Synthesis method and application of febuxostat key intermediate

Abstract

The invention provides a synthesis method of febuxostat and a key intermediate, and belongs to the technical field of medicine synthesis. 4-hydroxybenzaldehyde is used as a raw material and reacts with hydroxylamine hydrochloride and sulfur in continuous flow equipment under the conditions of a photocatalyst, a solvent and illumination to obtain 4-hydroxybenzenesulfamide; the preparation method comprises the following steps: reacting 4-hydroxybenzenesulfamide with ethyl 2-chloroacetoacetate to obtain ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-formate; the preparation method comprises the following steps: reacting 2-(4-hydroxyphenyl)-4-methylthiazole-5-ethyl formate with a cyano source under an illumination condition, so as to obtain 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-ethyl formate; the preparation method comprises the following steps: carrying out etherification reaction on 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-ethyl formate and bromo-iso-butane, so as to obtain the febuxostat key intermediate. The obtained febuxostat key intermediate does not need to be separated, and the febuxostat is synthesized by a two-step one-pot method.

Description

Technical Field

[0001] This application relates to a method for synthesizing febuxostat and key intermediates, belonging to the field of pharmaceutical synthesis technology. Background Technology

[0002] Febuxostat is a non-purine xanthine oxidase inhibitor that treats gout by reducing uric acid formation through inhibition of xanthine oxidase. The core technological logic behind its development lies in structural design targeting the active site of xanthine oxidase, enhancing drug selectivity and affinity through molecular modification. It holds significant development value in the gout treatment market. With the increasing severity of antibiotic resistance globally, the research and optimization of its synthetic process are particularly crucial.

[0003] Currently, the synthetic routes for febuxostat mainly revolve around the construction of key intermediates. Reported routes include those using p-hydroxybenzaldehyde, p-chlorobenzaldehyde, or 2-chloro-4-methylthiazol-5-carboxylic acid as starting materials. The synthesis of these intermediates requires multiple steps, including etherification, cyanation, and condensation. Cyanation reactions typically use highly toxic reagents (such as potassium cyanide and sodium cyanide), require harsh reaction conditions (anhydrous and oxygen-free environments), and pose safety risks. In etherification reactions, the nucleophilic substitution reaction between isobutanol and haloalkanes exhibits poor selectivity and easily generates byproducts, resulting in intermediate yields of only 50-70%, thus limiting the overall synthetic efficiency. Enzymatic catalysis is also an option, but it is too costly and has a long production cycle. Summary of the Invention

[0004] In view of this, this application provides a method for synthesizing a key intermediate of febuxostat, which has the advantages of being green and safe, having low production costs, and high product yield.

[0005] Specifically, this application is implemented through the following scheme: A method for synthesizing a key intermediate of febuxostat, comprising the following steps: Step 1: Using 4-hydroxybenzaldehyde as a raw material, thioamidation reaction is carried out with hydroxylamine hydrochloride and sulfur in a continuous flow device under the conditions of photocatalyst, solvent and light irradiation to obtain 4-hydroxybenzylthioamide. Step 2: 4-hydroxyphenylthioamide reacts with ethyl 2-chloroacetoacetate to give ethyl 2-(4-hydroxyphenyl)-4-methylthiazol-5-carboxylate; Step 3: Under light irradiation, ethyl 2-(4-hydroxyphenyl)-4-methylthiazol-5-carboxylate reacts with a cyano source to obtain ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazol-5-carboxylate. Step four: ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazol-5-carboxylate undergoes an etherification reaction with isobutane bromo to obtain the febuxostat key intermediate.

[0006] The structural formula of the key intermediate of febuxostat is as follows: .

[0007] Furthermore, as a preferred option: In step one, The photocatalyst is an eosin Y photocatalyst.

[0008] The amount of photocatalyst used is 5-20 mol of 4-hydroxybenzaldehyde.

[0009] The illumination refers to 400~420nm.

