CN108516938B - Method for preparing osteoarthritis treatment drug intermediate 6-carbonyl methyl hexanoate - Google Patents
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Abstract
The invention belongs to the technical field of chemical research and development, and particularly relates to a method for preparing an osteoarthritis treatment drug intermediate. The invention provides a preparation method of a zinc salt modified hydroxyapatite loaded ammonium ceric nitrate catalyst, which is obtained by ion exchange of zinc salt modified hydroxyapatite and ammonium ceric nitrate in an ethanol water solution; the zinc salt modified hydroxyapatite consists of Ca (NO)3)2.4H2O and diammonium hydrogen phosphate as raw materials and Zn (NO)3)2.6H2O is a modifier and is prepared by a chemical precipitation method under the alkaline condition; the catalyst prepared by the invention can be used for catalyzing 6-methyl hydroxycaproate to prepare the osteoarthritis drug cis-capsaicin intermediate 6-methyl carbonylhexanoate. The catalytic process has high yield and is green and environment-friendly.
Description
Technical Field
The invention belongs to the technical field of chemical research and development, and particularly relates to a method for preparing a medicament intermediate 6-carbonyl methyl hexanoate for treating osteoarthritis.
Background
Capsaicin (capsaicin) is a main spicy substance in hot peppers, has the effects of analgesia, anti-inflammation, antioxidation and the like, is mainly used for treating muscle, joint and nerve pain, but is easy to cause adverse reactions such as skin burning, pricking and flushing at the application part in the initial administration period, and limits clinical application. Compared with capsaicin, zucapsaicin (zucapsaicin) artificially synthesized by the zucapsaicin shows stronger analgesic activity and lower irritation, and has wide application prospect. WINSTON developed zucapsaicin cream (trade name: zuacta), marketed in canada on 15.07.2010, approved for the treatment of Osteoarthritis (OA).
The molecular formula of the cis-capsaicin (zucapsaicin) is C18H27NO3, the molecular weight is 305.41, the CAS number is 25775-90-0, and the structural formula is shown as the formula (1):
methyl 6-carbonyl hexanoate is an important intermediate for synthesizing cis-capsaicin (zucapsaicin), and is prepared by oxidizing a corresponding hydroxy substance, namely methyl 6-hydroxycaproate, and the reaction formula is shown in Scheme 1:
this oxidation process is reported in the prior art (J.org.chem.1988,53,1064-1071), using PCC (pyridine and CrO) with sodium acetate as base in dichloromethane3Complex salt in hydrochloric acid solution) as an oxidant, but the method generates heavy metal cadmium wastewater, which does not meet the requirements of the current green pharmaceutical production; in addition, the reaction process needs to be carried out under strict anhydrous conditions, and the water contained in the system can form hydrated aldehyde with the generated aldehyde, so that the carboxylic acid is obtained by continuous oxidation, and the reaction conditions are harsh.
Wuhan Daichaotao et al (catalytic science report, vol. 36, No. 8, 2015, No. 36, bimetallic concerted catalysis of copper oxide modified hydroxyapatite loaded gold on alcohol aerobic oxidation) discloses a copper oxide modified hydroxyapatite loaded gold catalyst prepared by a uniform deposition-precipitation method, wherein oxygen is used as an oxygen source to catalyze alcoholic hydroxyl groups to generate corresponding glycosyl compounds, but a substrate is only limited to benzyl alcohol or hydroxyl groups at allyl sites to generate corresponding aldehyde groups, and the catalyst cannot be applied to common alkyl alcohols.
Therefore, the development of a green and mild oxidation method for preparing the methyl 6-carbonyl hexanoate is of great significance.
Disclosure of Invention
The invention aims to overcome the defects that toxic oxidants are required to be used in the preparation process of cis-capsaicin intermediate 6-carbonyl methyl hexanoate for treating osteoarthritis in the prior art and the reaction conditions are harsh, and provides a zinc salt modified hydroxyapatite loaded ceric ammonium nitrate catalytic material to replace the oxidation process in the prior art.
