Preparation process of febuxostat

Abstract

The invention discloses a febuxostat preparation process, belongs to the technical field of medicine synthesis, and particularly relates to a preparation method and application of febuxostat. The method comprises the following steps: carrying out etherification reaction on 2-(3-aldehyde-4-isobutoxyphenyl)-4-methylthiazole-5-ethyl formate, carrying out cyanidation reaction, and carrying out ester hydrolysis reaction, so as to prepare the febuxostat bulk drug. According to the method, potassium trimethylsilanolate or sodium trimethylsilanolate is used for replacing sodium hydroxide in a traditional process in the ester hydrolysis step, so that side reaction of ester hydrolysis is avoided, production steps are reduced, and the production cycle and cost are greatly reduced. The purity of the prepared febuxostat finished product is greater than 99.9%, and the prepared febuxostat finished product has great market competitive advantages and is green and environment-friendly.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and particularly relates to an improved method for the preparation process of febuxostat. Background Art

[0002] Gout is a group of chronic metabolic disorders caused by purine metabolism disorder. For a long time, disabling arthritis headed by gout has been an important killer endangering human health, causing symptoms such as joint swelling, numbness, and limited movement at the mildest, and joint deformation and disability at the worst.

[0003] Febuxostat (2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid) is the first new generation non-xanthine xanthine oxidase inhibitor. It inhibits the activity of xanthine oxidase, prevents and reduces the synthesis of uric acid from hypoxanthine and xanthine, thereby achieving the purpose of lowering blood uric acid. Clinical trials have shown that it is well tolerated and can effectively control blood and urine levels. It is clinically used to treat gout.

[0004] The drug was first applied for listing in Japan by Teijin in early 2004, and IPSEN applied for listing in Europe. The FDA approved it for listing in the United States in February 2009. The domestic synthesis of the drug is mainly the following route:

[0005]

[0006] The finished product of Febuxostat is generated by etherification, cyanidation and hydrolysis. However, in the ester hydrolysis reaction, the existing patents all use sodium hydroxide as a hydrolysis agent (see CN109320474B, CN110229117B). It is found in the experiment that when sodium hydroxide is used to carry out the ester hydrolysis reaction, because the sodium hydroxide alkalinity is strong and non-selective, it must be reacted in an aqueous system at the same time, resulting in a large amount of hydrolysis of the cyano structure of intermediate 2 in this step reaction, generating amide impurities (impurity A) and carboxylic acid impurities (impurity B), which are both similar to the structure of Febuxostat and are difficult to remove. Such processes all need to be refined at least once in the later stage, to further remove the above two impurities, resulting in the quality of Febuxostat prepared by this process cannot be guaranteed. Therefore, the market is in urgent need of a kind of ester hydrolysis agent that can react in an anhydrous system and can be selective. Summary of the invention

[0007] The present invention provides an improved and efficient method for preparing 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid (febuxostat), wherein the febuxostat prepared by the method does not contain amide byproducts (impurity A) and carboxylic acid byproducts (impurity B). An improved method for preparing febuxostat of the present invention is carried out according to the following steps:

[0008] S1: 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester is used as a raw material and isobutyl bromide is reacted to obtain 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester as intermediate I;

[0009] S2: Using 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester as a raw material, adding hydroxylamine hydrochloride in an acidic system to carry out a cyanation reaction to obtain 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester as intermediate II;

[0010] S3: Using 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester as a raw material, an ester hydrolysis reaction is carried out in an anhydrous system of potassium trimethylsiliconate or sodium trimethylsiliconate to produce febuxostat.

[0011] Furthermore, the ratio of 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester to isobutane bromide is 1:1 to 2 eq.

[0012] Furthermore, the etherification reaction condition is 80-100°C.

[0013] Furthermore, the ratio of ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate to hydroxylamine hydrochloride is 1:2 eq.

[0014] Furthermore, the reaction conditions of the cyanation reaction are 90-100°C.

[0015] Furthermore, the usage ratio of ethyl 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylate to potassium trimethylsiliconate or sodium trimethylsiliconate is 1:1 to 2 eq.

[0016] Furthermore, the reaction conditions of the ester hydrolysis reaction are 20-25°C.

[0017] Furthermore, the content of febuxostat prepared by S3 is not less than 99.9%.

[0018] Furthermore, the acidic system described in S2 is a system with a pH of 4 to 6.

[0019] The present invention has found that potassium trimethylsiliconate or sodium trimethylsiliconate meets the characteristics of febuxostat in reacting in an anhydrous system and being able to selectively hydrolyze esters. Therefore, the ester hydrolysis reagent is replaced with potassium trimethylsiliconate or sodium trimethylsiliconate. Since potassium trimethylsiliconate or sodium trimethylsiliconate can react in an anhydrous system and has high selectivity in ester hydrolysis, byproduct impurities A and byproduct impurities B will not be generated, thereby obtaining febuxostat with higher purity.

[0020] Reaction routes such as:

[0021]

[0022] The structure of impurity A is as follows:

[0023]

[0024] The structure of impurity B is as follows:

[0025]

[0026] The present invention has the following beneficial effects:

[0027] 1) The route of the present invention replaces the aqueous sodium hydroxide solution used in the ester hydrolysis step in the domestic synthesis route with an anhydrous system of potassium trimethylsiliconate or sodium trimethylsiliconate, which can effectively avoid the side reaction of cyano hydrolysis during the ester hydrolysis process and produce high-purity febuxostat.

[0028] 2) In the previous process, the product produced during the ester hydrolysis process was more by-products, so it was necessary to purify the prepared product at least once to improve the purity. However, the product prepared by the route of the present invention does not need to be purified and can reach a content of 99.9%, which can effectively reduce the production steps and cycle and save costs.

