A preparation method of Febuxostat intermediate

Abstract

The present invention discloses a method for preparing a febuxostat intermediate, which relates to the technical field of pharmaceutical chemical synthesis. The method comprises the following steps: catalyzing p-cyanophenol and thioacetamide with polyphosphoric acid, zinc chloride, and Bi(OTf)₃, and then removing impurities and centrifuging the reaction solution to obtain a centrifuged wet product. The wet product is then reacted with ethyl 2-chloroacetoacetate to obtain ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate. Finally, the wet product is reacted with hexamethylenetetramine under the action of p-toluenesulfonic acid and concentrated sulfuric acid to obtain the febuxostat intermediate product. The method significantly shortens the reaction cycle, reduces production costs, and improves product yield and purity.

Description

Technical Field

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

[0002] Febuxostat is a novel xanthine oxidase inhibitor used to treat gout and hyperuricemia. The synthesis method of its key intermediate, ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate, directly impacts the quality and cost of the final product. Chinese patent CN110790720B discloses a novel method for preparing a febuxostat intermediate. This method utilizes an aldoxime route, requiring a Beckmann rearrangement. The yield is limited by the rearrangement efficiency, and the toluene / DMF mixed solvent increases solvent handling costs. Summary of the Invention

[0003] The technical problem to be solved by the present invention is: to address the deficiencies in the prior art and to provide a method for preparing a febuxostat intermediate, which has low cost and high product yield and purity.

[0004] In order to solve the above technical problems, the technical solution of the present invention is:

[0005] A method for preparing a febuxostat intermediate comprises the following steps:

[0006] A: Add polyphosphoric acid, zinc chloride, Bi(OTf)3 and purified water to a reactor, stir and dissolve, then heat to 90-95°C, add thioacetamide, and after the addition is complete, continue to add p-cyanophenol, maintain the temperature at 90-95°C, react for 3-4 hours, then cool to 60-65°C, continue to react for 12-16 hours, add methanol after the reaction is complete, keep warm for 2-3 hours, and remove impurities from the reaction solution and centrifuge to obtain a centrifugal wet product;

[0007] B: Add DMF to the centrifuged wet product and raise the temperature to 50-55°C. Begin to dropwise add ethyl 2-chloroacetoacetate. After the addition is complete, keep warm for 1-2 hours. Continue to add purified water and stir and keep warm for 4-6 hours. Then cool to 0°C and continue to keep warm for 1-2 hours. Centrifuge and rinse with methanol solution to obtain ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate.

[0008]

[0009] C: Nitrogen was introduced into the reactor for protection, and then DMF was added. The reflux condenser was turned on, and p-toluenesulfonic acid was added first. The temperature in the reactor was adjusted to 65-90°C. Then hexamethylenetetramine and ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate were added in sequence. Concentrated sulfuric acid was added dropwise, and the temperature in the reactor was controlled not to exceed 90°C. After the addition was completed, the temperature was raised to 150°C and kept warm for 12-16 hours. After the insulation was completed, the temperature was lowered to below 20°C, purified water was added, stirred, and kept warm for 20-40 minutes, and butyl acetate was continued to be added. Subsequently, sodium bicarbonate was added to adjust the pH to 5.0. Dichloromethane was added to separate the layers, and the lower layer was removed and distilled at 25-35°C under negative pressure to obtain the febuxostat intermediate product.

[0010]

[0011] Preferably, in step A, the molar ratio of p-cyanophenol, thioacetamide, zinc chloride and Bi(OTf)3 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.

[0012] Preferably, the impurity removal and centrifugation step of the reaction solution in step A is as follows: adding a 5% wt disodium EDTA solution accounting for 1 / 3 of the volume of the reaction solution, stirring for 20-30 minutes, then adding deionized water of an equal volume to the reaction solution, and continuing to stir for 10-15 minutes to obtain a mixed solution;

[0013] The mixed solution was transferred to a separatory funnel, and an equal volume of ethyl acetate was added to the mixed solution. After shaking, the mixture was allowed to stand for stratification. The upper organic phase was washed 1-2 times with a 5% wt disodium EDTA solution, then washed once with saturated brine, and then dried over anhydrous sodium sulfate. After filtering, it was concentrated to 1 / 3 of the original volume at 40-50°C and 0.01-0.05Mpa. Finally, n-heptane 3 times the volume of the concentrate was added, and the temperature was lowered to 0°C at a rate of 2-3°C / h. The crystals were grown for 1-1.5 hours and centrifuged to obtain a centrifuged wet product.

