Preparation method of febuxostat intermediate

Abstract

The invention belongs to the technical field of preparation of febuxostat intermediates, and particularly relates to a preparation method of a febuxostat intermediate. The preparation method comprises the following steps: taking thiourea and ethyl 2-butanone acid ester as raw materials, and carrying out nucleophilic addition-cyclization reaction to prepare 2-amino-4-methylthiazole-5-carboxylic acid ethyl ester; then, the 2-amino-4-methyl thiazole-5-carboxylic acid ethyl ester is subjected to a diazotization reaction, and 4-methyl-5-ethoxy carbonyl thiazole-2-diazonium chloride is obtained; the method comprises the following steps: taking 5-bromosalicylaldehyde and 4-methyl-5-ethoxycarbonyl thiazole-2-diazonium chloride as raw materials, and carrying out coupling reaction under the catalytic action to prepare the febuxostat intermediate. The synthetic route provided by the invention is efficient, economical and environment-friendly, is suitable for industrial production, can meet the market demand, and overcomes the technical defects existing in the preparation of the febuxostat intermediate in the prior art.

Description

Technical Field

[0001] The present invention belongs to the technical field of the preparation of febuxostat intermediates, and particularly relates to a preparation method of a febuxostat intermediate. Background Art

[0002] Febuxostat, as an effective xanthine oxidase inhibitor and a drug for treating hyperuricemia and gout, has remarkable effects in treating these diseases. Ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate is one of the important intermediates for the preparation of febuxostat. Therefore, how to efficiently prepare ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate is the key to the synthesis of febuxostat and is of great significance for the industrialization of febuxostat.

[0003] The existing preparation method uses 4-hydroxybenzonitrile as the starting material, provides an acidic environment with acidic reagents such as concentrated hydrochloric acid, first undergoes a thio reaction with thio reagents thioacetamide and sodium hydrosulfide, then undergoes a cyclization reaction with ethyl 2-chloroacetoacetate in different solvents to obtain a thiazole ring, and finally undergoes a formylation reaction with a protonic acid such as trifluoroacetic acid and hexamethylenetetramine to obtain the febuxostat intermediate ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate.

[0004] Although the existing technology method can obtain the febuxostat intermediate, it has the following technical defects: Toxicity problem: 4-hydroxybenzonitrile has high toxicity, and special care is required for handling and storage, increasing the operation risk. Complex purification steps: The thio reaction and cyclization reaction generate multiple by-products, and complex purification steps are required to improve the purity of the product, increasing the production cost. Environmental impact: The use of strong acidic reagents such as concentrated hydrochloric acid will generate a large amount of harmful waste, causing a greater impact on the environment. Harsh reaction conditions: The acidic environment and multi-step reaction conditions are relatively harsh, the operation is complex, increasing the process difficulty and uncontrollable factors. Safety problem: The use of strong acidic reagents increases the safety risk of operation, and strict protective measures and equipment are required. Cost problem: The use of 4-hydroxybenzonitrile as the starting material and various expensive reagents (such as trifluoroacetic acid) increases the overall production cost. Yield and selectivity problems: The multi-step reaction and complex reaction conditions result in low yield and selectivity, affecting the quality of the final product. Summary of the Invention

[0005] In view of the deficiencies of the above-mentioned existing technologies, the present invention provides a method for preparing a febuxostat intermediate. The present invention uses thiourea and ethyl 2-ketobutyrate as raw materials to carry out a nucleophilic addition-cyclization reaction to obtain ethyl 2-amino-4-methylthiazole-5-carboxylate; then, ethyl 2-amino-4-methylthiazole-5-carboxylate is subjected to a diazotization reaction to obtain 4-methyl-5-ethoxycarbonylthiazole-2-diazochloride; using 5-bromosalicylaldehyde and 4-methyl-5-ethoxycarbonylthiazole-2-diazochloride as raw materials, a coupling reaction occurs under catalysis to obtain a febuxostat intermediate. The synthetic route of the present invention is efficient, economical and environmentally friendly, overcoming the technical defects existing in the preparation of febuxostat intermediates in the above-mentioned existing technologies.

