Preparation method of febuxostat intermediate

Abstract

The invention discloses a preparation method of a febuxostat intermediate, and relates to the technical field of chemical synthesis of medicines, cyanophenol and thioacetamide are catalyzed by polyphosphoric acid, zinc chloride and Bi (OTf), and a reaction solution is subjected to impurity removal and centrifugation to obtain a centrifugal wet product; 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester reacts with 2-chloroacetoacetic acid ethyl ester to obtain 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, and finally 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester reacts with hexamethylenetetramine under the action of p-toluenesulfonic acid and concentrated sulfuric acid to obtain the febuxostat intermediate product. The reaction period is greatly shortened, the production cost is reduced, and the yield and the purity of the product are improved.

Description

Technical Field

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

[0002] Febuxostat is a novel xanthine oxidase inhibitor used for the treatment of gout and hyperuricemia. The synthesis method of its key intermediate ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate directly affects the quality and cost of the final product. Chinese Patent CN110790720B discloses a new preparation method of a febuxostat intermediate. It adopts an aldoxime route, requires Beckmann rearrangement, the yield is limited by the rearrangement efficiency, and the toluene / DMF mixed solvent increases the solvent treatment cost. Summary of the Invention

[0003] The technical problem to be solved by the present invention is: aiming at the deficiencies existing in the prior art, to provide a preparation method of a febuxostat intermediate with low cost, high yield and high purity of the product.

[0004] To solve the above technical problem, the technical solution of the present invention is: A preparation method of a febuxostat intermediate, comprising the following steps: A: Add polyphosphoric acid, zinc chloride, Bi(OTf)3 and purified water into a reaction kettle, stir and dissolve, then heat up to 90-95°C, add thioacetamide, after the feeding is completed, continue to add 4-cyanophenol, maintain the temperature at 90-95°C, react for 3-4 h, then cool down to 60-65°C, continue to react for 12-16 h, after the reaction is completed, add methanol, keep warm for 2-3 h, and obtain a centrifuged wet product after the reaction solution is purified by centrifugation; B: Add DMF to the centrifuged wet product, heat up the temperature to 50-55°C, start to dropwise add ethyl 2-chloroacetoacetate, after the dropping is completed, keep warm for 1-2 h, continue to add purified water, stir and keep warm for 4-6 h, then cool down to 0°C and continue to keep warm for 1-2 h, centrifuge, and rinse with a methanol solution to obtain ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate;

[0005] C: In the reaction kettle, nitrogen is introduced for protection, and then DMF is added. The reflux condenser is turned on. First, p-toluenesulfonic acid is added, and the temperature in the reaction kettle is adjusted to 65 - 90 °C. Then, hexamethylenetetramine and ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate are added in sequence. Concentrated sulfuric acid is added dropwise, and the temperature in the reaction kettle is controlled not to exceed 90 °C. After the addition is completed, the temperature is raised to 150 °C and kept warm for 12 - 16 h. After the heat preservation is completed, the temperature is lowered to below 20 °C, purified water is added and stirred and kept warm for 20 - 40 min. Butyl acetate is added continuously, and then sodium bicarbonate is added to adjust the pH to 5.0. Dichloromethane is added for liquid separation. The lower layer material is distilled at 25 - 35 °C under negative pressure to obtain the febuxostat intermediate product.

[0006]

[0007] Preferably, in step A, the molar ratio of p-cyanophenol, thioacetamide, zinc chloride, and Bi(OTf)3 for feeding is 1:1.85 - 2.15:0.05 - 0.10:0.01 - 0.03. The mass ratio of p-cyanophenol to polyphosphoric acid and purified water is 1:4.0 - 4.2:0.35 - 0.45. The mass-volume ratio of p-cyanophenol to methanol is 1:3.85 - 4.15 g / ml. Thioacetamide is added in 3 - 5 times at intervals of 10 - 15 min.