[0014] Preferably, after standing and stratifying, 10-12% wt NaOH solution is added dropwise to the lower aqueous phase to adjust the pH to 2-3, Bi(OTf)3 is recovered by filtration, and the filtrate is passed through a cation exchange resin to absorb Zn 2+ Rear discharge.

[0015] Preferably, after adding DMF to the centrifuged wet product in step B, 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 to react;

[0016] The ratio of the weight of the centrifuged wet product to the added volume of DMF is 1:2-3 g / ml.

[0017] Preferably, in step B, the molar ratio of p-cyanophenol to ethyl 2-chloroacetoacetate is 1:1.95-2.05, and the mass ratio of p-cyanophenol to purified water is 1:2-2.5;

[0018] After adding purified water and keeping warm, a gradient cooling method is used with a cooling rate of 10-12°C / h. The concentration of the methanol solution is 50-60%wt. The addition time of ethyl 2-chloroacetoacetate is 2-3h.

[0019] Preferably, ethanol is added to the distilled product in step C, the temperature is raised to 65° C. and then melted for 20-40 minutes, then the temperature is lowered to 40-43° C., and the crystals are grown at a stirring speed of 50-100 rpm for 1-1.5 hours. Finally, the temperature is lowered to 0° C., rinsed with ethanol, and then dried to obtain the febuxostat intermediate product.

[0020] Preferably, in step C, hexamethylenetetramine is added in 6-10 portions, with a feeding time of 1-1.5 hours.

[0021] 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.

[0022] Preferably, the mass volume ratio of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate to ethanol is 1:2-3 g / ml.

[0023] Due to the adoption of the above technical solution, the beneficial effects of the present invention are:

[0024] 1. Polyphosphoric acid provides protons (H⁺) to activate the C=S bond of thioacetamide and the C≡N bond of p-cyanophenol, promoting nucleophilic addition. Zn in zinc chloride 2+The coordination with the lone pair of electrons of the cyano group enhances the electrophilicity of the carbon atom and accelerates the nucleophilic attack of thioacetamide. In addition, by complexing the N or S atoms of the thiazole ring, the occurrence of side reactions is inhibited, and the yield and purity of the product are improved. Zinc chloride and polyphosphoric acid form a "proton acid-metal acid" dual activation center, which reduces the energy barrier of the cyclization reaction and allows the reaction temperature to be reduced from 105°C to 90-95°C, reducing energy consumption and heat-sensitive byproducts. The Bi in Bi(OTf)3 3+ The electron-deficient nature of ZnCl2 is very strong, which can further activate C≡N and C=S bonds, increase the reaction rate, and form a "double metal Lewis acid" synergistically with zinc chloride to cover a wider range of substrate activation (Zn 2+ Activated cyano, Bi 3+ activated thioamide), which greatly shortens the reaction cycle.

[0025] 2. Bi(OTf)3 and Zn 2+ They can all be recycled, reducing the cost of expensive catalysts and improving the economic benefits of the product. In addition, through synergistic activation with zinc chloride and Bi(OTf)3, the amount of polyphosphoric acid used is significantly reduced, and the burden of subsequent neutralization treatment is reduced.

[0026] 3. p-Toluenesulfonic acid provides a mild and continuous acidic environment. The aromatic ring structure can preferentially occupy the reaction site, avoiding violent exotherm or excessive sulfonation caused by excessive sulfuric acid in the early stage of the reaction. Concentrated sulfuric acid supplements 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 amount of concentrated sulfuric acid used, reduces corrosion to the reactor, reduces the generation of sulfonated impurities, and improves the yield of the product.

[0027] 4. The present invention adopts step-by-step feeding and gradient cooling, which is safer and suitable for industrialization. At the same time, the solvent is easy to recover, which reduces production costs.

