阅读说明：本技术 一种抗癌药物帕博西林中间体的绿色制备方法 (Green preparation method of anticancer drug palbocillin intermediate ) 是由 商立华 王金奎 于 2020-12-24 设计创作，主要内容包括：本发明属于化药技术领域,具体涉及一种抗癌瘤药物帕博西林中间体的绿色制备方法。本发明以硝酸锆、偏钨酸铵为原料,采用均相沉淀法制备出Zr/W复合氧化物,并经硫酸浸渍制备出酸化的钨/锆双金属氧化物,用于催化双氧水氧化2-氨基-5-溴吡啶制备2-硝基-5-溴吡啶。本发明催化氧化工艺绿色无污染,不会产生废酸；且氧化工艺较为温和,氧化过程中基本无3,5-二溴-2-氨基吡啶副产的生成,粗品纯度和收率较高。(The invention belongs to the technical field of chemical drugs, and particularly relates to a green preparation method of an anticancer drug palbocillin intermediate. Zirconium nitrate and ammonium metatungstate are used as raw materials, a homogeneous precipitation method is adopted to prepare Zr/W composite oxide, and sulfuric acid impregnation is carried out to prepare acidified tungsten/zirconium bimetallic oxide which is used for catalyzing hydrogen peroxide to oxidize 2-amino-5-bromopyridine to prepare 2-nitro-5-bromopyridine. The catalytic oxidation process is green and pollution-free, and waste acid is not generated; the oxidation process is mild, no 3, 5-dibromo-2-aminopyridine byproduct is generated in the oxidation process, and the purity and the yield of the crude product are high.)

1. A green preparation method of an anticancer drug palbocillin intermediate is characterized by comprising the following steps: in the presence of a solvent and a catalyst, dropwise adding an oxidant to oxidize the 2-amino-5-bromopyridine to obtain 2-nitro-5-bromopyridine;

the catalyst is acidified tungsten/zirconium bimetallic oxide, and the preparation method comprises the following steps:

1) dissolving zirconium nitrate, ammonium metatungstate and urea in water, stirring and dispersing uniformly, then heating and refluxing for reaction for 12-24h under the condition that the pH is =8.5-9.0, cooling to room temperature, filtering, washing with water, collecting a filter cake, carrying out heat treatment in a muffle furnace at the temperature of 600-700 ℃, and cooling to room temperature to obtain the Zr/W composite oxide; calculated according to molar ratio, zirconium nitrate: ammonium metatungstate: urea =1:2-5: 20;

2) the Zr/W composite oxide is crushed to the particle size of 200-fold sand 300 meshes and then is soaked in sulfuric acid water solution, after ultrasonic treatment is carried out for 10-30min, filtration and water washing are carried out, filter cakes are collected and are subjected to heat treatment in a muffle furnace at the temperature of 600-fold sand 700 ℃, and then the temperature is reduced to room temperature, thus obtaining the acidified tungsten/zirconium bimetallic oxide.

2. The method of claim 1, wherein: the method comprises the following specific steps:

1) uniformly stirring 2-amino-5-bromopyridine, a catalyst and a solvent at 20-30 ℃, then controlling the temperature of a reaction system to 10-15 ℃, and dropwise adding an oxidant;

2) after the dropwise addition of the oxidant is finished, carrying out heat preservation reaction at 10-15 ℃ for 1-2h, then heating to 30 ℃ at the heating rate of 2 ℃/min for carrying out heat preservation reaction for 2h, and finally heating to 40 ℃ at the heating rate of 1 ℃/min until the concentration of the substrate 2-amino-5-bromopyridine is not reduced by HPLC (high performance liquid chromatography);

3) cooling to room temperature, filtering to remove the catalyst, adding sodium hydrosulfite into the filtrate, and stirring for 1-2 h;

4) and (3) testing that no excessive oxidant exists in the system by adopting starch potassium iodide test paper, then dropwise adding an aqueous alkali solution to adjust the pH value of the system to 8.0, finally dropwise adding an anti-solvent to crystallize, filtering and drying to obtain the 2-nitro-5-bromopyridine.

3. The method of claim 2, wherein: the solvent is methanol, ethanol, acetone, water or mixed solution thereof in any proportion.

4. The production method according to claim 3, characterized in that: the solvent is a mixed solution of acetone and water, and the volume ratio of the acetone to the water is as follows: water =5-8: 1.

