Process for the preparation of a febuxostat intermediate

Abstract

The application belongs to the technical field of medicine synthesis, and discloses a preparation method of a febuxostat intermediate. The method uses water as a reaction solvent, reacts 4-hydroxybenzonitrile with sodium hydrosulfide, acidifies the obtained reaction system, performs solid-liquid separation, washes the obtained solid to neutral with water, and obtains 4-hydroxythiobenzamide wet product; the wet product is directly added into water, and reacts with 2-chloroacetoacetic acid ethyl ester to obtain 2-(4-hydroxyphenyl)-4-methyl-5-thiazole carboxylic acid ethyl ester. The application realizes effective connection of two-step water-phase reactions, reduces the use of organic solvents and intermediate processing steps, and the obtained product has high yield and purity, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, and specifically relates to a method for preparing febuxostat intermediates. Background Technology

[0002] Febuxostat is a non-purine selective inhibitor of xanthine oxidase that lowers serum uric acid levels by inhibiting uric acid production and is clinically used to treat hyperuricemia. 4-Hydroxythiobenzamide (hereinafter referred to as "FBQZ-I") and ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolylcarboxylate (hereinafter referred to as "FBQZ-II") are key intermediates in the preparation of febuxostat, and the safety, operating procedures, and production costs of their preparation process have a significant impact on the industrial production of febuxostat active pharmaceutical ingredient.

[0003] Currently, the main methods for preparing FBQZ-I are as follows: I. FBQZ-I is prepared from 4-hydroxybenzonitrile via a thiolation reaction. Some methods use water, ethanol, DMF, etc., as reaction solvents, and sodium hydrosulfide, hydrogen sulfide, thioacetamide, etc., as thiolation reagents. Among these, the method using hydrogen sulfide gas usually requires pressure equipment, posing a higher safety risk; other methods may involve the separation and treatment of organic solvents, amines, and by-product salts, making the process more complex (US20050075503A1, CN106928108A).

[0004]

[0005] II. Using 4-hydroxybenzamide as the starting material, tetrahydrofuran, toluene, xylene, or combinations thereof as the reaction solvent, and Lawson's reagent as the thioreaction agent. The solvents and reagents used are relatively expensive, and the production process generates sulfur-containing byproducts with an irritating odor and large amounts of phosphorus-containing wastewater, which is detrimental to industrial production. (European Journal of Medicinal Chemistry, vol. 126, 2017, pp. 604-613; Synthetic Communications, vol. 30, 2000, p. 1083-1094).

[0006]

[0007] III. FBQZ-I is prepared by reacting phenol as a starting material with thiocyanate and other thioreagents. This method has low reaction selectivity, is prone to producing byproducts, and is difficult to control in terms of product yield and quality. (Helvetica Chimica Acta, vol. 16, 1933, p. 1003; Academie des Sciences, vol. 196, p. 1031).

[0008] Currently, the common method for preparing FBQZ-II is to use FBQZ-I as a raw material and carry out a cyclization reaction with ethyl 2-chloroacetoacetate or ethyl 2-bromoacetoacetate in organic solvents such as ethanol, DMF, or 1,4-dioxane. Some existing technologies allow the use of unrefined FBQZ-I or FBQZ-I containing a certain amount of moisture in subsequent reactions, but the cyclization reaction usually still requires the use of organic solvents, or the previous step involves hydrogen sulfide gas, pressure equipment, or strong acid systems, resulting in high costs for solvent recovery and waste liquid treatment (CN101412699A, WO2011066803A1).

[0009] Therefore, it is still necessary to provide a method for preparing FBQZ-II that has low solvent cost, simple reaction medium connection, safe and controllable operation, and is suitable for industrial production. Summary of the Invention

[0010] The purpose of this invention is to provide a method for preparing febuxostat intermediates, in order to solve the problems in existing febuxostat intermediate preparation processes, such as the involvement of hydrogen sulfide gas and pressure equipment in some schemes, the common use of organic solvents in the FBQZ-II cyclization reaction, the relatively complex processing of FBQZ-I and the connection between the two reaction media, and the high cost of organic solvent recovery and waste liquid treatment.

