Febuxostat and its intermediates and their synthesis

Abstract

The present invention relates to Febuxostat and intermediates and their synthesis. Specifically, it relates to a method for synthesizing 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester, which comprises the following steps: (1) adding the reactant 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester to a mixture of polyphosphoric acid and methanesulfonic acid, and stirring evenly; (2) adding Duff reaction reagent hexamethylenetetramine to the above reaction mixture under stirring, continuing the reaction, and cooling; (3) adding saturated ice salt water, precipitating solids, filtering, washing the solids with water until neutral, and drying to obtain. It also relates to a 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester and its use for preparing Febuxostat. The method of the present invention has excellent performance.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and relates to a xanthine oxidase inhibitor, in particular to a drug compound Febuxostat for gout, and also to an intermediate for preparing the Febuxostat. The preparation method of Febuxostat and its intermediate of the present invention has excellent performance. Background Art

[0002] Hyperuricemia is caused by increased uric acid production and / or decreased renal uric acid secretion, and it is the most dangerous factor for inducing gout. Using drugs to reduce blood uric acid concentration is one of the common methods to prevent gout. Such drugs include uricosuric drugs and xanthine oxidase / xanthine dehydrogenase inhibitors that can block the absorption of uric acid by the renal tubular membrane. However, uricosuric drugs are contraindicated in patients with renal dysfunction, and patients with normal renal function will alkalinize their urine when using such drugs. Allopurinol is the only xanthine oxidase / xanthine dehydrogenase inhibitor currently on the market, but it is only used for the following three types of patients: patients whose blood uric acid concentration cannot be reduced to 70 mg / L by uricosuric drugs, patients who cannot tolerate uricosuric drugs, and patients with gout due to increased uric acid production and renal dysfunction. Allopurinol also has obvious adverse reactions, such as hepatitis, nephropathy, and allergic reactions.

[0003] Since the inhibition of xanthine oxidase is the mechanism for preventing gout, researchers have set their sights on the development of drugs that are safer and more effective than allopurinol. Looking back at the gout treatment drug market in the past two years, it is not difficult to see that it is difficult to see new products on the market in this field, and the market is still dominated by allopurinol and benzbromarone. Both drugs are used in the remission period, the former mainly inhibits the production of uric acid, and the latter mainly promotes excretion.

[0004] Febuxostat, also known as Febuxostat, chemical name: 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid, English name: 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid, its molecular formula is: C 16 H 16 N2O3S, molecular weight is 316.38, chemical structure is:

[0005]

[0006] Febuxostat is a new generation of anti-gout drugs synthesized by Teijin, which shows excellent activity. It is a selective xanthine oxidase / xanthine dehydrogenase inhibitor with good application prospects. Teijin submitted an application for Febuxostat tablets with a dosage of 20-40 mg in Japan in April 2004. Febuxostat compounds have been licensed to Ipsen in Europe and SK Chemical in South Korea for development. In May 2008, the European Union approved Ipsen's Febuxostat (Adenuric) for marketing, which is used to treat chronic hyperuricemia of gout. In February 2009, the FDA approved TAKEDA's Febuxostat (ULORIC) for marketing in the United States, with specifications of 40mg and 80mg.

[0007] There are not many anti-gout drugs currently, and clinical treatment mainly focuses on colchicine, nonsteroidal anti-inflammatory drugs, hormones, drugs that promote uric acid excretion (such as probenecid, sulfinpyrazone and benzbromarone) and drugs that inhibit uric acid synthesis (allopurinol). These drugs have defects in treatment. Poor efficacy and large side effects have become bottlenecks in their clinical application. Febuxostat is more effective and specific than allopurinol, the current standard drug for the treatment of gout, and is the first new drug for the treatment of hyperuricemia in 40 years.

[0008] Febuxostat is a non-purine xanthine oxidase inhibitor, and its basic mechanism of action is similar to that of allopurinol. However, allopurinol is associated with significant allergic reactions, while febuxostat has not shown cross-reaction with allopurinol. Moreover, febuxostat has a high safety profile in patients with renal failure. In terms of effectiveness, febuxostat 80 mg / d showed superior uric acid reduction than allopurinol 300 mg / d.

[0009] A multicenter, double-blind, randomized clinical study evaluated the safety and efficacy of Febuxostat for gout. A total of 136 male and 17 female gout patients were randomly assigned to receive placebo or this product (40, 80 or 120 mg / d). After 4 weeks, it was found that the serum uric acid (sUA) concentration of patients in each dose group of this product was significantly lower than that before treatment. The average decrease in each group from low to high dose was 37%, 44% and 59%, respectively, while the sUA concentration of patients in the placebo group was only reduced by 2%; and the sUA concentration of patients in the placebo group and each dose group from low to high dose dropped to below 60 mg / L accounted for 0%, 56%, 76% and 94%, respectively; the vast majority of patients persisted in completing the trial, and the incidence of adverse reactions in the Febuxostat and placebo groups was similar, 54% and 50%, respectively, and most of these adverse reactions were mild and self-limiting.

[0010] Like allopurinol, febuxostat blocks the formation of uric acid, which crystals deposit in the joints of gout patients, causing painful swelling. However, allopurinol inhibits a series of enzymes involved in the uric acid pathway, while febuxostat only inhibits xanthine oxidase, making its action more specific. Dr. MacDonald of TAP believes that this difference in action theoretically makes febuxostat safer than allopurinol. Allopurinol can cause side effects in about 1% to 2% of patients, 25% of which are even fatal. In particular, this product is mainly metabolized in the liver and may be more suitable for patients with renal failure, while allopurinol is excreted through the kidneys.

[0011] Febuxostat is a non-hygroscopic white crystalline powder that is easily soluble in dimethylformamide, dimethyl sulfoxide, slightly soluble in ethanol, slightly soluble in methanol and acetonitrile, and basically insoluble in water. The melting point ranges from 205°C to 208°C.

[0012] Prior art discloses many methods for preparing Febuxostat. For example, Chinese patent application No. 200910170029.3 (Meidi Kangxin) discloses an improved method for synthesizing Febuxostat, which uses p-cyanophenol as a starting material to prepare Febuxostat, first reacts with ethyl 2-bromoacetoacetate to form a thiazole ring; uses the Duff reaction to introduce an aldehyde group at the ortho position of the phenolic hydroxyl group to generate an aldehyde group substitution compound, then alkylates the 4-hydroxyl group, and then reduces the 3-aldehyde group to a cyano group to obtain a key intermediate 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester, and finally hydrolyzes under alkaline conditions to obtain Febuxostat. It is believed that the whole process of the method does not involve high temperature, high pressure, flammable, explosive, highly toxic and other operations, and the raw materials and reagents are all cheap common reagents, which are easily available on the market, and each step can obtain a solid product, which is easy to transport and store, and the cost is greatly reduced, which is very suitable for industrialized mass production.