[0008] Preferably, the impurity removal and centrifugation step of the reaction solution in step A is as follows: A 5%wt disodium EDTA solution accounting for 1 / 3 of its volume is added to the reaction solution, stirred for 20 - 30 min, then deionized water equal to the volume of the reaction solution is added, and stirring is continued for 10 - 15 min to obtain a mixed solution; The mixed solution is transferred to a separating funnel, ethyl acetate equal to the volume of the mixed solution is added, shaken and left to stand for liquid separation. The upper organic phase is washed 1 - 2 times with a 5%wt disodium EDTA solution, then washed once with saturated brine, then dried with anhydrous sodium sulfate, filtered and concentrated to 1 / 3 of the original volume at 40 - 50 °C, 0.01 - 0.05 Mpa. Finally, n-heptane three times the volume of the concentrated solution is added, and the temperature is lowered to 0 °C at a rate of 2 - 3 °C / h for crystal cultivation for 1 - 1.5 h. After centrifugation, the centrifuged wet product is obtained.

[0009] Preferably, a 10 - 12%wt NaOH solution is added dropwise to the lower aqueous phase after standing and liquid separation to adjust the pH to 2 - 3, and Bi(OTf)3 is recovered by filtration. The filtrate is absorbed by a cation exchange resin to remove Zn 2+ and then discharged.

[0010] Preferably, after DMF is added to the centrifuged wet product in step B, the methanol / n-heptane azeotrope is first distilled off at 50 - 55 °C, -0.05 - 0.08 Mpa, and 150 - 200 rpm, and then ethyl 2-chloroacetoacetate is added dropwise for reaction; The ratio of the weight of the centrifuged wet product to the added volume of DMF is 1:2 - 3 g / ml.

[0011] Preferably, in step B, the molar ratio of 4-cyanophenol to ethyl 2-chloroacetoacetate is 1:1.95 - 2.05, and the mass ratio of 4-cyanophenol to purified water is 1:2 - 2.5; After adding purified water and keeping warm, gradient cooling is adopted, the cooling rate is 10 - 12 °C / h, the concentration of the methanol solution is 50 - 60% wt, and the dropping time of ethyl 2-chloroacetoacetate is 2 - 3 h.

[0012] Preferably, in step C, ethanol is added to the distilled product, the temperature is raised to 65 °C and melted and clarified for 20 - 40 min, then the temperature is lowered to 40 - 43 °C, and crystallization is maintained for 1 - 1.5 h at a stirring speed of 50 - 100 rpm. Finally, the temperature is lowered to 0 °C, rinsed with ethanol and dried to obtain the febuxostat intermediate product.

[0013] Preferably, in step C, hexamethylenetetramine is added in 6 - 10 times, and the feeding time is 1 - 1.5 h.

[0014] Preferably, in step C, the molar ratio of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate to hexamethylenetetramine and p-toluenesulfonic acid is 1:1.1 - 1.3:0.2 - 0.5, the mass ratio of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate to DMF and concentrated sulfuric acid is 1:8 - 12:0.35 - 0.50, the mass-volume ratio of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate to purified water is 1:2 - 2.5 g / ml, the mass-volume ratio of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate to butyl acetate is 1:5 - 8 g / ml, and the mass-volume ratio of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate to dichloromethane is 1:4 - 6 g / ml.

[0015] Preferably, the mass-volume ratio of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate to ethanol is 1:2 - 3 g / ml.

[0016] Due to the adoption of the above technical solutions, the beneficial effects of the present invention are: 1. Polyphosphoric acid provides protons (H⁺), activates the C=S bond of thioacetamide and the C≡N bond of 4-cyanophenol, promotes nucleophilic addition, and Zn in zinc chloride 2+Coordinate with the lone pair electrons of the cyano group to enhance the electrophilicity of the carbon atom, accelerate the nucleophilic attack of thioacetamide. Additionally, by complexing with the N or S atoms of the thiazole ring, the occurrence of side reactions is inhibited, improving the yield and purity of the product. Zinc chloride and polyphosphoric acid form a "protonic acid - metal acid" dual activation center, reducing the energy barrier of the cyclization reaction, enabling the reaction temperature to be lowered from 105 °C to 90 - 95 °C, reducing energy consumption and thermally sensitive by-products. And the Bi in Bi(OTf)3 3+ has extremely strong electron deficiency, which can further activate the C≡N and C=S bonds, enhancing the reaction rate. It forms a "dual-metal Lewis acid" synergy with zinc chloride, covering a wider range of substrate activation (Zn 2+ activates the cyano group, and Bi 3+ activates thioamide), greatly shortening the reaction cycle.