[0011] To achieve the above objectives, the technical solution adopted by the present invention is as follows: This invention provides a method for preparing a febuxostat intermediate, comprising the following steps: Using water as the reaction solvent, 4-hydroxybenzonitrile was reacted with sodium hydrosulfide, and the resulting reaction system was acidified. After solid-liquid separation, the resulting solid was washed with water until neutral to obtain wet 4-hydroxythiobenzamide. The wet product of 4-hydroxythiobenzamide was directly added to water and reacted with ethyl 2-chloroacetoacetate to obtain ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolylcarboxylate.

[0012] In some embodiments, when preparing the wet product of 4-hydroxythiobenzamide, the mass ratio of water to 4-hydroxybenzonitrile is (3-4):1.

[0013] In some embodiments, the mass ratio of sodium hydrosulfide to 4-hydroxybenzonitrile is (0.6-0.9):1, based on sodium hydrosulfide solids; the sodium hydrosulfide is added in the form of an aqueous solution of sodium hydrosulfide, wherein the mass fraction of the aqueous solution of sodium hydrosulfide is 80-90%.

[0014] In some embodiments, the acidification is performed using an acidic reagent selected from one or more of formic acid, acetic acid, oxalic acid, hydrochloric acid, and sulfurous acid.

[0015] In some embodiments, the acidic reagent is formic acid, and the mass ratio of formic acid to 4-hydroxybenzonitrile is (0.6-0.9):1.

[0016] In some embodiments, the temperature at which 4-hydroxybenzonitrile reacts with sodium hydrosulfide is 60-100°C; And / or, the acidification temperature is 60-100°C; And / or, after acidification, the resulting system is cooled to 10-40℃ and kept at that temperature with stirring for 0.5-2 hours, and then the solid-liquid separation and water washing are performed.

[0017] In some embodiments, when the wet 4-hydroxythiobenzamide reacts with ethyl 2-chloroacetoacetate, the initial mass ratio of added water to 4-hydroxybenzonitrile is (7-9):1.

[0018] In some embodiments, the initial mass ratio of ethyl 2-chloroacetoacetate to 4-hydroxybenzonitrile is (1.2-1.4):1.

[0019] In some embodiments, the wet 4-hydroxythiobenzamide is reacted with ethyl 2-chloroacetoacetate at a temperature of 60-90°C for a reaction time of 0.5-2 h.

[0020] In some embodiments, after the reaction of the wet 4-hydroxythiobenzamide with ethyl 2-chloroacetoacetate is completed, the resulting system is cooled to 10-40°C, and the wet 2-(4-hydroxyphenyl)-4-methyl-5-thiazolylcarboxylate is obtained by solid-liquid separation, and the obtained wet product is dried at 60-70°C.

[0021] The beneficial effects achieved by this invention are as follows: This invention uses water as the reaction solvent in the preparation of FBQZ-I and FBQZ-II, allowing 4-hydroxybenzonitrile to react with sodium hydrosulfide in water. After acidification, solid-liquid separation, and washing with water to neutrality, wet FBQZ-I is obtained. This wet product is then directly added to water for subsequent cyclization reactions, effectively linking the two aqueous phase reactions. This method eliminates the drying and organic solvent replacement processes for wet FBQZ-I, simplifies intermediate processing steps, reduces the use of organic solvents and material losses during intermediate processing, and helps reduce production and wastewater treatment costs.

[0022] After being washed with water to neutral, the wet product of FBQZ-I contains fewer residual reactants, acids, and inorganic salts, which is beneficial for the smooth progress of subsequent cyclization reactions. At the same time, FBQZ-II has low solubility in water, which is beneficial for the precipitation and solid-liquid separation of the product after the reaction. The yield and quality of the obtained FBQZ-II product are stable, making it suitable for industrial production. Detailed Implementation

[0023] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to this invention. The preferred embodiments and materials described herein are for illustrative purposes only and do not limit the scope of this invention.

[0025] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the ranges, the endpoint values ​​of the ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein. For ease of description, 4-hydroxythiobenzamide will be abbreviated as FBQZ-I, and ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolylcarboxylate will be abbreviated as FBQZ-II.

[0026] This invention provides a method for preparing febuxostat intermediates, comprising the following steps: using water as a reaction solvent, reacting 4-hydroxybenzonitrile with sodium hydrosulfide, acidifying the resulting reaction system, washing the obtained solid with water to neutral after solid-liquid separation to obtain wet FBQZ-I; directly adding the wet FBQZ-I to water and reacting it with ethyl 2-chloroacetoacetate to obtain FBQZ-II.

