Preparation method of febuxostat key intermediate

Abstract

The invention relates to a preparation method of a key intermediate 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-ethyl formate of a new generation of a xanthine oxidase inhibitor Febuxostat (Febuxostat), and particularly relates to a preparation method of the key intermediate 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-ethyl formate of the xanthine oxidase inhibitor Febuxostat. According to the method, 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-ethyl formate is taken as a raw material, ammonium acetate / hydroxylamine hydrochloride is taken as a nitrogen source, copper acetate / copper chloride / copper oxide is taken as a catalyst, cyanation reaction of aldehyde group is carried out, and the 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-ethyl formate is obtained. And the 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-ethyl formate is prepared by using the 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-ethyl formate as a solvent. The purity of the 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-ethyl formate prepared by the preparation method disclosed by the invention reaches 99% or above, and the yield of the 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-ethyl formate can reach 94%; the solvent used in the invention is wide in source, easy to prepare, mild in reaction condition, easy to operate, low in production cost and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemical industry, and mainly relates to a method for preparing ethyl 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylate, a key intermediate of febuxostat. Background Art

[0002] Febuxostat, chemical name is 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid, chemical structure is as follows:

[0003]

[0004] Febuxostat is a new generation of non-purine selective xanthine oxidase inhibitor developed by Teijin Co., Ltd. of Japan. It is clinically used to treat hyperuricemia. It can reduce uric acid synthesis in the body and lower the uric acid level in the blood of patients with hyperuricemia and gout by acting highly selectively on this oxidase. This product is metabolized by the liver and does not rely on the kidneys for excretion. Therefore, there is no need to reduce the dose for patients with moderate to severe liver and kidney dysfunction.

[0005] There are multiple key intermediates in the synthesis process of Febuxostat, among which 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester is the key intermediate 1 in the synthesis process of Febuxostat, and 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester is the key intermediate 2 in the synthesis process of Febuxostat, and their chemical structures are as follows:

[0006]

[0007] The preparation of key intermediate 1 is generally carried out by cyanating the 3-position aldehyde group on the benzene ring of key intermediate 2 to generate a cyano group. The specific chemical reaction equation is as follows:

[0008]

[0009] Regarding the preparation method of key intermediate 1, patents JP1994329647, JP11060552 and CN201811325594 all reported a one-step synthesis method using formic acid, sodium formate and hydroxylamine hydrochloride, but the formic acid used in this method has a strong pungent odor and is highly corrosive, which is extremely dangerous in actual production operations and highly destructive to equipment. In addition, the difficulty of hazardous waste treatment is increased in terms of waste liquid treatment, thereby increasing production costs; patent CN201010592536 reported the use of N-methylpyrrolidone, DMF, and toluene as reaction solvents to directly react with hydroxylamine hydrochloride to prepare key intermediate 1, but this method has a high reaction temperature, a long reaction time, and a low yield, and the capacity of industrial production is low. Summary of the invention

[0010] Based on the technical problems existing in the background technology, the present invention proposes a method for preparing a key intermediate of Febuxostat, and particularly relates to a method for preparing ethyl 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylate (key intermediate 1). The solvent used in the method of the present invention is safer, the reaction temperature is relatively low, and the purity of the prepared key intermediate 1 can reach 99%, and the yield can reach more than 90%.

[0011] The objective of the present invention is achieved through the following technical solutions:

[0012] A method for preparing a key intermediate of Febuxostat, wherein the key intermediate of Febuxostat is ethyl 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylate, and the preparation method comprises the following steps:

[0013] Dissolve ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate, a nitrogen source reagent, and a catalyst in an organic solvent, raise the temperature to a reaction temperature for reaction, add water for crystallization after the reaction is completed, collect the crystallized product, and dry it to obtain ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate;

[0014] The organic solvent is selected from a mixture of one or more of dimethyl sulfoxide and acetonitrile;

[0015] The nitrogen source reagent is selected from a mixture of one or more of ammonium acetate and hydroxylamine hydrochloride;

[0016] The catalyst is selected from a mixture of one or more of cupric acetate, cupric chloride and cupric oxide.

[0017] Furthermore, the organic solvent is a mixed solution of dimethyl sulfoxide and acetonitrile.