[0017] 2. Both Bi(OTf)3 and Zn 2+ can be recycled, reducing the cost of expensive catalysts and improving the economic benefits of the product. Additionally, through the synergistic activation with zinc chloride and Bi(OTf)3, the dosage of polyphosphoric acid is significantly reduced, and the subsequent neutralization treatment burden is reduced.

[0018] 3. p-Toluenesulfonic acid provides a mild and continuous acidic environment. The aromatic ring structure can preferentially occupy the reaction site, avoiding the intense heat release or excessive sulfonation caused by excessive sulfuric acid at the initial stage of the reaction. Concentrated sulfuric acid replenishes strong acidity in the middle and late stages of the reaction to ensure the complete conversion of hexamethylenetetramine. At the same time, the use of p-toluenesulfonic acid reduces the dosage of concentrated sulfuric acid, reduces the corrosion of the reaction kettle, and reduces the generation of sulfonation impurities, improving the yield of the product.

[0019] 4. The present invention adopts stepwise feeding and gradient cooling, with higher safety, being suitable for industrialization. At the same time, the solvent is easily recycled, reducing the production cost.

[0020] 5. The purity of the febuxostat intermediate product of the present invention by HPLC is ≥99.8%, reducing the subsequent refining steps. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 is the HPLC chart of the febuxostat intermediate product in Example 1 of the present invention; Figure 2 is the HPLC chart of the febuxostat intermediate product in Example 2 of the present invention; Figure 3 is the HPLC chart of the febuxostat intermediate product in Example 3 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0022] The present invention will be further described below in conjunction with the examples. Example 1

[0023] A preparation method of febuxostat intermediate, comprising the following steps: A: Add 1000 g of polyphosphoric acid, 14.3 g of zinc chloride, 13.77 g of Bi(OTf)3 and 87.5 g of purified water into a reaction kettle, premix and dissolve at 200 rpm and 60 °C for 10 min, then raise the temperature to 90 °C, add 291.7 g of thioacetamide in 3 portions with a time interval of 10 min. After the feeding is completed, continue to add 250 g of 4-cyanophenol, maintain the temperature at 90 °C, and the stirring speed at 150 rpm. After reacting for 3 h, cool down to 60 °C and continue to react at a stirring speed of 100 rpm for 12 h. After the reaction is completed, add 950 ml of methanol, control the temperature at 60 °C, and continue to keep warm for 2 h; Add a 5%wt disodium EDTA solution accounting for 1 / 3 of the volume of the reaction solution, stir for 20 min, then add deionized water with the same volume as the reaction solution, and continue to stir for 10 min to obtain a mixed solution; Transfer the mixed solution to a separatory funnel, add ethyl acetate with the same volume as the mixed solution, shake and then let it stand for stratification. Take the upper organic phase and wash it once with a 5%wt disodium EDTA solution, then wash it once with saturated brine, then dry it with anhydrous sodium sulfate, filter, concentrate it to 1 / 3 of the original volume at 40 °C and 0.01 Mpa, finally add n-heptane with 3 times the volume of the concentrated solution, cool it down to 0 °C at a rate of 2 °C / h, crystallize for 1 h, and centrifuge to obtain a centrifuged wet product; Add a 10%wt NaOH solution dropwise to the lower aqueous phase after standing and stratifying to adjust the pH to 2, filter to recover Bi(OTf)3, and absorb Zn in the filtrate through a cation exchange resin 2+ and then discharge it; B: Add DMF to the centrifuged wet product (the weight ratio of the centrifuged wet product to the added volume of DMF is 1:3 g / ml), raise the temperature to 50 °C, and dropwise add 673.57 g of ethyl 2-chloroacetoacetate within 2 h, keep the stirring speed at 180 rpm. After the dropping is completed, keep warm for 1 h, add 500 g of purified water, adjust the stirring speed to 150 rpm, stir and keep warm for 4 h, then adopt gradient cooling with a cooling rate of 10 °C / h. After cooling down to 0 °C, continue to keep warm for 1 h, centrifuge, and rinse with a 50%wt methanol solution to obtain 328 g of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate, with a yield of 96.2%; C: In the reaction kettle, nitrogen was introduced for protection, then 2400 g of DMF was added, the stirring speed was 250 rpm, reflux condensation was started, first 39.24 g of p-toluenesulfonic acid was added, the temperature in the reaction kettle was adjusted to 65 °C, and then 175.7 g of hexamethylenetetramine was added in 6 portions within 1 h. Then 300 g of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate was added, and 105 g of concentrated sulfuric acid was dropped in while controlling the temperature in the reaction kettle not to exceed 65 °C. After the dropping was completed, it was stirred at 500 rpm and 65 °C for 10 min, heated to 150 °C and kept warm for 12 h, then cooled to below 20 °C, 600 ml of purified water was added and stirred and kept warm for 20 min. Then 1500 ml of butyl acetate was added, and the temperature was kept at 15 °C. Subsequently, sodium bicarbonate was added to adjust the pH to 5.0, then 1200 ml of dichloromethane was added and stirred for 10 min for liquid separation. The lower layer material was distilled at 25 °C, -0.08 MPa and a stirring speed of 100 rpm. 600 ml of ethanol was added to the distillation product, heated to 65 °C and melted and clarified for 20 min, then cooled to 40 °C, and kept warm and crystallized at a stirring speed of 50 rpm for 1 h. Finally, it was cooled to 0 °C, rinsed with ethanol and dried to obtain 255 g of febuxostat intermediate product, with a yield of 95.8% and an HPLC purity of 99.844%. Example 2