[0010] The continuous flow device is an AF multi-channel photocatalytic reactor.

[0011] The solvent is at least one of water and acetonitrile.

[0012] In step two, at least one of water and ethanol is added as a solvent.

[0013] In step three, The cyano source is any one of acetonitrile, potassium thiocyanate, or benzoyl cyanide.

[0014] The illumination refers to 400~420nm.

[0015] In step four, N,N-dimethylacetamide (DMAC) was added as a solvent.

[0016] Anhydrous potassium carbonate was added as an alkali.

[0017] The key intermediate for febuxostat synthesized by the above method is used in the synthesis of febuxostat: the synthesis process can directly use the etherification product without separation, and febuxostat can be synthesized in a two-step one-pot method. The process is as follows: sodium hydroxide solution and ethanol are directly added to the etherification reaction product to carry out an alkalization reaction, and then acidified to obtain febuxostat.

[0018] Compared with the prior art, the beneficial effects of this application are as follows: 1) This application uses hydroxylamine hydrochloride as the starting material and combines it with a photocatalytic method to carry out a multi-step photocatalytic and continuous flow process to achieve the synthesis of key intermediates, which greatly reduces the reaction conditions and production costs.

[0019] 2) In the reaction process of this application, acetonitrile and other substances are used as cyano sources to introduce cyano groups under light conditions, which avoids the use of highly toxic reagents such as traditional potassium cyanide and the reaction system is pollution-free.

[0020] 3) This application can obtain a key intermediate with high yield and high purity. This key intermediate does not need to be separated and can be directly obtained from febuxostat in a one-pot two-step process. The process is simple and the conditions are mild. Attached Figure Description

[0021] To more clearly illustrate the technical solutions in the embodiments of this application, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application.

[0022] Figure 1 This is the synthesis roadmap for this application.

[0023] Figure 2 This is the hydrogen NMR spectrum of febuxostat in this application.

[0024] Figure 3 This is the carbon NMR spectrum of febuxostat in this application.

[0025] Figure 4 This is the liquid phase spectrum of febuxostat in this application. Detailed Implementation

[0026] To make the technical problems, technical solutions, and beneficial effects to be solved by this application clearer, the technical solutions in the embodiments of this application will be further described in detail below with reference to the accompanying drawings. It should be understood that the specific embodiments described herein are only used to explain this application and are not intended to limit the technical solutions of this application. All other embodiments obtained by those skilled in the art based on the embodiments in this application without creative effort are within the scope of protection of this application.

[0027] Example 1 This embodiment involves the synthesis of a key intermediate for febuxostat, combined with... Figure 1 The process is as follows: Step 1: Synthesis of 4-hydroxyphenylthioamide: 1.22 g of 4-hydroxybenzaldehyde, 0.71 g of hydroxylamine hydrochloride (NH4OH·HCl), 2.5 g of sulfur (S8), and 0.06 g of Eosin Y photocatalyst were dissolved in 10 mL of acetonitrile. The reaction was carried out in a continuous flow reactor (AF multichannel photocatalytic reactor, Shanghai Shanshi) for 48 h under irradiation with a 20 W, 420 nm blue light source to obtain 4-hydroxybenzylthioamide with a yield of 90.1%.

[0028] Step 2, synthesis of ethyl 2-(4-hydroxyphenyl)-4-methylthiazol-5-carboxylate: 2 g of 4-hydroxyphenylthioamide and 16 mL of ethanol were added to a three-necked flask. The mixture was heated to about 50 °C to dissolve the ethanol. 2.354 g of ethyl 2-chloroacetoacetate was added dropwise using a constant pressure dropping funnel. After the addition was complete, the mixture was heated to reflux and reacted for 2 h. After the reaction was completed, the mixture was cooled to room temperature and 150 mL of water was added. The mixture was then cooled to about 5 °C in an ice bath and stirred to allow crystals to precipitate for 1 h. The crystals were filtered and dried to obtain a white solid, ethyl 2-(4-hydroxyphenyl)-4-methylthiazolyl-5-carboxylate, with a yield of 98.9%.