[0027] The reaction of 4-hydroxybenzonitrile with sodium hydrosulfide using water as the reaction solvent refers to using water as the reaction medium for the reaction of 4-hydroxybenzonitrile and sodium hydrosulfide. This allows sodium hydrosulfide to undergo a thiolation reaction with 4-hydroxybenzonitrile in an aqueous phase, forming a reaction system containing the FBQZ-I salt. Using water as the reaction solvent allows sodium hydrosulfide to participate in the reaction in an aqueous phase, reducing the use of organic reaction solvents.

[0028] Acidifying the resulting reaction system means adding an acidic reagent to the reaction system after the reaction of 4-hydroxybenzonitrile with sodium hydrosulfide, so that the FBQZ-I salt formed in the reaction is converted into free FBQZ-I, thereby enabling FBQZ-I to be collected through subsequent solid-liquid separation.

[0029] After acidification, the resulting reaction system was subjected to solid-liquid separation, and the obtained solid was washed with water until neutral to obtain wet FBQZ-I. Residual sodium hydrosulfide, acid, inorganic salts, and other water-soluble substances in the reaction system can be separated from FBQZ-I along with the mother liquor and washing water. Washing the obtained solid with water until neutral can reduce the impact of these residues on the quality of FBQZ-I and subsequent cyclization reactions.

[0030] The FBQZ-I wet product refers to a solid material containing water obtained after acidification of FBQZ-I through solid-liquid separation and washing with water to neutrality. Adding the FBQZ-I wet product directly to water means keeping the FBQZ-I wet product, after solid-liquid separation and washing to neutrality, in a water-containing state and adding it directly to the water used in subsequent reactions. Because the water carried by the FBQZ-I wet product is compatible with the water used in subsequent reactions, the water in the wet product will not introduce other types of reaction solvents; at the same time, the FBQZ-I wet product has been washed to neutrality, and contains fewer residual reactants, acids, and inorganic salts, thus it can be directly used for subsequent cyclization reactions.

[0031] After adding wet FBQZ-I to water, FBQZ-I undergoes a cyclization reaction with ethyl 2-chloroacetoacetate to yield FBQZ-II. Experiments show that this reaction is relatively undemanding in terms of the reaction solvent; water can be used as the reaction solvent under suitable reaction conditions. Furthermore, the low solubility of FBQZ-II in water facilitates the precipitation of the generated FBQZ-II from the reaction system and makes subsequent collection easier.

[0032] Using the above preparation method, after acidification, solid-liquid separation and washing with water to neutrality, FBQZ-I is directly added to water in wet form for subsequent cyclization reaction. This allows the preparation process of FBQZ-I to be connected with the preparation process of FBQZ-II through an aqueous medium, simplifying the processing of FBQZ-I and the medium conversion process between the two reactions.

[0033] Furthermore, the reaction of 4-hydroxybenzonitrile with sodium hydrosulfide and the acidification of the resulting reaction system are both carried out in an atmospheric pressure reactor. This invention uses sodium hydrosulfide as the thioreagent to induce the thioreagent reaction of 4-hydroxybenzonitrile in water, eliminating the need for continuous pressurization of hydrogen sulfide gas into the reaction system. Therefore, FBQZ-I can be prepared using conventional atmospheric pressure reactor equipment. Compared to processes using hydrogen sulfide gas and pressurized equipment, this method reduces the requirements for the pressure resistance and pressure control system of the reaction equipment, improving the safety and controllability of the production process, and reducing equipment investment and operational complexity. The subsequent cyclization reaction of wet FBQZ-I with ethyl 2-chloroacetoacetate can also be carried out in an atmospheric pressure reactor, enabling the preparation of both FBQZ-I and FBQZ-II to be completed using conventional production equipment, which is beneficial for process scale-up and industrial production.