[0013] Chinese patent application No. 201010022543.5 (drug source drug) relates to a method for preparing Febuxostat. In this method, the cheap and readily available 2,4-dihalogenated phenol (compound 1) is used as the starting material, and Febuxostat is synthesized through a new route of alkylation, cyanation, thioformylation, cyclization, and deprotection. It is believed that this method has a short route and uses low-toxic cuprous cyanide for cyanation, avoiding the use of highly toxic compounds such as potassium cyanide and sodium cyanide, so the process safety is greatly improved.

[0014] Chinese patent application No. 201210471769.2 (Ge Changle) relates to a new process for preparing Febuxostat, comprising reacting 2-hydroxy-5-cyano-benzaldehyde with NaSH in a solvent to obtain 3-formyl-4-hydroxythiobenzamide; then reacting 3-formyl-4-hydroxythiobenzamide with 2-halogenated ethyl acetoacetate to close the ring to obtain 2-(3-formyl-4-hydroxyphenyl)-4-methyl-5-ethoxycarbonylthiazole; then reacting with hydroxylamine in a formic acid solution to obtain 2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-ethoxycarbonylthiazole; then reacting with halogenated isobutane under the action of potassium carbonate to obtain 2-(3-formyl-4-isobutyloxyphenyl)-4-methyl-5-ethoxycarbonylthiazole; finally, hydrolyzing with sodium hydroxide to remove the ester group to obtain the product Febuxostat. It is believed that this method has a relatively simple process, good reproducibility, and the raw materials and reagents used are easily available and less toxic, avoiding the use of cyanide, with few by-products, low pollution, high yield, low cost, short production cycle, and easy quality control, making it suitable for industrial production.

[0015] Chinese patent application No. 201210518579.1 (China Resources Secco) relates to a method for preparing high-purity febuxostat, which uses 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester and distilled isobutyl bromide to form an ether, and then obtains a crude febuxostat by cyanation and hydrolysis, and obtains high-purity febuxostat after recrystallization. In the febuxostat prepared by this method, the impurity 2-[3-cyano-4-n-propoxyphenyl]-4-methylthiazole-5-carboxylic acid content is less than 0.10%.

[0016] Chinese patent application No. 201210556647.3 (Yuekang Kaiyue) relates to a method for preparing Febuxostat, which comprises adding 29.5-30.5 kg of a compound of formula (I) and 20-25 L of DMF to a reaction vessel, stirring and dissolving, adding 4.15-4.25 kg of anhydrous potassium carbonate and 3.3-3.5 kg of isobutyl bromide, heating to 94-97 ° C for reaction for 5-7 hours; cooling to room temperature after the reaction, adding 22-24 L of water, extracting with the same volume of ethyl acetate three times, combining the organic layers, concentrating to obtain a light yellow solid, and recrystallizing with 24-26 L of DMF; filtering, washing the filter cake with DMF, and drying to obtain a white solid, i.e., a compound of formula (II). It is believed that the method has a simple preparation process, is suitable for industrial production, has a high yield, and effectively shortens the reaction time. At the same time, the refining process is relatively simple and the product purity is high.

[0017] Chinese patent application No. 201310220003.1 (South China University of Technology) discloses a method for preparing Febuxostat, which uses 4-hydroxybenzonitrile and thioacetamide as raw materials, reacts in a hydrochloric acid solution to obtain 4-hydroxythiobenzamide, reacts the 4-hydroxythiobenzamide with ethyl 2-chloroacetoacetate to obtain ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate, reacts the obtained compound with hexamethylenetetramine in a mixed acid system of methanesulfonic acid and trifluoroacetic acid to obtain ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate, and reacts the compound with hydroxylamine hydrochloride, potassium carbonate, isobutane bromide, etc. in a polar protic solvent to synthesize ethyl 2-(3-nitrile-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate in a "one-pot method", and finally hydrolyzes the compound under alkaline conditions to obtain the target product Febuxostat. It is believed that the method has an overall yield of up to 66%, reduces the number of separation steps, does not involve any highly toxic substances, and has less environmental pollution.

[0018] The following reaction process is a method summarized in patents JP1998045733 and JP1994329647 using hydroxythiobenzamide as the starting material, which are respectively referred to as method 3 (synthetic route 3) and method 4 (synthetic route 4). The reaction process is: using 4-hydroxythiobenzamide as a raw material, first reacting with ethyl 2-bromoacetoacetate under reflux to form a thiazole ring; introducing an aldehyde group at the ortho position of the phenolic hydroxyl group through the Duff reaction to generate an aldehyde substituted compound, then alkylating the 4-hydroxyl group, and then reducing the 3-aldehyde group to a cyano group. The reaction order of method 4 is opposite to that of method 3; the last step is to generate febuxostat by hydrolysis of the ester group.

[0019]

[0020] In the above-mentioned Duff reaction of introducing an aldehyde group at the ortho position of a phenolic hydroxyl group to generate an aldehyde group-substituted compound, a typical method (e.g., CN102086169) is to react 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester to generate 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester in the presence of methanesulfonic acid, polyphosphoric acid, and hexamethylenetetramine. In this method, a large amount of methanesulfonic acid is used, which has a strong corrosive effect on metals such as iron, and has a strong irritating effect on skin and mucous membranes, such as methanesulfonic acid. The amount of methanesulfonic acid is seven times the amount of the reactant 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester added. Therefore, it is still a pressing expectation of those skilled in the art to improve the existing method for synthesizing 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester, and then contribute to improving the synthetic method of Febuxostat. Summary of the invention

[0021] The purpose of the present invention is to provide a method for synthesizing ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate, and it is expected that the method will present one or more desired technical effects, thereby contributing to improving the synthesis method of febuxostat. The inventors have found that the use of the synthesis process of the present invention can not only improve the yield of chemical synthesis, but also reduce the amount of harmful chemical reagents used and reduce production costs.

[0022] To this end, the present invention relates to a method for synthesizing ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate, which comprises the following steps:

[0023] (1) adding the reactant ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate to a uniform mixture of polyphosphoric acid and methanesulfonic acid preheated to 70 to 100° C. and stirring uniformly;

[0024] (2) adding hexamethylenetetramine, a Duff reaction reagent, to the above reaction mixture under stirring, and continuing the reaction at a temperature of 70 to 100° C. for 4 to 8 hours. After the reaction is completed, the reaction mixture is cooled to 35 to 40° C.;

[0025] (3) Slowly add saturated ice brine to the cooled reaction mixture, filter after the precipitated solid, wash the solid with water until it is neutral, and dry to obtain the product.