5. The method of claim 2, wherein: the oxidant is hydrogen peroxide or sodium hypochlorite, and the molar ratio of the dosage of the oxidant to the 2-amino-5-bromopyridine is 2-5: 1.

6. The method of claim 5, wherein: the oxidant is hydrogen peroxide, and the molar ratio of the hydrogen peroxide to the 2-amino-5-bromopyridine is 3-4: 1.

7. The method of claim 2, wherein: the weight of the catalyst is 0.01-0.4 of that of the 2-amino-5-bromopyridine.

8. The method of claim 7, wherein: the weight of the catalyst is 0.1-0.2 of the weight of 2-amino-5-bromopyridine.

9. The method of claim 2, wherein: the anti-solvent is purified water or a mixed solution of the purified water and isopropanol.

10. The method of claim 9, wherein: the anti-solvent is a mixed solution of purified water and isopropanol.

Technical Field

The invention belongs to the technical field of chemical drugs, and particularly relates to a green preparation method of an anticancer drug palbocillin intermediate.

Background

The pabocillin serving as a novel anti-cancer drug- (CDK)4/6 inhibitor can inhibit cyclin-dependent kinase with high selectivity and reversibility. In 2 months 2015, the united states Food and Drug Administration (FDA) approved ibance (palbociclib) in combination with letrozole as the initial regimen for endocrine therapy based on endocrine therapy was used to treat ER +/HER 2-postmenopausal advanced breast cancer. Palbocillin (palbociclib) is the first approved CDK4/6 inhibitor for the treatment of breast cancer.

The 2-nitro-5-bromopyridine is a key intermediate for preparing a palbocillin bulk drug (the master's academic thesis of the university of jian, 6 months in 2017, and the research on the synthesis process of the palbocillin key intermediate), and is prepared by oxidizing 2-amino-5-bromopyridine, wherein the reaction formula is shown in Scheme 1:

at present, most of the oxidation reaction adopts H under acidic condition₂O₂Or peroxy acid is used as an oxidant for oxidation reaction, for example, glacial acetic acid is used as a solvent and peroxyacetic acid is used as an oxidant in CN106187867B, part of acetic acid is evaporated after the reaction, then an alkaline aqueous solution is added to adjust the pH value for crystallization to obtain a target product, and the yield can reach about 80%; however, a large amount of alkali is required for neutralization in the post-reaction treatment process, and high-salinity wastewater is generated. Bioorganic and Medicinal Chemistry, 1999,7 (3): 467-H and 479 uses₂SO₄/H₂O₂The system was subjected to oxidation reaction, and the yield was only 73%. The process Res.Dev.2017,21,451-459 have detailed reaction heat and reaction process researches on the oxidation reaction, and the researches show that H is adopted₂SO₄/H₂O₂The oxidation of the system can generate a remarkable amount of byproducts such as 3, 5-dibromo-2-aminopyridine, 1, 2-bis (5-bromopyridine-2-yl) azo oxide and the like; the paper focuses on how to control the heat of reaction to make the reaction favorable for production scale-up, but the final yield is 48.6%.

Disclosure of Invention

The invention aims to overcome the defects of high waste acid yield, more side reactions and low yield of the existing production process of 2-nitro-5-bromopyridine, and provides a high-yield green method for preparing the anticancer drug of the intermediate 2-nitro-5-bromopyridine. The method adopts the home-made acidified tungsten/zirconium bimetallic oxide as the catalyst, and forms an active oxidation species with the oxidant for preparing the 2-nitro-5-bromopyridine by catalytically oxidizing the 2-amino-5-bromopyridine, and the catalytic oxidation process is green and pollution-free, and does not generate waste acid; and the oxidation process is mild, and no 3, 5-dibromo-2-aminopyridine byproduct is generated in the oxidation process, so that the purity and the yield of the crude product are high.