[0034] In some embodiments, when preparing the FBQZ-I wet product, the mass ratio of water to 4-hydroxybenzonitrile is (3-4):1, for example, it can be 3:1, 3.2:1, 3.5:1, 3.8:1, 4:1, etc. The water refers to the water added as a reaction solvent when 4-hydroxybenzonitrile reacts with sodium hydrosulfide, excluding the water used to wash the obtained solid after solid-liquid separation. Controlling the mass ratio of water to 4-hydroxybenzonitrile within the above range provides a suitable aqueous reaction environment for the reaction of 4-hydroxybenzonitrile with sodium hydrosulfide, which is beneficial for the dispersion, stirring, and mass transfer of materials. If the amount of water is too small, the material concentration in the reaction system will be high, which may affect the dispersion and stirring of materials; if the amount of water is too large, it will reduce the material concentration in the reaction system and increase the load on subsequent cooling, solid-liquid separation, and wastewater treatment.

[0035] In some embodiments, the mass ratio of sodium hydrosulfide to 4-hydroxybenzonitrile, based on sodium hydrosulfide solids, is (0.6-0.9):1, for example, 0.6:1, 0.65:1, 0.7:1, 0.73:1, 0.75:1, 0.8:1, 0.85:1, 0.9:1, etc. "Based on sodium hydrosulfide solids" refers to calculating the amount of sodium hydrosulfide added based on the actual mass of sodium hydrosulfide contained in the aqueous solution. Sodium hydrosulfide is used to induce a thiolation reaction in 4-hydroxybenzonitrile, and its amount affects the degree of reaction of 4-hydroxybenzonitrile. If the amount of sodium hydrosulfide is too small, the 4-hydroxybenzonitrile may not react completely, which will reduce the yield of FBQZ-I and the final FBQZ-II. Once the amount of sodium hydrosulfide is sufficient to allow the 4-hydroxybenzonitrile to react completely, further increasing the amount of sodium hydrosulfide will have little effect on improving the product yield, and will also increase the load on subsequent acidification and washing processes.

[0036] Specifically, when the mass ratio of sodium hydrosulfide to 4-hydroxybenzonitrile was 0.5:1, the reaction of 4-hydroxybenzonitrile was incomplete, and the yield of FBQZ-II was 88%. When the mass ratios were 0.6:1, 0.73:1, and 0.9:1, the yields of FBQZ-II were 90.5%, 92.0%, and 92.5%, respectively. Therefore, controlling the mass ratio of sodium hydrosulfide to 4-hydroxybenzonitrile at (0.6-0.9):1 allows for a more complete reaction of 4-hydroxybenzonitrile while balancing product yield and the amount of sodium hydrosulfide used.

[0037] The sodium hydrosulfide is added in the form of an aqueous solution of sodium hydrosulfide, with a mass fraction of 80-90%, such as 80%, 82%, 85%, 87%, 88%, 90%, etc. Adding the sodium hydrosulfide after preparing or adjusting it into an aqueous solution facilitates its dispersion in the aqueous reaction system and makes it easier to control the addition process, ensuring sufficient contact between the sodium hydrosulfide and 4-hydroxybenzonitrile.

[0038] In some embodiments, the acidic reagent used for acidification is selected from one or more of formic acid, acetic acid, oxalic acid, hydrochloric acid, and sulfurous acid. The acidic reagent is used to convert the FBQZ-I salt formed by the thioreaction into free FBQZ-I, so that FBQZ-I can be collected by solid-liquid separation. The aforementioned acidic reagent can provide the acidic conditions required for acidification in an aqueous system and is compatible with the aforementioned aqueous reaction system.

[0039] In some specific embodiments, the acidic reagent is formic acid, and the mass ratio of formic acid to 4-hydroxybenzonitrile is (0.6-0.9):1, for example, 0.6:1, 0.65:1, 0.7:1, 0.75:1, 0.8:1, 0.85:1, 0.9:1, etc. Formic acid can acidify the reaction system obtained from the thioreaction, causing FBQZ-I to be released from the reaction system. Controlling the amount of formic acid within the above range is beneficial for sufficient acidification of the reaction system; insufficient formic acid may lead to incomplete release of FBQZ-I, while excessive formic acid will increase the removal of residual formic acid and the load on subsequent water washing.

[0040] When formic acid is used, the hydrogen sulfide formed during the reaction can be discharged from the reaction system, and the residual small amounts of sodium hydrosulfide, formic acid, inorganic salts, and other water-soluble substances can be separated from FBQZ-I with the mother liquor and washing water. After washing to neutrality, the residual sodium hydrosulfide, formic acid, and inorganic salts in the obtained wet FBQZ-I are minimal, and therefore will not have a significant adverse effect on the subsequent preparation of FBQZ-II.