[0026] According to the method of the first aspect of the present invention, the amount of polyphosphoric acid added is 1.5 to 3 molar times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

[0027] According to the method of the first aspect of the present invention, the amount of polyphosphoric acid added is 1.5 to 2.5 mole times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

[0028] According to the method of the first aspect of the present invention, the amount of polyphosphoric acid added is 1.5 to 2 molar times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

[0029] According to the method of the first aspect of the present invention, the amount of methanesulfonic acid added is 2 to 4 molar times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

[0030] According to the method of the first aspect of the present invention, the amount of methanesulfonic acid added is 2 to 3.5 mole times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

[0031] According to the method of the first aspect of the present invention, the amount of methanesulfonic acid added is 2 to 3 molar times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

[0032] According to the method of the first aspect of the present invention, the amount of hexamethylenetetramine added is 1 to 1.5 mole times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

[0033] According to the method of the first aspect of the present invention, the amount of hexamethylenetetramine added is 1.1 to 1.5 mole times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

[0034] According to the method of the first aspect of the present invention, the amount of hexamethylenetetramine added is 1.2 to 1.5 mole times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

[0035] According to the method of the first aspect of the present invention, cyclohexane is also added to the mixture of polyphosphoric acid and methanesulfonic acid. In one embodiment, the amount of cyclohexane added is 0.02 to 0.05 mole times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate. In one embodiment, the amount of cyclohexane added is 0.02 to 0.04 mole times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

[0036] According to the method of the first aspect of the present invention, boric acid is also added to the mixture of polyphosphoric acid and methanesulfonic acid. In one embodiment, the addition of the boric acid is 0.002 to 0.01 mole times of 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester. In one embodiment, the addition of the boric acid is 0.002 to 0.005 mole times of 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester. It has been unexpectedly found that adding a trace amount of cyclohexane and boric acid in the reactant simultaneously can make it possible to achieve a reaction yield comparable or even higher than the existing method when the addition of methanesulfonic acid is less, and the purity of the reaction product has not deteriorated.

[0037] According to the method of the first aspect of the present invention, in step (1), the reaction reagent is preheated to a temperature of 80 to 100° C. For example, in step (1), the reaction reagent is preheated to a temperature of 80° C. For example, in step (1), the reaction reagent is preheated to a temperature of 90° C. For example, in step (1), the reaction reagent is preheated to a temperature of 100° C.

[0038] According to the method of the first aspect of the present invention, the reaction is continued at a temperature of 80 to 100° C. for 4 to 8 hours in step (1). For example, the reaction is continued at a temperature of 80 to 100° C. for 5 to 8 hours in step (1). For example, the reaction is continued at a temperature of 80 to 100° C. for 5 to 8 hours in step (1). For example, the reaction is continued at a temperature of 80° C. for 5 to 8 hours in step (1). For example, the reaction is continued at a temperature of 90° C. for 5 to 8 hours in step (1). For example, the reaction is continued at a temperature of 100° C. for 5 to 8 hours in step (1).

[0039] Further, the second aspect of the present invention provides ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate, which is prepared by a method comprising the following steps:

[0040] (1) adding the reactant ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate to a uniform mixture of polyphosphoric acid and methanesulfonic acid preheated to 70 to 100° C. and stirring uniformly;

[0041] (2) adding hexamethylenetetramine, a Duff reaction reagent, to the above reaction mixture under stirring, and continuing the reaction at a temperature of 70 to 100° C. for 4 to 8 hours. After the reaction is completed, the reaction mixture is cooled to 35 to 40° C.;

[0042] (3) Slowly add saturated ice brine to the cooled reaction mixture, filter after the precipitated solid, wash the solid with water until it is neutral, and dry to obtain the product.

[0043] According to the second aspect of the present invention, the amount of polyphosphoric acid added is 1.5 to 3 molar times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

[0044] According to the second aspect of the present invention, the amount of polyphosphoric acid added is 1.5 to 2.5 molar times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

[0045] According to the second aspect of the present invention, the amount of polyphosphoric acid added is 1.5 to 2 molar times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

[0046] According to the second aspect of the present invention, the amount of methanesulfonic acid added is 2 to 4 molar times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

[0047] According to the second aspect of the present invention, the amount of methanesulfonic acid added is 2 to 3.5 molar times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

[0048] According to the second aspect of the present invention, the amount of methanesulfonic acid added is 2 to 3 molar times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

[0049] According to the second aspect of the present invention, 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester, cyclohexane is also added to the mixture of polyphosphoric acid and methanesulfonic acid. In one embodiment, the amount of cyclohexane added is 0.02 to 0.05 molar times the amount of 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester. In one embodiment, the amount of cyclohexane added is 0.02 to 0.04 molar times the amount of 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester.

[0050] According to the second aspect of the present invention, 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester, wherein the mixture of polyphosphoric acid and methanesulfonic acid is also added with boric acid. In one embodiment, the addition amount of the boric acid is 0.002 to 0.01 mole times of the amount of 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester. In one embodiment, the addition amount of the boric acid is 0.002 to 0.005 mole times of the amount of 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester. It has been unexpectedly found that adding a trace amount of cyclohexane and boric acid in the reactant simultaneously can achieve a reaction yield comparable to or even higher than the existing method when the addition amount of methanesulfonic acid is less, and the purity of the reaction product has not deteriorated.

[0051] According to the second aspect of the present invention, ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate, wherein the reaction reagent in step (1) is preheated to a temperature of 80 to 100° C. For example, the reaction reagent in step (1) is preheated to a temperature of 80° C. For example, the reaction reagent in step (1) is preheated to a temperature of 90° C. For example, the reaction reagent in step (1) is preheated to a temperature of 100° C.

[0052] According to the second aspect of the present invention, ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate, wherein the reaction is continued at a temperature of 80 to 100° C. for 4 to 8 hours in step (1). For example, the reaction is continued at a temperature of 80 to 100° C. for 5 to 8 hours in step (1). For example, the reaction is continued at a temperature of 80 to 100° C. for 5 to 8 hours in step (1). For example, the reaction is continued at a temperature of 80° C. for 5 to 8 hours in step (1). For example, the reaction is continued at a temperature of 90° C. for 5 to 8 hours in step (1). For example, the reaction is continued at a temperature of 100° C. for 5 to 8 hours in step (1).

[0053] Further, the third aspect of the present invention provides the use of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate prepared by the method described in the first aspect of the present invention or ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate described in the second aspect of the present invention in the synthesis of Febuxostat. This use is, for example, a method for preparing Febuxostat as described below.

[0054] To this end, the present invention provides a method for preparing febuxostat, comprising the following steps:

[0055] (a) preparing ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate according to any one of claims 1 to 7;

[0056] (b) reacting the product obtained in step (a) in DMF in the presence of potassium carbonate and isobutyl bromide at 90 to 100° C. for 5 to 7 hours, adding water and ethyl acetate for extraction, concentrating the obtained organic layer, and recrystallizing from DMF to obtain 2-(3-formyl-4-isobutoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester;

[0057] (c) subjecting the product obtained in step (b) to a reflux reaction in formic acid in the presence of hydroxylamine hydrochloride and sodium formate for 12 to 18 hours, adding methanol after cooling, filtering out the precipitate, washing with methanol, and drying to obtain 2-(3-cyano-4-isobutoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester;

[0058] (d) reacting the product obtained in step (c) in a mixed solution of ethanol and THF in the presence of sodium hydroxide at a temperature of 75 to 85° C., cooling, adding hydrochloric acid, concentrating, precipitating a solid, adding water and stirring, filtering, washing the filter cake with 75% ethanol to obtain Febuxostat, and optionally refining it.

