CN109574952B - Synthetic method of febuxostat intermediate - Google Patents
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- CN109574952B CN109574952B CN201710900248.7A CN201710900248A CN109574952B CN 109574952 B CN109574952 B CN 109574952B CN 201710900248 A CN201710900248 A CN 201710900248A CN 109574952 B CN109574952 B CN 109574952B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
The invention discloses a synthetic method of a febuxostat intermediate, which comprises the following steps: 3-methyl-4-hydroxybenzonitrile and isobutyl bromide react in sodium hydroxide aqueous solution to obtain 3-methyl-4-isobutoxy benzonitrile; then reacting with hydrogen peroxide, hydrogen bromide and tetramethyl piperidine nitrogen oxide to obtain a substance A; then reacting with sodium hydrosulfide and sodium hydroxide to obtain a substance B; then reacting with 2-chloroacetoacetic acid ethyl ester to obtain the febuxostat intermediate. The synthetic route of the invention has good selectivity, is green and environment-friendly, has cheap and easily-obtained raw materials, convenient and controllable operation, low cost, high yield and good purity of the prepared febuxostat intermediate, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of chemical substance preparation, in particular to a synthetic method of a febuxostat intermediate.
Background
Febuxostat (trade name: febuxostat; Adenuric; also known as TEI 26720; TMX267) is a novel non-purine XO inhibitor and is clinically used for preventing and treating hyperuricemia and gout caused by the hyperuricemia. Japan's imperial corporation was marketed in japanese applications in 2004, in the united states at the end of the year, and the european union has approved it in month 5 in 2008 and FDA approved it in month 2 in 2009.
Febuxostat is a brand-new non-purine high-efficiency selective xanthine oxidase inhibitor, is an effective substitute for allopurinol allergic or intolerant gout patients, and is particularly suitable for gout patients with renal insufficiency. The dissolution rate of the medicine on the tophus is high, and the lethal anaphylactic syndrome is rarely generated.
The ethyl 2- (3-formyl-4-isobutoxyphenyl) -4-methylthiazole-5-carboxylate is a key intermediate for synthesizing febuxostat. The intermediate needs to be synthesized in most of the currently common febuxostat synthetic routes.
The current synthetic routes for febuxostat mainly comprise the following steps:
route one, US patent US5614520 reports a synthetic route starting from 3-nitro-3-methyl-4-hydroxybenzonitrile:
the route is long, the yield is low, and particularly, the route uses highly toxic cyanide and reaction conditions are harsh, so that the industrial production is difficult to realize.
The second route is that Japanese patent JP1994329647 reports the following synthetic route using p-hydroxy-phenyl-methionine amide as starting material:
the route is an industrially preferred route, but the starting materials of the route are expensive and difficult to prepare, and besides, the yield of aldehyde groups introduced by the route is not high, and the use of trifluoroacetic acid is more irritating to personnel and more equipment.
Route three, a synthetic route using p-hydroxybenzonitrile as a starting material reported in chinese patent CN 103880775B:
although the route is novel in the design, the route is long, the total yield is low, the two steps of introducing chloromethyl and hydrolyzing are complicated, and in addition, the reaction conditions are complicated in introducing methionine, so that the route is difficult to realize industrial production.
According to the above review, the existing synthetic route of the febuxostat intermediate 2- (3-formyl-4-isobutoxyphenyl) -4-methylthiazole-5-ethyl formate has a wide prospect for developing a route for synthesizing the febuxostat intermediate which is green, environment-friendly and strong in operability because expensive reagent raw materials are used, or because a highly toxic reagent is used, or because the route is long and the yield is low, and the like, industrial production is difficult to realize.
Disclosure of Invention
Based on the technical problems in the background art, the invention provides a synthetic method of a febuxostat intermediate, and the synthetic route has the advantages of good selectivity, environmental protection, cheap and easily-obtained raw materials, convenient and controllable operation, low cost, suitability for industrial production, high yield and good purity of the prepared febuxostat intermediate.
The invention provides a synthetic method of a febuxostat intermediate, which comprises the following steps: 3-methyl-4-hydroxybenzonitrile and isobutyl bromide react in sodium hydroxide aqueous solution to obtain 3-methyl-4-isobutoxy benzonitrile; then reacting with hydrogen peroxide, hydrogen bromide and tetramethyl piperidine nitrogen oxide to obtain a substance A; then reacting with sodium hydrosulfide and sodium hydroxide to obtain a substance B; and reacting with 2-chloroacetoacetic acid ethyl ester to obtain a febuxostat intermediate, wherein the structural formulas of the substance A, the substance B and the febuxostat intermediate are as follows:
preferably, a phase transfer catalyst is added to prepare 3-methyl-4-isobutoxybenzonitrile.