[0006] To solve the above technical problems, the present invention adopts the following technical solutions:

[0007] The present invention protects a method for preparing a febuxostat intermediate, including the following steps:

[0008] S1. In an inert atmosphere, thiourea and ethyl 2-ketobutyrate are mixed in an organic solvent, and through a nucleophilic addition-cyclization reaction, ethyl 2-amino-4-methylthiazole-5-carboxylate is obtained.

[0009] S2. In an inert atmosphere, ethyl 2-amino-4-methylthiazole-5-carboxylate is subjected to a diazotization reaction to obtain 4-methyl-5-ethoxycarbonylthiazole-2-diazochloride.

[0010] S3. In an inert atmosphere, using 5-bromosalicylaldehyde and 4-methyl-5-ethoxycarbonylthiazole-2-diazochloride as raw materials, a coupling reaction occurs under catalysis to obtain a febuxostat intermediate, namely ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate.

[0011] The reactions in steps S1 and S3 are both carried out in an organic solvent. The organic solvent in step S1 is selected from ethanol, methanol or DMF, and the organic solvent in step S3 is a mixture of DMSO and water; the reaction in step S2 is carried out in water.

[0012] Preferably, in step S1, the molar ratio of ethyl 2-ketobutyrate to thiourea is 1:1 to 2.5.

[0013] Preferably, in step S1, the conditions for the nucleophilic addition-cyclization reaction are: stirring and reacting at 50°C to 100°C for 4h to 8h.

[0014] Preferably, in step S2, the operation of the diazotization reaction is: first dissolve ethyl 2-amino-4-methylthiazole-5-carboxylate in an acidic reagent, and then dropwise add a diazotizing reagent to carry out the diazotization reaction.

[0015] Preferably, the acidic reagent in step S2 is selected from hydrochloric acid, and it is dilute hydrochloric acid with a concentration of 10% w / w to 20% w / w; the diazotizing reagent is selected from sodium nitrite, potassium nitrite, n-butyl nitrite or tert-butyl nitrite.

[0016] Preferably, in step S2, the conditions for diazotization are: the conditions for the diazotization reaction are: stirring at 0°C to 5°C for 0.5 h to 1 h.

[0017] Preferably, in step S3, the molar ratio of 4-methyl-5-ethoxycarbonylthiazole-2-diazochloride to 5-bromosalicylaldehyde is 1:1 to 2.5.

[0018] Preferably, in step S3, the catalyst for the coupling reaction includes a main catalyst and a co-catalyst. The main catalyst is selected from copper powder, cuprous iodide, copper chloride, cuprous chloride, copper bromide, copper acetate or copper complex supported on aminophosphonic acid resin; the co-catalyst is selected from iodine catalysts, and the co-catalyst promotes the oxidative addition process, specifically selected from potassium iodide, sodium iodide, tetrabutylammonium iodide, copper iodide or iodobenzene; the amount of the catalyst used is 5% to 15% of the molar amount of the substrate.

[0019] Preferably, in step S3, the catalyst further includes a ligand reagent, and the ligand reagent is selected from 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline, 2-(1,2,3-triazole)-1,10-phenanthroline, 2,9-bis(2-methoxypyridine)-1,10-phenanthroline or 3-bromo-4-methylthiopyridine. Adding the ligand reagent promotes the progress of the reaction.

[0020] Preferably, in step S3, the conditions for the coupling reaction are: first stirring and reacting at 70°C to 90°C for 1 h to 2 h, and then stirring and reacting at 120°C to 130°C for 10 h to 12 h.

[0021] Preferably, after steps S1 - S3 are prepared, purification is carried out, and the purification method is:

[0022] In step S1, first cool in an ice bath to precipitate the solid product, then filter, and then wash the filter cake with cold organic solvent to remove unreacted raw materials and by-products.

[0023] In step S2, after cooling to room temperature, first extract with an organic solvent to obtain the organic phase, and then wash the organic phase successively with saturated brine, dry with anhydrous sodium sulfate, and distill off the solvent under reduced pressure.