[0024] A preparation method of a febuxostat intermediate, comprising the following steps: A: Add 1025 g of polyphosphoric acid, 22.88 g of zinc chloride, 27.54 g of Bi(OTf)3 and 100 g of purified water into the reaction kettle, premix and dissolve at a stirring speed of 250 rpm and 60 °C for 12 min, heat up to 92 °C, and then add 316 g of thioacetamide in 4 portions at an interval of 12 min. After the feeding is completed, continue to add 250 g of p-cyanophenol, keep the temperature at 92 °C, the stirring speed is 200 rpm, react for 3.5 h and then cool to 62 °C, and continue to react at a stirring speed of 150 rpm for 14 h. After the reaction is completed, add 1000 ml of methanol, control the temperature at 62 °C, and continue to keep warm for 2.5 h; Add a 5%wt disodium EDTA solution accounting for 1 / 3 of its volume to the reaction solution, stir for 25 min, then add deionized water with the same volume as the reaction solution, and continue to stir for 12 min to obtain a mixed solution; Transfer the mixed solution to a separatory funnel, add ethyl acetate with the same volume as the mixed solution, shake and let it stand for liquid separation. Take the upper organic phase and wash it twice with a 5%wt disodium EDTA solution, then wash it once with saturated brine, then dry it with anhydrous sodium sulfate, filter and concentrate it to 1 / 3 of the original volume at 45 °C and 0.03 Mpa. Finally, add n-heptane 3 times the volume of the concentrated solution, cool it to 0 °C at a rate of 2.5 °C / h, crystallize for 1.2 h, and centrifuge to obtain a centrifuged wet product; 11% wt of NaOH solution was added dropwise to the lower aqueous phase after standing and layering to adjust the pH to 3. Bi(OTf)3 was recovered by filtration, and Zn in the filtrate was adsorbed by a cation exchange resin. 2+ Then it was discharged. B: DMF was added to the centrifuged wet product (the weight ratio of the centrifuged wet product to the added volume of DMF was 1:2 g / ml). The temperature was raised to 52 °C, and 690.1 g of ethyl 2-chloroacetoacetate was added dropwise within 2.5 h while maintaining a stirring speed of 220 rpm. After the addition was completed, it was kept warm for 1.5 h. 550 g of purified water was added, the stirring speed was adjusted to 180 rpm, and it was stirred and kept warm for 5 h. Then gradient cooling was adopted with a cooling rate of 11 °C / h. After cooling to 0 °C, it was kept warm for 1.5 h and centrifuged. It was rinsed with a 55% wt methanol solution to obtain 332 g of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate with a yield of 97.1%. C: In a reaction kettle, nitrogen was introduced for protection, and then 3000 g of DMF was added. The stirring speed was 300 rpm, and reflux condensation was started. First, 58.86 g of p-toluenesulfonic acid was added to adjust the temperature in the reaction kettle to 80 °C. Then, 191.7 g of hexamethylenetetramine was added in 8 portions within 1.2 h. Then, 300 g of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate was added, and 120 g of concentrated sulfuric acid was added dropwise while controlling the temperature in the reaction kettle not to exceed 80 °C. After the addition was completed, it was stirred at 700 rpm and 80 °C for 12 min, heated to 150 °C and kept warm for 14 h. Then it was cooled to below 20 °C, 660 ml of purified water was added and stirred and kept warm for 30 min. Then, 2100 ml of butyl acetate was added, and the temperature was maintained at 15 - 20 °C. Subsequently, sodium bicarbonate was added to adjust the pH to 5.0, and then dichloromethane was added and stirred for 10 - 20 min for layering. The lower layer material was distilled at 30 °C, -0.090 MPa, and a stirring speed of 120 rpm. The distilled product was added with 750 ml of ethanol, heated to 65 °C and melted and clarified for 30 min. Then it was cooled to 42 °C and kept warm for crystal cultivation at a stirring speed of 80 rpm for 1.2 h. Finally, it was cooled to 0 °C, rinsed with ethanol and dried to obtain 257 g of the febuxostat intermediate product with a yield of 96.5% and an HPLC purity of 99.864%. Example 3