[0029] 3) In the previous process, the reaction temperature of the ester hydrolysis step needs to be 40-60°C, while the ester hydrolysis temperature of the route of the present invention only needs to be room temperature, which can effectively reduce the production cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 is the HPLC spectrum of intermediate I;

[0031] Figure 2 is the HPLC spectrum of intermediate II;

[0032] Figure 3 HPLC profile of febuxostat prepared by this process;

[0033] Figure 4 HPLC spectrum of Febuxostat prepared by sodium hydroxide hydrolysis process (other patented process). DETAILED DESCRIPTION

[0034] In order to make the objectives, technical solutions and advantages of the embodiments of the present invention more clearly understood, the spirit of the contents disclosed by the present invention will be described in detail below. After understanding the embodiments of the contents of the present invention, any technician in the relevant technical field can change and modify them according to the techniques taught by the contents of the present invention without departing from the spirit and scope of the contents of the present invention.

[0035] The exemplary embodiments of the present invention and the description thereof are used to explain the present invention but are not intended to limit the present invention.

[0036] Example

[0037] Example 1: Preparation of ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate

[0038] Add 3.7 kg N,N-dimethylacetamide, 1.0 kg ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate to the reactor, start stirring, add 0.95 kg potassium carbonate, add 0.7 kg isobutane bromide; heat to 90°C and start timing reaction for 4 hours, then stop the reaction; cool the feed liquid to 0-10°C; add 8.0 kg purified water, stir and crystallize at 0-10°C for 0.5 hours, discharge, centrifuge, wash with 4.0 kg purified water, spin dry, and dry; obtain ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate as intermediate I; intermediate I is about 1.2 kg, and the yield is 99%. The HPLC spectrum of intermediate I is shown in Figure 1 .

[0039] Example 2: Preparation of ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate

[0040] Add 11.5 kg of formic acid, 1.2 kg of ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate, 0.3 kg of hydroxylamine hydrochloride and 0.4 kg of sodium formate to the reaction kettle, and start stirring; heat the liquid to 100°C, react for 8 hours, then cool the liquid to 0-10°C, add 9.4 kg of purified water, stir and crystallize for 0.5 hours; discharge the material and centrifuge, wash with 4.7 kg of purified water, spin dry, and dry; obtain ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate as intermediate II; intermediate II is about 1.1 kg, and the yield is 98%. The HPLC spectrum of intermediate II is shown in Figure 2 .

[0041] Example 3: Preparation of Febuxostat

[0042] Add 7.1 kg of THF, 1.1 kg of ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate, and 492 g of potassium trimethylsilanol into the reactor; start stirring, react at 25°C, react for 3-4 hours, and then stop the reaction; filter, collect the filtrate, and add 1 M hydrochloric acid dropwise with stirring to adjust the pH to 2-3; after the addition is complete, add 9.0 kg of purified water and stir for 0.5 hour; discharge, wash with 4.5 kg of purified water, spin dry, and dry to obtain about 1.0 kg of Febuxostat, with a yield of 99% and a purity of >99.9%.

[0043] Example 4: Preparation of Febuxostat

[0044] Add 7.1 kg of THF, 1.1 kg of ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate, and 430 g of sodium trimethylsiliconol into the reactor; start stirring, react at 25°C, react for 3-4 hours, and then stop the reaction; filter, collect the filtrate, and add 1 M hydrochloric acid dropwise with stirring to adjust the pH to 2-3; after the addition is complete, add 9.0 kg of purified water and stir for 0.5 hour; discharge, wash with 4.5 kg of purified water, spin dry, and dry to obtain about 1.0 kg of Febuxostat, with a yield of 99% and a purity of >99.9%.

[0045] The HPLC profile of Febuxostat API is shown in Figure 3 .

[0046] The HPLC spectrum of Febuxostat (sodium hydroxide hydrolysis process) API is shown in Figure 4 .

[0047] By comparison, it can be seen that the hydrolysis process of Febuxostat sodium hydroxide ( Figure 4 ) are both greater than the impurities A and B in the Febuxostat sodium trimethylsiliconate / potassium trimethylsiliconate process ( Figure 3 ).

Claims

1. A process for preparing Febuxostat, characterized in that It is carried out according to the following steps: S1: 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester is used as a raw material and isobutyl bromide is reacted to obtain 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester as intermediate I; S2: Using 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester as a raw material, adding hydroxylamine hydrochloride in an acidic system to carry out a cyanation reaction to obtain 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester as intermediate II; S3: Using 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester as a raw material, an ester hydrolysis reaction is carried out in an anhydrous system of potassium trimethylsiliconate or sodium trimethylsiliconate to produce febuxostat.

2. A process for preparing Febuxostat according to claim 1, characterized in that The dosage ratio of 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester to brominated isobutane is 1:1 to 2 eq.

3. A process for preparing Febuxostat according to claim 1, characterized in that The etherification reaction condition is 80-100°C.

4. A process for preparing Febuxostat according to claim 1, characterized in that The ratio of ethyl 2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylate to hydroxylamine hydrochloride is 1:2eq.

5. A process for preparing Febuxostat according to claim 1, characterized in that The reaction condition of the cyanidation reaction is 90-100°C.

6. A process for preparing Febuxostat according to claim 1, characterized in that The usage ratio of ethyl 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylate to potassium trimethylsiliconate or sodium trimethylsiliconate is 1:1 to 2 eq.

7. A process for preparing Febuxostat according to claim 1, characterized in that The reaction condition of the ester hydrolysis reaction is 20-25°C.

8. A process for preparing Febuxostat according to claim 1, characterized in that The content of febuxostat prepared by S3 is not less than 99.9%.

9. A process for preparing Febuxostat according to claim 1, characterized in that The acidic system described in S2 is a system with a pH of 4 to 6.

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