[0024] In step S3, after cooling to room temperature, precipitate the solid in ice water, then filter and wash with water to remove the residual solvent and catalyst. Then dissolve the solid in an organic solvent, wash with saturated brine to obtain the organic phase, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness under reduced pressure, and recrystallize with an organic solvent and then dry.

[0025] The purified organic solvent is selected from one of ethanol, methanol, isopropanol, dioxane, ethyl acetate, dichloromethane, chloroform, acetonitrile, toluene, ether, n-hexane, methyl tert-butyl ether, acetone, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).

[0026] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0027] 1. In the present invention, thiourea and ethyl 2-oxobutanoate are used as raw materials. Thiourea attacks the keto carbonyl group of ethyl 2-oxobutanoate as a nucleophile, and then ethanol or water is cyclically removed to generate intermediate 1, and ethyl 2-amino-4-methylthiazole-5-carboxylate is obtained; the diazotization reaction is carried out on ethyl 2-amino-4-methylthiazole-5-carboxylate, and the amino group is converted into a diazonium salt group during the diazotization process to obtain 4-methyl-5-ethoxycarbonylthiazole-2-diazotization chloride; finally, 5-bromosalicylaldehyde and 4-methyl-5-ethoxycarbonylthiazole-2-diazotization chloride are used as raw materials for the coupling reaction, so that a new carbon-carbon bond is formed between the two under the action of a catalyst to obtain the intermediate of febuxostat, that is, ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate.

[0028] 2. Compared with the prior art preparation methods of febuxostat intermediates, the present invention has the following advantages:

[0029] (1) None of the synthetic raw materials of the present invention contain a cyano group (CN), avoiding the safety problems of the synthetic route introducing a cyano group, reducing the health risks of operators, and then reducing the strict regulations and compliance requirements, lowering the supervision and compliance costs, and simplifying the production and management processes.

[0030] (2) The preparation raw materials of the present invention are easily available in the market, the price is relatively reasonable, and the reaction efficiency is high, improving the purity and yield of the product, which is conducive to large-scale production.

[0031] (3) In the preparation method of the present invention, the reaction conditions are mild, and there is no need to use a large amount of organic solvents and extreme conditions such as high temperature and high pressure, reducing energy consumption and environmental pollution. By reducing the generation of harmful waste, the impact on the environment is reduced, the environmental protection performance of the synthesis process is improved, and it conforms to the principles of green chemistry.

[0032] (4) The synthetic route of the preparation method of the present invention improves the synthesis efficiency. This synthetic route has strong scalability, is suitable for industrial production, can meet the market demand, and provides strong support for the efficient, economic and sustainable production of febuxostat.

[0033] (5) The purification method of the present invention is simple, and the yields of intermediate 1, intermediate 2 and febuxostat intermediate after purification are high, overcoming the problem of increased cost caused by complex purification using the existing method. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 It is a process flow chart for the preparation of the febuxostat intermediate of the present invention.

[0035] Figure 2 It is a liquid chromatography detection chart of the febuxostat intermediate in Example 1 of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0036] The following is a detailed description of the specific embodiments of the present invention, but it should be understood that the protection scope of the present invention is not limited by the specific embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts fall within the protection scope of the present invention. The experimental methods described in the embodiments of the present invention are all conventional methods unless otherwise specified.

[0037] Considering the technical defects in the preparation of febuxostat intermediate in the prior art, the present invention provides a simple and efficient method for the preparation of febuxostat intermediate. The method of the present invention adopts the principles of green chemistry, and by the availability of raw materials and the recycling of reagents, the generation of three wastes is greatly reduced. The characteristics of simple operation and mild conditions of the present invention make it suitable for large-scale production, while ensuring the high purity and stability of the product. These advantages make the method of the present invention have a good development prospect and provide strong technical support for the large-scale production and application of febuxostat intermediate.