[0025] A preparation method of a febuxostat intermediate, comprising the following steps: A: Add 1050 g of polyphosphoric acid, 28.6 g of zinc chloride, 41.31 g of Bi(OTf)3 and 112.5 g of purified water into the reactor. Premix and dissolve at 300 rpm and 60 °C for 15 min, then heat up to 95 °C. Then add 339 g of thioacetamide in 5 portions with an interval of 15 min. After the feeding is completed, continue to add 250 g of 4-cyanophenol, maintain the temperature at 90 °C, and the stirring speed at 250 rpm. After reacting for 4 h, cool down to 65 °C and continue to react at a stirring speed of 200 rpm for 16 h. After the reaction is completed, add 1037.5 ml of methanol, control the temperature at 65 °C, and continue to keep warm for 3 h; Add a 5%wt disodium EDTA solution accounting for 1 / 3 of its volume to the reaction solution, stir for 30 min, then add deionized water with the same volume as the reaction solution, and continue to stir for 15 min to obtain a mixed solution; Transfer the mixed solution to a separatory funnel, add ethyl acetate with the same volume as the mixed solution, shake and then let it stand for stratification. Take the upper organic phase and wash it twice with a 5%wt disodium EDTA solution, then wash it once with saturated brine, then dry it with anhydrous sodium sulfate, filter, and concentrate it to 1 / 3 of the original volume at 50 °C and 0.05 Mpa. Finally, add n-heptane with 3 times the volume of the concentrated solution, cool it down to 0 °C at a rate of 3 °C / h, and carry out crystal cultivation for 1.5 h. After centrifugation, obtain the centrifuged wet product; Dropwise add a 12%wt NaOH solution to the lower aqueous phase after standing and stratifying to adjust the pH to 3, filter to recover Bi(OTf)3, and absorb Zn in the filtrate through a cation exchange resin 2+ and then discharge it; B: Add DMF to the centrifuged wet product (the weight ratio of the centrifuged wet product to the added volume of DMF is 1:3 g / ml), raise the temperature to 55 °C, and dropwise add 708 g of ethyl 2-chloroacetoacetate within 3 h, keep the stirring speed at 250 rpm. After the dropping is completed, keep warm for 2 h, add 625 g of purified water, adjust the stirring speed to 200 rpm, stir and keep warm for 6 h, then adopt gradient cooling with a cooling rate of 12 °C / h. After cooling down to 0 °C, continue to keep warm for 2 h, centrifuge, and rinse with a 60%wt methanol solution to obtain 337 g of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate, with a yield of 98.3%; C: In the reaction kettle, nitrogen was introduced for protection, and then 3600 g of DMF was added. The stirring speed was 350 rpm, and the reflux condenser was turned on. First, 98.09 g of p-toluenesulfonic acid was added, and the temperature in the reaction kettle was adjusted to 90 °C. Then, 207.6 g of hexamethylenetetramine was added in 10 portions within 1.5 h. Next, 300 g of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate was added, and 150 g of concentrated sulfuric acid was dropped in while controlling the temperature in the reaction kettle not to exceed 90 °C. After the dropping was completed, it was stirred at 800 rpm and 90 °C for 15 min, heated to 150 °C and kept warm for 16 h, then cooled to below 20 °C, 750 ml of purified water was added and stirred and kept warm for 40 min. Then, 2400 ml of butyl acetate was added, and the temperature was maintained at 20 °C. Subsequently, sodium bicarbonate was added to adjust the pH to 5.0, and then 1800 ml of dichloromethane was added and stirred for 20 min for layering. The lower layer material was distilled at 35 °C, -0.095 MPa, and a stirring speed of 150 rpm. 900 ml of ethanol was added to the distillation product, heated to 65 °C and melted and clarified for 40 min, then cooled to 43 °C, and crystallized at a stirring speed of 100 rpm for 1.5 h while keeping warm. Finally, it was cooled to 0 °C, rinsed with ethanol and dried to obtain 26.0 g of febuxostat intermediate product, with a yield of 97.0% and an HPLC purity of 99.843%. Comparative Example 1