[0018] Furthermore, the organic solvent is a mixed solution of dimethyl sulfoxide and acetonitrile, and the mass ratio of dimethyl sulfoxide to acetonitrile in the mixed solution of dimethyl sulfoxide and acetonitrile is (0.2-8):1;

[0019] Preferably, the mass ratio of dimethyl sulfoxide to acetonitrile in the mixed solution of dimethyl sulfoxide and acetonitrile is (0.2-2):1.

[0020] Furthermore, the mass ratio of the organic solvent to ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate is (5-10):1;

[0021] Preferably, the mass ratio of the organic solvent to ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate is (6-8):1.

[0022] Furthermore, the nitrogen source reagent is hydroxylamine hydrochloride.

[0023] Further, the molar ratio of the nitrogen source reagent to ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate is (1-5):1;

[0024] Preferably, the molar ratio of the nitrogen source reagent to ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate is (1.5-3):1.

[0025] Furthermore, the catalyst is copper acetate.

[0026] Further, the molar ratio of the catalyst to ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate is (0.1-0.5):1;

[0027] Preferably, the molar ratio of the catalyst to ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate is (0.1-0.3):1.

[0028] Further, the reaction temperature is 60-90°C; preferably, the reaction temperature is 80-90°C; further preferably, the reaction temperature is 80°C.

[0029] The technical solution of the present invention has the following beneficial effects compared with the prior art:

[0030] The above is the preparation method and preferred process conditions of the key intermediate 1 of Febuxostat described in the present invention. The present invention selects the type of solvent, nitrogen source reagent and catalyst, and optimizes the material ratio and reaction temperature to determine a safer and more economical preparation method, with a purity of more than 99% and a yield of 94%. DETAILED DESCRIPTION

[0031] The present invention is further explained below with reference to the examples, but the examples do not limit the present invention in any form.

[0032] The key intermediate 1 of the present invention refers to: ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate;

[0033] The key intermediate 2 of the present invention refers to: ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate.

[0034] Embodiment 1:

[0035] 7 g (20 mmol) of key intermediate 2, 2.32 g (30 mmol) of ammonium acetate and 0.4 g (2 mmol) of copper acetate were dissolved in 60 g of dimethyl sulfoxide, heated to 90°C, and air was blown into the mixture for 40 hours. After the reaction was completed, water was added to crystallize, and the key intermediate 1 was collected by suction filtration and dried to obtain a purity of 92.34% and a yield of 87.5%.

[0036] Embodiment 2:

[0037] 7 g (20 mmol) of key intermediate 2, 2.2 g (30 mmol) of hydroxylamine hydrochloride and 0.4 g (2 mmol) of cupric acetate were dissolved in 60 g of dimethyl sulfoxide, and the temperature was raised to 90°C for reaction for 5 h. After the reaction was completed, water was added for crystallization, and the key intermediate 1 was collected by suction filtration and dried to obtain a purity of 93.16% and a yield of 88.1%.

[0038] Embodiment 3:

[0039] 7 g (20 mmol) of key intermediate 2, 2.2 g (30 mmol) of hydroxylamine hydrochloride and 0.14 g (2 mmol) of cupric chloride were dissolved in 60 g of dimethyl sulfoxide, and the temperature was raised to 90°C for reaction for 7 h. After the reaction was completed, water was added for crystallization, and the key intermediate 1 was collected by suction filtration and dried to obtain a purity of 91.91% and a yield of 87.5%.

[0040] Embodiment 4:

[0041] 7 g (20 mmol) of key intermediate 2, 2.2 g (30 mmol) of hydroxylamine hydrochloride and 0.16 g (2 mmol) of copper oxide were dissolved in 60 g of dimethyl sulfoxide, and the temperature was raised to 90°C for reaction for 10 h. After the reaction was completed, water was added for crystallization, and the key intermediate 1 was collected by suction filtration and dried to obtain a purity of 91.62% and a yield of 86.8%.

[0042] Embodiment 5:

[0043] 7 g (20 mmol) of key intermediate 2, 4.4 g (60 mmol) of hydroxylamine hydrochloride and 1 g (5 mmol) of cupric acetate were dissolved in 60 g of dimethyl sulfoxide, and the temperature was raised to 60°C for reaction for 20 h. After the reaction was completed, water was added for crystallization, and the key intermediate 1 was collected by suction filtration and dried to obtain a purity of 94.14% and a yield of 89.5%.