[0059] Any technical feature of any aspect of the present invention or any embodiment of the aspect is also applicable to any other embodiment or any other embodiment of the aspect, as long as they do not contradict each other. Of course, when they are applicable to each other, the corresponding features can be appropriately modified if necessary. The various aspects and features of the present invention are further described below.

[0060] All documents cited in the present invention are incorporated herein by reference in their entirety, and if the meanings expressed in these documents are inconsistent with the present invention, the description of the present invention shall prevail. In addition, the various terms and phrases used in the present invention have the general meanings known to those skilled in the art. Even so, the present invention still hopes to provide a more detailed description and explanation of these terms and phrases. If the terms and phrases mentioned are inconsistent with the known meanings, the meanings expressed in the present invention shall prevail.

[0061] Febuxostat is a selective xanthine oxidase (XO) / xanthine dehydrogenase inhibitor. In vitro studies have shown that Febuxostat has a complex inhibitory effect on bovine milk xanthine oxidase and rat and human liver xanthine oxidase, with IC50, Ki and Ki' all below the nM range. Febuxostat metabolites are also involved in the pharmacodynamic effects of Febuxostat.

[0062] In vivo, a single dose of febuxostat reduced the excretion of uric acid and allantoin in normal rats, while increasing the urinary excretion of xanthines in a dose-dependent manner.

[0063] In a rat hyperuricemia model, oxonate was used to inhibit uricase for 6 days. Febuxostat inhibited xanthine oxidase and reduced serum uric acid concentration in a dose-dependent manner (EDT of febuxostat was 2.3 ± 0.05). 50 The effect of febuxostat is 5-6 times that of allopurinol. In another study on a rat model of hyperuricemia, oxonate was used to inhibit uricase for 1 hour. The ED of febuxostat and allopurinol in reducing serum uric acid concentration was 1.6 mg / kg, while that of allopurinol was 9.1 mg / kg. 50 The values ​​were 1.5 mg / kg and 5.0 mg / kg, respectively. Febuxostat and allopurinol simultaneously reduce serum uric acid and allantoin concentrations in ED 50 The values ​​were 2.1 mg / kg and 6.9 mg / kg, respectively, indicating that the potency of febuxostat is about three times that of allopurinol.

[0064] In chimpanzee experiments, oral administration of 2, 5 and 12.5 mg / kg of febuxostat can reduce serum uric acid levels in a dose-dependent manner by inhibiting xanthine oxidase. In terms of general toxicology studies, acute toxicity tests showed that the approximate oral lethal dose of febuxostat for rats was less than 300 and 600 mg / kg. The highest non-lethal oral dose of febuxostat for rats was 300 mg / kg. Animal deaths occurred 6 hours to 4 days after administration. No animal deaths occurred in Beagle dogs at a single oral dose of febuxostat up to 2000 mg / kg, so the highest non-lethal oral dose was 2000 mg / kg.

[0065] Long-term toxicity studies have shown that the main toxic target organs of Febuxostat are the kidney, bladder, thyroid, liver and hematopoietic system. Febuxostat has dose- and time-dependent kidney and bladder effects on mice, rats and dogs. The results of biochemical indices and histological examinations showed kidney damage, kidney stones, bladder stones and mucosal epithelial hyperplasia caused by administration. The pathological changes in the kidney and bladder can be judged to be caused by xanthine crystal deposition, which is caused by the main pharmacodynamic effect of this product and is therefore acceptable.

[0066] In terms of special toxicological studies, a series of in vivo / in vitro mutagenicity tests were conducted on Febuxostat according to conventional methods, including 5 in vitro tests (Ames test and E. coli test, mouse lymphoma cell gene mutation test, Chinese hamster lung fibroblast chromosome aberration test, human peripheral blood lymphocyte chromosome aberration test), 3 in vivo tests (BDF1 mouse and Wistar rat bone marrow micronucleus test, F344 rat hepatocyte extracellular DNA synthesis test). The results showed that the mutagenicity test results of Febuxostat were all negative.

[0067] Febuxostat was used in reproductive toxicity studies in rats and rabbits in three dose groups of 3, 12 and 48 mg / kg. No embryotoxicity was observed in rats and rabbits. Febuxostat had no teratogenic effects in either animal. In the rat prenatal and postnatal developmental toxicity tests, toxic reactions occurred in the F1 generation of the 48 mg / kg dose group of Febuxostat, indicating that Febuxostat should not be used during lactation.

[0068] In the 104-week carcinogenicity study on B6C3F1 mice and the 104-week carcinogenicity study on F344 rats, an increased incidence of bladder tumors related to this product was observed. Comprehensive analysis showed that the increased incidence of bladder tumors in female mice and male rats may be secondary to the long-term and continuous stimulation of xanthine stones on the bladder epithelium.

[0069] In terms of pharmacokinetic studies, after oral administration of febuxostat, >80% can be rapidly and extensively absorbed, and tmax is approximately 1.0 to 1.8 hours. There is no accumulation of febuxostat in the body after multiple oral single doses per day. The effect of multiple doses of febuxostat 80 mg in reducing serum uric acid concentration is not affected by food, so food factors can be ignored when taking febuxostat clinically. After oral administration of 10 mg to 300 mg of febuxostat, the steady-state apparent distribution volume (Vss / F) is 29 to 75 L. The plasma protein binding rate of febuxostat is approximately 99.2% (mainly albumin). Oral [ 14 C]-Febuxostat, after 4 hours, plasma prototype drug accounts for 84%-96% of total radioactivity. The plasma half-life of febuxostat is 5-8 hours, and taking the drug once a day will reach steady-state blood concentration within 1 week. Febuxostat is mainly eliminated from the blood by being metabolized by the liver into glucuronic acid conjugates, and a small part is oxidatively metabolized by CYP450 in the liver. Febuxostat conjugated with glucuronic acid is excreted in the urine, and only less than 4% of febuxostat is excreted in the urine in its original form after oral administration.