According to one aspect of the invention, the invention provides a green preparation method of an anticancer drug palbocillin intermediate, under the existence of a solvent and a catalyst, dropwise adding an oxidant to oxidize 2-amino-5-bromopyridine to obtain 2-nitro-5-bromopyridine;

the catalyst is acidified tungsten/zirconium bimetallic oxide, and the preparation method comprises the following steps:

1) dissolving zirconium nitrate, ammonium metatungstate and urea in water, stirring and dispersing uniformly, then heating and refluxing for reaction for 12-24h under the condition that the pH value is 8.5-9.0, cooling to room temperature, filtering, washing with water, collecting a filter cake, carrying out heat treatment in a muffle furnace at the temperature of 600-700 ℃, and cooling to room temperature to obtain a Zr/W composite oxide; calculated according to molar ratio, zirconium nitrate: ammonium metatungstate: urea 1:2-5: 20; the Zr/W composite oxide is prepared by adopting a homogeneous precipitation method, wherein urea plays a role of a precipitator, so that the prepared Zr/W composite oxide particles are more uniform;

2) the Zr/W composite oxide is crushed to the particle size of 200-fold sand 300 meshes and then is soaked in sulfuric acid water solution, after ultrasonic treatment is carried out for 10-30min, filtration and water washing are carried out, filter cakes are collected and are subjected to heat treatment in a muffle furnace at the temperature of 600-fold sand 700 ℃, and then the temperature is reduced to room temperature, thus obtaining the acidified tungsten/zirconium bimetallic oxide.

Preferably, in the presence of a solvent and a catalyst, the 2-amino-5-bromopyridine is oxidized by hydrogen peroxide to obtain the 2-nitro-5-bromopyridine, and the method comprises the following specific steps:

1) uniformly stirring 2-amino-5-bromopyridine and a catalyst at 20-30 ℃ by adopting a solvent, controlling the temperature of a reaction system to 10-15 ℃, and then dropwise adding an oxidant; the reaction temperature is adjusted by dropping the oxidant at a speed, so that the generation of byproducts such as 3, 5-dibromo-2-aminopyridine and the like caused by local overheating due to violent reaction is avoided;

2) after the dropwise addition of the oxidant is finished, carrying out heat preservation reaction at 10-15 ℃ for 1-2h, then heating to 30 ℃ at the heating rate of 2 ℃/min for carrying out heat preservation reaction for 2h, and finally heating to 40 ℃ at the heating rate of 1 ℃/min until the concentration of the substrate 2-amino-5-bromopyridine is not reduced by HPLC (high performance liquid chromatography);

3) cooling to room temperature, filtering to remove the catalyst, adding sodium hydrosulfite into the filtrate, and stirring for 1-2 h;

4) and (3) testing that no excessive oxidant exists in the system by adopting starch potassium iodide test paper, then dropwise adding an aqueous alkali solution to adjust the pH value of the system to 8.0, finally dropwise adding an anti-solvent to crystallize, filtering and drying to obtain the 2-nitro-5-bromopyridine.

Preferably, the solvent is methanol, ethanol, acetone, water or a mixed solution thereof in any proportion; more preferably, the volume ratio of the mixed solution of acetone and water is acetone: water is 5-8: 1;

preferably, the oxidant is hydrogen peroxide or sodium hypochlorite, and further preferably hydrogen peroxide; the molar ratio of the using amount of the oxidant to the 2-amino-5-bromopyridine is 2-5:1, and the more preferable ratio is 3: 1;

preferably, the weight of the catalyst is 0.01-0.4 of the weight of the 2-amino-5-bromopyridine; more preferably, the weight of the catalyst is 0.1-0.2 of the weight of the 2-amino-5-bromopyridine;

preferably, the antisolvent is purified water or a mixed solution of purified water and isopropanol; purifying water according to volume ratio: 3-5 parts of isopropanol: 1.

the Zr/W composite oxide is prepared by a homogeneous precipitation method for the first time, the catalyst with catalytic oxidation performance is prepared by sulfuric acid impregnation, and tungsten and zirconium transition metals in the acidified tungsten/zirconium bimetallic oxide and an oxidant can form active oxidation species, so that the catalytic oxidation effect is achieved; the method can be used for preparing the anticancer drug of the intermediate 2-nitro-5-bromopyridine of the palbocillin by catalytic oxidation of the 2-amino-5-bromopyridine, and compared with the prior oxidation process, the method has the following advantages:

1) organic acid or inorganic acid is not required to be added in the oxidation process, so that the generation of acidic wastewater in the post-treatment process is avoided;

2) in the catalytic oxidation process of the catalyst, the reaction conditions are mild, no by-product is generated basically, the purity and the yield of the 2-nitro-5-bromopyridine are greatly improved, the yield is stabilized at about 93 percent, the purity of a crude product can reach more than 99.8 percent, and further purification is not needed;

3) the catalyst can be separated from the reaction system by filtration and can be recycled, so that the production cost is greatly reduced;

4) the catalyst can be recovered and reused for many times, and the activity of the catalyst can be reactivated by methods of calcining and acid dipping.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the description is intended to be exemplary only, and is not intended to limit the scope of the present invention.