According to one aspect of the invention, the invention provides a preparation method of a zinc salt modified hydroxyapatite-loaded ammonium ceric nitrate catalyst, wherein the zinc salt modified hydroxyapatite-loaded ammonium ceric nitrate catalyst is obtained by performing ion exchange on zinc salt modified hydroxyapatite and ammonium ceric nitrate in an ethanol water solution; the zinc salt modified hydroxyapatite consists of Ca (NO)3)2.4H2O and diammonium hydrogen phosphate as raw materials and Zn (NO)3)2.6H2O is a modifier and is prepared by a chemical precipitation method under the alkaline condition.
Preferably, the preparation method of the zinc salt modified hydroxyapatite-supported ammonium cerium nitrate catalyst specifically comprises the following steps:
(A) preparation of zinc salt modified hydroxyapatite:
A-1)Ca(NO3)2.4H2o and Zn (NO)3)2.6H2Dissolving O in water, and then dropwise adding the solution into an ammonia water solution with the pH value of 11, and uniformly stirring to obtain a calcium-zinc mixed solution;
a-2) dropwise adding an aqueous solution of diammonium hydrogen phosphate into an ammonia aqueous solution with the pH value of 11, and uniformly stirring to obtain a phosphate solution;
a-3) heating the calcium-zinc mixed solution to 50-60 ℃, stirring at the rotation speed of 600-800rpm, dropwise adding a phosphate solution into the calcium-zinc mixed solution to form a colloidal precipitate, controlling the dropwise adding time of the phosphate solution to be 1-2h, and then carrying out reflux reaction for 30-60 min;
a-4) cooling to room temperature to obtain precipitate, centrifuging, washing with water until the washing liquid becomes neutral, and calcining at 400-450 ℃ to obtain zinc salt modified hydroxyapatite;
(B) the zinc salt modified hydroxyapatite loaded cerium ammonium nitrate working procedure:
b-1) dissolving ammonium ceric nitrate and urea in 90% V ethanol water solution, and uniformly stirring to form uniform mixed solution; the method takes the mixed solution of ethanol and water as a solvent and urea as a precipitator auxiliary agent, and is beneficial to precipitation of ammonium ceric nitrate on zinc salt modified hydroxyapatite and cation exchange;
b-2) adding zinc salt modified hydroxyapatite into the uniform mixed solution, and heating to reflux for 6-8 h;
b-3) cooling to room temperature after the reaction is finished, centrifuging, washing with water, collecting a filter cake, drying at 60-80 ℃ to constant weight, and transferring to a calcining furnace to calcine at 200-500 ℃ in the air atmosphere to obtain the zinc salt modified hydroxyapatite loaded ammonium cerium nitrate catalyst;
preferably, Ca (NO) is present in step (A) in terms of mole ratios3)2.4H2O and Zn (NO)3)2.6H2The ratio of the sum of the moles of O to the moles of diammonium phosphate is 1.7: 1;
preferably, in step (B), the cerium ammonium nitrate: urea: zinc salt modified hydroxyapatite is 3-5:1: 50-60; the urea is a precipitator auxiliary agent, is beneficial to precipitation of ammonium ceric nitrate on zinc salt modified hydroxyapatite, and the addition amount of the urea is not required to be excessive; the weight ratio of ammonium ceric nitrate and zinc salt modified hydroxyapatite is mainly adjusted in the feeding process;
preferably, the zinc salt modified hydroxyapatite supported cerium ammonium nitrate catalyst is obtained by calcining at 400 ℃ under 350-400 ℃ in the air atmosphere in the step B-3).
According to another aspect of the invention, the invention provides a use of zinc salt modified hydroxyapatite loaded cerium ammonium nitrate catalyst in the presence of a solvent and an oxidant for catalyzing 6-hydroxycaproic acid methyl ester to generate 6-carbonyl caproic acid methyl ester.
Preferably, the solvent is acetonitrile, ethanol, acetone or isopropanol;
preferably, the oxidant is hydrogen peroxide, sodium hypochlorite or tert-butyl hydroperoxide, and further preferably hydrogen peroxide;
preferably, the zinc salt modified hydroxyapatite supported cerium ammonium nitrate catalyst is used in an amount of 5-20% by weight of methyl 6-hydroxycaproate.