[0070] Material purity determination method (i.e. [High Performance Liquid Chromatography A], this method can be used to determine the purity and content of Febuxostat API and various intermediates involved in the synthesis of Febuxostat, for example, it can be used to determine the purity of 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester):

[0071]

High Performance Liquid Chromatography A

[0072] A1) According to the high performance liquid chromatography method listed in Appendix ⅤD of Part II of the Chinese Pharmacopoeia 2010 edition;

[0073] A2) Chromatographic conditions and system suitability test: A chromatographic column with octylsilane bonded silica as filler (ZORBAX Eclipse XDB-C8, 4.6*150mm, 5μm chromatographic column was used in the specific test); 0.1% phosphoric acid solution (pH adjusted to 3.10±0.05 with triethylamine)-acetonitrile (57:43) as mobile phase A, acetonitrile as mobile phase B, linear gradient elution was performed as shown in the table below:

[0074] Time (min) A(％) B(％) 0 100 0 12 100 0 40 60 40

[0075] The flow rate is about 1 ml per minute so that the retention time of the Febuxostat peak is within the range of 7 to 11 minutes, the detection wavelength is 219 nm, and the column temperature is 55°C; take an appropriate amount of the test solution, place it at a light intensity of about 15,000 lux for 16 to 20 hours, take 10 ul and inject it into the liquid chromatograph, and record the chromatogram. The retention time of the Febuxostat peak is about 7 to 11 minutes, and the number of theoretical plates calculated based on the Febuxostat peak should be no less than 3,000. An impurity peak should appear at about 1.1 relative to the retention time of the Febuxostat peak, and the separation degree from the Febuxostat peak should meet the requirements;

[0076] A3) Take an appropriate amount of the test sample (which can be the febuxostat API, or various intermediates involved in the synthesis of febuxostat, such as ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate), accurately weigh it, add an appropriate amount of acetonitrile-water (1:1), ultrasonically dissolve and quantitatively dilute to make a solution containing about 500 μg of the test sample per 1 ml, filter if necessary, and use it as the test solution; accurately measure 5 ml of the test solution and put it into a 500 ml volumetric flask, dilute it to the scale with acetonitrile-water (1:1), shake well, and use it as the control solution; take 10 μl of the control solution and inject it into the liquid chromatograph, adjust the detection sensitivity so that the peak height of the main component chromatographic peak is about 20% of the full scale, then accurately measure 10 μl of the test solution and the control solution, respectively, inject them into the liquid chromatograph, and record the chromatogram;

[0077] A4) Read the peak area of ​​the main component peak in the chromatogram of the control solution; read the peak area of ​​the main component peak in the chromatogram of the test solution, and the peak area of ​​the impurity peaks in the chromatogram whose peak area percentage is greater than 0.01% calculated by the area normalization method (i.e., deducting the impurity peaks whose peak area percentage is less than 0.01%), and calculate the chromatographic purity of the test sample by the area normalization method.

[0078] The method for preparing ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate provided by the invention exhibits excellent technical effects. DETAILED DESCRIPTION

[0079] The present invention is further described below by means of specific embodiments / experimental examples. However, it should be understood that these embodiments and experimental examples are only used for more detailed and specific description and should not be construed as limiting the present invention in any form.

[0080] The present invention provides a general and / or specific description of the materials and test methods used in the test. Although many materials and operating methods used to achieve the purpose of the present invention are well known in the art, the present invention is still described as detailed as possible. It is clear to those skilled in the art that, hereinafter, unless otherwise specified, the materials and operating methods used in the present invention are well known in the art.

[0081] Example 1: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate

[0082] (1) adding 1 mol of the reactant ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (actual amount: 80 g) to a uniform mixture of 1.75 mol of polyphosphoric acid and 2.5 mol of methanesulfonic acid preheated to 80° C. (in a 1 L reaction bottle) and stirring uniformly;

[0083] (2) adding 1.4 mol of hexamethylenetetramine, a Duff reaction reagent, to the above reaction mixture under stirring, and continuing the reaction at 80° C. for 6 hours. After the reaction is completed, the reaction mixture is cooled to 40° C.;

[0084] (3) Saturated icy brine was slowly added to the cooled reaction mixture (to about 80% of the total volume of the reaction flask), and after the precipitated solid was filtered, the solid was washed with water until neutral, and dried to obtain a light yellow solid of 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester, with a yield of 53.3% (calculated as molar yield from the start of the addition of 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester, unless otherwise specified, the yield referred to herein has the same meaning).

[0085] Example 2: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate

[0086] (1) adding 1 mol of the reactant ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (actual amount 80 g) to a uniform mixture of 3 mol of polyphosphoric acid and 2 mol of methanesulfonic acid preheated to 70° C. (in a 1 L reaction bottle) and stirring uniformly;

[0087] (2) adding 1.5 mol of hexamethylenetetramine, a Duff reaction reagent, to the above reaction mixture under stirring, and continuing the reaction at 70° C. for 8 hours. After the reaction is completed, the reaction mixture is cooled to 37° C.;

[0088] (3) Saturated ice-salt water was slowly added to the cooled reaction mixture (to about 80% of the total capacity of the reaction flask), and after the precipitated solid was filtered, the solid was washed with water until neutral, and dried to obtain a light yellow solid of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate with a yield of 48.8%.

[0089] Example 3: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate

[0090] (1) adding 1 mol of the reactant ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (actual amount: 80 g) to a uniform mixture of 1.5 mol of polyphosphoric acid and 2 mol of methanesulfonic acid preheated to 100° C. (in a 1 L reaction bottle) and stirring uniformly;

[0091] (2) adding 1.2 mol of hexamethylenetetramine, a Duff reaction reagent, to the above reaction mixture under stirring, and continuing the reaction at 75° C. for 7 hours. After the reaction is completed, the reaction mixture is cooled to 38° C.;

[0092] (3) Saturated icy brine was slowly added to the cooled reaction mixture (to about 80% of the total capacity of the reaction flask), and after the precipitated solid was filtered, the solid was washed with water until neutral, and dried to obtain a light yellow solid of 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester with a yield of 56.1%.

[0093] Example 4: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate

[0094] (1) adding 1 mol of the reactant ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (actual amount: 80 g) to a uniform mixture of 2.5 mol of polyphosphoric acid and 3 mol of methanesulfonic acid preheated to 90° C. (in a 1 L reaction bottle) and stirring uniformly;

[0095] (2) adding 1.3 mol of hexamethylenetetramine, a Duff reaction reagent, to the above reaction mixture under stirring, and continuing the reaction at 85° C. for 6 hours. After the reaction is completed, the reaction mixture is cooled to 35° C.;

[0096] (3) Saturated icy brine was slowly added to the cooled reaction mixture (to about 80% of the total capacity of the reaction flask), and after the precipitated solid was filtered, the solid was washed with water until neutral, and dried to obtain a light yellow solid of 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester with a yield of 50.1%.

[0097] Example 5: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate

[0098] (1) adding 1 mol of the reactant ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (actual amount: 80 g) to a uniform mixture of 2 mol of polyphosphoric acid and 2.5 mol of methanesulfonic acid preheated to 85° C. (in a 1 L reaction bottle) and stirring uniformly;

[0099] (2) adding 1.5 mol of hexamethylenetetramine, a Duff reaction reagent, to the above reaction mixture under stirring, and continuing the reaction at 95° C. for 5 hours. After the reaction is completed, the reaction mixture is cooled to 40° C.;

[0100] (3) Saturated icy brine was slowly added to the cooled reaction mixture (to about 80% of the total capacity of the reaction flask), and after the precipitated solid was filtered, the solid was washed with water until neutral, and dried to obtain a light yellow solid of 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester with a yield of 53.6%.