[0041] In some embodiments, the reaction temperature between 4-hydroxybenzonitrile and sodium hydrosulfide is 60-100°C, for example, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, etc. Controlling the reaction temperature within this range is beneficial for increasing the reaction rate between the materials and promoting the conversion of 4-hydroxybenzonitrile. If the reaction temperature is too low, the thiolation reaction rate may be slow, and the 4-hydroxybenzonitrile may not react completely; if the reaction temperature is too high, it may increase water evaporation and energy consumption, and increase the difficulty of controlling the reaction process.

[0042] In some embodiments, the acidification temperature is 60-100℃, for example, 60℃, 65℃, 70℃, 75℃, 80℃, 85℃, 90℃, 95℃, 100℃, etc. Controlling the acidification temperature within the above range is beneficial for the uniform dispersion of the acidic reagent in the reaction system, allowing the FBQZ-I salt formed by the thioreaction to be fully converted into free FBQZ-I, and facilitating the subsequent precipitation of FBQZ-I by cooling.

[0043] In some embodiments, after acidification, the resulting system is cooled to 10-40°C and stirred at this temperature for 0.5-2 hours before solid-liquid separation and water washing. Specifically, the resulting system can be cooled to 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, etc. Lowering the temperature of the reaction system facilitates the precipitation of FBQZ-I from the aqueous phase system, improving the collection efficiency of FBQZ-I during solid-liquid separation.

[0044] Furthermore, after cooling, the mixture can be kept at this temperature and stirred for 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, etc. Continuing to stir after cooling promotes further precipitation of FBQZ-I and maintains a good dispersion of the resulting solid in the reaction system, facilitating subsequent solid-liquid separation. After solid-liquid separation, the resulting solid is washed with water until neutral to remove residual sodium hydrosulfide, acid, inorganic salts, and other water-soluble substances from the solid surface and interior, yielding a wet FBQZ-I product that can be directly used for subsequent aqueous cyclization reactions.

[0045] In some embodiments, when the FBQZ-I wet product reacts with ethyl 2-chloroacetoacetate, the initial mass ratio of added water to 4-hydroxybenzonitrile is (7-9):1, for example, it can be 7:1, 7.5:1, 8:1, 8.5:1, 9:1, etc. The added water refers to water added separately during the reaction of the FBQZ-I wet product with ethyl 2-chloroacetoacetate, and its amount is calculated based on the initial mass of 4-hydroxybenzonitrile.

[0046] During the later stages of the cyclization reaction between FBQZ-I and ethyl 2-chloroacetoacetate, the reaction system gradually becomes viscous. Controlling the amount of added water within the aforementioned range facilitates the dispersion of wet FBQZ-I in water, improves the stirring and mass transfer conditions of the reaction system, and facilitates solid-liquid separation after the reaction. Insufficient added water may lead to difficulties in dispersion and stirring due to the viscosity of the reaction system, affecting sufficient contact between materials and subsequent product collection; excessive added water will increase the total volume of the reaction system and the load on subsequent solid-liquid separation and wastewater treatment. Furthermore, FBQZ-II has low solubility in water; using water as a reaction solvent facilitates the precipitation of FBQZ-II from the reaction system, improving the convenience of product collection.

[0047] In some embodiments, the initial feed mass ratio of ethyl 2-chloroacetoacetate to 4-hydroxybenzonitrile is (1.2-1.4):1, for example, it can be 1.2:1, 1.25:1, 1.3:1, 1.35:1, 1.4:1, etc. Since FBQZ-I is added in wet form, its actual feed mass will be affected by the moisture content of the wet product. Therefore, using the initial feed mass of 4-hydroxybenzonitrile as the calculation basis for the amount of ethyl 2-chloroacetoacetate is beneficial for unifying the feed standards for different batches.

[0048] Ethyl 2-chloroacetoacetate is used in the cyclization reaction with FBQZ-I, and its dosage affects the extent of FBQZ-I reaction. If too little ethyl 2-chloroacetoacetate is used, FBQZ-I may react incompletely, resulting in raw material residue and reducing the yield of FBQZ-II; if too much is used, the further improvement in product yield is minimal, and it also leads to material waste and may affect product quality due to the decomposition of unreacted ethyl 2-chloroacetoacetate at higher temperatures.

