A method for preparing febuxostat

Abstract

This invention provides a method for preparing febuxostat. The route uses ethyl 2-(3-aldehyde-4-hydroxyphenyl)-4-methylthiazolium-5-carboxylate as the starting material, first alkylating the 4-hydroxyl group, then reducing the 3-aldehyde group to a cyano group, and finally hydrolyzing to generate febuxostat. This method is simple to operate, has mild reaction conditions, high yield, low cost, is environmentally friendly, and is suitable for large-scale industrial production of febuxostat.

Description

Technical Field

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

[0002] Febuxostat, as a selective XO inhibitor, has played a significant role in the long-term uric acid-lowering treatment of gout patients. This article summarizes the synthetic route and process of febuxostat. This experiment developed a more optimized method using ethyl 2-(3-aldehyde-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate as the starting material. The method involves first alkylating the 4-hydroxyl group, then reducing the 3-aldehyde group to a cyano group, and finally hydrolyzing to generate febuxostat. This synthetic route, starting from ethyl 2-(3-aldehyde-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate, reduces the process and cost of synthesizing ethyl 2-(3-aldehyde-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate from 3-nitro-4-hydroxybenzaldehyde and p-nitrobenzocyanate, and provides a more optimized route for the synthesis and process of febuxostat. This route is a simple and efficient way to synthesize febuxostat.

[0003] According to the literature review, the main reported synthetic routes are as follows: Route 1: Using 3-nitro-4-hydroxybenzaldehyde as the starting material, the reaction involves 7 steps. Step 5 employs palladium hydroxide / carbon-catalyzed hydrogenation, which is time-consuming and requires harsh conditions, making it unsuitable for industrial production. Step 6 uses highly toxic reagents such as potassium cyanide and cuprous cyanide, posing significant hazards to operators and the environment.

[0004] .

[0005] Route 2: Starting with p-nitrobenzocyanate, this involves 5 steps. Step 1, the preparation of 4-isopropoxy-1,3-phenylenedionitrile, uses the highly toxic reagent potassium cyanide. Furthermore, in step 2, the preparation of 3-cyano-4-isopropoxyphenylthioamide, the selectivity of thioacetamide for the two cyano groups in 4-isopropoxy-1,3-phenylenedionitrile is low, resulting in numerous impurities and a low yield. Therefore, 4-isopropoxy-1,3-phenylenedionitrile is unsuitable as a starting material. Also, 3-cyano-4-isopropoxyphenylthioamide is unstable in acids and easily decomposes, making it unsuitable as a starting material as well.

[0006]

[0007]

[0008] .

[0009] Route 3: Using p-hydroxybenzyl thioamide as the starting material, there are 5 steps in the reaction. Step 2 of the reaction uses polyphosphoric acid (PPA) and hexamethylenetetramine (HMTA). Hexamethylenetetramine is flammable and can easily cause dermatitis and eczema in production personnel. Polyphosphoric acid is too viscous and difficult to stir during the reaction, which will make it difficult for the reaction to proceed completely.

[0010] . Summary of the Invention

[0011] The present invention aims to provide a method for preparing febuxostat that is simple to operate, has mild reaction conditions, high yield, low cost, and is environmentally friendly.

[0012] To achieve the above-mentioned objectives, the present invention provides a method for preparing febuxostat, the specific implementation of which is as follows: The present invention discloses a method for preparing febuxostat, the synthetic route of which is as follows: .

[0013] The present invention discloses a method for preparing febuxostat, the synthetic route of which includes the following steps: 1) Starting with ethyl 2-(3-aldehyde-4-hydroxyphenyl)-4-methylthiazol-5-carboxylate as the starting material I, it reacts with isobutane under heating conditions to obtain intermediate I: ethyl 2-(3-aldehyde-4-isobutoxyphenyl)-4-methylthiazol-5-carboxylate; 2) Intermediate I and hydroxylamine hydrochloride react in a formic acid reflux system to generate intermediate II: ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazol-5-carboxylate; 3) Hydrolysis of intermediate II: using ethanol as solvent, hydrolysis is carried out with sodium hydroxide aqueous solution. After hydrolysis, the pH is adjusted to acidic with dilute hydrochloric acid to obtain crude febuxostat. 4) Febuxostat crude product was recrystallized from anhydrous ethanol to obtain febuxostat.