[0038] The following uses examples to further explain and illustrate the technical solutions of the present invention. The reaction equations in the preparation process are as Figure 1 , as specifically shown below:

[0039] Example 1

[0040] A method for the preparation of a febuxostat intermediate, comprising the following steps:

[0041] S1. Add 7.61 g of thiourea and 100 mL of ethanol into a dry three-necked flask. Protect it by introducing nitrogen gas. Install a reflux condenser, turn on the magnetic stirrer, and add 13.02 g of ethyl 2-ketobutyrate dropwise into the three-necked flask. Continue stirring for 10 min to ensure uniform mixing and obtain a mixture. Heat the mixture to the reflux temperature of 78 °C and maintain the reflux reaction for 6 h. During this period, monitor the reaction progress by TLC (the developing agent is a mixture of ethyl acetate and petroleum ether with a volume ratio of 1:1). After the reaction is completed, stop heating, cool to room temperature, and then cool it in an ice bath to precipitate the product. Filter and collect the solid product, wash the filter cake with cold ethanol to remove unreacted raw materials and by-products, and vacuum dry the filter cake at 50 °C for 4 h to obtain 15.2 g of intermediate 1. Intermediate 1 is ethyl 2-amino-4-methylthiazole-5-carboxylate, and the yield is 81.6%.

[0042] The chemical reaction equation is:

[0043] S2. In an ice-salt bath, dissolve 15.2 g of ethyl 2-amino-4-methylthiazole-5-carboxylate in 50 mL of hydrochloric acid (10% w / w) aqueous solution. Dropwise add an aqueous solution of sodium nitrite (dissolve 6.76 g of sodium nitrite in 100 mL of water), control the temperature at 0 °C. After the addition is completed, continue stirring for 0.5 h to ensure complete formation of the diazonium salt. During this period, monitor the reaction progress by HPLC. After the reaction is completed, cool to room temperature to obtain the reaction solution. Extract the reaction solution with 100 mL of ethyl acetate, combine the organic phases. First, wash the organic phase with saturated brine (50 mL each time, for 1 time), then dry it with 10 g of anhydrous sodium sulfate for 15 min, filter, and remove the solvent by vacuum distillation to obtain 15.72 g of crude intermediate 2. Intermediate 2 is 4-methyl-5-ethoxycarbonylthiazole-2-diazonium chloride, and the yield is 82.3%.

[0044] The chemical reaction equation is:

[0045] S3. Add 12.0 g of 5-bromosalicylaldehyde and 15.72 g of 4-methyl-5-ethoxycarbonylthiazole-2-diazonium chloride into a 250 mL three-necked flask. Then add a mixed solvent composed of 150 mL of DMSO and 50 mL of water into the three-necked flask. Start mechanical stirring and stir until completely dissolved (about 15 min). Sequentially add 0.32 g of copper powder, 0.90 g of 1,10-phenanthroline, and 0.083 g of potassium iodide, and continue stirring for 10 min to obtain a mixed solution. Pass nitrogen into the mixed solution and purge the reaction system at a flow rate of 1 L / min for 15 min to remove oxygen. First, slowly heat up to 80 °C and keep it for 1 h, then heat up to 120 °C and continue the reaction for 12 h. Take samples every 2 h and monitor the reaction progress by TLC (the developing agent is a mixture of ethyl acetate and petroleum ether with a volume ratio of 1:3) or HPLC. After the reaction is completed, cool the reaction solution to room temperature, pour it into 500 mL of ice water, stir for 30 min, and precipitate solids. Filter the solids and wash them 3 times with 100 mL of cold water each time to remove the residual DMSO and catalyst to obtain the crude product. Dissolve the crude product in 200 mL of ethyl acetate, transfer it to a separatory funnel, wash it 2 times with 100 mL of saturated brine each time. Dry the organic phase with anhydrous sodium sulfate for 30 min, filter, concentrate the filtrate under reduced pressure to dryness, then recrystallize it with 100 mL of ethanol and dry it to obtain 16.2 g of the febuxostat intermediate, with a yield of 82.5% and a purity of ≥98.0% (monitored by HPLC).

[0046] The chemical reaction equation is:

[0047] The HPLC monitoring results of the febuxostat intermediate in Example 1 are as Figure 2 and shown in Table 1.