[0028] 5. The HPLC purity of the febuxostat intermediate product of the present invention is ≥99.8%, which reduces the subsequent purification steps. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 This is an HPLC chart of the febuxostat intermediate product in Example 1 of the present invention;

[0030] Figure 2 This is an HPLC chart of the febuxostat intermediate product in Example 2 of the present invention;

[0031] Figure 3 HPLC chart of the febuxostat intermediate product in Example 3 of the present invention. DETAILED DESCRIPTION

[0032] The present invention will be further described below with reference to the embodiments. Example 1

[0033] A method for preparing a febuxostat intermediate comprises the following steps:

[0034] A: Add 1000g polyphosphoric acid, 14.3g zinc chloride, 13.77g Bi(OTf)3 and 87.5g purified water to the reactor and premix and dissolve at 200rpm and 60℃ for 10min. Then heat to 90℃ and add 291.7g thioacetamide in 3 portions with an interval of 10min. After the addition is completed, add 250g p-cyanophenol. Maintain the temperature at 90℃ and stir at 150rpm. After reacting for 3h, cool to 60℃ and continue to react at 100rpm for 12h. After the reaction is completed, add 950ml methanol, control the temperature at 60℃, and continue to keep warm for 2h.

[0035] Add 5% wt disodium EDTA solution accounting for 1 / 3 of the volume of the reaction solution and stir for 20 minutes. Then add deionized water of equal volume to the reaction solution and continue stirring for 10 minutes to obtain a mixed solution.

[0036] The mixture was transferred to a separatory funnel, and an equal volume of ethyl acetate was added. After shaking, the mixture was allowed to stand for stratification. The upper organic phase was washed once with a 5% wt disodium EDTA solution and once with saturated brine. The phase was then dried over anhydrous sodium sulfate, filtered, and concentrated to 1 / 3 of the original volume at 40°C and 0.01 MPa. Finally, n-heptane (3 times the volume of the concentrate) was added, and the temperature was lowered to 0°C at a rate of 2°C / h. The crystals were grown for 1 h, and the wet product was obtained by centrifugation.

[0037] After standing and stratification, 10% wt NaOH solution was added to the lower aqueous phase to adjust the pH to 2, and Bi(OTf)3 was recovered by filtration. The filtrate was passed through a cation exchange resin to absorb Zn 2+ rear discharge;

[0038] B: DMF was added to the centrifuged wet product (the ratio of the weight of the centrifuged wet product to the added volume of DMF was 1:3 g / ml), the temperature was raised to 50°C, and 673.57 g of ethyl 2-chloroacetoacetate was added dropwise over 2 h, with stirring maintained at 180 rpm. After the addition was complete, the mixture was incubated for 1 h, 500 g of purified water was added, the stirring speed was adjusted to 150 rpm, and the mixture was stirred and incubated for 4 h. The temperature was then gradually decreased at a rate of 10°C / h. After cooling to 0°C and continuing to incubate for 1 h, the mixture was centrifuged and rinsed with 50% wt methanol solution to obtain 328 g of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate, with a yield of 96.2%.

[0039] C: In the reactor, nitrogen was introduced for protection, and then 2400g DMF was added, the stirring speed was 250rpm, and the reflux condenser was turned on. 39.24g p-toluenesulfonic acid was added first, and the temperature in the reactor was adjusted to 65℃. Within 1h, 175.7g hexamethylenetetramine was added in 6 times, and then 300g ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate was added. Then 105g concentrated sulfuric acid was added dropwise, and the temperature in the reactor was controlled not to exceed 65℃. After the addition was completed, the mixture was stirred at a speed of 500rpm and 65℃ for 10min, the temperature was raised to 150℃ and kept warm for 12h, and then the temperature was lowered to below 20℃. 600ml purified water was added and stirred for 20min. 1500 ml of butyl acetate was added, and the temperature was maintained at 15 ° C. Then, sodium bicarbonate was added to adjust the pH to 5.0, and 1200 ml of dichloromethane was added and stirred for 10 min to separate the layers. The lower layer material was taken and distilled at 25 ° C, -0.08 MPa, and a stirring speed of 100 rpm. 600 ml of ethanol was added to the distillation product, and the temperature was raised to 65 ° C and melted for 20 minutes. Then the temperature was lowered to 40 ° C, and the crystal was kept at a stirring speed of 50 rpm for 1 hour. Finally, the temperature was lowered 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

[0040] A method for preparing a febuxostat intermediate comprises the following steps:

[0041] A: Add 1025g polyphosphoric acid, 22.88g zinc chloride, 27.54g Bi(OTf)3 and 100g purified water to a reactor, premix and dissolve at 60°C with a stirring speed of 250rpm for 12min, then heat to 92°C, then add 316g thioacetamide in 4 portions with an interval of 12min. After the addition is completed, add 250g p-cyanophenol, maintain the temperature at 92°C, stir at 200rpm, react for 3.5h, then cool to 62°C, stir at 150rpm and continue to react for 14h. After the reaction is complete, add 1000ml methanol, control the temperature at 62°C, and continue to keep warm for 2.5h.

