CN110642804A - Preparation method of certain specific impurity of febuxostat - Google Patents
Preparation method of certain specific impurity of febuxostat Download PDFInfo
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
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Abstract
The invention provides a preparation method of a certain specific impurity of febuxostat, which comprises the following steps: the method comprises the following steps: firstly, two aldehyde groups are introduced on a benzene ring through the reaction of N1 and HMTA to generate thiazole ring N2, and the yield reaches 90 percent due to the reduction of steric hindrance; secondly, the step of: n2 is coupled with N3 to generate A, and the yield reaches 70%; ③: reacting the A with hydroxylamine hydrochloride to generate B with the yield of about 80%; fourthly, the method comprises the following steps: hydrolyzing B to obtain C with yield of about 90%; the total yield of the synthetic C of the preparation method of a certain specific impurity of febuxostat reaches about 45%, compared with the prior art, the yield is greatly improved, the starting materials N1 and N3 of the new synthetic route are cheap and easy to obtain, and the preparation method is suitable for mass synthesis, and avoids the defects of accumulation and difficult purification in the process of synthesizing A by M3 in the prior art.
Description
Technical Field
The invention belongs to the field of febuxostat preparation, and particularly relates to a preparation method of a certain specific impurity of febuxostat.
Background
The febuxostat mainly comprises febuxostat, is a 2- [ (3-cyano-4-isobutoxy) phenyl ] -4-methyl-5-thiazolecarboxylic acid serving as a Xanthine Oxidase (XO) inhibitor, is suitable for long-term treatment of hyperuricemia with gout symptoms, and is prepared from certain specific impurities in the prior art as follows: firstly, generating thiazole ring M3 through cyclization reaction of M1 and M2, wherein the yield is about 90%; ② M3 two aldehyde groups are introduced on the benzene ring by the reaction with HMTA to generate A, the yield is about 3%; ③ reacting A with hydroxylamine hydrochloride to generate B with about 80 percent of yield; fourthly, hydrolyzing the B to obtain C, wherein the yield is about 90 percent; the following figures:
however, the reaction conversion rate of the generation of A by M3 in the prior art is very low, the yield after purification is about 3%, the synthesis of C is difficult, and the total yield is only about 2%.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a preparation method of a certain specific impurity of febuxostat, the total yield of the synthesis C of the preparation method of the certain specific impurity of febuxostat reaches about 45%, compared with the prior art, the yield is greatly improved, the starting materials N1 and N3 of the new synthesis route are cheap and easy to obtain, and the preparation method is suitable for mass synthesis, and avoids the defects of accumulation and difficult purification when synthesizing A from M3 in the prior art.
In order to achieve the purpose, the invention is realized by the following technical scheme: a preparation method of a specific impurity of febuxostat comprises the following steps:
the method comprises the following steps: firstly, two aldehyde groups are introduced on a benzene ring through the reaction of N1 and HMTA to generate thiazole ring N2, and the yield reaches 90 percent due to the reduction of steric hindrance;
the specific process is as follows: adding N1, HMTA and TFA into a reaction bottle, heating to 120 ℃ for reacting for 16 hours, pouring the reaction solution into a 40% dilute sulfuric acid solution, stirring for 2 hours, carrying out suction filtration on the system, leaching and pumping a filter cake with water, dissolving the filter cake into DCM, mixing silica gel with a sample, and purifying by a column to obtain an N2 pure product with the purity of 99.83% and the yield of 90%;
secondly, the step of: n2 is coupled with N3 to generate A, and the yield reaches 70%;
the specific process is as follows: weighing N2, N3 and a proper amount of Pd (dpp)f)Cl2Adding cuprous bromide, potassium bicarbonate, isobutyric acid and toluene into a three-necked bottle, heating to 110 ℃ for reacting for 16 hours, cooling to room temperature, performing suction filtration on the system, leaching a filter cake with DCM, drying an organic phase to obtain a crude product, mixing the crude product with a sample, and purifying by a column to obtain a pure product A, wherein the purity of the pure product A is as follows: 98.8 percent and the yield is 70 percent;
③: reacting the A with hydroxylamine hydrochloride to generate B with the yield of about 80%;
the specific process is as follows: at room temperature, adding anhydrous formic acid into a reaction bottle, stirring, adding hydroxylamine hydrochloride and sodium formate dihydrate, dissolving to obtain colorless clear liquid, adding A, uniformly stirring to obtain a yellow solid-liquid mixture, heating the system to 95-105 ℃, keeping the temperature of the system at 95-105 ℃, reacting for 3 hours, monitoring the complete reaction of the raw material A by TLC, cooling to 30-40 ℃, precipitating a large amount of solid, adding water into the reaction liquid to promote crystallization, cooling the system to 15-25 ℃, performing suction filtration to obtain a filter cake, pulping the filter cake with water for 0.5-1 hour, performing suction filtration to obtain a wet product (the water content is about 28 percent), performing blast drying at 60 ℃ to obtain a light yellow powdery solid B, and obtaining the purity: 99.1%, yield: 80 percent;
fourthly, the method comprises the following steps: hydrolyzing B to obtain C with yield of about 90%;
the specific process is as follows: at room temperature, adding absolute ethyl alcohol into a reaction bottle, stirring, adding B, uniformly stirring to obtain a white slurry system, dropwise adding 1N sodium hydroxide aqueous solution, heating to 50-55 ℃ until the system is still slurry, gradually clarifying the system, keeping the system temperature at 50-55 ℃ for reacting for 2 hours, monitoring by TLC (thin layer chromatography) that the raw material B is completely reacted, cooling the reaction system to 25-35 ℃, dropwise adding 1N hydrochloric acid ethanol solution, precipitating a large amount of solid, filtering, washing, and drying to obtain a white solid C with purity: 99.3%, yield: 90 percent.