Preferably, the phase transfer catalyst is at least one of tetrabutylammonium chloride, tetrabutylammonium bromide, tetramethylammonium chloride and tetramethylammonium bromide.
Preferably, the phase transfer catalyst is tetrabutylammonium bromide.
Preferably, the reaction temperature for preparing the 3-methyl-4-isobutoxy benzonitrile is 30-80 ℃; preferably 50 deg.c.
Preferably, the reaction time for preparing the 3-methyl-4-isobutoxy benzonitrile is 12 to 24 hours.
Preferably, in the process for preparing 3-methyl-4-isobutoxy benzonitrile, the molar ratio of 3-methyl-4-hydroxybenzonitrile to sodium hydroxide is 1: 1.2-2; preferably 1: 1.5.
preferably, the molar ratio of 3-methyl-4-hydroxybenzonitrile to isobutyl bromide is 1: 1.05-1.5; preferably 1: 1.2.
preferably, the specific steps for preparing the 3-methyl-4-isobutoxy benzonitrile are as follows: and (2) uniformly mixing the sodium hydroxide aqueous solution and the 3-methyl-4-hydroxybenzonitrile, adding a phase transfer catalyst, dropwise adding isobutyl bromide, reacting, and purifying to obtain the 3-methyl-4-isobutoxy benzonitrile.
Preferably, the purification comprises the following specific steps: adjusting the pH value to be neutral, extracting an organic phase by using ethyl acetate, drying and concentrating to obtain the 3-methyl-4-isobutoxy benzonitrile.
Preferably, the reaction solvent for the preparation of substance a is acetonitrile.
Preferably, the reaction temperature for preparing substance a is room temperature.
Preferably, the reaction time for the preparation of substance A is 4-12 h.
Preferably, the molar ratio of the 3-methyl-4-isobutoxy benzonitrile to the hydrogen peroxide is 1: 3-5; preferably 1: 4.
preferably, the molar ratio of the 3-methyl-4-isobutoxy benzonitrile to the hydrogen bromide is 1: 0.1-0.5; preferably 1: 0.2.
preferably, the molar ratio of the 3-methyl-4-isobutoxy benzonitrile to the tetramethylpiperidine nitroxide is 1: 0.005-0.1; preferably 1: 0.01.
preferably, the specific steps for preparing substance a are: mixing 3-methyl-4-isobutoxy benzonitrile and a reaction solvent, adding hydrogen bromide and tetramethylpiperidine nitric oxide, dropwise adding hydrogen peroxide, reacting, and purifying to obtain a substance A.
Preferably, the specific steps of purification are: adjusting pH to neutral, adding sodium bisulfite to destroy oxidability, extracting with ethyl acetate to obtain organic phase, drying, and concentrating to obtain substance A.
Preferably, the reaction solvent for preparing substance B is N, N-dimethylformamide.
Preferably, the reaction temperature for preparing the substance B is 30-80 ℃; preferably 50 deg.c.
Preferably, the reaction time for preparing the substance B is 12 to 24 hours.
Preferably, during the preparation of substance B, the molar ratio of substance a to sodium hydroxide is 1: 1.05-1.5; preferably 1: 1.2.
preferably, the molar ratio of substance a to sodium hydrosulfide is 1: 2-4; preferably 1: 3.
preferably, the specific steps for preparing substance B are: and (3) uniformly mixing the substance A, a sodium hydroxide aqueous solution and a reaction solvent, adding sodium hydrosulfide, reacting, and purifying to obtain a substance B.
Preferably, the specific steps of purification are: adjusting pH to neutral, extracting with ethyl acetate to obtain organic phase, drying, and concentrating to obtain substance B.
Preferably, the reaction solvent for preparing the febuxostat intermediate is N, N-dimethylformamide.
Preferably, the reaction temperature for preparing the febuxostat intermediate is 40-100 ℃; preferably 60 deg.c.
Preferably, the reaction time for preparing the febuxostat intermediate is 4-12 h.
Preferably, the molar ratio of substance B to ethyl 2-chloroacetoacetate is 1: 1.05-2.