[0026] In step A, zinc chloride and Bi(OTf)3 were omitted, and at the same time, the reaction temperature in step A was changed to 105 °C, and the rest was exactly the same as in Example 2 to obtain the febuxostat intermediate, with a yield of 82.3% and an HPLC purity of 98.521%. Comparative Example 2

[0027] In step A, zinc chloride was omitted, and the rest was exactly the same as in Example 2 to obtain the febuxostat intermediate product, with a yield of 88.7% and an HPLC purity of 99.125%. Comparative Example 3

[0028] In step A, Bi(OTf)3 was omitted, and the rest was exactly the same as in Example 2 to obtain the febuxostat intermediate product, with a yield of 91.4% and an HPLC purity of 99.342%. Comparative Example 4

[0029] In step C, p-toluenesulfonic acid was omitted, and the rest was exactly the same as in Example 2 to obtain the febuxostat intermediate product, with a yield of 89.6% and an HPLC purity of 98.876%. Comparative Example 5

[0030] In step C, concentrated sulfuric acid was omitted, and the rest was exactly the same as in Example 2 to obtain the febuxostat intermediate product, with a yield of 78.3% and an HPLC purity of 99.012%.

[0031] It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. In addition, it should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. A preparation method of febuxostat intermediate, characterized in that It includes the following steps: A: Add polyphosphoric acid, zinc chloride, Bi(OTf)3 and purified water into a reaction kettle. After stirring and dissolving, heat up to 90 - 95 °C, add thioacetamide. After the feeding is completed, continue to add p-cyanophenol, maintain the temperature at 90 - 95 °C, react for 3 - 4 h, then cool down to 60 - 65 °C and continue to react for 12 - 16 h. After the reaction is completed, add methanol, keep warm for 2 - 3 h, and obtain a centrifuged wet product after impurity removal by centrifugation of the reaction solution; B: Add DMF to the centrifuged wet product, heat up the temperature to 50 - 55 °C, start to dropwise add ethyl 2-chloroacetoacetate. After the dropping is completed, keep warm for 1 - 2 h, continue to add purified water, stir and keep warm for 4 - 6 h, then cool down to 0 °C and continue to keep warm for 1 - 2 h, centrifuge, and rinse with a methanol solution to obtain ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate; C: In the reaction kettle, introduce nitrogen for protection, then add DMF, turn on the reflux condenser. First add p-toluenesulfonic acid, adjust the temperature in the reaction kettle to 65 - 90 °C, then successively add hexamethylenetetramine and ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate, dropwise add concentrated sulfuric acid, control the temperature in the reaction kettle not to exceed 90 °C. After the dropping is completed, heat up to 150 °C and keep warm for 12 - 16 h. After the heat preservation is completed, cool down to below 20 °C, add purified water and stir to keep warm for 20 - 40 min, continue to add butyl acetate, then add sodium bicarbonate to adjust the pH to 5.0, add dichloromethane for liquid separation, take the lower layer material and distill it at 25 - 35 °C under negative pressure to obtain the febuxostat intermediate product.