[0101] Example 6: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate

[0102] (1) adding 1 mol of the reactant ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (actual amount 80 g) to a uniform mixture of 2.25 mol of polyphosphoric acid and 2.25 mol of methanesulfonic acid preheated to 75° C. (in a 1 L reaction bottle) and stirring uniformly;

[0103] (2) adding 1.4 mol of hexamethylenetetramine, a Duff reaction reagent, to the above reaction mixture under stirring, and continuing the reaction at 100° C. for 4 hours. After the reaction is completed, the reaction mixture is cooled to 35° C.;

[0104] (3) Saturated icy brine was slowly added to the cooled reaction mixture (to about 80% of the total capacity of the reaction flask), and after the precipitated solid was filtered, the solid was washed with water until neutral, and dried to obtain a light yellow solid of 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester with a yield of 49.6%.

[0105] Example 7: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate

[0106] (1) adding 1 mol of the reactant ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (actual amount: 80 g) to a uniform mixture of 2.75 mol of polyphosphoric acid and 2.75 mol of methanesulfonic acid preheated to 95° C. (in a 1 L reaction bottle) and stirring uniformly;

[0107] (2) adding 1.25 mol of hexamethylenetetramine, a Duff reaction reagent, to the above reaction mixture under stirring, and continuing the reaction at 70° C. for 8 hours. After the reaction is completed, the reaction mixture is cooled to 38° C.;

[0108] (3) Saturated icy brine was slowly added to the cooled reaction mixture (to about 80% of the total capacity of the reaction flask), and after the precipitated solid was filtered, the solid was washed with water until neutral, and dried to obtain a light yellow solid of 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester with a yield of 51.8%.

[0109] Example 8: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate

[0110] (1) adding 1 mol of the reactant ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (actual amount: 80 g) to a uniform mixture of 2 mol of polyphosphoric acid and 3 mol of methanesulfonic acid preheated to 80° C. (in a 1 L reaction bottle) and stirring uniformly;

[0111] (2) adding 1.35 mol of hexamethylenetetramine, a Duff reaction reagent, to the above reaction mixture under stirring, and continuing the reaction at 80° C. for 7 hours. After the reaction is completed, the reaction mixture is cooled to 40° C.;

[0112] (3) Slowly add saturated ice brine to the cooled reaction mixture (to about 80% of the total capacity of the reaction flask), filter after the precipitated solid, wash the solid with water until neutral, and dry to obtain a light yellow solid of 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester with a yield of 49.8%.

[0113] Example 9: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate

[0114] (1) adding 1 mol of the reactant ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (actual amount: 80 g) to a uniform mixture of 2.5 mol of polyphosphoric acid and 2.5 mol of methanesulfonic acid preheated to 80° C. (in a 1 L reaction bottle) and stirring uniformly;

[0115] (2) adding 1.4 mol of hexamethylenetetramine, a Duff reaction reagent, to the above reaction mixture under stirring, and continuing the reaction at 90° C. for 5 hours. After the reaction is completed, the reaction mixture is cooled to 35° C.;

[0116] (3) Saturated icy brine was slowly added to the cooled reaction mixture (to about 80% of the total capacity of the reaction flask), and after the precipitated solid was filtered, the solid was washed with water until neutral, and dried to obtain a light yellow solid of 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester with a yield of 52.4%.

[0117] Example 10: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (#169E10)

[0118] A: 400 g of polyphosphoric acid and 200 g of methanesulfonic acid were weighed into a 1 L reaction bottle, stirred at 80° C., 80 g of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (II) was added, and after stirring, 58.5 g of hexamethylenetetramine was weighed and added thereto, and the reaction was continued at 80° C. for 6 hours. After the reaction was completed, the mixture was cooled to 40° C., and 1 L of saturated ice brine was slowly added. A large amount of solid precipitated, which was filtered, washed with water until neutral, and dried to obtain a light yellow solid, which was ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate, with a yield of 80.8%.

[0119] B: Weigh 200 g of polyphosphoric acid and 200 g of methanesulfonic acid in a 1 L reaction bottle, stir evenly at 100° C., add 80 g of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (II), and stir evenly. Then weigh 58.5 g of hexamethylenetetramine three times and add it every half an hour. Continue to react at 100° C. for 5 hours. After the reaction is completed, cool to 40° C., slowly add 1 L of saturated ice brine, a large amount of solid precipitates, filter, wash with water until neutral, and dry to obtain a light yellow solid, which is ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate, with a yield of 85.2%.

[0120] According to the comparison between the above Examples 1 to 9 and Example 10, it can be seen that when the amount of methane sulfonic acid used in the reaction is reduced to 2 to 3 equivalents, the product yield is significantly reduced, which is equivalent to 60% (50 / 82x100%) of the yield obtained by using 7 equivalents of methane sulfonic acid in Example 10.

[0121] Example 11: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate

[0122] (1) adding 1 mol of the reactant ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (actual amount 80 g) to a uniform mixture of 1.75 mol of polyphosphoric acid, 2.5 mol of methanesulfonic acid, 0.03 mol of cyclohexane, and 0.004 mol of boric acid preheated to 80° C. (in a 1 L reaction bottle), and stirring the mixture uniformly;

[0123] (2) adding 1.4 mol of hexamethylenetetramine, a Duff reaction reagent, to the above reaction mixture under stirring, and continuing the reaction at 80° C. for 6 hours. After the reaction is completed, the reaction mixture is cooled to 40° C.;

[0124] (3) Saturated ice-salt water was slowly added to the cooled reaction mixture (to about 80% of the total capacity of the reaction flask), and after the precipitated solid was filtered, the solid was washed with water until neutral, and dried to obtain a light yellow solid of 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester with a yield of 88.6%.

[0125] Example 12: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate

[0126] (1) adding 1 mol of the reactant ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (actual amount 80 g) to a uniform mixture of 3 mol of polyphosphoric acid and 2 mol of methanesulfonic acid, 0.02 mol of cyclohexane and 0.01 mol of boric acid preheated to 70° C. (in a 1 L reaction bottle), and stirring the mixture uniformly;

[0127] (2) adding 1.5 mol of hexamethylenetetramine, a Duff reaction reagent, to the above reaction mixture under stirring, and continuing the reaction at 70° C. for 8 hours. After the reaction is completed, the reaction mixture is cooled to 37° C.;

[0128] (3) Saturated ice-salt water (to about 80% of the total capacity of the reaction flask) was slowly added to the cooled reaction mixture, and after the precipitated solid was filtered, the solid was washed with water until neutral, and dried to obtain a light yellow solid of 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester with a yield of 86.4%.