[0048] Table 1 The peak data table obtained via Figure 2 obtained

[0049] Peak number Retention time Label Area Height Area % 1 14.990 M 467 58 0.006 2 20.041 M 225 29 0.003 3 25.722 M 316 35 0.004 4 26.158 M 553 60 0.007 5 27.514 M 381 41 0.005 6 28.395 M 557 68 0.007 7 30.018 1413 157 0.017 8 30.456 M 169 21 0.002 9 31.100 3174 318 0.038 10 34.071 M 1091 79 0.013 11 34.877 2862 221 0.035 12 35.603 VM 8268403 798638 99.777 13 37.288 SVM 973 84 0.012 14 39.349 M 809 85 0.010 15 41.236 5476 157 0.066 Total 8286869 800050 100.000

[0050] Example 2

[0051] A preparation method of a febuxostat intermediate, comprising the following steps:

[0052] S1. Add 152.2 g of thiourea and 200 mL of methanol into a dry 500 mL three-necked flask. Pass nitrogen for protection, install a reflux condenser, start mechanical stirring, and slowly drop 104 g of ethyl 2-ketobutyrate into the three-necked flask. Continue stirring for 10 min to ensure uniform mixing and obtain a mixture. Heat the mixture to 50 °C and keep stirring and reacting for 8 h. During this period, monitor the reaction progress by TLC (the developing agent is a mixture of ethyl acetate and petroleum ether with a volume ratio of 1:1). After the reaction is completed, stop heating, cool to room temperature, and then cool in an ice bath to precipitate the product. Filter and collect the solid product, wash the filter cake with cold methanol, 100 mL each time, for a total of 3 times. Vacuum dry the filter cake at 50 °C for 4 h to obtain 121.3 g of intermediate 1. Intermediate 1 is ethyl 2-amino-4-methylthiazole-5-carboxylate, yield: 81.5%.

[0053] S2. In an ice-salt bath, dissolve 121.3 g of ethyl 2-amino-4-methyl-1,3-thiazole-5-carboxylate in 200 mL of hydrochloric acid (15% w / w) aqueous solution, and dropwise add an aqueous solution of potassium nitrite (dissolve 148.2 g of potassium nitrite in 200 mL of water). Control the temperature at 5 °C. After the addition is complete, continue stirring for 30 min to ensure complete formation of the diazonium salt. During this period, monitor the reaction progress by TLC (the developing agent is a mixture of ethyl acetate and petroleum ether with a volume ratio of 1:1). After the reaction is completed, cool to room temperature to obtain the reaction solution. Extract the reaction solution with 1 L of ethyl acetate, combine the organic phases. First, wash the organic phase with saturated brine (500 mL each time, for a total of 1 time), then dry it with 100 g of anhydrous sodium sulfate for 15 min, filter, and distill off the solvent under reduced pressure to obtain 125.6 g of crude intermediate 2. Intermediate 2 is 4-methyl-5-ethoxycarbonylthiazole-2-diazonium chloride, yield: 82.4%.

[0054] S3. Add 271 g of 5-bromosalicylaldehyde and 125.6 g of 4-methyl-5-ethoxycarbonylthiazole-2-diazonium chloride into a 250 mL three-necked flask. Then add a mixed solvent composed of 300 mL of DMSO and 100 mL of water into the three-necked flask. Start mechanical stirring and stir until completely dissolved (about 15 min). Sequentially add 9.52 g of cuprous iodide, 10.8 g of 2,9-dimethyl-1,10-phenanthroline, and 0.75 g of sodium iodide, and continue stirring for 10 min to obtain a mixed solution. Pass nitrogen into the mixed solution and purge the reaction system at a flow rate of 1 L / min for 15 min to remove oxygen. First, slowly heat up to 70 °C and keep it for 2 h, then heat up to 120 °C and continue the reaction for 12 h. Sample every 2 h and monitor the reaction process by TLC (the developing agent is a mixture of ethyl acetate and petroleum ether with a volume ratio of 1:3) or HPLC. After the reaction is completed, cool the reaction solution to room temperature (25 °C), pour it into 1 L of ice water, stir for 30 min, and precipitate solids. Filter the solids with a Buchner funnel, wash the filter cake with cold water 3 times, 200 mL each time, to remove the residual DMSO and catalyst, and obtain the crude product. Dissolve the crude product in 500 mL of ethyl acetate, transfer it to a separatory funnel, wash it with saturated brine 2 times, 200 mL each time, dry the organic phase with 100 g of anhydrous sodium sulfate for 30 min, filter, concentrate the filtrate under reduced pressure to dryness, and then recrystallize it with 500 mL of ethanol and dry it to obtain 131.2 g of febuxostat intermediate. Yield: 83.9%, purity ≥ 98.0% (monitored by HPLC).