[0014] The present invention discloses a method for preparing febuxostat, wherein in step 1), the reaction temperature is 50-80℃, the molar ratio of starting material I to bromoisobutane is 1:2-6, the system is cooled to 10-30℃ under stirring to crystallize, and the reaction time is 4-8 hours; the solvent used is one or more combinations of DMF, acetonitrile, petroleum ether, ethanol, and methanol; the molar ratio of starting material I to bromoisobutane is 1:2 to 1:6; the reaction temperature is 50-90℃; and the catalyst used is one or more combinations of potassium iodide, potassium chloride, and potassium bromide.

[0015] The present invention discloses a method for preparing febuxostat, wherein in step 2), the reaction temperature is 90-120℃, preferably 100℃-110℃, the molar ratio of intermediate I to hydroxylamine hydrochloride is 1:1-1:4, the system is stirred and reacted for 6-10 hours, and the solvent used is one or a combination of formic acid, acetic acid, ethanol, and methanol.

[0016] The present invention discloses a method for preparing febuxostat, wherein in step 3), the system is hydrolyzed under alkaline conditions and crystallized under acidic conditions with stirring for 2 hours. The conditions used are hydrolysis with sodium hydroxide aqueous solution and pH adjustment to 2-5 with dilute hydrochloric acid; the solvent used is one or a combination of ethanol, methanol, and ethyl acetate.

[0017] The present invention discloses a method for preparing febuxostat, wherein the solvent used in step 1) is DMF; the molar ratio of starting material I to bromoisobutane is 1:5; the reaction temperature is 70℃; and the catalyst used is potassium iodide.

[0018] The present invention discloses a method for preparing febuxostat, wherein in step 2), the molar ratio of intermediate I to hydroxylamine hydrochloride is 1:2, and the solvent used is formic acid.

[0019] The present invention discloses a method for preparing febuxostat, wherein step 3) involves crystallization under acidic conditions of pH 2-3; and the solvent used is ethanol.

[0020] The present invention discloses a method for preparing febuxostat, the specific steps of which are as follows: 1) 2-(3-aldehyde-4-hydroxyphenyl)-4-methylthiazol-5-carboxylic acid ethyl ester and bromoisobutane, with DMF as solvent, potassium carbonate and potassium iodide added, reacted upon heating to give intermediate I; 2-(3-aldehyde-4-isobutoxyphenyl)-4-methylthiazol-5-carboxylic acid ethyl ester 2) Intermediate I—2-(3-aldehyde-4-isobutoxyphenyl)-4-methylthiazol-5-carboxylic acid ethyl ester was added to hydroxylamine hydrochloride, formic acid, and sodium formate and refluxed to give intermediate II—2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazol-5-carboxylic acid ethyl ester; 3) Intermediate II-2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazol-5-carboxylic acid ethyl ester was hydrolyzed with ethanol as solvent and sodium hydroxide aqueous solution. After hydrolysis, the pH was adjusted to acidic with dilute hydrochloric acid and crystallized to obtain febuxostat crude product. 4) Add the crude febuxostat to anhydrous ethanol, heat until completely dissolved, add activated carbon for decolorization, filter while hot, cool to about 0°C and let stand to crystallize for more than 4 hours, and dry the crystals under vacuum at 60°C for more than 8 hours to obtain the finished febuxostat product.

[0021] Analysis of the beneficial effects of this invention: The present invention overcomes the shortcomings of existing febuxostat preparation methods and technologies in its febuxostat synthesis process. Following the atom-economic synthesis concept of green chemistry, it provides an improved febuxostat preparation method. This method uses ethyl 2-(3-aldehyde-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate as a raw material, enabling the synthesis of febuxostat that meets clinical needs at a lower cost. Furthermore, it is simple to operate, has mild reaction conditions, high yield, low cost, and is environmentally friendly, thus being more environmentally friendly and saving reagents, avoiding solid waste pollution, achieving the goal of green synthesis, and is suitable for large-scale industrial production of febuxostat.

[0022] This invention addresses the problems of expensive and difficult-to-procure materials in existing technologies and processes, as well as the potential for impurities in subsequent reactions during the synthesis route. The product yield prepared by this invention is higher than that of previous processes (the overall yield reaches about 80%), and it uses mild reagents, resulting in less environmental harm and pollution.