The invention has the following advantages:
1) the invention provides a zinc salt modified hydroxyapatite loaded cerium ammonium nitrate catalyst, which can efficiently catalyze 6-hydroxycaproic acid methyl ester to generate 6-carbonyl methyl hexanoate; the defect that heavy metal wastewater is generated by PCC oxidation in the prior art is overcome;
2) according to the invention, ammonium ceric nitrate and zinc salt modified hydroxyapatite are subjected to ion exchange, so that the catalytic activity of the catalyst is greatly improved, and the conversion rate has a surprising experimental effect;
3) the zinc salt modified hydroxyapatite loaded ammonium cerium nitrate catalyst prepared by the invention is a heterogeneous catalyst, and the catalyst is easy to separate from a reaction system; and can be used for application after recovery;
4) the invention optimizes the catalytic system and obtains the 6-carbonyl methyl hexanoate with high yield.
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.
Methyl 6-hydroxycaproate (GC purity of 99.85% or more, area normalization) was obtained from Shanghai Bigdi pharmaceutical science and technology, Inc., and the remaining raw materials in the examples were commercially available conventional laboratory analytical grade reagents (AR grade).
The detection of the reaction solution of the invention is carried out by GC-MS (Agilent model 5975C in USA), and a chromatographic column DB-5MSx chromatographic column (30m multiplied by 0.25mm multiplied by 0.25 mu m); the temperature of a column box is 80 ℃, the sample injection temperature is 250.00 ℃, the flow control pressure is 107.3kPa, the total flow is 42.1mL/min, the column flow is 0.68mL/min, and the split ratio is 50.0; the initial temperature of the chromatographic column is 80 deg.C, and maintaining for 2 min; heating to 180 deg.C at a rate of 10 deg.C/min, and maintaining for 30 min; and (3) cooling, synchronously heating the modulator at 30 ℃ higher than the furnace temperature, wherein the modulation period is 4s, the cold and hot modulation time is 0.8 s and 1.2s respectively, the ion source is an EI (electron impact ionization) source, the ionization voltage is 70eV, the temperature is 230 ℃, the interface temperature is 290 ℃, full-scan monitoring is adopted, the scanning rate is 100 spectrums/s, and the scanning range is 100-800 m/z.
Example 1
Preparing a zinc salt modified hydroxyapatite loaded cerium ammonium nitrate catalyst:
first with Ca (NO)3)2.4H2O and diammonium hydrogen phosphate as raw materials and Zn (NO)3)2.6H2O is a modifier, and the zinc salt modified hydroxyapatite is prepared by a chemical precipitation method under the alkaline condition; then, zinc salt modified hydroxyapatite and ammonium ceric nitrate are subjected to ion exchange in an ethanol water solution to prepare the zinc salt modified hydroxyapatite-loaded ammonium ceric nitrate catalyst.
The preparation process comprises the following steps:
(A) preparation of zinc salt modified hydroxyapatite:
A-1)10mmol Ca(NO3)2.4H2o and 7mmol Zn (NO)3)2.6H2Dissolving O in 50ml of water, and then dropwise adding the dissolved O into 100ml of ammonia water solution with the pH value of 11, and uniformly stirring to obtain a calcium-zinc mixed solution;
a-2) adding 50ml of diammonium hydrogen phosphate aqueous solution (containing 10mmol of diammonium hydrogen phosphate) dropwise into ammonia aqueous solution with pH of 11, and stirring uniformly to obtain phosphate solution;
a-3) heating the calcium-zinc mixed solution to 50-60 ℃, stirring at the rotation speed of 600-800rpm, dropwise adding a phosphate solution into the calcium-zinc mixed solution to form a colloidal precipitate, controlling the dropwise adding time of the phosphate solution to be 1-2h, and then carrying out reflux reaction for 30-60 min;
a-4) cooling to room temperature to obtain precipitate, centrifuging, washing with water until the washing liquid becomes neutral, and calcining at 400-450 ℃ to obtain zinc salt modified hydroxyapatite (abbreviated as Zn/HAP);
(B) the zinc salt modified hydroxyapatite loaded cerium ammonium nitrate working procedure:
b-1) dissolving 5.0g of ammonium ceric nitrate and 1.0g of urea in 200ml of 90% V ethanol aqueous solution, and uniformly stirring to form uniform mixed solution;
b-2) adding 50.0g of zinc salt modified hydroxyapatite into the uniform mixed solution, and heating to reflux for 6-8 h;
b-3) cooling to room temperature after the reaction is finished, centrifuging, washing with water, collecting a filter cake, drying at 60-80 ℃ to constant weight, and transferring to a calcining furnace to calcine at 200-500 ℃ in the air atmosphere to obtain the zinc salt modified hydroxyapatite loaded ammonium cerium nitrate catalyst;
the zinc salt modified hydroxyapatite loaded cerium ammonium nitrate catalyst obtained at different calcination temperatures in B-3) is defined as Zn/Ce/HAP/X, and X represents the corresponding calcination temperature.