[0055] Example 3

[0056] A preparation method of a febuxostat intermediate, comprising the following steps:

[0057] S1. Add 11.72 kg of thiourea and 10 L of DMF into a dry 50 L reaction kettle, introduce nitrogen for protection, install a reflux condenser, start mechanical stirring, and drop 13.37 kg of ethyl 2-oxobutyrate into the reaction kettle. Continue stirring for 30 min to ensure uniform mixing to obtain a mixture. Heat the mixture to 100 °C and keep stirring and reacting for 4 h. During this period, monitor the reaction process by TLC (the developing agent is a mixture of ethyl acetate and petroleum ether with a volume ratio of 1:1). After the reaction is completed, stop heating, cool to room temperature, and then cool it in an ice bath to precipitate the product. Filter and collect the solid product, wash the filter cake with cold methanol (3 L each time, for a total of 3 times) to remove the unreacted raw materials and by-products, and vacuum dry the filter cake at 50 °C for 4 h to obtain 15.8 kg of intermediate 1. Intermediate 1 is ethyl 2-amino-4-methylthiazole-5-carboxylate, yield: 80.7%.

[0058] S2. In an ice-salt bath, dissolve 14.94 kg of ethyl 2-amino-4-methyl-1,3-thiazole-5-carboxylate in 25 L of hydrochloric acid (20% w / w) aqueous solution. Dropwise add an aqueous solution of potassium nitrite (dissolve 10.71 kg of potassium nitrite in 10 L of water) while controlling the temperature at 0 °C. After the addition is complete, continue stirring for 1 h to ensure the complete formation of the diazonium salt. Monitor the reaction progress by TLC during this period (the developing agent is a mixture of ethyl acetate and petroleum ether with a volume ratio of 1:1). After the reaction is completed, cool to room temperature to obtain the reaction solution. Extract the reaction solution with 50 L of ethyl acetate, combine the organic phases. Wash the organic phases first with saturated brine (20 L each time, 1 time in total), then dry with 5 kg of anhydrous sodium sulfate for 15 min, filter, and remove the solvent by distillation under reduced pressure to obtain 15.1 kg of crude product Intermediate 2. Intermediate 2 is 4-methyl-5-ethoxycarbonylthiazole-2-diazoniochloride, yield: 80.5%.

[0059] S3. Add 18.2 kg of 5-bromosalicylaldehyde and 15.1 kg of 4-methyl-5-ethoxycarbonylthiazole-2-diazoniochloride to a 50 L reaction kettle. Then add a mixed solvent composed of 9 L of DMSO and 3 L of water to the reaction kettle, start mechanical stirring, and stir until completely dissolved (about 30 min). Sequentially add 202 g of copper powder, 687.9 g of 2-(1,2,3-triazole)-1,10-phenanthroline, and 117.8 g of tetrabutylammonium iodide, and continue stirring for 10 min to obtain a mixed solution. Pass nitrogen into the mixed solution and purge the reaction system at a flow rate of 1 L / min for 15 min to remove oxygen. First, slowly heat up to 90 °C and maintain for 1 h, then heat up to 130 °C and continue the reaction for 10 h. Take samples every 2 h and monitor the reaction progress by TLC (the developing agent is a mixture of ethyl acetate and petroleum ether with a volume ratio of 1:3) or HPLC. After the reaction is completed, cool the reaction solution to room temperature, pour it into 35 L of ice water, and stir for 30 min to precipitate a solid. Filter the solid and wash it 3 times with cold water, 5 L each time, to remove the residual DMSO and catalyst to obtain the crude product. Dissolve the crude product in 15 L of ethyl acetate, transfer it to a separatory funnel, wash it 2 times with saturated brine, 5 L each time. Dry the organic phase with 1.3 kg of anhydrous sodium sulfate for 30 min, filter, concentrate the filtrate to dryness under reduced pressure, and then recrystallize with 6.5 L of ethanol and dry to obtain 15.6 kg of febuxostat intermediate, yield: 83.0%, purity ≥ 98.0% (monitored by HPLC).