[0042] Add 5% wt disodium EDTA solution accounting for 1 / 3 of the volume of the reaction solution and stir for 25 minutes. Then add deionized water of equal volume to the reaction solution and continue stirring for 12 minutes to obtain a mixed solution.

[0043] The mixture was transferred to a separatory funnel, and an equal volume of ethyl acetate was added. After shaking, the mixture was allowed to stand for stratification. The upper organic phase was washed twice with a 5% wt disodium EDTA solution and once with saturated brine. The phase was then dried over anhydrous sodium sulfate, filtered, and concentrated to 1 / 3 of its original volume at 45°C and 0.03 MPa. Finally, n-heptane (3 times the volume of the concentrate) was added, and the temperature was lowered to 0°C at a rate of 2.5°C / h. The crystals were grown for 1.2 h, and the wet product was obtained by centrifugation.

[0044] After standing and stratification, 11% wt NaOH solution was added dropwise to the lower aqueous phase to adjust the pH to 3, and Bi(OTf)3 was recovered by filtration. The filtrate was passed through a cation exchange resin to absorb Zn 2+ rear discharge;

[0045] B: DMF was added to the centrifuged wet product (the ratio of the weight 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 over 2.5 hours with stirring at 220 rpm. After the addition was complete, the mixture was kept warm for 1.5 hours. 550 g of purified water was added with stirring at 180 rpm and the mixture was stirred and kept warm for 5 hours. The temperature was then gradually decreased at a rate of 11°C / h. After cooling to 0°C, the mixture was kept warm for 1.5 hours. The mixture was centrifuged and rinsed with 55% wt methanol solution to obtain 332 g of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate with a yield of 97.1%.

[0046] C: In the reactor, nitrogen was introduced for protection, and then 3000g DMF was added, the stirring speed was 300rpm, and the reflux condenser was turned on. 58.86g p-toluenesulfonic acid was added first, and the temperature in the reactor was adjusted to 80℃. Within 1.2h, 191.7g hexamethylenetetramine was added in 8 portions, and then 300g ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate was added. 120g concentrated sulfuric acid was added dropwise, and the temperature in the reactor was controlled not to exceed 80℃. After the addition was completed, the mixture was stirred at a speed of 700rpm and 80℃ for 12min, the temperature was raised to 150℃ and kept warm for 14h, then the temperature was lowered to below 20℃, 660ml purified water was added, and the mixture was stirred and kept warm for 30min. 2100 ml of butyl acetate was added, and the temperature was maintained at 15-20 ° C. Then, sodium bicarbonate was added to adjust the pH to 5.0, and dichloromethane was added and stirred for 10-20 minutes to separate the layers. The lower layer material was distilled at 30 ° C, -0.090 MPa, and a stirring speed of 120 rpm. 750 ml of ethanol was added to the distillation product, and the temperature was raised to 65 ° C and melted for 30 minutes. Then, the temperature was lowered to 42 ° C, and the crystal was kept at a stirring speed of 80 rpm for 1.2 hours. Finally, the temperature was lowered to 0 ° C, rinsed with ethanol, and dried to obtain 257 g of Febuxostat intermediate product with a yield of 96.5% and an HPLC purity of 99.864%. Example 3

[0047] A method for preparing a febuxostat intermediate comprises the following steps:

[0048] A: Add 1050g polyphosphoric acid, 28.6g zinc chloride, 41.31g Bi(OTf)3 and 112.5g purified water to a reactor, premix and dissolve at 300rpm and 60℃ for 15min, heat to 95℃, then add 339g thioacetamide in 5 portions with an interval of 15min. After the addition is completed, add 250g p-cyanophenol, maintain the temperature at 90℃, stir at 250rpm, react for 4h, cool to 65℃, continue to react at 200rpm for 16h, add 1037.5ml methanol after the reaction is completed, control the temperature at 65℃, and continue to keep warm for 3h;

[0049] Add 5% wt disodium EDTA solution accounting for 1 / 3 of the reaction solution and stir for 30 minutes. Then add deionized water of equal volume to the reaction solution and continue stirring for 15 minutes to obtain a mixed solution.