As a preferred embodiment of the present invention, in the above (r), HMTA: n1 ═ (1-3) eq: 1eq, preferably 2: 1, the solvent can be selected from: acetic acid and trifluoroacetic acid, preferably trifluoroacetic acid, and the reaction temperature can be selected from: 100 ℃ and 130 ℃, preferably 120 ℃ (for 16 hours).
As a preferred embodiment of the present invention, N3: n2 ═ (1-3) eq: 1eq, preferably 1.2: 1, Pd (dppf) Cl2：CuCl：KHCO3: isobutyric acid is 1:10:20:4 (mass ratio), and the reaction temperature can be selected as follows: 100 ℃ and 130 ℃, preferably 110 ℃ (for 16 hours).
In a preferred embodiment of the present invention, the dropwise addition of the 1N aqueous sodium hydroxide solution in the fourth step is completed within 0.5 to 1 hour.
The invention has the beneficial effects that:
the total yield of the synthetic C of the preparation method of a certain specific impurity of febuxostat reaches about 45%, compared with the prior art, the yield is greatly improved, the starting materials N1 and N3 of the new synthetic route are cheap and easy to obtain, and the preparation method is suitable for mass synthesis, and avoids the defects of accumulation and difficult purification in the process of synthesizing A by M3 in the prior art.
Drawings
FIG. 1 is a synthesis scheme of a process for the preparation of a particular impurity of febuxostat;
FIG. 2 is a hydrogen spectrum of a process for the preparation of a particular impurity of febuxostat;
FIG. 3 is a carbon spectrum of a process for the preparation of a particular impurity of febuxostat;
Detailed Description
In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further described with the specific embodiments.
Referring to fig. 1, the present invention provides a technical solution: a preparation method of a specific impurity of febuxostat;
example 1:
the method comprises the following steps: adding N1(100g, 578mmol, 1.0eq), HMTA (162g, 1156mmol, 2.0eq) and TFA (1000ml) into a reaction bottle, heating to 120 ℃ for reacting for 16 hours, monitoring by TLC that the reaction of the raw material N1 is complete, dropping the reaction solution to room temperature, stirring for 2 hours in a dilute sulfuric acid solution (1200ml) with the mass fraction of 40%, filtering, leaching the filter cake with water (500ml), draining to obtain a filter cake, dissolving the filter cake in DCM, adding silica gel for sample stirring, purifying by a column (petroleum ether: ethyl acetate: 3:1) to obtain a pure N2 product (119g), the purity is 99.83%, the yield is 90%,
secondly, the step of: n2(110g, 480.3mmol, 1.0eq), N3(98.7g, 576.4mmol, 1.2eq), appropriate amount of Pd (dppf) Cl were weighed2Adding (0.5g), cuprous bromide (5.0g), potassium bicarbonate (10.0g), isobutyric acid (2.0g) and toluene (500ml) into a three-necked bottle, heating to 110 ℃ for reaction for 16 hours, monitoring the reaction completion of a raw material N2 by TLC, cooling to room temperature, performing suction filtration on the system, leaching a filter cake with DCM (500ml), drying an organic phase to obtain a crude product, mixing the crude product with a sample, and performing column purification (petroleum ether: ethyl acetate: 5:1) to obtain a pure product A (107g) with the purity: 98.8 percent, the yield is 70 percent,
③: adding anhydrous formic acid (900g) into a reaction bottle at room temperature, stirring, adding hydroxylamine hydrochloride (54.4g, 782.5mmol, 2.5eq) and sodium formate dihydrate (81.4g, 782.5mmol, 2.5eq), dissolving to obtain colorless clear liquid, adding A (100g, 313mmol, 1.0eq) into the solution, stirring uniformly to obtain a yellow solid-liquid mixture, heating the system to 95-105 ℃, keeping the temperature of the system at 95-105 ℃ for reflux reaction for 3 hours, monitoring the complete reaction of the raw material A by TLC, cooling to 30-40 ℃, precipitating a large amount of solid, adding water (600g) into the reaction solution to promote crystallization, cooling the system to 15-25 ℃, and performing suction filtration to obtain a filter cake; the filter cake was slurried with water (600g) for 0.5-1 hour, suction filtered to give a wet product (water content about 28%), air dried at 60 ℃ for 16 hours to give pale yellow powdered solid B (78.5g), purity: 99.1%, yield: 80 percent of the total weight of the mixture,