Preferably, the specific steps for preparing the febuxostat intermediate are as follows: and (3) uniformly mixing the substance B, the reaction solvent and the 2-chloroacetoacetic acid ethyl ester, reacting, and purifying the febuxostat intermediate.
Preferably, the specific steps of purification are: cooling to 0 ℃ for crystallization, filtering to obtain a filter cake, and recrystallizing with ethyl acetate to obtain the febuxostat intermediate.
In the above-mentioned preparation of 3-methyl-4-isobutoxy benzonitrile, the amount of the phase transfer catalyst is not specified, and is determined according to the specific operation.
In the preparation of the substance A, the amount of the reaction solvent is not specified, and is determined according to the specific operation.
In the preparation of the substance B, the amount of the reaction solvent is not specified, and is determined according to the specific operation.
In the preparation process of the febuxostat intermediate, the dosage of the reaction solvent is not specified, and is determined according to specific operation.
The preferred synthetic route of the present invention is as follows:
the TEMPO is tetramethylpiperidine oxynitride.
The synthetic route of the invention has cheap and easily obtained raw materials, convenient and controllable operation and obvious cost advantage; 3-methyl-4-hydroxybenzonitrile and isobutyl bromide react in an aqueous solution of sodium hydroxide to obtain 3-methyl-4-isobutoxy benzonitrile without adding an organic solvent, so that the method is green and environment-friendly; the hydrogen peroxide, the hydrogen bromide and the tetramethyl piperidine nitrogen oxide are compounded to form an oxidation system, a metal catalyst is not required to be added, the oxidation system is green and environment-friendly, the compound A is reacted with the 3-methyl-4-isobutoxy benzonitrile to obtain a substance A, the yield and the purity are greatly increased, and the operation is simple and controllable; the substance A reacts with sodium hydrosulfide and sodium hydroxide, and the methionine amide is introduced to prepare the substance B, so that the operation is simple, the reaction condition is mild and controllable, and the method is suitable for industrial production; the method has high yield, and the prepared febuxostat intermediate has high purity.
Detailed Description
The technical solution of the present invention will be described in detail below with reference to specific examples.
Example 1
A synthetic method of a febuxostat intermediate comprises the following steps: 3-methyl-4-hydroxybenzonitrile and isobutyl bromide react in sodium hydroxide aqueous solution to obtain 3-methyl-4-isobutoxy benzonitrile; then reacting with hydrogen peroxide, hydrogen bromide and tetramethyl piperidine nitrogen oxide to obtain a substance A; then reacting with sodium hydrosulfide and sodium hydroxide to obtain a substance B; then reacting with 2-chloroacetoacetic acid ethyl ester to obtain the febuxostat intermediate.
Example 2
A synthetic method of a febuxostat intermediate comprises the following steps:
uniformly mixing a sodium hydroxide aqueous solution and 3-methyl-4-hydroxybenzonitrile, adding tetrabutylammonium chloride, dropwise adding isobutyl bromide, heating to 30 ℃, keeping the temperature for reaction for 12 hours, adjusting the pH to be neutral, extracting with ethyl acetate to obtain an organic phase, drying and concentrating to obtain the 3-methyl-4-isobutoxy benzonitrile, wherein the molar ratio of the 3-methyl-4-hydroxybenzonitrile to the sodium hydroxide is 1: the molar ratio of the 2, 3-methyl-4-hydroxybenzonitrile to the isobutyl bromide is 1: 1.05;
mixing 3-methyl-4-isobutoxy benzonitrile and acetonitrile, adding hydrogen bromide and tetramethylpiperidine nitric oxide, then adding hydrogen peroxide dropwise, reacting for 12 hours at room temperature, adjusting pH to neutral, adding sodium bisulfite to destroy oxidability, keeping starch potassium iodide test paper unchanged to blue, extracting with ethyl acetate, taking an organic phase, drying and concentrating to obtain a substance A, wherein the molar ratio of the 3-methyl-4-isobutoxy benzonitrile to the hydrogen peroxide is 1: the mol ratio of the 3, 3-methyl-4-isobutoxy benzonitrile to the hydrogen bromide is 1: 0.1, 3-methyl-4-isobutoxy benzonitrile and tetramethylpiperidine nitroxide in a molar ratio of 1: 0.005;
uniformly mixing the substance A, a sodium hydroxide aqueous solution and N, N-dimethylformamide, adding sodium hydrosulfide, heating to 30 ℃, keeping the temperature for reaction for 12 hours, adjusting the pH value to be neutral, extracting an organic phase by using ethyl acetate, drying and concentrating to obtain a substance B, wherein the molar ratio of the substance A to the sodium hydroxide is 1: 1.5, the molar ratio of the substance A to the sodium hydrosulfide is 1: 2;
uniformly mixing B, N, N-dimethylformamide and 2-chloroacetoacetic acid ethyl ester, heating to 40 ℃, carrying out heat preservation reaction for 12h, cooling to 0 ℃ for crystallization, filtering to obtain a filter cake, and recrystallizing with ethyl acetate to obtain a febuxostat intermediate, wherein the molar ratio of the substance B to the 2-chloroacetoacetic acid ethyl ester is 1: 1.05.
