CN108516938A - A method of preparing treatment osteoarthritis drugs intermediate - Google Patents

Abstract

The invention belongs to chemical drug research and development technology fields, and in particular to a method of preparing treatment osteoarthritis drugs intermediate.The present invention provides the preparation methods that a kind of zinc salt modifies Hydroxyapatite-Supported ammonium ceric nitrate catalyst, are carried out obtained by ion exchange in ethanol water with ammonium ceric nitrate by the hydroxyapatite of zinc salt modification；The hydroxyapatite of the zinc salt modification is by with Ca (NO₃)₂.4H₂O and diammonium hydrogen phosphate are raw material, with Zn (NO₃)₂.6H₂O is modifying agent, under alkaline condition as obtained by chemical precipitation method preparation；The catalyst prepared using the present invention can be catalyzed 6 hydroxycaproic acid methyl esters and prepare 6 carbonyl methyl caproate for the treatment of osteoarthritis drugs cis-capsaicin intermediate.Catalytic processes high income of the present invention and environmentally protective.

Description

A kind of method for preparing medicine intermediate for treating osteoarthritis

technical field

The invention belongs to the technical field of chemical drug research and development, and in particular relates to a method for preparing a drug intermediate for treating osteoarthritis.

Background technique

Capsaicin (capsaicin) is the main spicy substance in peppers. It has analgesic, anti-inflammatory and anti-oxidative effects. It is mainly used to treat muscle, joint and nerve pain. However, skin burning and stinging are prone to occur at the drug site at the initial stage of administration. Adverse reactions such as flu and flushing limit clinical application. Compared with capsaicin, zucapsaicin, which is artificially synthesized by zucapsaicin, exhibits stronger analgesic activity and lower irritation, and has broad application prospects. WINSTON developed zucapsaicin cream (trade name: zuacta), which was approved for marketing in Canada on July 15, 2010, and the approved indication is the treatment of osteoarthritis (OA).

The molecular formula of cis-capsaicin (zucapsaicin) is C18H27NO3, the molecular weight is 305.41, the CAS number is 25775-90-0, and the structural formula is shown in formula (1):

Methyl 6-oxohexanoate is an important intermediate for the synthesis of cis-capsaicin (zucapsaicin), which is formed by oxidation of the corresponding hydroxyl compound 6-hydroxyhexanoate methyl ester. The reaction formula is shown in Scheme 1:

This step oxidation method has been reported in the prior art (J.Org.Chem.1988,53,1064-1071), using PCC (pyridine and _CrO complexation in hydrochloric acid solution) with sodium acetate as base in dichloromethane Salt) is oxidized as an oxidizing agent, but the waste water of heavy metal cadmium is produced in this method, which does not meet the requirements of current green pharmaceutical production; and it needs to be carried out under strict anhydrous conditions in the reaction process, and the aldehyde contained in the system will interact with the generated aldehyde Form aldehyde hydrate, and then continue to oxidize to obtain carboxylic acid, so the reaction conditions are relatively harsh.

Tian Tao of Wuhan University et al. (Acta Catalysis, Volume 36, No. 8, 2015, Bimetallic Synergistic Catalysis of Copper Oxide-Modified Hydroxyapatite-supported Gold on the Aerobic Oxidation of Alcohols) disclosed a method using uniform deposition-precipitation method Copper oxide-modified hydroxyapatite-supported gold catalysts were prepared, using oxygen as the oxygen source to catalyze alcoholic hydroxyl groups to generate corresponding glycosyl compounds, but the substrates were limited to benzyl alcohol or allylic hydroxyl groups to generate corresponding aldehyde groups. The catalyst cannot be applied to common alkyl alcohols.

Therefore, it is of great significance to develop a green and mild oxidation method to prepare methyl 6-oxohexanoate.

Contents of the invention

The object of the present invention overcomes the shortcomings of the prior art in the preparation process of the cis-capsaicin intermediate 6-carbonylhexanoate methyl ester, a drug for the treatment of osteoarthritis, which requires the use of toxic oxidants and harsh reaction conditions, and provides a zinc salt-modified hydroxyphosphorus Limestone-loaded cerium ammonium nitrate catalytic material to replace the oxidation process in the prior art, the present invention uses zinc salt-modified hydroxyapatite-loaded cerium ammonium nitrate as a catalyst, which can efficiently catalyze the preparation of 6-hydroxyhexanoic acid methyl ester for the treatment of bone joints Inflammation drug cis-capsaicin intermediate 6-oxomethylhexanoate.

According to one aspect of the present invention, the present invention provides a method for preparing a zinc salt-modified hydroxyapatite-supported cerium ammonium nitrate catalyst. Limestone and ammonium cerium nitrate are obtained by ion exchange in ethanol aqueous solution; the zinc salt-modified hydroxyapatite is made of Ca(NO ₃ ) ₂ .4H ₂ O and diammonium hydrogen phosphate as raw materials, Zn(NO ₃ ) ₂ .6H ₂ O is a modifier, which is prepared by chemical precipitation under alkaline conditions.