[0050] The mixture was transferred to a separatory funnel, and an equal volume of ethyl acetate was added. After shaking, the mixture was allowed to stand for separation. The upper organic phase was washed twice with a 5% wt disodium EDTA solution and once with saturated brine. The phase was then dried over anhydrous sodium sulfate, filtered, and concentrated to 1 / 3 of its original volume at 50°C and 0.05 MPa. Finally, n-heptane (3 times the volume of the concentrate) was added, and the temperature was lowered to 0°C at a rate of 3°C / h. The crystals were grown for 1.5 h, and the wet product was obtained by centrifugation.

[0051] After standing and stratification, 12% wt NaOH solution was added dropwise to the lower aqueous phase to adjust the pH to 3, and Bi(OTf)3 was recovered by filtration. The filtrate was passed through a cation exchange resin to absorb Zn 2+ rear discharge;

[0052] B: DMF was added to the centrifuged wet product (the ratio of the weight of the centrifuged wet product to the added volume of DMF was 1:3 g / ml), the temperature was raised to 55°C, and 708 g of ethyl 2-chloroacetoacetate was added dropwise over 3 h, with stirring maintained at 250 rpm. After the addition was complete, the mixture was kept warm for 2 h. 625 g of purified water was added, the stirring speed was adjusted to 200 rpm, and the mixture was stirred and kept warm for 6 h. The temperature was then gradually decreased at a cooling rate of 12°C / h. After cooling to 0°C, the mixture was kept warm for another 2 h, centrifuged, and rinsed with 60% wt methanol solution to obtain 337 g of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate, with a yield of 98.3%.

[0053] C: In the reactor, nitrogen was introduced for protection, and then 3600g DMF was added, the stirring speed was 350rpm, the reflux condenser was turned on, 98.09g p-toluenesulfonic acid was added first, the temperature in the reactor was adjusted to 90℃, and then 207.6g hexamethylenetetramine was added in 10 times within 1.5h, and then 300g ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate was added, and 150g concentrated sulfuric acid was added dropwise. The temperature in the reactor was controlled not to exceed 90℃. After the addition was completed, the mixture was stirred at a speed of 800rpm and 90℃ for 15min, the temperature was raised to 150℃ and kept warm for 16h, then the temperature was lowered to below 20℃, 750ml purified water was added, stirred and kept warm for 40min, and the mixture was continued to be added. Add 2400 ml of butyl acetate, maintain the temperature at 20 ° C, then add sodium bicarbonate to adjust the pH to 5.0, add 1800 ml of dichloromethane and stir for 20 minutes to separate the layers, take the lower layer material and distill it at 35 ° C, -0.095 MPa, and a stirring speed of 150 rpm. Add 900 ml of ethanol to the distillation product, heat it to 65 ° C and melt it for 40 minutes, then cool it to 43 ° C, keep it warm at a stirring speed of 100 rpm for 1.5 hours to grow the crystals, and finally cool it to 0 ° C, rinse with ethanol and dry it 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

[0054] Zinc chloride and Bi(OTf)3 were omitted in step A, and the reaction temperature in step A was changed to 105°C. The rest was exactly the same as in Example 2, and the febuxostat intermediate was obtained with a yield of 82.3% and an HPLC purity of 98.521%. Comparative Example 2

[0055] Zinc chloride was omitted in step A, and the rest of the process 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

[0056] Bi(OTf)3 was omitted in step A, 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

[0057] The p-toluenesulfonic acid was omitted in step C, and the rest of the process 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

[0058] Concentrated sulfuric acid was omitted in step C, and the rest of the process 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%.

[0059] It should be understood that these embodiments are only used to illustrate the present invention and are not intended 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 limited by the appended claims of the application.