example 3
A synthetic method of a febuxostat intermediate comprises the following steps:
uniformly mixing a sodium hydroxide aqueous solution and 3-methyl-4-hydroxybenzonitrile, adding tetramethylammonium chloride, dropwise adding isobutyl bromide, heating to 60 ℃, keeping the temperature for reacting for 18 hours, adjusting the pH to be neutral, extracting with ethyl acetate to obtain an organic phase, drying and concentrating to obtain the 3-methyl-4-isobutoxybenzonitrile, wherein the molar ratio of the 3-methyl-4-hydroxybenzonitrile to the sodium hydroxide is 1: 1, the molar ratio of the 2, 3-methyl-4-hydroxybenzonitrile to the isobutyl bromide is 1: 1.5;
mixing 3-methyl-4-isobutoxy benzonitrile and acetonitrile, adding hydrogen bromide and tetramethylpiperidine nitric oxide, then dropwise adding hydrogen peroxide, reacting for 4 hours at room temperature, adjusting pH to be neutral, adding sodium bisulfite to destroy oxidability, keeping starch potassium iodide test paper unchanged to be blue, extracting with ethyl acetate, taking an organic phase, drying and concentrating to obtain a substance A, wherein the molar ratio of the 3-methyl-4-isobutoxy benzonitrile to the hydrogen peroxide is 1: 4, the mol ratio of 5, 3-methyl-4-isobutoxy benzonitrile to hydrogen bromide is 1: 0.4, 3-methyl-4-isobutoxy benzonitrile and tetramethylpiperidine nitroxide in a molar ratio of 1: 0.05;
uniformly mixing the substance A, a sodium hydroxide aqueous solution and N, N-dimethylformamide, adding sodium hydrosulfide, heating to 60 ℃, keeping the temperature for reacting for 18 hours, adjusting the pH value to be neutral, extracting an organic phase by using ethyl acetate, drying and concentrating to obtain a substance B, wherein the molar ratio of the substance A to the sodium hydroxide is 1: 1.05, the molar ratio of the substance A to the sodium hydrosulfide is 1: 4;
uniformly mixing B, N, N-dimethylformamide and 2-chloroacetoacetic acid ethyl ester, heating to 100 ℃, carrying out heat preservation reaction for 4 hours, cooling to 0 ℃ for crystallization, filtering to obtain a filter cake, and recrystallizing with ethyl acetate to obtain a febuxostat intermediate, wherein the molar ratio of the substance B to the 2-chloroacetoacetic acid ethyl ester is 1: 2.