Example 2
The Zn/Ce/HAP/X prepared by the invention is used as a catalyst, the catalytic performance of the catalyst on 6-carbonyl methyl hexanoate generated by 6-hydroxy methyl hexanoate is considered, and the catalytic process comprises the following steps:
adding 10mmol of 6-hydroxy methyl hexanoate and a catalyst (0.15g, about 10 wt%) into 20ml of ethanol in a parallel synthesizer, then adding 30 wt% of hydrogen peroxide solution (containing 20mmol of hydrogen peroxide, 2.0eq), stirring and reacting at 20-30 ℃ (room temperature reaction), detecting the catalytic effects of different catalysts by GC-MS, and counting the reaction conditions of the reaction solution after the reaction is finished, including the time for the reaction to reach equilibrium, the conversion rate of 6-hydroxy methyl hexanoate and the selectivity of the target product of 6-carbonyl methyl hexanoate, wherein the results are shown in Table 1:
TABLE 1 catalytic Effect of different catalysts
| Catalyst and process for preparing same | Reaction time/h | Conversion rate/% | Selectivity/%) |
| Zn/HAP | 16 | 33.9 | 96.2 |
| Zn/Ce/HAP/100 | 12 | 67.8 | 98.2 |
| Zn/Ce/HAP/200 | 8 | 72.6 | 98.1 |
| Zn/Ce/HAP/300 | 8 | 80.3 | 98.2 |
| Zn/Ce/HAP/400 | 6 | 93.9 | 98.1 |
| Zn/Ce/HAP/500 | 6 | 94.2 | 94.3 |
| Zn/Ce/HAP/600 | 6 | 94.0 | 90.2 |
| Zn/Ce/HAP/350 | 6 | 92.8 | 98.2 |
The results show that the catalytic activity of the hydroxyapatite modified by the pure zinc salt is weak, and the conversion rate of the 6-hydroxycaproic acid methyl ester is only 33.9 percent; after the cerium ammonium nitrate is subjected to ion exchange, the catalytic activity of the cerium ammonium nitrate is greatly enhanced, the catalytic activity is continuously improved along with the improvement of the final calcination temperature, but after the calcination temperature is higher than 500 ℃, the selectivity of the catalyst to a target product is greatly reduced, and a byproduct, namely mono-methyl hexanedioate, is excessively oxidized; therefore, the final calcination temperature is preferably fixed at 350-400 ℃.
Example 3
When Zn/Ce/HAP/400 is determined as a catalyst, the reaction solvent, the temperature, the catalyst dosage, the oxidant and the oxidant dosage are further optimized:
adding 10mmol of 6-methyl hydroxycaproate and a catalyst Zn/Ce/HAP/400 (44-440 mg, 3.0-30% wt) into 20ml of solvent in a parallel synthesizer, then adding an oxidant (the molar amount is 1.5-3.0eq of the substrate 6-methyl hydroxycaproate), stirring and reacting at 0-60 ℃, detecting the catalytic effects of different catalysts by GC-MS, and counting the reaction conditions of a reaction solution after the reaction is finished, including the time for the reaction to reach equilibrium, the conversion rate of the 6-methyl hydroxycaproate and the selectivity of a target product 6-methyl hydroxycaproate, wherein the results are shown in Table 2:
TABLE 2 catalyst system optimization results tabulation
Note: DCM refers to dichloromethane; EA means ethyl acetate; h2O230% wt of hydrogen peroxide solution; aqueous solution with NaClO of 10 percent by weight; t-BuOOH is 70 wt% of tert-butyl hydroperoxide aqueous solution; air means that the oxidation is carried out without any addition of oxidizing agent, i.e. with a portion of the oxygen brought into the air by stirring at 25 ℃.