[0029] Step 3: Synthesis of ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazol-5-carboxylate 2.63 g of ethyl 2-(4-hydroxyphenyl)-4-methylthiazol-5-carboxylate was dissolved in 10 mL of acetonitrile and reacted continuously for 24 h under irradiation with a 20 W, 420 nm blue light source to obtain ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazol-5-carboxylate with a yield of 91.7%.

[0030] Step 4: Take 2g of ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazol-5-carboxylate, add 8mL of DMAC, stir and clarify, then add 1.88g of anhydrous potassium carbonate and 1.4g of bromoisobutane, heat to 90 ℃ and react for 4 h to obtain the key intermediate.

[0031] The key intermediate was identified and detected: it showed a characteristic peak at a residence time of 28.071 min in liquid chromatography, and the yield was as high as 91.7%.

[0032] Example 2 This embodiment has the same setup as Embodiment 1, except that in step three, the cyano source is replaced by acetonitrile with benzoyl cyanide or potassium thiocyanate.

[0033] Under the same conditions, the yield of ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate decreased from 91.7% in Example 1 to 75.5% and 80.2%, respectively.

[0034] Example 3 This embodiment has the same setup as Embodiment 1, except that the light source in Step 1 and Step 3 is replaced by violet light, green light and sunlight, respectively.

[0035] Under the same conditions, the yield of ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate decreased from 91.7% in Example 1 to 87.7%, 85.2%, and 63.2%, respectively.

[0036] Example 4 This embodiment is set up the same as in Example 1, except that in step three, the duration of the continuous reaction is replaced by 6 hours, 12 hours, and 36 hours, respectively. The yields of ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazolium-5-carboxylate were 82.5%, 87.5%, and 91.7%, respectively.

[0037] Example 5 This embodiment describes the synthesis of febuxostat, as follows: Step 1: Synthesis of 4-hydroxyphenylthioamide: 1.22 g of 4-hydroxybenzaldehyde, 0.71 g of hydroxylamine hydrochloride (NH4OH·HCl), 2.5 g of sulfur (S8), and 0.06 g of Eosin Y photocatalyst were dissolved in 10 mL of acetonitrile. The reaction was carried out in a continuous flow reactor in an AF multichannel photocatalytic reactor under irradiation with a 20 W, 420 nm blue light source for 48 h to obtain 4-hydroxybenzylthioamide with a yield of 90.1%.

[0038] Step 2, synthesis of ethyl 2-(4-hydroxyphenyl)-4-methylthiazol-5-carboxylate: 2 g of 4-hydroxyphenylthioamide and 16 mL of ethanol were added to a three-necked flask. The mixture was heated to about 50 °C to dissolve the ethanol. 2.354 g of ethyl 2-chloroacetoacetate was added dropwise using a constant pressure dropping funnel. After the addition was complete, the mixture was heated to reflux and reacted for 2 h. After the reaction was completed, the mixture was cooled to room temperature and 150 mL of water was added. The mixture was then cooled to about 5 °C in an ice bath and stirred to allow crystals to precipitate for 1 h. The crystals were filtered and dried to obtain a white solid, ethyl 2-(4-hydroxyphenyl)-4-methylthiazolyl-5-carboxylate, with a yield of 98.9%.

[0039] Step 3: Synthesis of ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazol-5-carboxylate 2.63 g of ethyl 2-(4-hydroxyphenyl)-4-methylthiazol-5-carboxylate was dissolved in 10 mL of acetonitrile and reacted continuously for 24 h under irradiation with a 20 W, 420 nm blue light source to obtain ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazol-5-carboxylate with a yield of 91.7%.