fourthly, the method comprises the following steps: adding absolute ethyl alcohol (441g) into a reaction bottle at room temperature, stirring, adding B (70g, 223.4mmol, 1.0eq), uniformly stirring to obtain a white slurry system, dropwise adding a 1N sodium hydroxide aqueous solution (242.2g, 257mmol, 1.15eq), dropwise adding after 0.5-1 hour, cooling the reaction system to 25-35 ℃, dropwise adding a 1N hydrochloric acid ethanol solution (302.4g, 277mmol, 1.24eq), precipitating a large amount of solids, filtering, washing once (a mixed solution of 100g of ethanol and 12g of water), and drying to obtain a white solid C (57.4g), wherein the purity: 99.3%, yield: 90 percent.
Example 2:
the method comprises the following steps: adding N1(10.0g, 57.8mmol, 1.0eq), HMTA (8.1g, 57.8mmol, 1.0eq) and TFA (100.0ml) into a reaction bottle, heating to 120 ℃ for reaction for 16 hours, monitoring the completion of the reaction of a raw material N1 by TLC, dropping the reaction solution into a dilute sulfuric acid solution (120.0ml) with the mass fraction of 40% after the reaction solution is cooled to room temperature, stirring for 2 hours, performing suction filtration, leaching the filter cake with water (50.0ml) once, then draining to obtain a filter cake, dissolving the filter cake into DCM, adding silica gel for sample stirring, performing column purification (petroleum ether: ethyl acetate: 3:1) to obtain an N2 pure product (11.0g), the purity is 99.5%, and the yield is 83.2%,
secondly, the step of: n2(11.0g, 48.0mmol, 1.0eq), N3(9.87g, 57.64mmol, 1.2eq), and an appropriate amount of Pd (dppf) Cl were weighed2(0.05g), cuprous bromide (0.5g), potassium bicarbonate (1.0g), isobutyric acid (0.2g) and toluene (50.0ml) are added into a three-necked bottle, the temperature is increased to 110 ℃ for reaction for 16 hours, TLC monitors that the raw material N2 is completely reacted, the temperature is reduced to room temperature, a pumping filtration system is adopted, a filter cake is rinsed with DCM (50.0ml), an organic phase is dried and dried in a spinning mode to obtain a crude product, and the crude product is mixed with a sample and is subjected to column purification (petroleum ether: ethyl acetate: 5:1) to obtain a pure product A (10.5g) with the purity: 99.0 percent and the yield is 68.7 percent,
③: adding anhydrous formic acid (90.0g) into a reaction bottle at room temperature, stirring, adding hydroxylamine hydrochloride (5.44g, 78.25mmol, 2.5eq) and sodium formate dihydrate (8.14g, 78.25mmol, 2.5eq) into the reaction bottle, dissolving to obtain colorless clear liquid, adding A (10.0g, 31.3mmol, 1.0eq) into the solution, stirring uniformly to obtain a yellow solid-liquid mixture, heating the system to 95-105 ℃, keeping the temperature of the system at 95-105 ℃ for reflux reaction for 3 hours, monitoring the reaction completion of the raw material A by TLC, cooling to 30-40 ℃, precipitating a large amount of solid, adding water (60.0g) into the reaction solution to promote crystallization, cooling the system to 15-25 ℃, and performing suction filtration to obtain a filter cake; the filter cake was slurried with water (60.0g) for 0.5-1 hour, suction filtered to give a wet product (water content about 28%), and air-dried at 60 ℃ for 16 hours to give a pale yellow powdery solid B (7.85g), purity: 99.2%, yield: 80 percent of the total weight of the mixture,
fourthly, the method comprises the following steps: adding absolute ethyl alcohol (44.1g) into a reaction bottle at room temperature, stirring, adding B (7.0g, 22.34mmol and 1.0eq), uniformly stirring to obtain a white slurry system, dropwise adding 1N sodium hydroxide aqueous solution (24.22g, 25.7mmol and 1.15eq), dropwise adding for 0.5-1 hour, cooling the reaction system to 25-35 ℃ after the dropwise adding is finished and the system is still in a slurry state, heating to 50-55 ℃, gradually clarifying the system, keeping the system temperature at 50-55 ℃ for reacting for 2 hours, monitoring the reaction completion of the raw material B by TLC, dropwise adding 1N ethanol hydrochloride solution (30.24g, 27.7mmol and 1.24eq), precipitating a large amount of solid, filtering, washing once (a mixed solution of 10.0g of ethanol and 1.2g of water), and drying to obtain a white solid C (5.7g) with purity: 99.5%, yield: 90 percent.