The results show that the polar solvent is beneficial to the reaction, the nonpolar solvents such as esters, chlorohydrocarbons and benzenes are not easy to react, and the polar solvent has the best reaction effect by acetonitrile and acetone; hydrogen peroxide and sodium hypochlorite in the oxidant have good oxidation effect, but the oxidant is selected from hydrogen peroxide in consideration of water obtained after the hydrogen peroxide is oxidized and is more green; however, the invention can also select air as the oxidant, the conversion rate is 6.1%, if the air can be improved in the later period to improve the conversion rate, the air is adopted as the oxygen source to better meet the requirement of green pharmaceutical production; the complete conversion of the substrate can be realized when the dosage of the hydrogen peroxide is between 2.0 and 2.5 eq; the oxidation temperature is not suitable to be too high, is most suitable at 0-30 ℃, probably because the oxidation reaction belongs to weak exothermic reaction and is beneficial to the reaction at low temperature; in addition, the hydrogen peroxide with too high temperature can be decomposed in an accelerated way under the catalysis of the catalyst, so that the utilization rate of the hydrogen peroxide is low, the conversion rate of raw materials is reduced, and byproducts are more easily generated.
Example 4
The reactions were scaled up using the reaction conditions in sequence 20 of Table 2, and the experimental conditions were as follows:
adding a substrate of methyl 6-hydroxycaproate (146.2g, 1mol), acetonitrile (1.2L) and a catalyst of Zn/Ce/HAP/400(17.5g, 12% wt) into a 1L three-opening jacket reaction bottle, then starting a stirrer (IKA overhead stirrer, stirring paddle is paddle type), and then controlling the temperature in the jacket reaction bottle to be 0-5 ℃ by adopting a high-low temperature circulating pump;
dropping 30 wt% hydrogen peroxide solution (2.5mol, 2.5eq) into the reaction bottle for 30-60min by using a constant pressure dropping funnel; after the dropwise addition, carrying out heat preservation and stirring reaction at 5-10 ℃, sampling every 1h to detect the reaction liquid, and after 6h, finishing the reaction (the residual quantity of the raw material 6-methyl hydroxycaproate is 0.08%, the target product 6-methyl carbonyl hexanoate is 99.1%, the monomethyl adipate is 0.34%, and the rest is unknown impurities, which are calculated by an area normalization method in GC); adding 2.0mol of sodium hydrosulfite after the reaction is finished and stirring
Filtering to remove the catalyst Zn/Ce/HAP/400 to obtain filtrate, concentrating the filtrate at 40-45 ℃ until the residual amount is 600-700ml, adding 1L of purified water, stirring uniformly, extracting with n-heptane (1.5LX3), combining the three n-heptane extracts, and distilling under reduced pressure at 80 ℃ and 0.2mmHg to obtain 129.03g of 6-carbonyl methyl hexanoate with the yield of 89.5%; the GC purity was 99.68%; 1H-NMR (300MHz, CDCl)3)：1.60-1.68(4H，-CH2)，2.33(2H，-CH2CO2)，2.45(2H，-CH2＝O)，3.65(3H，-CH3O)，9.86(1H，-CHO)。
Example 5
The Zn/Ce/HAP/400 separated by filtration in example 4 is ultrasonically washed by acetonitrile, dried at 50-60 ℃ to constant weight and recycled for use (the acetonitrile is ultrasonically washed for each recycling and then dried at 50-60 ℃ to constant weight), the change of catalytic performance along with the use times is examined, the catalytic process is carried out according to the reaction conditions in the sequence 20 in example 2 (the test scale is 10mmol of 6-methyl hydroxycaproate), and the reaction conditions are shown in Table 3:
TABLE 3 Table of variation of catalytic performance with the number of recyclings
| Number of times of application | 1 | 2 | 3 | 4 | 5 |
| Conversion rate/% | 99.8 | 99.2 | 98.5 | 92.1 | 86.3 |
| Selectivity/%) | 99.1 | 99.2 | 99.0 | 99.1 | 99.0 |
The test result shows that the conversion rate of the raw material is continuously reduced along with the increase of the application times, but the selectivity of the target product is not changed; when the recovery and reuse are carried out for the fourth time, the conversion rate is obviously reduced, and the next reaction can not be carried out after the fifth time.