[0040] Step 4: Take 2g of ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazol-5-carboxylate, add 8mL of DMAC, stir until clear, then add 1.88g of anhydrous potassium carbonate and 1.4g of bromoisobutane. Heat to 90℃ and react for 4 hours. Then, directly add 8mL of 1M NaOH aqueous solution, stir and heat to 50℃. After 2 hours, the reaction is complete. Adjust the pH to around 2 with 1M HCl solution while stirring. Cool to room temperature, add 100mL of purified water, stir for 0.5 hours, filter, wash the filter cake with purified water, and dry in a 60℃ drying oven for 8 hours. Obtain white solid febuxostat, yield 93.5%.

[0041] The obtained febuxostat was tested, and the results were as follows: Figure 2 , 3 As shown in Figure 4, its f1 = 8.23 ​​(d, ) in the proton spectrum J =2.2 Hz, 1H), 8.14 (dd, J = 8.8, 2.3 Hz, 1H), 7.06 (d, J = 8.9 Hz, 1H), 3.94(d, J = 6.5 Hz, 2H), 2.83 (s, 3H), 2.25 (dq, J = 13.3, 6.6 Hz, 1H), 1.13 (d, J A characteristic peak appears at 6.7 Hz (6H), and on the carbon spectrum, it appears at f1=168.68, 167.28, 163.08, 162.76, 132.79, 132.30, 125.76, 121.21, 115.38, 112.70, 103.09, 75.79, 28.21, 19.11, 17.76 ppm. In liquid chromatography, it appears at a residence time of 28.071 min, which is consistent with the characteristic peak of known febuxostat.

[0042] Comparative Example 1 The preparation process of this comparative example is the same as that of Example 5, except that a conventional process is used, that is, the AF multi-channel photocatalytic reactor is replaced with a reaction vessel. The process differences between the two are shown in Table 1.

[0043] Table 1: Differences between different process routes .

[0044] The conventional process route using a reactor not only requires multiple feeding steps but also suffers from transfer losses, making it cumbersome and potentially dangerous. Furthermore, it suffers from issues such as inaccurate feeding, difficulty in feeding during the reaction, incomplete reaction, inability to obtain solids, and the product remaining in the solvent without crystallization. Consequently, the product yield is significantly lower than that of this application.

[0045] This application employs a continuous flow synthesis process for 4-hydroxyphenylthioamide. In terms of safety and operability, the reaction process only requires adjusting the feed pump flow rate and ensuring the feed enters the reaction column in the correct proportions. Furthermore, this application's process route offers fast discharge and reaction rates, facilitating condition screening and variable adjustment in preparation for final crystal precipitation.

[0046] In conclusion, continuous flow processes are more suitable for this reaction.

[0047] Comparative Example 2 CN117924211A is used as comparative example 2.

[0048] Comparative Example 2 prepared febuxostat active pharmaceutical ingredient from p-hydroxybenzonitrile through steps such as sulfidation, Hantzsch cyclization, Duff reaction, etherification, cyanation, hydrolysis, and purification. The Hantzsch cyclization reaction was changed to a two-step process, and lithium hydroxide and barium hydroxide were used instead of sodium hydroxide in the traditional process for the hydrolysis reaction.

[0049] Compared with Comparative Example 2, this application simplifies the process route and reduces the process cost. The seven steps of Comparative Example 2 are reduced to four steps in this application. In the synthesis of 4-hydroxyphenylthioamide, photocatalysis S8 and hydroxylamine hydrochloride are used to introduce thioamide, avoiding the use of strong acid reagents in Comparative Example 2. At the same time, photocatalytic acetonitrile is used as a clean cyano source in this application to directly introduce cyano groups, which simplifies the process flow.

[0050] Comparative Example 3 CN120398736A is used as comparative example 3.

[0051] Comparative Example 3 uses sulfur powder, keto acid and amine as starting materials, and adds a photocatalyst such as eosin Y. At room temperature and under blue light irradiation, thioamide compounds are synthesized through dehydration condensation, photo-oxidation-reduction decarboxylation and coupling sulfur insertion.