[0049] Specifically, experiments investigating the dosage of ethyl 2-chloroacetobenzoate showed that, with a fixed mass ratio of sodium hydrosulfide to 4-hydroxybenzonitrile of 0.73:1, when the initial mass ratio of ethyl 2-chloroacetobenzoate to 4-hydroxybenzonitrile was 1.1:1, the reaction of FBQZ-I was incomplete, resulting in a yield of 87% for FBQZ-II. When the mass ratios were 1.2:1, 1.3:1, and 1.4:1, the yields of FBQZ-II were 91.5%, 91.6%, and 92.0%, respectively. Therefore, controlling the initial mass ratio of ethyl 2-chloroacetobenzonitrile to 4-hydroxybenzonitrile within the range of (1.2-1.4):1 allows for a more complete reaction of FBQZ-I while balancing the yield of FBQZ-II with the amount of ethyl 2-chloroacetobenzoate used.

[0050] In some embodiments, the reaction temperature of the wet FBQZ-I product with ethyl 2-chloroacetoacetate is 60-90°C, for example, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, etc. The cyclization reaction of FBQZ-I with ethyl 2-chloroacetoacetate is relatively undemanding in terms of the reaction solvent; the reaction temperature is a crucial factor affecting the rate and extent of the cyclization reaction. Controlling the reaction temperature within the above-mentioned range can promote the cyclization reaction of FBQZ-I with ethyl 2-chloroacetoacetate in water. If the reaction temperature is too low, the cyclization reaction rate may be slow, and FBQZ-I may not react completely; if the reaction temperature is too high, it will increase energy consumption and may accelerate the decomposition of ethyl 2-chloroacetoacetate, affecting product quality.

[0051] The reaction time is 0.5-2 hours, for example, 0.5 hours, 0.75 hours, 1 hour, 1.25 hours, 1.5 hours, 2 hours, etc. Controlling the reaction time within this range provides a suitable reaction time for the cyclization reaction of FBQZ-I with ethyl 2-chloroacetoacetate. If the reaction time is too short, FBQZ-I may not react sufficiently; if the reaction time is too long, the further improvement in the conversion degree of FBQZ-I is minimal, and it may also prolong the production cycle and increase the possibility of side reactions.

[0052] In some embodiments, after the reaction of the FBQZ-I wet product with ethyl 2-chloroacetoacetate is completed, the resulting system is cooled to 10-40°C, and the FBQZ-II wet product is obtained by solid-liquid separation, and the obtained wet product is dried at 60-70°C.

[0053] Specifically, after the reaction is complete, the resulting system can be cooled to 10℃, 15℃, 20℃, 25℃, 30℃, 35℃, 40℃, etc. Since FBQZ-II has low solubility in water, lowering the temperature of the reaction system facilitates further precipitation of FBQZ-II and improves the collection efficiency of FBQZ-II during solid-liquid separation. Solid-liquid separation of the cooled reaction system allows the precipitated FBQZ-II to be separated from the aqueous phase, yielding wet FBQZ-II.

[0054] The resulting FBQZ-II wet product can be dried at temperatures of 60℃, 62℃, 65℃, 68℃, and 70℃. Controlling the drying temperature at 60-70℃ can remove the moisture contained in the FBQZ-II wet product while balancing drying efficiency and product quality, ultimately yielding FBQZ-II.

[0055] The present invention will be described below through specific embodiments. It should be noted that these embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0056] Example 1: Add 1050 kg of water to the reactor and start stirring. Add 350 kg of 4-hydroxybenzonitrile and stir until dissolved. Control the system temperature at 60-100℃ and add dropwise an 80% sodium hydrosulfide aqueous solution containing 210 kg of sodium hydrosulfide. After the addition is complete, control the system temperature at 60-100℃ and add 210 kg of formic acid. After the addition is complete, continue stirring the reaction for 0.5-2 hours.

[0057] After the reaction is complete, the resulting system is cooled to 10-40℃ and stirred for 0.5-1h. The solid is collected by centrifugation and washed with process water until neutral. The pH is controlled at 6-7 to obtain FBQZ-I wet product.