example 4
A synthetic method of a febuxostat intermediate comprises the following steps:
uniformly mixing a 5 wt% sodium hydroxide aqueous solution and 3-methyl-4-hydroxybenzonitrile, adding tetrabutylammonium bromide, dropwise adding isobutyl bromide, heating to 50 ℃, keeping the temperature for reaction for 24 hours, adjusting the pH value to be neutral, extracting with ethyl acetate to obtain an organic phase, drying with anhydrous sodium sulfate, and concentrating to obtain the 3-methyl-4-isobutoxy benzonitrile, wherein the molar ratio of the 3-methyl-4-hydroxybenzonitrile to the sodium hydroxide is 1: 1, the molar ratio of 5, 3-methyl-4-hydroxybenzonitrile to isobutyl bromide is 1: the weight ratio of 2, 3-methyl-4-hydroxybenzonitrile to tetrabutylammonium bromide is 133: 16;
uniformly mixing 3-methyl-4-isobutoxy benzonitrile and acetonitrile, adding 40 wt% of hydrogen bromide water solution and tetramethylpiperidine nitric oxide, slowly dropwise adding 30 wt% of hydrogen peroxide, reacting at room temperature for 8 hours, adjusting pH to be neutral, adding sodium bisulfite to destroy oxidability, keeping starch potassium iodide test paper from changing blue, extracting with ethyl acetate to obtain an organic phase, drying with anhydrous sodium sulfate, and concentrating to obtain a substance A, wherein the molar ratio of 3-methyl-4-isobutoxy benzonitrile to hydrogen peroxide is 1: the mol ratio of the 4, 3-methyl-4-isobutoxy benzonitrile to the hydrogen bromide is 1: 0.2, 3-methyl-4-isobutoxy benzonitrile and tetramethylpiperidine nitroxide in a molar ratio of 1: 0.01, 3-methyl-4-isobutoxy benzonitrile, acetonitrile in a weight to volume (g/ml) ratio of 1: 100, respectively;
stirring and uniformly mixing the substance A, a 5 wt% sodium hydroxide aqueous solution and N, N-dimethylformamide for 15min, adding sodium hydrosulfide in batches, heating to 50 ℃, keeping the temperature for reaction for 24h, adjusting the pH to be neutral by using a 5 wt% hydrochloric acid aqueous solution, extracting with ethyl acetate, taking an organic phase, drying and concentrating to obtain a substance B, wherein the molar ratio of the substance A to the sodium hydroxide is 1: 1.2, the molar ratio of the substance A to the sodium hydrosulfide is 1: 3, the weight to volume (g/ml) ratio of substance a to N, N-dimethylformamide is 1: 6;
uniformly mixing B, N, N-dimethylformamide and 2-chloroacetoacetic acid ethyl ester, heating to 60 ℃, carrying out heat preservation reaction for 6h, cooling to 0 ℃ for crystallization, filtering to obtain a filter cake, and recrystallizing with ethyl acetate to obtain a febuxostat intermediate, wherein the molar ratio of the substance B to the 2-chloroacetoacetic acid ethyl ester is 1: 1.2, substance B, N, weight volume of N-dimethylformamide (g/ml) 1: 5.
example 5
A synthetic method of a febuxostat intermediate comprises the following steps:
uniformly mixing a 5 wt% sodium hydroxide aqueous solution and 3-methyl-4-hydroxybenzonitrile, adding tetrabutylammonium bromide, dropwise adding isobutyl bromide, heating to 80 ℃, keeping the temperature for reaction for 24 hours, adjusting the pH value to be neutral, extracting with ethyl acetate to obtain an organic phase, drying with anhydrous sodium sulfate, and concentrating to obtain the 3-methyl-4-isobutoxy benzonitrile, wherein the molar ratio of the 3-methyl-4-hydroxybenzonitrile to the sodium hydroxide is 1: 1, the molar ratio of 5, 3-methyl-4-hydroxybenzonitrile to isobutyl bromide is 1: the weight ratio of 2, 3-methyl-4-hydroxybenzonitrile to tetrabutylammonium bromide is 133: 16;
uniformly mixing 3-methyl-4-isobutoxy benzonitrile and acetonitrile, adding 40 wt% of hydrogen bromide water solution and tetramethylpiperidine nitric oxide, slowly dropwise adding 30 wt% of hydrogen peroxide, reacting at room temperature for 8 hours, adjusting pH to be neutral, adding sodium bisulfite to destroy oxidability, keeping starch potassium iodide test paper from changing blue, extracting with ethyl acetate to obtain an organic phase, drying with anhydrous sodium sulfate, and concentrating to obtain a substance A, wherein the molar ratio of 3-methyl-4-isobutoxy benzonitrile to hydrogen peroxide is 1: the mol ratio of the 5, 3-methyl-4-isobutoxy benzonitrile to the hydrogen bromide is 1: 0.5, the molar ratio of 3-methyl-4-isobutoxy benzonitrile to tetramethylpiperidine nitroxide is 1: 0.1, 3-methyl-4-isobutoxy benzonitrile, acetonitrile in a weight to volume (g/ml) ratio of 1: 100, respectively;
stirring and uniformly mixing the substance A, a 5 wt% sodium hydroxide aqueous solution and N, N-dimethylformamide for 15min, adding sodium hydrosulfide in batches, heating to 80 ℃, keeping the temperature for reaction for 24h, adjusting the pH to be neutral by using a 5 wt% hydrochloric acid aqueous solution, extracting with ethyl acetate, taking an organic phase, drying and concentrating to obtain a substance B, wherein the molar ratio of the substance A to the sodium hydroxide is 1: 1.2, the molar ratio of the substance A to the sodium hydrosulfide is 1: 3, the weight to volume (g/ml) ratio of substance a to N, N-dimethylformamide is 1: 6;
uniformly mixing B, N, N-dimethylformamide and 2-chloroacetoacetic acid ethyl ester, heating to 80 ℃, carrying out heat preservation reaction for 6h, cooling to 0 ℃ for crystallization, filtering to obtain a filter cake, and recrystallizing with ethyl acetate to obtain a febuxostat intermediate, wherein the molar ratio of the substance B to the 2-chloroacetoacetic acid ethyl ester is 1: 1.2, substance B, N, weight volume of N-dimethylformamide (g/ml) 1: 5.