[0052] This invention provides a method for preparing febuxostat. This method reduces production costs and solves the problems associated with existing processes that require the use of highly toxic reagents such as potassium cyanide. The method of this invention ensures the safety of the reaction conditions, has a simple post-processing procedure, and uses safe, clean, and inexpensive solvents.

[0053] The above-described embodiments are merely illustrative of several feasible implementations of the present invention, and their descriptions are relatively specific and detailed. However, they should not be construed as limiting the scope of the present invention, nor are the embodiments intended to limit the scope of protection in the claims of the present invention. For those skilled in the art, various modifications and improvements can be made without departing from the concept of the present invention. All equivalent implementations or changes that do not depart from the present invention should be included in the technology of the present invention.

Claims

1. A method for synthesizing a key intermediate of febuxostat, characterized in that, The steps are as follows: Step 1: Using 4-hydroxybenzaldehyde as a raw material, 4-hydroxybenzaldehyde is reacted with hydroxylamine hydrochloride and sulfur in a continuous flow device under photocatalyst, solvent and light conditions to obtain 4-hydroxybenzylthioamide. Step 2: 4-hydroxyphenylthioamide reacts with ethyl 2-chloroacetoacetate to give ethyl 2-(4-hydroxyphenyl)-4-methylthiazol-5-carboxylate; Step 3: Under light irradiation, ethyl 2-(4-hydroxyphenyl)-4-methylthiazol-5-carboxylate reacts with a cyano source to obtain ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazol-5-carboxylate. Step four involves the etherification reaction of ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate with bromoisobutane to yield the key Febuxostat intermediate.

2. The method for synthesizing a key intermediate of febuxostat according to claim 1, characterized in that: In step one, the photocatalyst is eosin Y, and the amount of photocatalyst used is 5 to 20% of the molar amount of 4-hydroxybenzaldehyde.

3. The method for synthesizing a key intermediate of febuxostat according to claim 1, characterized in that: The illumination refers to 400~420nm.

4. The method for synthesizing a key intermediate of febuxostat according to claim 1, characterized in that: The continuous flow device is an AF multi-channel photocatalytic reactor.

5. The method for synthesizing a key intermediate of febuxostat according to claim 1, characterized in that: In step one, the solvent is at least one of water and acetonitrile.

6. The method for synthesizing a key intermediate of febuxostat according to claim 1, characterized in that: In step two, at least one of water and ethanol is added as a solvent.

7. The method for synthesizing a key intermediate of febuxostat according to claim 1, characterized in that: In step three, the cyano source is any one of acetonitrile, potassium thiocyanate, or benzoyl cyanide.

8. The method for synthesizing a key intermediate of febuxostat according to claim 1, characterized in that: In step four, DMAC is added as a solvent.

9. A method for synthesizing febuxostat using the key intermediate described in claim 1.

10. The method for synthesizing febuxostat according to claim 9, characterized in that, The steps are as follows: Step 1: Using 4-hydroxybenzaldehyde as a raw material, 4-hydroxybenzaldehyde is reacted with hydroxylamine hydrochloride and sulfur in a continuous flow device under photocatalyst, solvent and light conditions to obtain 4-hydroxybenzylthioamide. Step 2: 4-hydroxyphenylthioamide reacts with ethyl 2-chloroacetoacetate to give ethyl 2-(4-hydroxyphenyl)-4-methylthiazol-5-carboxylate; Step 3: Under light irradiation, ethyl 2-(4-hydroxyphenyl)-4-methylthiazol-5-carboxylate reacts with a cyano source to obtain ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazol-5-carboxylate. Step four: After the etherification reaction of ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazol-5-carboxylate with isobutane bromide, sodium hydroxide solution and ethanol are directly added to the etherification product for alkalization reaction, followed by acidification to obtain febuxostat.

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