[0023] Then, based on the stability of raw materials and intermediates and market supply, the process was successfully optimized, eliminating the cumbersome and complex reactions of the traditional route. This ensures stable and controllable quality while avoiding highly toxic reagents such as potassium cyanide and cuprous cyanide, which pose significant hazards to operators and the environment. Furthermore, this route offers high selectivity, relatively low cost, fewer product impurities, simple operation, mild reaction conditions, and high yield, making it more suitable for practical industrial production. Detailed Implementation

[0024] The following examples are only for further illustration of the present invention and do not limit the scope of the present invention in any way. Example

[0025] Step 1): Preparation of Intermediate I DMF was added to a reaction flask, 1000 ml of which was stirred at 100-150 rpm, and heated to 50-60℃. The temperature was then maintained at 60-70℃. 300 g of starting material I, ethyl 2-(3-aldehyde-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate, was added, along with 20 g of potassium carbonate and 20 g of potassium iodide. The mixture was stirred until homogeneous, and the reaction was maintained at this temperature. Crystallization occurred upon cooling. After centrifugation and washing of the filter cake, a pale yellow solid was obtained. This solid was dried under reduced pressure (vacuum degree ≤ -0.08 MPa) at 40-50℃ for 2-6 hours until constant weight was achieved, yielding 292 g of a yellow solid powder (intermediate I), with a yield of 95.8%. Step 2): Preparation of Intermediate II 1000 ml of formic acid was added to the reaction flask, and the stirrer was started at 100-200 rpm. 292 g of intermediate I was added while stirring, and the mixture was heated to 100-110 °C and refluxed. After the system was dissolved, 40 g of hydroxylamine hydrochloride and 60 g of sodium formate were added. The reaction was maintained at this temperature for 6 hours, and then cooled to allow crystals to precipitate. After centrifugation and washing of the filter cake, 264 g of a white solid powder was obtained (intermediate II), yield 96.8%. Step 3): Preparation of crude product 1000 ml of anhydrous ethanol was added to the reaction flask. 264 g of intermediate II was added with stirring, and the feed port of the reaction flask was rinsed with a small amount of anhydrous ethanol. After the addition was complete, the temperature was maintained at 60-70℃ with stirring. After the solution was dissolved, 200 ml of sodium hydroxide aqueous solution was added for hydrolysis for 1 h. After hydrolysis, the pH was adjusted to 2-3 with dilute hydrochloric acid, and the temperature was lowered to 0-10℃ for crystallization for 2-4 h. The mixture was filtered, and the filter cake was washed twice with cold purified water, then washed twice with cold anhydrous ethanol, and then dried under vacuum. The filter cake was dried under reduced pressure at 40-50℃ (vacuum degree ≤ -0.08 MPa) for 2-6 h until constant weight was obtained, yielding 269 g of a white to off-white solid (crude febuxostat), with a yield of 93.8%. Step 4): Preparation of febuxostat product 1000 ml of anhydrous ethanol and 242 g of crude febuxostat were added to a reaction flask. After complete dissolution by heating, 2.4 g of activated carbon was added. The mixture was filtered while hot, and then slowly cooled to 0-10 °C to allow crystals to precipitate. After filtration and washing, 226 g of white to off-white solid febuxostat was obtained, with a yield of 95.8%. Example

[0026] Step 1) The three-necked reaction flask was heated to 40-50°C, and the other conditions were the same as in Example 1. The yield of intermediate I in Step 1) was only 80.87%. Example

[0027] Step 2) The three-necked reaction flask was heated to 80-90°C, and the other conditions were the same as in Example 1. The yield of intermediate I in Step 1) was 82.87%. Example

[0028] In step 2), the solvent formic acid was replaced with acetic acid, and the other conditions were the same as in Example 1. The yield of intermediate II in step 2) was only 82.95%. Example

[0029] In step 3), the solvent ethanol was replaced with methanol, and the other conditions were the same as in Example 1. The yield of febuxostat crude product in step 3) was only 81.05%. Example

[0030] In step 3), the solvent ethanol was replaced with methanol, and the other conditions were the same as in Example 1. The yield of febuxostat crude product in step 3) was 79.87%.

[0031] Through the above embodiments, it was found that the most preferred conditions for the preparation method of the present invention are: in step 1), the reaction temperature is 60-70℃; in step 2), the solvent is formic acid; and in step 3), the solvent is ethanol. The final yield of intermediate I is 95.8%, the yield of intermediate II is 96.8%, and the yield of febuxostat crude product is 95.8%. The yields of each step are all above 95%, and the purity of febuxostat can also reach above 99%.