Claims

1. A method for preparing a Febuxostat intermediate, characterized in that The following steps are involved: A: Add polyphosphoric acid, zinc chloride, Bi(OTf)3 and purified water to a reactor, stir and dissolve, then heat to 90-95°C, add thioacetamide, and after the addition is complete, continue to add p-cyanophenol, maintain the temperature at 90-95°C, react for 3-4 hours, then cool to 60-65°C, continue to react for 12-16 hours, add methanol after the reaction is complete, keep warm for 2-3 hours, add 5% wt disodium EDTA solution accounting for 1 / 3 of the volume of the reaction solution, stir for 20-30 minutes, then add deionized water equal to the volume of the reaction solution, continue stirring for 10-15 minutes to obtain a mixed solution; The mixture was transferred to a separatory funnel, and an equal volume of ethyl acetate was added. After shaking, the mixture was allowed to stand for separation. The upper organic phase was washed 1-2 times with a 5% wt disodium EDTA solution, then washed once with saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated to 1 / 3 of the original volume at 40-50°C and 0.01-0.05 MPa. Finally, n-heptane was added in an amount 3 times the volume of the concentrate, and the temperature was lowered to 0°C at a rate of 2-3°C / h. The crystals were grown for 1-1.5 hours, and the wet product was obtained after centrifugation. B: Add DMF to the centrifuged wet product and raise the temperature to 50-55°C. Distill off the methanol / n-heptane azeotrope at -0.05--0.08 MPa and 150-200 rpm. Then, begin adding ethyl 2-chloroacetoacetate dropwise. After the addition is complete, keep the mixture warm for 1-2 hours. Continue adding purified water, stir and keep the mixture warm for 4-6 hours. Then, cool the mixture to 0°C and continue keeping the mixture warm for 1-2 hours. Centrifuge the mixture and rinse with methanol solution to obtain ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate. C: Nitrogen was introduced into the reactor for protection, and then DMF was added. The reflux condenser was turned on, and p-toluenesulfonic acid was added first. The temperature in the reactor was adjusted to 65-90°C. Then hexamethylenetetramine and ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate were added in sequence. Concentrated sulfuric acid was added dropwise, and the temperature in the reactor was controlled not to exceed 90°C. After the addition was completed, the temperature was raised to 150°C and kept warm for 12-16 hours. After the insulation was completed, the temperature was lowered to below 20°C, purified water was added, stirred, and kept warm for 20-40 minutes, and butyl acetate was continued to be added. Subsequently, sodium bicarbonate was added to adjust the pH to 5.

0. Dichloromethane was added to separate the layers, and the lower layer was removed and distilled at 25-35°C under negative pressure to obtain the febuxostat intermediate product.

2. The method for preparing a febuxostat intermediate according to claim 1, wherein: In step A, the molar ratio of p-cyanophenol, thioacetamide, zinc chloride and Bi(OTf)3 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 portions at an interval of 10-15 minutes.

3. The method for preparing a febuxostat intermediate according to claim 1, wherein: After standing and stratification, 10-12% wt NaOH solution was added dropwise to the lower aqueous phase to adjust the pH to 2-3, and Bi(OTf)3 was recovered by filtration. The filtrate was passed through a cation exchange resin to absorb Zn 2+ Rear discharge.

4. The method for preparing a febuxostat intermediate according to claim 1, wherein: The ratio of the weight of the centrifuged wet product to the added volume of DMF in step B is 1:2-3 g / ml.

5. The method for preparing a febuxostat intermediate according to claim 1, wherein: In step B, the molar ratio of p-cyanophenol to ethyl 2-chloroacetoacetate is 1:1.95-2.05, and the mass ratio of p-cyanophenol to purified water is 1:2-2.5; After adding purified water and keeping warm, a gradient cooling method is used with a cooling rate of 10-12°C / h. The concentration of the methanol solution is 50-60%wt. The addition time of ethyl 2-chloroacetoacetate is 2-3h.

6. The method for preparing a febuxostat intermediate according to claim 1, wherein: The distilled product in step C is added with ethanol, heated to 65° C. and melted for 20-40 minutes, then cooled to 40-43° C., stirred at 50-100 rpm, and crystallized for 1-1.5 hours. Finally, the temperature is cooled to 0° C., rinsed with ethanol, and dried to obtain a Febuxostat intermediate product.

7. The method for preparing a febuxostat intermediate according to claim 1, wherein: In step C, hexamethylenetetramine is added in 6-10 portions over a feeding time of 1-1.5 hours.

8. The method for preparing 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.

9. The method for preparing a febuxostat intermediate according to claim 6, wherein: 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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