HPLC detection method: the instrument is Agilent 1260; the chromatographic column is a Phenomenex Luna phenyl-hexyl column with the diameter of 4.6X 150mm and the diameter of 5 mu m; the column temperature is 35 ℃; mobile phase A is phosphate buffer solution with pH 7.0, and mobile phase B is methanol; the flow rate is 1.0mL/min, and the detection wavelength is 210 nm; the sample injection amount is 5 mu L; the diluent was mobile phase a/B50/50. Gradient elution was performed as in table 1:

TABLE 1 mobile phase gradient elution Table

Time/min	Mobile phase A/V%	Mobile phase B/V%
			0	70	30
2	70	30
			20	10	90
22	10	90
			22.1	70	30
26	70	30

The 2-amino-5-bromopyridine is from Shanxi Asia chemical industry Co., Ltd, and has a custom purity of more than 99.6 percent and maximum single impurity of less than 0.1 percent; ammonium metatungstate hydrate was obtained from sigma aldrich trade ltd, molecular weight calculated as 3060.46 (anhydrous form); the other raw materials are all commercial analytical grade reagents without description.

Example 1

The catalyst was prepared as follows:

1) adding 10mmol of Zr (NO)₃)₄·5H₂Dissolving O, 30mmol ammonium metatungstate hydrate and 200mmol urea in 500ml water, stirring and dispersing uniformly, dropwise adding an ammonia water solution to adjust the pH value to 8.5-9.0, then carrying out reflux reaction for 12-24h, cooling to room temperature, filtering, washing with water, collecting a filter cake, carrying out heat treatment in a muffle furnace at 600-700 ℃ for 1-2h, and cooling to room temperature to obtain a Zr/W composite oxide (abbreviated as ZW);

2) 10.0g of Zr/W composite oxide is crushed to the particle size of 200-fold sand 300 meshes and then is soaked in 100ml of 2mol/L sulfuric acid aqueous solution, after ultrasonic treatment for 10-30min, filtration and water washing are carried out, filter cake is collected and is subjected to heat treatment in a muffle furnace at the temperature of 600-fold sand 700 ℃, and then the temperature is reduced to room temperature, thus obtaining the acidified tungsten/zirconium bimetallic oxide (abbreviated as S/ZW).

Example 2

2-Nitro-5-bromopyridine was prepared by catalytic oxidation of 2-amino-5-bromopyridine using as additives the Zr/W composite oxide (abbreviated as ZW) prepared in example 1 and the acidified tungsten/zirconium bimetallic oxide (abbreviated as S/ZW) as follows:

adding a substrate of 2-amino-5-bromopyridine (1.73g, 10mmol), an additive (0.30g, 17.3 wt%) and 15ml of methanol into a reaction bottle, uniformly stirring, and then controlling the temperature of the reaction solution to be 0-5 ℃ and dropwise adding H with the concentration of 30 wt%₂O₂(50mmol, 5.0 eq); after the dropwise addition, the temperature is raised to 20 ℃ for reaction for 2h, the temperature is raised to 30 ℃ for reaction for 2h, then the temperature is raised to 40 ℃ until the area percentage of 2-amino-5-bromopyridine in the reaction solution taken in the previous 2h and the next 2h is not reduced, sodium hydrosulfite (42mmol) is added to remove excessive oxidant in the reaction solution, and the sum of the product 2-amino-5-bromopyridine, the product 2-nitro-5-bromopyridine, the by-product 3, 5-dibromo-2-aminopyridine (abbreviated as dibromo by-product) and other unknown impurities in the reaction solution after reduction is counted, and the results are shown in table 2:

TABLE 2 catalytic Oxidation Effect of the catalyst

Note: ND means that no additives in any form have been added as catalysts.