the yields of the intermediates of examples 4 and 5 and the febuxostat intermediate were counted and the purity was checked, and the results are shown in the following table:
as can be seen from the table above, the yield of the invention is high, and the purity of the prepared febuxostat intermediate is good.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (9)
1. A synthetic method of a febuxostat intermediate is characterized by comprising the following steps: 3-methyl-4-hydroxybenzonitrile and isobutyl bromide react in sodium hydroxide aqueous solution to obtain 3-methyl-4-isobutoxy benzonitrile, and a phase transfer catalyst is required to be added when the 3-methyl-4-isobutoxy benzonitrile is prepared; then reacting with hydrogen peroxide, hydrogen bromide and tetramethyl piperidine nitrogen oxide to obtain a substance A; then reacting with sodium hydrosulfide and sodium hydroxide to obtain a substance B; and reacting with 2-chloroacetoacetic acid ethyl ester to obtain a febuxostat intermediate, wherein the structural formulas of the substance A, the substance B and the febuxostat intermediate are as follows:
2. the method for synthesizing the febuxostat intermediate according to claim 1, wherein the phase transfer catalyst is at least one of tetrabutylammonium chloride and tetrabutylammonium bromide.
3. The method for synthesizing the febuxostat intermediate according to claim 1 or 2, wherein the reaction temperature for preparing the 3-methyl-4-isobutoxy benzonitrile is 30-80 ℃; the reaction time for preparing the 3-methyl-4-isobutoxy benzonitrile is 12 to 24 hours.
4. The method for synthesizing the febuxostat intermediate according to claim 1, wherein in the process of preparing the 3-methyl-4-isobutoxy benzonitrile, the molar ratio of the 3-methyl-4-hydroxybenzonitrile to the sodium hydroxide is 1: 1.2-2; the molar ratio of 3-methyl-4-hydroxybenzonitrile to isobutyl bromide is 1: 1.05-1.5.
5. The method for synthesizing the febuxostat intermediate according to claim 1, wherein a reaction solvent for preparing the substance A is acetonitrile; the reaction temperature for preparing the substance A is room temperature; the reaction time for preparing the substance A is 4-12 h.
6. The method for synthesizing the febuxostat intermediate according to claim 1, wherein the molar ratio of 3-methyl-4-isobutoxy benzonitrile to hydrogen peroxide is 1: 3-5; the mol ratio of the 3-methyl-4-isobutoxy benzonitrile to the hydrogen bromide is 1: 0.1-0.5; the mol ratio of the 3-methyl-4-isobutoxy benzonitrile to the tetramethylpiperidine oxynitride is 1: 0.005-0.1.
7. The method for synthesizing the febuxostat intermediate according to claim 1, wherein a reaction solvent for preparing the substance B is N, N-dimethylformamide; the reaction temperature for preparing the substance B is 30-80 ℃; the reaction time for preparing the substance B is 12-24 h.
8. The method for synthesizing the febuxostat intermediate according to claim 1, wherein the molar ratio of the substance A to the sodium hydroxide in the preparation process of the substance B is 1: 1.05-1.5; the molar ratio of the substance A to the sodium hydrosulfide is 1: 2-4.
9. The method for synthesizing the febuxostat intermediate according to claim 1, wherein a reaction solvent for preparing the febuxostat intermediate is N, N-dimethylformamide; the reaction temperature for preparing the febuxostat intermediate is 40-100 ℃; the reaction time for preparing the febuxostat intermediate is 4-12 h.
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