structure of the 3-bromo-1-methyl-5-arylpyrrole [3,4-c ] pyrazole-4, 6(1H,5H) -dione derivatives is shown as the following formula A,
wherein R is1、R2Each independently selected from hydrogen, halogen, C1-C10 alkyl, aryl;
the synthetic method route of the 3-bromo-1-methyl-5-arylpyrrole [3,4-c ] pyrazole-4, 6(1H,5H) -dione derivative is shown as the following route I:
route I:
wherein R is1、R2As defined above;
the specific operation steps are as follows:
step 1, cooling a raw material compound A-1 and organic sodium in the presence of a mixed solvent and bromine for bromination reaction, and performing post-treatment to obtain a compound A-2;
step 2, intermediate Compounds A-2 and R1R2Heating a substituted arylamine compound A-3 in the presence of an organic solvent and trimethylaluminum to perform condensation reaction, and performing post-treatment to obtain a compound A-4;
step 3, intermediate compound A-4, NaNO2Carrying out cyclization reaction with cuprous cyanide under acidic condition, and carrying out post-treatment to obtain the target product 3-bromo-1-methyl-5-arylpyrrole [3,4-c]Pyrazole-4, 6(1H,5H) -dione derivatives.
2. The method of claim 1,
the C1-C10 alkyl is C1-C10 straight chain or branched chain alkyl;
the halogen is fluorine, chlorine, bromine or iodine;
the aryl is C5-C10 aryl including or not including hetero atoms.
3. The method according to claim 1, wherein in the step 1, the mixed solvent is a mixed solvent of alcohol and water; the weight-volume ratio of the compound A-1 to the mixed solvent is 1: 50-1: 60; in the mixed solvent, the volume ratio of alcohol to water is 1: 1-1: 2; the weight ratio of the compound A-1 to the bromine is 1: 4-1: 5; the weight ratio of the compound A-1 to the organic acid sodium is 1: 4-1: 5.
4. The method according to claim 1, wherein in the step 2, the organic solvent is one or more of benzene, toluene, DMF and DMSO; the weight-volume ratio of the compound A-2 to the organic solvent is 1: 20-1: 30; the compounds A-2 and R1R2The weight ratio of the substituted arylamine compound A-3 is 1: 0.5-1: 1; the weight-volume ratio of the compound A-2 to the toluene solution of trimethylaluminum is 1: 5-1: 10.
5. The method according to claim 1, wherein in the step 3, the acid is one or more of hydrochloric acid, sulfuric acid and nitric acid; the compound A-4 and NaNO2The weight ratio of the copper cyanide to the cuprous cyanide is 1:0.4: 0.3-1: 0.5: 0.4; the weight-volume ratio of the compound A-4 to the acid is 1: 10-1: 15.
6. The method of claim 1, wherein said 3-bromo-1-methyl-5-arylpyrrole [3,4-c]A novel method for preparing pyrazole-4, 6(1H,5H) -diketone derivatives, wherein the specific operation of the step 1 is as follows: adding a raw material compound A-1 into an alcohol solvent, adding organic sodium into water, dissolving and mixing, cooling to 0-10 ℃, adding bromine, stirring for 2-5 hours, and performing post-treatment to obtain an intermediate compound A-2; the specific operation of the step 2 is as follows: r1 R2Adding a toluene solvent into a substituted arylamine compound A-3, cooling to 0-10 ℃, adding a 2N toluene solution of trimethylaluminum, stirring for 20-30 minutes, adding an intermediate compound A-2, heating a reaction solution to 80-100 ℃, stirring for 5-12 hours, and carrying out aftertreatment to obtain an intermediate compound A-4; the specific operation of the step 3 is as follows: adding the intermediate compound A-4 into concentrated hydrochloric acid, and cooling to 0-10 DEGAdding a NaNO2 aqueous solution, stirring for 20-30 minutes, adding cuprous cyanide, continuing stirring for 2-3 hours, and performing aftertreatment to obtain a target product 3-bromo-1-methyl-5-arylpyrrole [3,4-c ]]Pyrazole-4, 6(1H,5H) -dione derivatives.
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