[0060] Obviously, those skilled in the art can make various modifications and variations to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalent technologies, the present invention also intends to include these modifications and variations. The above-described embodiments are merely preferred embodiments given to fully illustrate the present invention, and the scope of protection is not limited thereto. Equivalent substitutions or transformations made by those skilled in the art on the basis of the present invention are all within the scope of protection of the present invention, and the scope of protection of the present invention shall be subject to the claims.

Claims

1. A method for preparing a febuxostat intermediate, characterized in that: The steps include: In an inert atmosphere, thiourea and ethyl 2-ketobutyrate are mixed in an organic solvent, and ethyl 2-amino-4-methylthiazole-5-carboxylate is obtained through a nucleophilic addition-cyclization reaction; In an inert atmosphere, 2-amino-4-methylthiazole-5-carboxylic acid ethyl ester is subjected to a diazotization reaction to convert the amino group into a diazonium salt group to obtain 4-methyl-5-ethoxycarbonylthiazole-2-diazo chloride; In an inert atmosphere, 5-bromosalicylaldehyde and 4-methyl-5-ethoxycarbonylthiazole-2-diazo chloride are used as raw materials, and a coupling reaction occurs under the action of a catalyst to form a new carbon-carbon bond to obtain a febuxostat intermediate.

2. The method for preparing a febuxostat intermediate according to claim 1, characterized in that: The molar ratio of ethyl 2-ketobutyrate to thiourea is 1:1-2.

5.

3. The method for preparing a febuxostat intermediate according to claim 1, characterized in that: The conditions for the nucleophilic addition-cyclization reaction are: stirring the reaction at 50°C to 100°C for 4h to 8h.

4. The method for preparing a febuxostat intermediate according to claim 1, characterized in that: The operation of the diazotization reaction is as follows: ethyl 2-amino-4-methylthiazole-5-carboxylate is firstly dissolved in an acidic reagent, and then a diazotization reagent is added dropwise to carry out a diazotization reaction.

5. The method for preparing a febuxostat intermediate according to claim 4, characterized in that: The acidic reagent is selected from hydrochloric acid with a mass percentage of 10% to 20%, and the diazotizing reagent is selected from sodium nitrite, potassium nitrite, n-butyl nitrite or tert-butyl nitrite.

6. The method for preparing a febuxostat intermediate according to claim 4, characterized in that: The conditions of the diazotization reaction are: stirring at 0°C to 5°C for 0.5h to 1h.

7. The method for preparing a febuxostat intermediate according to claim 1, characterized in that: The molar ratio of 4-methyl-5-ethoxycarbonylthiazole-2-diazo chloride to 5-bromosalicylaldehyde is 1:1-2.

5.

8. The method for preparing a febuxostat intermediate according to claim 1, characterized in that: The catalyst for the coupling reaction includes a main catalyst and a co-catalyst. The main catalyst is selected from copper powder, cuprous iodide, cupric chloride, cuprous chloride, cupric bromide, cupric acetate or aminophosphonic acid resin-supported copper complex; the co-catalyst is selected from iodine catalyst.

9. The method for preparing a febuxostat intermediate according to claim 8, characterized in that: The catalyst further comprises a ligand agent, which is selected from 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline, 2-(1,2,3-triazole)-1,10-phenanthroline, 2,9-di(2-methoxypyridine)-1,10-phenanthroline or 3-bromo-4-thiomethylpyridine.

10. The method for preparing a febuxostat intermediate according to claim 1, characterized in that: The conditions of the coupling reaction are: first, stirring the reaction at 70°C to 90°C for 1h to 2h, and then stirring the reaction at 120°C to 130°C for 10h to 12h.

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