Example 6
The zinc salt modified hydroxyapatite loaded ammonium cerium nitrate catalyst prepared by the invention is a heterogeneous catalyst, and generally the catalytic activity of the heterogeneous catalyst is reduced, and the catalyst is deactivated by the factors such as the morphology (aperture and granularity) of the catalyst, the chemical composition or carbon deposition (the active sites of the catalyst are deposited by small organic molecules, so the active sites are shielded).
In order to solve the problem of catalyst deactivation, the invention tries the following schemes to activate the Zn/Ce/HAP/400 catalyst which is recycled for 5 times as a research object:
high-temperature calcination
The recovered Zn/Ce/HAP/400 catalyst is subjected to ultrasonic treatment for 2-3h at 40 ℃ in acetonitrile, filtered, calcined for 1-2h at different temperatures in a nitrogen atmosphere to obtain an activated catalyst, and then the activated catalyst is subjected to catalysis of methyl 6-hydroxycaproate (reaction conditions of a sequence 20 in a table 2 of an example 2), wherein the catalytic performances of the catalysts obtained at different calcination temperatures are shown in a table 4:
TABLE 4 Effect of different calcination temperatures on catalyst activation
| Calcination temperature/. degree.C | 100 | 200 | 300 | 400 | 500 | 600 | 700 |
| Conversion rate | 89.2 | 90.9 | 92.8 | 86.1 | 65.2 | 60.2 | 56.7 |
The results show that the activity of the catalyst is partially reactivated with the continuous increase of the calcination activation temperature, but the catalytic activity of the catalyst is only up to 92.8% at the maximum by the activation through a simple high-temperature calcination activation mode.
Di, oxidation/calcination activation
Considering that if the active sites of the catalyst are shielded by organic small molecules such as methyl 6-hydroxycaproate or methyl 6-carbonylhexanoate, a strong oxidant can be used to oxidize the blocked organic small molecules in the pore diameter of the catalyst into acid, then alkali ultrasound is used to remove the small molecules, and finally the activity of the catalyst can be activated by high-temperature calcination and activation, the specific steps are as follows:
putting 1.0g of the recovered Zn/Ce/HAP/400 catalyst into 10ml of 0.1mol/L hydrogen peroxide for ultrasonic treatment for 2-3h for oxidation treatment, then filtering, putting a filter cake into 10ml of 0.1mol/L potassium hydroxide aqueous solution for ultrasonic treatment at 40-50 ℃ for 20-30min, filtering and washing until a washing solution becomes neutral, collecting the filter cake, and calcining at 300 ℃ for 1h to obtain an activated catalyst; the activated catalyst is adopted to carry out catalytic reaction according to the optimal process conditions (the reaction conditions of the sequence 20 in the table 2 of the embodiment 2), the conversion rate reaches 99.8%, the selectivity reaches 99.2%, and the catalytic performance of a fresh catalyst is almost reached, namely, the catalyst can be activated by the method, so that the catalytic cost is reduced.
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.
Claims (9)
1. A preparation method of zinc salt modified hydroxyapatite loaded ammonium cerium nitrate catalyst is characterized by comprising the following steps: the zinc salt modified hydroxyapatite loaded ammonium ceric nitrate catalyst is obtained by performing ion exchange on zinc salt modified hydroxyapatite and ammonium ceric nitrate in an ethanol water solution; the zinc salt modified hydroxyapatite consists of Ca (NO)3)2.4H2O and diammonium hydrogen phosphate areStarting material, Zn (NO)3)2.6H2O is a modifier and is prepared by a chemical precipitation method under the alkaline condition.