2. The preparation method of a febuxostat intermediate according to claim 1, characterized in that: In step A, the molar ratio of p-cyanophenol, thioacetamide, zinc chloride and Bi(OTf)3 for feeding is 1:1.85 - 2.15:0.05 - 0.10:0.01 - 0.03, the mass ratio of p-cyanophenol to polyphosphoric acid and purified water is 1:4.0 - 4.2:0.35 - 0.45, the mass-volume ratio of p-cyanophenol to methanol is 1:3.85 - 4.15 g / ml, and thioacetamide is added in 3 - 5 times with a time interval of 10 - 15 min.

3. The preparation method of a febuxostat intermediate according to claim 1, characterized in that, The impurity removal and centrifugation step of the reaction solution in step A is as follows: Add a 5%wt disodium EDTA solution accounting for 1 / 3 of its volume to the reaction solution, stir for 20 - 30 min, then add deionized water with the same volume as the reaction solution, and continue to stir for 10 - 15 min to obtain a mixed solution; Transfer the mixed solution to a separatory funnel, add ethyl acetate with the same volume as the mixed solution, shake and let it stand for liquid separation. Take the upper organic phase and wash it with a 5%wt disodium EDTA solution for 1 - 2 times, then wash it with saturated brine for 1 time, then dry it with anhydrous sodium sulfate, filter, concentrate it to 1 / 3 of the original volume at 40 - 50 °C under 0.01 - 0.05 Mpa, finally add n-heptane with 3 times the volume of the concentrated solution, cool it down to 0 °C at a rate of 2 - 3 °C / h, carry out crystal cultivation for 1 - 1.5 h, and obtain a centrifuged wet product after centrifugation.

4. The preparation method of a febuxostat intermediate according to claim 3, characterized in that: Add 10 - 12%wt NaOH solution dropwise to the lower aqueous phase after static stratification to adjust the pH to 2 - 3, filter to recover Bi(OTf)3, and absorb Zn in the filtrate through a cation exchange resin 2+ and then discharge.

5. The preparation method of a febuxostat intermediate according to claim 3, characterized in that: In step B, after adding DMF to the centrifuged wet product, the methanol / n-heptane azeotrope is first distilled off at 50 - 55 °C, -0.05 to -0.08 Mpa, and 150 - 200 rpm, and then ethyl 2-chloroacetoacetate is added dropwise for reaction; The weight ratio of the centrifuged wet product to the added volume of DMF is 1:2 - 3 g / ml.

6. The preparation method of a febuxostat intermediate according to claim 1, characterized in that: In step B, the molar ratio of 4-cyanophenol to ethyl 2-chloroacetoacetate is 1:1.95 - 2.05, and the mass ratio of 4-cyanophenol to purified water is 1:2 - 2.5; After adding purified water and keeping warm, gradient cooling is adopted, the cooling rate is 10 - 12 °C / h, the concentration of the methanol solution is 50 - 60% wt, and the dropping time of ethyl 2-chloroacetoacetate is 2 - 3 h.

7. The preparation method of a febuxostat intermediate according to claim 1, characterized in that: In step C, ethanol is added to the distilled product, the temperature is raised to 65 °C and melted and clarified for 20 - 40 min, then the temperature is lowered to 40 - 43 °C, and crystallization is maintained for 1 - 1.5 h at a stirring speed of 50 - 100 rpm. Finally, the temperature is lowered to 0 °C, rinsed with ethanol and dried to obtain the febuxostat intermediate product.

8. The preparation method of a febuxostat intermediate according to claim 1, characterized in that: In step C, hexamethylenetetramine is added in 6 - 10 portions, and the feeding time is 1 - 1.5 h.

9. The preparation method of a febuxostat intermediate according to claim 1, wherein: In step C, the molar ratio of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate to hexamethylenetetramine and p-toluenesulfonic acid is 1:1.1 - 1.3:0.2 - 0.5, the mass ratio of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate to DMF and concentrated sulfuric acid is 1:8 - 12:0.35 - 0.50, the mass-volume ratio of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate to purified water is 1:2 - 2.5 g / ml, the mass-volume ratio of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate to butyl acetate is 1:5 - 8 g / ml, and the mass-volume ratio of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate to dichloromethane is 1:4 - 6 g / ml.

10. The preparation method of a febuxostat intermediate according to claim 7, characterized in that: The mass-volume ratio of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate to ethanol is 1:2 - 3 g / ml.

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