[0044] Embodiment 6:

[0045] 7 g (20 mmol) of key intermediate 2, 4.4 g (60 mmol) of hydroxylamine hydrochloride and 1 g (5 mmol) of cupric acetate were dissolved in 60 g of dimethyl sulfoxide, and the temperature was raised to 90°C for reaction for 3 h. After the reaction was completed, water was added for crystallization, and the key intermediate 1 was collected by suction filtration and dried to obtain a purity of 94.23% and a yield of 90.0%.

[0046] Embodiment 7:

[0047] 7 g (20 mmol) of key intermediate 2, 2.2 g (30 mmol) of hydroxylamine hydrochloride and 0.4 g (2 mmol) of cupric acetate were dissolved in 60 g of acetonitrile, and the temperature was raised to 80°C for reaction for 40 h. After the reaction was completed, water was added for crystallization, and the key intermediate 1 was collected by suction filtration and dried to obtain a purity of 91.78% and a yield of 86.0%.

[0048] Embodiment 8:

[0049] 7 g (20 mmol) of key intermediate 2, 4.4 g (60 mmol) of hydroxylamine hydrochloride and 1 g (5 mmol) of cupric acetate were dissolved in 60 g of acetonitrile and 12 g of dimethyl sulfoxide, and the temperature was raised to 80°C for reaction for 3 h. After the reaction was completed, water was added for crystallization, and the key intermediate 1 was collected by suction filtration and dried to obtain a purity of 96.66% and a yield of 89.5%.

[0050] Embodiment 9:

[0051] 7 g (20 mmol) of key intermediate 2, 2.2 g (30 mmol) of hydroxylamine hydrochloride, and 0.4 g (2 mmol) of cupric acetate were dissolved in 20 g of acetonitrile and 40 g of dimethyl sulfoxide, and the temperature was raised to 80°C for reaction for 6 h. After the reaction was completed, water was added for crystallization, and the key intermediate 1 was collected by suction filtration and dried to obtain a purity of 97.38% and a yield of 90.3%.

[0052] Embodiment 10:

[0053] 7 g (20 mmol) of key intermediate 2, 4.4 g (60 mmol) of hydroxylamine hydrochloride, and 0.4 g (2 mmol) of cupric acetate were dissolved in 20 g of acetonitrile and 40 g of dimethyl sulfoxide, and the temperature was raised to 80°C for reaction for 3 h. After the reaction was completed, water was added for crystallization, and the key intermediate 1 was collected by suction filtration and dried to obtain a purity of 99.17% and a yield of 91.2%.

[0054] Embodiment 11:

[0055] 7 g (20 mmol) of key intermediate 2, 4.4 g (60 mmol) of hydroxylamine hydrochloride and 1 g (5 mmol) of cupric acetate were dissolved in 20 g of acetonitrile and 40 g of dimethyl sulfoxide, and the temperature was raised to 80°C for reaction for 3 h. After the reaction was completed, water was added for crystallization, and the key intermediate 1 was collected by suction filtration and dried to obtain a purity of 99.53% and a yield of 92.5%.

[0056] Embodiment 12:

[0057] 7 g (20 mmol) of key intermediate 2, 2.2 g (30 mmol) of hydroxylamine hydrochloride and 1 g (5 mmol) of cupric acetate were dissolved in 20 g of acetonitrile and 40 g of dimethyl sulfoxide, and the temperature was raised to 80°C for reaction for 3 h. After the reaction was completed, water was added for crystallization, and the key intermediate 1 was collected by suction filtration and dried to obtain a purity of 99.67% and a yield of 92.5%.

[0058] Embodiment 13:

[0059] 7 g (20 mmol) of key intermediate 2, 2.2 g (30 mmol) of hydroxylamine hydrochloride and 1 g (5 mmol) of cupric acetate were dissolved in 14 g of acetonitrile and 28 g of dimethyl sulfoxide, and the temperature was raised to 80°C for reaction for 3 h. After the reaction was completed, water was added for crystallization, and the key intermediate 1 was collected by suction filtration and dried to obtain a purity of 99.51% and a yield of 90.5%.

[0060] Embodiment 14:

[0061] 35 g (100 mmol) of key intermediate 2, 22 g (300 mmol) of hydroxylamine hydrochloride and 2 g (10 mmol) of cupric acetate were dissolved in 100 g of acetonitrile and 200 g of dimethyl sulfoxide, and the temperature was raised to 80°C for reaction for 3 h. After the reaction was completed, water was added for crystallization, and the key intermediate 1 was collected by suction filtration and dried to obtain the key intermediate 1 with a purity of 98.87% and a yield of 90.5%.