Test results show that H is directly adopted without adding any catalyst₂O₂As the oxidant, almost no oxidation reaction occurs, and only about 10 percent of target products are generated; the Zr/W composite oxide (abbreviated as ZW) and the acidified tungsten/zirconium bimetallic oxide (abbreviated as S/ZW) prepared by the method greatly improve the conversion rate of a substrate, and particularly for the Zr/W composite oxide, the area percentage of the product can reach 79.7 percent; the oxidation-reduction capability of the catalyst is improved due to the change of the surface acidity of the catalyst after sulfuric acid impregnation, and only a small amount of dibromo by-products are generated in the oxidation process and can be separated by post-treatmentAnd step (4) removing along the belt.

Example 3

In order to further improve the conversion rate of the substrate, the invention further optimizes the types of the solvent and the oxidant in the oxidation reaction, and the method comprises the following steps:

adding a substrate 2-amino-5-bromopyridine (1.73g, 10mmol), an acidified tungsten/zirconium bimetallic oxide (abbreviated as S/ZW) (0.30g, 17.3 wt%) and 15ml of solvent into a reaction bottle, uniformly stirring, and then controlling the temperature of the reaction solution to be 0-5 ℃ and dropwise adding an oxidant (50mmol, 5.0 eq); after the dropwise addition, the temperature is raised to 20 ℃ for reaction for 2h, the temperature is raised to 30 ℃ for reaction for 2h, then the temperature is raised to 40 ℃ until the area percentage of 2-amino-5-bromopyridine in the reaction solution taken in the previous 2h and the next 2h is not reduced, sodium hydrosulfite (42mmol) is added to remove excessive oxidant in the reaction solution, and the sum of the product 2-amino-5-bromopyridine, the product 2-nitro-5-bromopyridine, the by-product 3, 5-dibromo-2-aminopyridine (abbreviated as dibromo by-product) and other unknown impurities in the reduced reaction solution is counted, and the results are shown in Table 3:

TABLE 3 influence of solvent and oxidant species on the reaction

Note: acetone/water refers to a mixture of acetone and water, with a volume ratio of acetone/water of 7/1.

The test result shows that the acidified tungsten/zirconium bimetallic oxide (abbreviated as S/ZW) prepared by the invention is used as a catalyst, and a solvent has certain solvent effect in the oxidation reaction process, wherein acetone/H is used₂The best reaction effect is achieved by using a mixed solution of O (acetone/water in volume ratio of 7/1) as a solvent; reaction effect H in the oxidizing agent₂O₂>NaOCl>AcOOH, a catalyst has strong bonding with active oxygen in hydrogen peroxide, so H is finally determined₂O₂As an oxidizing agent.

Example 4

The invention further optimizes H₂O₂And the amount of catalyst-acidified tungsten/zirconium double metal oxide (abbreviated as S/ZW), and a methodThe following were used:

1) uniformly stirring 2-amino-5-bromopyridine (1.73g, 10mmol) and a catalyst S/ZW (17-865mg, 1.0-50.0 wt%) by using 15ml of acetone/water mixed solution (the volume ratio of acetone/water is 7/1) at 20-30 ℃, controlling the temperature of a reaction system to 10-15 ℃, and then dropwise adding 30 wt% of H₂O₂(10-80mmol，1.0-8.0eq)；

2) After the dropwise addition of the oxidant is finished, carrying out heat preservation reaction at 10-15 ℃ for 1-2h, then heating to 30 ℃ at the heating rate of 2 ℃/min for carrying out heat preservation reaction for 2h, and finally heating to 40 ℃ at the heating rate of 1 ℃/min until the concentration of the substrate 2-amino-5-bromopyridine is not reduced by HPLC (high performance liquid chromatography);

3) cooling to room temperature, filtering to remove the catalyst, adding sodium hydrosulfite into the filtrate, and stirring for 1-2 h;

4) adopting starch potassium iodide test paper to test that no excessive oxidant exists in a system, heating to 45-55 ℃, stirring for 10-30min, cooling to room temperature, counting the total of the substrate 2-amino-5-bromopyridine, the product 2-nitro-5-bromopyridine, the byproduct 3, 5-dibromo-2-aminopyridine (abbreviated as dibromo byproduct) and other unknown impurities in the reaction solution after reduction, and the results are shown in table 4:

TABLE 4 Effect of catalyst and oxidant amounts on the reaction

The experimental result shows that the dosage of the oxidant is required to be more than 2 times of the molar weight of the substrate 2-amino-5-bromopyridine, and 3.0eq is suitable for reducing the cost and reducing the dosage of the oxidant; the dosage of the catalyst needs to be more than 5.0 wt% of the weight of the substrate 2-amino-5-bromopyridine, when the dosage is more than 30.0 wt%, other unknown impurities are increased, and other oxidation side reactions occur; the amount of the catalyst is preferably 10.0 to 20.0% by weight based on the weight of the substrate, 2-amino-5-bromopyridine.