[0129] Example 13: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate

[0130] (1) adding 1 mol of the reactant ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (actual amount 80 g) to a uniform mixture of 1.5 mol of polyphosphoric acid, 2 mol of methanesulfonic acid, 0.05 mol of cyclohexane and 0.002 mol of boric acid preheated to 100° C. (in a 1 L reaction bottle), and stirring the mixture uniformly;

[0131] (2) adding 1.2 mol of hexamethylenetetramine, a Duff reaction reagent, to the above reaction mixture under stirring, and continuing the reaction at 75° C. for 7 hours. After the reaction is completed, the reaction mixture is cooled to 38° C.;

[0132] (3) Saturated ice-salt water (to about 80% of the total capacity of the reaction flask) was slowly added to the cooled reaction mixture, and after the precipitated solid was filtered, the solid was washed with water until neutral, and dried to obtain a light yellow solid of 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester with a yield of 91.2%.

[0133] Example 14: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate

[0134] (1) adding 1 mol of the reactant ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (actual amount 80 g) to a uniform mixture of 2.5 mol of polyphosphoric acid and 3 mol of methanesulfonic acid, 0.04 mol of cyclohexane and 0.005 mol of boric acid preheated to 90° C. (in a 1 L reaction bottle), and stirring uniformly;

[0135] (2) adding 1.3 mol of hexamethylenetetramine, a Duff reaction reagent, to the above reaction mixture under stirring, and continuing the reaction at 85° C. for 6 hours. After the reaction is completed, the reaction mixture is cooled to 35° C.;

[0136] (3) Saturated ice-salt water was slowly added to the cooled reaction mixture (to about 80% of the total capacity of the reaction flask), and after the precipitated solid was filtered, the solid was washed with water until neutral, and dried to obtain a light yellow solid of 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester with a yield of 89.5%.

[0137] Example 15: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate

[0138] (1) adding 1 mol of the reactant ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (actual amount 80 g) to a uniform mixture of 2 mol of polyphosphoric acid, 2.5 mol of methanesulfonic acid, 0.03 mol of cyclohexane and 0.003 mol of boric acid preheated to 85° C. (in a 1 L reaction bottle), and stirring uniformly;

[0139] (2) adding 1.5 mol of hexamethylenetetramine, a Duff reaction reagent, to the above reaction mixture under stirring, and continuing the reaction at 95° C. for 5 hours. After the reaction is completed, the reaction mixture is cooled to 40° C.;

[0140] (3) Slowly add saturated ice brine to the cooled reaction mixture (to about 80% of the total capacity of the reaction flask), filter after the precipitated solid, wash the solid with water until neutral, and dry to obtain a light yellow solid of 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester with a yield of 90.3%.

[0141] Example 16: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate

[0142] (1) adding 1 mol of the reactant ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (actual amount 80 g) to a uniform mixture of 2.25 mol of polyphosphoric acid and 2.25 mol of methanesulfonic acid, 0.035 mol of cyclohexane and 0.0035 mol of boric acid preheated to 75° C. (in a 1 L reaction bottle), and stirring the mixture uniformly;

[0143] (2) adding 1.4 mol of hexamethylenetetramine, a Duff reaction reagent, to the above reaction mixture under stirring, and continuing the reaction at 100° C. for 4 hours. After the reaction is completed, the reaction mixture is cooled to 35° C.;

[0144] (3) Saturated ice-salt water was slowly added to the cooled reaction mixture (to about 80% of the total capacity of the reaction flask), and after the precipitated solid was filtered, the solid was washed with water until neutral, and dried to obtain a light yellow solid of 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester with a yield of 89.3%.

[0145] Example 17: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate

[0146] (1) adding 1 mol of the reactant ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (actual amount 80 g) to a uniform mixture of 2.75 mol of polyphosphoric acid and 2.75 mol of methanesulfonic acid, 0.025 mol of cyclohexane and 0.0045 mol of boric acid preheated to 95° C. (in a 1 L reaction bottle), and stirring uniformly;

[0147] (2) adding 1.25 mol of hexamethylenetetramine, a Duff reaction reagent, to the above reaction mixture under stirring, and continuing the reaction at 70° C. for 8 hours. After the reaction is completed, the reaction mixture is cooled to 38° C.;

[0148] (3) Slowly add saturated ice brine to the cooled reaction mixture (to about 80% of the total capacity of the reaction flask), filter after the precipitated solid, wash the solid with water until neutral, and dry to obtain a light yellow solid of 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester with a yield of 86.3%.

[0149] Example 18: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate

[0150] (1) adding 1 mol of the reactant ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (actual amount 80 g) to a uniform mixture of 2 mol of polyphosphoric acid and 3 mol of methanesulfonic acid, 0.03 mol of cyclohexane and 0.003 mol of boric acid preheated to 80° C. (in a 1 L reaction bottle), and stirring uniformly;

[0151] (2) adding 1.35 mol of hexamethylenetetramine, a Duff reaction reagent, to the above reaction mixture under stirring, and continuing the reaction at 80° C. for 7 hours. After the reaction is completed, the reaction mixture is cooled to 40° C.;

[0152] (3) Saturated ice-salt water was slowly added to the cooled reaction mixture (to about 80% of the total capacity of the reaction flask), and after the precipitated solid was filtered, the solid was washed with water until neutral, and dried to obtain a light yellow solid of 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester with a yield of 87.4%.

[0153] Example 19: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate

[0154] (1) adding 1 mol of the reactant ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (actual amount 80 g) to a uniform mixture of 2.5 mol of polyphosphoric acid and 2.5 mol of methanesulfonic acid, 0.025 mol of cyclohexane and 0.004 mol of boric acid preheated to 80° C. (in a 1 L reaction bottle), and stirring the mixture uniformly;

[0155] (2) adding 1.4 mol of hexamethylenetetramine, a Duff reaction reagent, to the above reaction mixture under stirring, and continuing the reaction at 90° C. for 5 hours. After the reaction is completed, the reaction mixture is cooled to 35° C.;

[0156] (3) Slowly add saturated ice brine to the cooled reaction mixture (to about 80% of the total capacity of the reaction flask), filter after the precipitated solid, wash the solid with water until neutral, and dry to obtain a light yellow solid of 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester with a yield of 88.5%.

[0157] From the above examples 11 to 19, it can be seen that, under the condition that the amount of methanesulfonic acid used is greatly reduced relative to example 10, adding trace amounts of cyclohexane and boric acid to the reactants can significantly increase the yield of the product, and even reach a higher yield than example 10. In the supplementary experiments, referring to examples 11 to 19, the only difference is that a corresponding amount of cyclohexane is added to the reactants, and the resulting yields are all lower than 55%; in the supplementary experiments, referring to examples 11 to 19, the only difference is that a corresponding amount of boric acid is added to the reactants, and the resulting yields are all lower than 58%; this shows that adding cyclohexane or boric acid alone to the reactants cannot effectively increase the yield. In terms of cost-effectiveness and environmental protection requirements, the schemes of examples 11 to 19 by adding trace amounts of cyclohexane and boric acid are significantly better than the scheme of example 10 using a large amount of methanesulfonic acid.