[0062] Embodiment 15:

[0063] 35 g (100 mmol) of key intermediate 2, 22 g (300 mmol) of hydroxylamine hydrochloride, and 5 g (25 mmol) of cupric acetate were dissolved in 100 g of acetonitrile and 200 g of dimethyl sulfoxide, and the temperature was raised to 80°C for reaction for 3 h. After the reaction was completed, water was added for crystallization, and the key intermediate 1 was collected by suction filtration and dried to obtain the key intermediate 1 with a purity of 99.50% and a yield of 93.3%.

[0064] Embodiment 16:

[0065] 35 g (100 mmol) of key intermediate 2, 11 g (150 mmol) of hydroxylamine hydrochloride and 5 g (25 mmol) of cupric acetate were dissolved in 100 g of acetonitrile and 200 g of dimethyl sulfoxide, and the temperature was raised to 80°C for reaction for 3 h. After the reaction was completed, water was added for crystallization, and the key intermediate 1 was collected by suction filtration and dried to obtain the key intermediate 1 with a purity of 99.63% and a yield of 94.1%.

[0066] Comparative Example 1:

[0067] In a 500mL three-necked flask, add 70g of key intermediate 2 and 180mL of DMF, stir, add 28g of hydroxylamine hydrochloride, react at 100°C for 14 hours, TLC shows that the reaction is basically complete, cool down with stirring, pour into a large amount of water, precipitate solid, filter and dry to obtain 56.4g of yellow solid with a purity of 86.84% and a yield of 81.3%.

[0068] Comparative Example 2:

[0069] In a 500mL three-necked flask, add 70g of key intermediate 2 and 180mL of N-methylpyrrolidone, stir, add hydroxylamine hydrochloride, react at 110°C for 12 hours, TLC shows that the reaction is basically complete, cool down with stirring, pour into a large amount of water, precipitate solid, filter and dry to obtain 57.4g of yellow solid with a purity of 87.52% and a yield of 82.7%.

[0070] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing a key intermediate of Febuxostat, characterized in that: The key intermediate of Febuxostat is ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate, and the preparation method comprises the following steps: Dissolve ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate, a nitrogen source reagent, and a catalyst in an organic solvent, raise the temperature to a reaction temperature for reaction, add water for crystallization after the reaction is completed, collect the crystallized product, and dry it to obtain ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate; The nitrogen source reagent is selected from a mixture of one or more of ammonium acetate and hydroxylamine hydrochloride; The catalyst is selected from a mixture of one or more of copper acetate, copper chloride, and copper oxide; The organic solvent is selected from a mixture of one or more of dimethyl sulfoxide and acetonitrile.

2. The method for preparing the key intermediate of Febuxostat according to claim 1, characterized in that: The organic solvent is a mixed solution of dimethyl sulfoxide and acetonitrile.

3. The method for preparing the key intermediate of Febuxostat according to claim 2, characterized in that: The mass ratio of dimethyl sulfoxide to acetonitrile in the mixed solution of dimethyl sulfoxide and acetonitrile is (0.2-8):1; Preferably, the mass ratio of dimethyl sulfoxide to acetonitrile in the mixed solution of dimethyl sulfoxide and acetonitrile is (0.2-2):

1.

4. The method for preparing the key intermediate of Febuxostat according to claim 1, characterized in that: The mass ratio of the organic solvent to ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate is (5-10):1; Preferably, the mass ratio of the organic solvent to ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate is (6-8):

1.

5. The method for preparing the key intermediate of Febuxostat according to claim 1, characterized in that: The nitrogen source reagent is hydroxylamine hydrochloride.

6. The method for preparing the key intermediate of Febuxostat according to claim 1, characterized in that: The molar ratio of the nitrogen source reagent to ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate is (1-5):1; Preferably, the molar ratio of the nitrogen source reagent to ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate is (1.5-3):

1.

7. The method for preparing the key intermediate of Febuxostat according to claim 1, characterized in that: The catalyst is copper acetate.

8. The method for preparing the key intermediate of Febuxostat according to claim 1, characterized in that: The molar ratio of the catalyst to ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate is (0.1-0.5):1; Preferably, the molar ratio of the catalyst to ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate is (0.1-0.3):

1.

9. The method for preparing the key intermediate of Febuxostat according to claim 1, characterized in that: The reaction temperature is 60-90°C; preferably, the reaction temperature is 80-90°C; further preferably, the reaction temperature is 80°C.

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