Example 5

By adopting the optimized process conditions, the invention carries out laboratory scale amplification reaction, and the specific method is as follows:

1) 2-amino-5-bromopyridine (173g, 1) was added to a 5L three-necked glass bottle0mol), catalyst S/ZW (26.0g, 15.0 wt%), 1.5L acetone/water mixed liquor (volume ratio acetone/water is 7/1) are stirred evenly at 20-30 deg.C by a mechanical stirrer, then the reaction system is controlled to 10-15 deg.C, 30 wt% H is dropped by a constant pressure dropping funnel₂O₂(3.5mol，3.0eq)；

2)H₂O₂After the dropwise addition is finished, carrying out heat preservation reaction at 10-15 ℃ for 1-2h, then heating to 30 ℃ at the heating rate of 2 ℃/min for 2h, and finally heating to 40 ℃ at the heating rate of 1 ℃/min until the concentration of the substrate 2-amino-5-bromopyridine is not reduced by HPLC detection; (the reaction is carried out for 4 hours at the temperature of 40 ℃, the area percentage of materials detected by HPLC is 0.18 percent of substrate, 99.4 percent of product, 0.16 percent of dibromo byproduct and 0.26 percent of other unknown impurities, and the difference with the small test reaction result is not large, which indicates that the oxidation reaction can be amplified according to the prior art);

3) cooling to room temperature, filtering to remove the catalyst, adding sodium hydrosulfite into the filtrate, and stirring for 1-2 h;

4) after no excessive oxidant is detected in a starch potassium iodide test paper, the temperature is raised to 45-55 ℃ and stirred for 10-30min, then an aqueous alkali solution is dripped to adjust the pH value of the system to 8.0, finally 2.0L (volume ratio, purified water/isopropanol is 4/1) of an anti-solvent is dripped to crystallize, the temperature is reduced to room temperature and filtered, 188.4g of 2-nitro-5-bromopyridine is obtained after drying (the yield is 92.8%), the HPLC detection purity is 99.82%, and the maximum single impurity is 0.06% of a dibromo byproduct.¹H-NMR(DMSO):8.83(1H,dd,),8.51(1H,dd),8.26(1H).LC/MS:202.9[M+H]⁺,204.8[M+H]⁺

Ultrasonically washing the catalyst obtained by filtering with acetone, airing, and drying in vacuum at 45 ℃ until the weight is constant to obtain 25.2g, wherein the recovery rate is 96.9%, and supplementing 0.8g of fresh catalyst to 26.0 g; the recycling and applying test is carried out according to the method, the area percentage of each material in the reaction liquid after the reaction is finished is counted, the service life of the catalyst is measured, and the result is shown in table 5:

TABLE 5 results of catalyst application

Note: w-5 is the catalytic result of the activation treatment of the catalyst applied for 5 times.

The recycling and applying result shows that the conversion rate of the substrate shows a descending trend along with the increase of the applying times, and particularly after 5 times of recycling and applying, the residual amount of the substrate reaches 5.96 percent; but the catalytic effect of the first catalyst and the second catalyst is almost unchanged, so the catalyst prepared by the method has certain stability; w-5 is the activation treatment of the catalyst which is recovered and reused for 5 times, and the method comprises the following steps:

ultrasonically washing the catalyst obtained by filtering and separating for 1-2h by acetone, then thermally treating for 1-2h in a muffle furnace at 600-700 ℃, cooling to room temperature, dipping in 2mol/L sulfuric acid aqueous solution, ultrasonically treating for 10-30min, filtering, washing, collecting filter cakes, thermally treating the filter cakes in the muffle furnace at 600 ℃, and cooling to room temperature to obtain the activated acidified tungsten/zirconium bimetallic oxide (abbreviated as R-S/ZW).

The catalyst used for many times is activated by heat treatment and acid impregnation of the catalyst, so that the defect that the activity of the catalyst is lowered after the catalyst is used for many times can be overcome.

Although the embodiments of the present invention have been described in detail, it should be understood that various changes, substitutions, and alterations can be made hereto without departing from the spirit and scope of the invention.