2. The method of claim 1, wherein: the method specifically comprises the following steps:
(A) preparation of zinc salt modified hydroxyapatite:
A-1）Ca(NO3)2.4H2o and Zn (NO)3)2.6H2Dissolving O in water, and then dropwise adding the dissolved O into an ammonia water solution with the pH =11, and uniformly stirring to obtain a calcium-zinc mixed solution;
a-2) dropwise adding an aqueous solution of diammonium hydrogen phosphate into an ammonia aqueous solution with pH =11, and uniformly stirring to obtain a phosphate solution;
a-3) heating the calcium-zinc mixed solution to 50-60 ℃, stirring at the rotation speed of 600-800rpm, then dropwise adding a phosphate solution into the calcium-zinc mixed solution to form a colloidal precipitate, controlling the dropwise adding time of the phosphate solution to be within 1-2h, and carrying out reflux reaction for 30-60min after the dropwise adding is finished;
a-4) cooling to room temperature to obtain a precipitate, centrifuging, washing with water until the washing liquid becomes neutral, and then calcining at 400-450 ℃ to obtain zinc salt modified hydroxyapatite;
(B) the zinc salt modified hydroxyapatite loaded cerium ammonium nitrate working procedure:
b-1) dissolving ammonium ceric nitrate and urea in 90% V ethanol water solution, and uniformly stirring to form uniform mixed solution;
b-2) adding zinc salt modified hydroxyapatite into the uniform mixed solution, and heating to reflux for 6-8 h;
and B-3) cooling to room temperature after the reaction is finished, centrifuging, washing with water, collecting a filter cake, drying at 60-80 ℃ to constant weight, and then transferring to a calcining furnace to calcine at 200-500 ℃ in the air atmosphere to obtain the zinc salt modified hydroxyapatite loaded ammonium cerium nitrate catalyst.
3. The method of claim 2, wherein: in terms of molar ratio, Ca (NO) in step (A)3)2.4H2O and Zn (N)O3)2.6H2The ratio of the sum of the moles of O to the moles of diammonium phosphate was 1.7: 1.
4. The method of claim 2, wherein: in the step (B), cerium ammonium nitrate: urea: zinc salt modified hydroxyapatite =3-5:1: 50-60.
5. The method of claim 2, wherein: calcining at 350-400 ℃ in the air atmosphere to obtain the zinc salt modified hydroxyapatite loaded cerium ammonium nitrate catalyst in the step B-3).
6. Use of the zinc salt modified hydroxyapatite supported cerium ammonium nitrate catalyst according to any one of claims 1 to 5, characterized in that: in the presence of a solvent and an oxidant, for catalyzing methyl 6-hydroxycaproate to methyl 6-carbonylhexanoate.
7. Use according to claim 6, characterized in that: the solvent is acetonitrile, ethanol, acetone or isopropanol.
8. Use according to claim 6, characterized in that: the oxidant is hydrogen peroxide, sodium hypochlorite or tert-butyl hydroperoxide.
9. Use according to claim 6, characterized in that: the dosage of the zinc salt modified hydroxyapatite loaded cerium ammonium nitrate catalyst is 5-20% of the weight of the methyl 6-hydroxycaproate.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005060319A (en) * | 2003-08-14 | 2005-03-10 | Nissei Kagaku Kogyosho:Kk | Method for producing (di)quinone derivative |
| JP2005254068A (en) * | 2004-03-09 | 2005-09-22 | Daiso Co Ltd | Catalyst for cyclic carbonate, manufacturing method therefor and manufacturing method for cyclic carbonate using the catalyst |
| CN102989490A (en) * | 2012-12-04 | 2013-03-27 | 复旦大学 | Copper-hydroxyapatite catalyst for synthesizing methyl glycolate and ethylene glycol and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005060319A (en) * | 2003-08-14 | 2005-03-10 | Nissei Kagaku Kogyosho:Kk | Method for producing (di)quinone derivative |
| JP2005254068A (en) * | 2004-03-09 | 2005-09-22 | Daiso Co Ltd | Catalyst for cyclic carbonate, manufacturing method therefor and manufacturing method for cyclic carbonate using the catalyst |
| CN102989490A (en) * | 2012-12-04 | 2013-03-27 | 复旦大学 | Copper-hydroxyapatite catalyst for synthesizing methyl glycolate and ethylene glycol and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| 羟基磷灰石作催化剂和催化剂载体的应用;张定林;《化学进展》;20110424;第23卷(第4期);第92-94页 * |
| 铈硝酸盐及其硝酸铵复盐的结晶制法及性质;王晓铁;《中国稀土学报》;20021230;第20卷;第687-694页 * |
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