[0158] Purity detection: All batches of 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester obtained in Examples 1 to 19 were measured using the [High Performance Liquid Chromatography A] of the present invention. As a result, their chromatographic purities were all within the range of 95 to 97%, with no significant difference between them, and this purity was fully sufficient for further chemical synthesis to prepare febuxostat. During the purity detection process, no residues of cyclohexane and boric acid were found, and the impurity spectra of Examples 11 to 19 were substantially the same as those of Examples 1 to 10, that is, the impurity spectra of all the above Examples were substantially the same, indicating that cyclohexane and boric acid did not cause the generation of unexpected impurities.

[0159] Example 20: Preparation of Febuxostat

[0160] Febuxostat was prepared by using 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester prepared by the present invention as a starting material according to the following method:

[0161] Step 1: Preparation of 2-(3-formyl-4-isobutoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester

[0162] Add 0.3kg (1.04mol) of 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester and 2.3L of DMF to a 5L multifunctional reactor, start stirring, stir and dissolve at 300rpm, add 0.42kg (3.04mol) of anhydrous potassium carbonate and 0.34kg (2.48mol) of isobutyl bromide, and heat to 95°C for 6h. After the reaction is completed, cool to room temperature, add 2.3L of water, extract with the same volume of ethyl acetate three times, combine the organic layers, concentrate to obtain a light yellow solid, and recrystallize with 2.5L of DMF. Filter by suction, wash the filter cake with DMF, and dry to obtain 0.207kg of white solid, i.e. 2-(3-formyl-4-isobutoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester, with a yield of about 57.2%, mp 160~161°C.

[0163] Step 2: Preparation of 2-(3-cyano-4-isobutoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester

[0164] In a 5L multifunctional reactor, 1.8L of formic acid, 0.207kg of ethyl 2-(3-formyl-4-isobutoxy-phenyl)-4-methyl-thiazole-5-carboxylate, 0.049kg of hydroxylamine hydrochloride and 0.065kg of sodium formate were added, stirring (300rpm) was started, and the mixture was heated to 135°C for reflux reaction for 15 hours. The reaction solution was cooled to room temperature, 1.8L of methanol was added, and the mixture was stirred (300rpm) to precipitate solids, which were filtered, washed with methanol, and vacuum dried at 60°C for 2 hours to obtain 0.165kg of off-white solids, i.e., ethyl 2-(3-cyano-4-isobutoxy-phenyl)-4-methyl-thiazole-5-carboxylate, with a yield of about 82.9%.

[0165] Step 3: Preparation of Febuxostat

[0166] In a 5L multifunctional reactor, 0.165kg of ethyl 2-(3-cyano-4-isobutoxy-phenyl)-4-methyl-thiazole-5-carboxylate, 1.2L of ethanol, 1.2L of THF and 0.664L of 1N sodium hydroxide solution were added, the stirrer (300rpm) was turned on, and the mixture was reacted at 80°C for one hour. After cooling, 0.664L of 1N hydrochloric acid was added, and the mixture was concentrated under reduced pressure to half the volume. A large amount of solid was precipitated, 1.2L of water was added, and the mixture was stirred for 30min. The mixture was filtered, and the filter cake was washed with 0.1L of 75% ethanol (volume percentage) to obtain about 0.139kg of a crude product of Febuxostat.

[0167] Step 4: Purification of Crude Febuxostat

[0168] The above-mentioned crude febuxostat and 0.13 L of ethanol were added to a 0.5 L round-bottom flask, heated under reflux to dissolve, 0.052 L of water was added, stirred at 80 ° C for 30 min, cooled to room temperature, filtered, and the filter cake was vacuum dried at 90 ° C and 20 mmHg for 5 hours to obtain 0.131 kg of off-white crystalline powder, i.e., refined febuxostat.

[0169] The above disclosure is only the preferred embodiment of the present invention, which certainly cannot be used to limit the scope of rights of the present invention. Therefore, equivalent changes made according to the scope of the patent application of the present invention are still within the scope covered by the present invention.

Claims

1. A method for synthesizing ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate, the method comprising the following steps: (1) adding the reactant 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester to a uniform mixture of polyphosphoric acid, methanesulfonic acid, cyclohexane, and boric acid preheated to 70-100° C., and stirring uniformly; (2) adding hexamethylenetetramine, a Duff reaction reagent, to the above reaction mixture under stirring, and continuing the reaction at a temperature of 70-100° C. for 4-8 hours. After the reaction is completed, the reaction mixture is cooled to 35-40° C.; (3) slowly adding saturated ice brine to the cooled reaction mixture, filtering after the solid precipitates, washing the solid with water until it is neutral, and drying to obtain; wherein, The amount of polyphosphoric acid added is 1.5 to 3 molar times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate. The amount of methanesulfonic acid added is 2 to 4 molar times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate. The amount of cyclohexane added is 0.02 to 0.05 mole times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate, The amount of boric acid added is 0.002 to 0.01 mole times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate, The amount of hexamethylenetetramine added is 1 to 1.5 times by mole of the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

2. according to the method for claim 1, wherein the addition of polyphosphoric acid is 1.5 to 2.5 mole times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

3. according to the method for claim 1, wherein the addition of polyphosphoric acid is 1.5 to 2 molar times of the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

4. according to the method for claim 1, wherein the addition amount of methanesulfonic acid is 2 to 3.5 mole times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

5. according to the method for claim 1, wherein the addition amount of methanesulfonic acid is 2 to 3 mole times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

6. The method according to claim 1, wherein the amount of hexamethylenetetramine added is 1.1 to 1.5 mole times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

7. The method according to claim 1, wherein the amount of hexamethylenetetramine added is 1.2 to 1.5 mole times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

8. according to the method for claim 1, wherein the addition amount of cyclohexane is 0.02~0.04 mole times of the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

9. The method according to claim 1, wherein the amount of boric acid added is 0.002 to 0.005 mole times the amount of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate.

10. The method according to claim 1, wherein the reaction reagents in step (1) are preheated to a temperature of 80-100°C.

11. The method according to claim 1, wherein the reaction reagents in step (1) are preheated to a temperature of 80°C.

12. The method according to claim 1, wherein the reaction reagents in step (1) are preheated to a temperature of 90°C.

13. The method according to claim 1, wherein the reaction reagents in step (1) are preheated to a temperature of 100°C.

14. The method according to claim 1, wherein the reaction in step (2) is continued at a temperature of 80-100° C. for 4-8 hours.

15. The method according to claim 1, wherein the reaction in step (2) is continued at a temperature of 80-100°C for 5-8 hours.

16. The method according to claim 1, wherein the reaction in step (2) is continued at a temperature of 80°C for 5 to 8 hours.

17. The method according to claim 1, wherein the reaction in step (2) is continued at a temperature of 90°C for 5 to 8 hours.

18. The method according to claim 1, wherein the reaction in step (2) is continued at a temperature of 100°C for 5 to 8 hours.

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