[0058] Add 2450 kg of water to another reaction vessel, start stirring, add the obtained wet FBQZ-I, heat to 60-90℃, and add 420 kg of ethyl 2-chloroacetoacetate dropwise under controlled temperature. After the addition is complete, continue stirring for 0.5-2 h. After the reaction is complete, cool the resulting system to 10-40℃, maintain the temperature and stir for 0.5-2 h, collect the solid by centrifugation to obtain wet FBQZ-II. Dry the obtained wet FBQZ-II at 60-70℃ to obtain FBQZ-II, with a yield of 90.5% and a purity of 99%.

[0059] Example 2: Add 1400 kg of water to the reactor and start stirring. Add 350 kg of 4-hydroxybenzonitrile and stir until dissolved. Control the system temperature at 75-95℃ and add dropwise an 87% sodium hydrosulfide aqueous solution containing 315 kg of sodium hydrosulfide. After the addition is complete, control the system temperature at 75-95℃ and add 315 kg of formic acid. After the addition is complete, continue stirring the reaction for 0.5-1 hour.

[0060] After the reaction is complete, the resulting system is cooled to 20-30℃ and stirred for 0.5-1h. The solid is collected by centrifugation and washed with process water until neutral. The pH is controlled at 6-7 to obtain FBQZ-I wet product.

[0061] Add 2800 kg of water to another reaction vessel, start stirring, add the obtained wet FBQZ-I, heat to 60-90℃, and add 455 kg of ethyl 2-chloroacetoacetate dropwise under controlled temperature. After the addition is complete, continue stirring for 0.5-1 h. After the reaction is complete, cool the resulting system to 20-30℃, maintain the temperature and stir for 0.5-1 h, collect the solid by centrifugation to obtain wet FBQZ-II. Dry the obtained wet FBQZ-II at 60-70℃ to obtain FBQZ-II, with a yield of 92.5% and a purity of 99%.

[0062] Example 3: Add 1400 kg of water to the reactor and start stirring. Add 350 kg of 4-hydroxybenzonitrile and stir until dissolved. Control the system temperature at 75-95℃ and add dropwise an 87% sodium hydrosulfide aqueous solution containing 255 kg of sodium hydrosulfide. After the addition is complete, control the system temperature at 75-95℃ and add 264 kg of formic acid. After the addition is complete, continue stirring the reaction for 0.5-1 hour.

[0063] After the reaction is complete, the resulting system is cooled to 20-30℃ and stirred for 0.5-1h. The solid is collected by centrifugation and washed with process water until neutral. The pH is controlled at 6-7 to obtain FBQZ-I wet product.

[0064] Add 3150 kg of water to another reaction vessel, start stirring, add the obtained wet FBQZ-I, heat to 60-90℃, and add 490 kg of ethyl 2-chloroacetoacetate dropwise under controlled temperature. After the addition is complete, continue stirring for 0.5-1 h. After the reaction is complete, cool the resulting system to 20-30℃, maintain the temperature and stir for 0.5-1 h, collect the solid by centrifugation to obtain wet FBQZ-II. Dry the obtained wet FBQZ-II at 60-70℃ to obtain FBQZ-II, with a yield of 92.0% and a purity of 99%.

[0065] Comparative Example 1: The preparation method of this comparative example is basically the same as that of Example 3, except that the amount of sodium hydrosulfide added is adjusted to 175 kg based on sodium hydrosulfide solid, so that the mass ratio of sodium hydrosulfide to 4-hydroxybenzonitrile is 0.5:1.

[0066] FBQZ-I was prepared according to the above method, and FBQZ-II was then prepared. Due to the small amount of sodium hydrosulfide used, the reaction of 4-hydroxybenzonitrile was incomplete, resulting in a low yield of FBQZ-I. The final yield of FBQZ-II was 88%.

[0067] Comparative Example 2: The preparation method of this comparative example is basically the same as that of Example 3, except that the amount of ethyl 2-chloroacetoacetate is adjusted to 385 kg, so that the initial mass ratio of ethyl 2-chloroacetoacetate to 4-hydroxybenzonitrile is 1.1:1.

[0068] FBQZ-II was prepared according to the above method. Due to the small amount of ethyl 2-chloroacetoacetate, the reaction of FBQZ-I was incomplete, and the final yield of FBQZ-II was 87%.