Example 3:
the method comprises the following steps: adding N1(100g, 578mmol, 1.0eq), HMTA (162g, 1156mmol, 2.0eq) and AcOH (1000ml) into a reaction bottle, heating to 120 ℃ for reaction for 16 hours, monitoring the reaction completion of the raw material N1 by TLC, dropping the reaction solution to room temperature, stirring for 2 hours in a dilute sulfuric acid solution (1200ml) with the mass fraction of 40%, filtering, leaching the filter cake with water (500ml), draining to obtain a filter cake, dissolving the filter cake in DCM, adding silica gel for sample mixing, purifying by a column (petroleum ether: ethyl acetate: 3:1) to obtain an N2 pure product (112g), the purity is 99.83%, the yield is 84.7%,
secondly, the step of: n2(110g, 480.3mmol, 1.0eq), N3(164.3g, 960.6mmol, 2.0eq), appropriate amount of Pd (dppf) Cl were weighed2Adding (0.5g), cuprous bromide (5.0g), potassium bicarbonate (10.0g), isobutyric acid (2.0g) and toluene (500ml) into a three-necked bottle, heating to 110 ℃ for reaction for 16 hours, monitoring the reaction completion of a raw material N2 by TLC, cooling to room temperature, performing suction filtration on the system, leaching a filter cake with DCM (500ml), drying an organic phase to obtain a crude product, mixing the crude product with a sample, and performing column purification (petroleum ether: ethyl acetate: 5:1) to obtain a pure product A (104g), wherein the purity: 98.5 percent, the yield is 68 percent,
③: adding anhydrous formic acid (900g) into a reaction bottle at room temperature, stirring, adding hydroxylamine hydrochloride (54.4g, 782.5mmol, 2.5eq) and sodium formate dihydrate (81.4g, 782.5mmol, 2.5eq), dissolving to obtain colorless clear liquid, adding A (100g, 313mmol, 1.0eq) into the solution, stirring uniformly to obtain a yellow solid-liquid mixture, heating the system to 95-105 ℃, keeping the temperature of the system at 95-105 ℃ for reflux reaction for 3 hours, monitoring the complete reaction of the raw material A by TLC, cooling to 30-40 ℃, precipitating a large amount of solid, adding water (600g) into the reaction solution to promote crystallization, cooling the system to 15-25 ℃, and performing suction filtration to obtain a filter cake; the filter cake was slurried with water (600g) for 0.5-1 hour, suction filtered to give a wet product (water content about 28%), air dried at 60 ℃ for 16 hours to give pale yellow powdered solid B (78.5g), purity: 99.3%, yield: 80 percent of the total weight of the mixture,
fourthly, the method comprises the following steps: adding absolute ethyl alcohol (441g) into a reaction bottle at room temperature, stirring, adding B (70g, 223.4mmol, 1.0eq), uniformly stirring to obtain a white slurry system, dropwise adding a 1N sodium hydroxide aqueous solution (242.2g, 257mmol, 1.15eq), dropwise adding after 0.5-1 hour, cooling the reaction system to 25-35 ℃, dropwise adding a 1N hydrochloric acid ethanol solution (302.4g, 277mmol, 1.24eq), precipitating a large amount of solids, filtering, washing once (a mixed solution of 100g of ethanol and 12g of water), and drying to obtain a white solid C (57.4g), wherein the purity: 99.3%, yield: 90 percent.