Claims

1. A method for preparing febuxostat, characterized in that, The synthetic route of this method is as follows: 。 2. The method for preparing febuxostat according to claim 1, characterized in that, The synthesis route steps of this method are as follows: 1) Starting with ethyl 2-(3-aldehyde-4-hydroxyphenyl)-4-methylthiazol-5-carboxylate as the starting material I, it reacts with isobutane under heating conditions to obtain intermediate I: ethyl 2-(3-aldehyde-4-isobutoxyphenyl)-4-methylthiazol-5-carboxylate; 2) Intermediate I and hydroxylamine hydrochloride react in a formic acid reflux system to generate intermediate II: ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazol-5-carboxylate; 3) Hydrolysis of intermediate II: using ethanol as solvent, hydrolysis is carried out with sodium hydroxide aqueous solution. After hydrolysis, the pH is adjusted to acidic with dilute hydrochloric acid to obtain crude febuxostat. 4) Febuxostat crude product was recrystallized from anhydrous ethanol to obtain febuxostat.

3. The method for preparing febuxostat according to claim 2, characterized in that, In step 1), the reaction temperature is 50-80℃, the molar ratio of starting material I to bromoisobutane is 1:2-6, the system is cooled to 10-30℃ under stirring to crystallize, and the reaction time is 4-8 hours; the solvent used is one or more combinations of DMF, acetonitrile, petroleum ether, ethanol, and methanol; the molar ratio of starting material I to bromoisobutane is 1:2 to 1:6; the reaction temperature is 50-90℃; the catalyst used is one or more combinations of potassium iodide, potassium chloride, and potassium bromide.

4. The method for preparing febuxostat according to claim 2, characterized in that, In step 2), the reaction temperature is 90-120℃, preferably 100℃-110℃ during reflux reaction. The molar ratio of intermediate I to hydroxylamine hydrochloride is 1:1-1:

4. The system is stirred during reaction, and the reaction time is 6-10 hours. The solvent used is one or a combination of formic acid, acetic acid, ethanol, and methanol.

5. The method for preparing febuxostat according to claim 2, characterized in that, The system in step 3) is hydrolyzed under alkaline conditions and crystallized under acidic conditions with stirring for 2 hours. The conditions used are hydrolysis with sodium hydroxide aqueous solution and pH adjustment to 2-5 with dilute hydrochloric acid. The solvent used is one or a combination of ethanol, methanol, and ethyl acetate.

6. The method for preparing febuxostat according to claim 3, characterized in that, The solvent used in step 1) is DMF; the molar ratio of starting material I to bromoisobutane is 1:5; the reaction temperature is 70℃; and the catalyst used is potassium iodide.

7. The method for preparing febuxostat according to claim 4, characterized in that, In step 2), the molar ratio of intermediate I to hydroxylamine hydrochloride is 1:2, and the solvent used is formic acid.

8. The method for preparing febuxostat according to claim 5, characterized in that, Step 3) is performed under acidic conditions at pH 2-3 for crystallization; the solvent used is ethanol.

9. A method for preparing febuxostat according to any one of claims 1-8, characterized in that, The specific steps of this method are as follows: 1) 2-(3-aldehyde-4-hydroxyphenyl)-4-methylthiazol-5-carboxylic acid ethyl ester and bromoisobutane, with DMF as solvent, potassium carbonate and potassium iodide added, reacted upon heating to give intermediate I; 2-(3-aldehyde-4-isobutoxyphenyl)-4-methylthiazol-5-carboxylic acid ethyl ester 2) Intermediate I—2-(3-aldehyde-4-isobutoxyphenyl)-4-methylthiazol-5-carboxylic acid ethyl ester was added to hydroxylamine hydrochloride, formic acid, and sodium formate and refluxed to give intermediate II—2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazol-5-carboxylic acid ethyl ester; 3) Intermediate II-2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazol-5-carboxylic acid ethyl ester was hydrolyzed with ethanol as solvent and sodium hydroxide aqueous solution. After hydrolysis, the pH was adjusted to acidic with dilute hydrochloric acid and crystallized to obtain febuxostat crude product. 4) Add the crude febuxostat to anhydrous ethanol, heat until completely dissolved, add activated carbon for decolorization, filter while hot, cool to about 0°C and let stand to crystallize for more than 4 hours, and dry the crystals under vacuum at 60°C for more than 8 hours to obtain the finished febuxostat product.

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