[0069] Results analysis: Examples 1-3 show that using water as the reaction solvent in the preparation of FBQZ-I and FBQZ-II, and directly adding the acidified, solid-liquid separated, and water-washed FBQZ-I wet product to water to neutrality for subsequent cyclization reaction, the yield of FBQZ-II obtained is 90.5-92.5% and the purity is 99%, indicating that this two-step aqueous phase preparation method can obtain relatively stable product yield and quality.

[0070] In Comparative Example 1, when the mass ratio of sodium hydrosulfide to 4-hydroxybenzonitrile was reduced to 0.5:1, the reaction of 4-hydroxybenzonitrile was incomplete, and the yield of FBQZ-II decreased to 88%, indicating that appropriately increasing the amount of sodium hydrosulfide is beneficial for the complete reaction of 4-hydroxybenzonitrile. In Comparative Example 2, when the initial mass ratio of ethyl 2-chloroacetoacetate to 4-hydroxybenzonitrile was reduced to 1.1:1, the reaction of FBQZ-I was incomplete, and the yield of FBQZ-II decreased to 87%, indicating that controlling the amount of ethyl 2-chloroacetoacetate within the range specified in this invention is beneficial for improving the degree of reaction of FBQZ-I and the yield of FBQZ-II.

[0071] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0072] The above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the protection scope of the present invention.

Claims

1. A method for preparing a febuxostat intermediate, characterized in that, Includes the following steps: Using water as the reaction solvent, 4-hydroxybenzonitrile was reacted with sodium hydrosulfide, and the resulting reaction system was acidified. After solid-liquid separation, the resulting solid was washed with water until neutral to obtain wet 4-hydroxythiobenzamide. The wet product of 4-hydroxythiobenzamide was directly added to water and reacted with ethyl 2-chloroacetoacetate to obtain ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolylcarboxylate.

2. The preparation method according to claim 1, characterized in that, When preparing the wet product of 4-hydroxythiobenzamide, the mass ratio of water to 4-hydroxybenzonitrile is (3-4):

1.

3. The preparation method according to claim 1, characterized in that, The mass ratio of sodium hydrosulfide to 4-hydroxybenzonitrile is (0.6-0.9):1, based on sodium hydrosulfide solids; the sodium hydrosulfide is added in the form of an aqueous solution of sodium hydrosulfide, and the mass fraction of the aqueous solution of sodium hydrosulfide is 80-90%.

4. The preparation method according to claim 1, characterized in that, The acidic reagent used in the acidification is selected from one or more of formic acid, acetic acid, oxalic acid, hydrochloric acid, and sulfurous acid.

5. The preparation method according to claim 4, characterized in that, The acidic reagent is formic acid, and the mass ratio of formic acid to 4-hydroxybenzonitrile is (0.6-0.9):

1.

6. The preparation method according to claim 1, characterized in that, The temperature at which 4-hydroxybenzonitrile reacts with sodium hydrosulfide is 60-100℃. And / or, the acidification temperature is 60-100°C; And / or, after acidification, the resulting system is cooled to 10-40℃ and kept at that temperature with stirring for 0.5-2 hours, and then the solid-liquid separation and water washing are performed.

7. The preparation method according to claim 1, characterized in that, When the wet product of 4-hydroxythiobenzamide reacts with ethyl 2-chloroacetoacetate, the initial mass ratio of added water to 4-hydroxybenzonitrile is (7-9):

1.

8. The preparation method according to claim 1, characterized in that, The initial mass ratio of ethyl 2-chloroacetoacetate to 4-hydroxybenzonitrile is (1.2-1.4):

1.

9. The preparation method according to claim 1, characterized in that, The wet product of 4-hydroxythiobenzamide is reacted with ethyl 2-chloroacetoacetate at a temperature of 60-90℃ for a time of 0.5-2h.

10. The preparation method according to claim 1, characterized in that, After the reaction of the wet 4-hydroxythiobenzamide with ethyl 2-chloroacetoacetate is completed, the resulting system is cooled to 10-40℃, and the wet 2-(4-hydroxyphenyl)-4-methyl-5-thiazolylcarboxylate is obtained by solid-liquid separation. The obtained wet product is then dried at 60-70℃.

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