While there have been shown and described what are at present considered the fundamental principles and essential features of the invention and its advantages, it will be apparent to those skilled in the art that the invention is not limited to the details of the foregoing exemplary embodiments, but is capable of other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.
Claims (4)
1. A preparation method of a specific impurity of febuxostat is characterized by comprising the following steps:
the method comprises the following steps: firstly, two aldehyde groups are introduced on a benzene ring through the reaction of N1 and HMTA to generate thiazole ring N2, and the yield reaches 90 percent due to the reduction of steric hindrance;
the specific process is as follows: adding N1, HMTA and TFA into a reaction bottle, heating to 120 ℃ for reacting for 16 hours, pouring the reaction solution into a 40% dilute sulfuric acid solution, stirring for 2 hours, carrying out suction filtration on the system, leaching and pumping a filter cake with water, dissolving the filter cake into DCM, mixing silica gel with a sample, and purifying by a column to obtain an N2 pure product with the purity of 99.83% and the yield of 90%;
secondly, the step of: n2 is coupled with N3 to generate A, and the yield reaches 70%;
the specific process is as follows: weighing N2, N3 and a proper amount of Pd (dppf) Cl2Adding cuprous bromide, potassium bicarbonate, isobutyric acid and toluene into a three-necked bottle, heating to 110 ℃ for reacting for 16 hours, cooling to room temperature, performing suction filtration on the system, leaching a filter cake with DCM, drying an organic phase to obtain a crude product, mixing the crude product with a sample, and purifying by a column to obtain a pure product A, wherein the purity of the pure product A is as follows: 98.8 percent and the yield is 70 percent;
③: reacting the A with hydroxylamine hydrochloride to generate B with the yield of about 80%;
the specific process is as follows: at room temperature, adding anhydrous formic acid into a reaction bottle, stirring, adding hydroxylamine hydrochloride and sodium formate dihydrate, dissolving to obtain colorless clear liquid, adding A, uniformly stirring to obtain a yellow solid-liquid mixture, heating the system to 95-105 ℃, keeping the temperature of the system at 95-105 ℃, reacting for 3 hours, monitoring the complete reaction of the raw material A by TLC, cooling to 30-40 ℃, precipitating a large amount of solid, adding water into the reaction liquid to promote crystallization, cooling the system to 15-25 ℃, performing suction filtration to obtain a filter cake, pulping the filter cake with water for 0.5-1 hour, performing suction filtration to obtain a wet product (the water content is about 28 percent), performing blast drying at 60 ℃ to obtain a light yellow powdery solid B, and obtaining the purity: 99.1%, yield: 80 percent;
fourthly, the method comprises the following steps: hydrolyzing B to obtain C with yield of about 90%;
the specific process is as follows: at room temperature, adding absolute ethyl alcohol into a reaction bottle, stirring, adding B, uniformly stirring to obtain a white slurry system, dropwise adding 1N sodium hydroxide aqueous solution, heating to 50-55 ℃ until the system is still slurry, gradually clarifying the system, keeping the system temperature at 50-55 ℃ for reacting for 2 hours, monitoring by TLC (thin layer chromatography) that the raw material B is completely reacted, cooling the reaction system to 25-35 ℃, dropwise adding 1N hydrochloric acid ethanol solution, precipitating a large amount of solid, filtering, washing, and drying to obtain a white solid C with purity: 99.3%, yield: 90 percent.
2. The method for preparing a specific impurity of febuxostat according to claim 1, which is characterized in that: in the above description, HMTA: n1 ═ (1-3) eq: 1eq, preferably 2: 1, the solvent can be selected from: acetic acid and trifluoroacetic acid, preferably trifluoroacetic acid, and the reaction temperature can be selected from: 100 ℃ and 130 ℃, preferably 120 ℃ (for 16 hours).
3. The method for preparing a specific impurity of febuxostat according to claim 1, which is characterized in that: n3: n2 ═ (1-3) eq: 1eq, preferably 1.2: 1, Pd (dppf) Cl2：CuCl：KHCO3: isobutyric acid is 1:10:20:4 (mass ratio), and the reaction temperature can be selected as follows: 100 ℃ and 130 ℃, preferably 110 ℃ (for 16 hours).
4. The method for preparing a specific impurity of febuxostat according to claim 1, which is characterized in that: and (4) when the 1N sodium hydroxide aqueous solution is dripped into the solution, the dripping is finished within 0.5-1 hour.
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