Preferably, the preparation method of the zinc salt modified hydroxyapatite supported cerium ammonium nitrate catalyst specifically comprises the following steps:

(A) Preparation of zinc salt modified hydroxyapatite:

A-1) Ca(NO ₃ ) ₂ .4H ₂ O and Zn(NO ₃ ) ₂ .6H ₂ O were dissolved in water, then added dropwise to ammonia solution with pH=11 and stirred evenly to obtain calcium-zinc mixed solution;

A-2) The aqueous solution of diammonium hydrogen phosphate is added dropwise to the ammonia solution of pH=11 and stirred evenly to obtain a phosphate solution;

A-3) Heat the calcium-zinc mixed solution to 50-60°C, keep stirring at a speed of 600-800rpm, then add the phosphate solution dropwise to the calcium-zinc mixed solution to form a colloidal precipitate, and the time for adding the phosphate solution Control the dropwise addition between 1-2h, and then reflux for 30-60min;

A-4) cooling down to room temperature to obtain the precipitate, centrifuging, washing with water until the washing solution becomes neutral, and then calcining at 400-450°C to obtain zinc salt-modified hydroxyapatite;

(B) Zinc salt modified hydroxyapatite loaded ammonium cerium nitrate process:

B-1) cerium ammonium nitrate and urea are dissolved in the aqueous ethanol solution of 90% V and stirred to form a homogeneous mixed solution; the present invention uses the mixed solution of ethanol water as a solvent and urea as a precipitant auxiliary agent, which is beneficial to the ceric ammonium nitrate in the ethanol solution Zinc salt modified hydroxyapatite precipitation and cation exchange;

B-2) Add zinc salt-modified hydroxyapatite to the homogeneous mixture, and heat up to reflux for 6-8 hours;

B-3) After the reaction, cool down to room temperature, centrifuge, wash with water, then collect the filter cake and dry it to constant weight at 60-80°C, then transfer it to a calciner and calcinate at 200-500°C in air atmosphere to obtain zinc salt modification Hydroxyapatite supported cerium ammonium nitrate catalyst;

Preferably, calculated according to the molar ratio, the ratio of the sum of the moles of Ca(NO ₃ ) ₂ .4H ₂ O and Zn(NO ₃ ) ₂ .6H ₂ O to the moles of diammonium hydrogen phosphate in step (A) is 1.7 :1;

Preferably, in step (B), calculated according to weight ratio, cerium ammonium nitrate: urea: zinc salt modified hydroxyapatite=3-5:1:50-60; Zinc-salt-modified hydroxyapatite precipitation does not need to be added too much; during the feeding process, the weight ratio of ceric ammonium nitrate to zinc-salt-modified hydroxyapatite is mainly adjusted;

Preferably, in step B-3), the catalyst is calcined at 350-400° C. under air atmosphere to obtain a zinc salt-modified hydroxyapatite-supported cerium ammonium nitrate catalyst.

According to another aspect of the present invention, the present invention provides the application of a zinc salt modified hydroxyapatite supported cerium ammonium nitrate catalyst, in the presence of a solvent and an oxidizing agent, for catalyzing the generation of 6-hydroxyhexanoic acid methyl ester to 6- Methyl carbonyl hexanoate.

Preferably, the solvent is acetonitrile, ethanol, acetone or isopropanol;

Preferably, the oxidant is hydrogen peroxide, sodium hypochlorite or tert-butyl hydroperoxide, more preferably hydrogen peroxide;

Preferably, the amount of the zinc salt-modified hydroxyapatite-supported cerium ammonium nitrate catalyst is 5-20% of the weight of methyl 6-hydroxyhexanoate.

The present invention has the following advantages:

1) The present invention provides a zinc salt-modified hydroxyapatite-supported cerium ammonium nitrate catalyst, and can efficiently catalyze methyl 6-hydroxyhexanoate to generate methyl 6-oxohexanoate; overcome the oxidation of PCC in the prior art to produce Defects of heavy metal wastewater;

2) The present invention carries out ion exchange with ammonium cerium nitrate and zinc salt-modified hydroxyapatite, which greatly improves the catalytic activity of the catalyst, and the conversion rate has played a surprising experimental effect;

3) The zinc salt-modified hydroxyapatite-supported cerium ammonium nitrate catalyst prepared by the present invention is a heterogeneous catalyst, which is easy to separate the catalyst from the reaction system; and can be applied mechanically after recovery;

4) The present invention optimizes the catalytic system, and obtains high-yield methyl 6-oxohexanoate.

Detailed ways

In order to make the object, technical solution and advantages of the present invention clearer, the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that these descriptions are exemplary only, and are not intended to limit the scope of the present invention.

Methyl 6-hydroxyhexanoate (GC purity is more than 99.85%, area normalization method) comes from Shanghai Bi De Pharmaceutical Technology Co., Ltd., and the rest of the raw materials in the examples are commercially available routine laboratory analysis grade reagents (AR grade) .

The detection of the reaction solution of the present invention is carried out by GC-MS (Agilent 5975C type in the United States), and the chromatographic column DB-5MSx chromatographic column (30m × 0.25mm × 0.25 μm); the column oven temperature is 80 ° C, the sampling temperature is 250.00 ° C, and the split injection is , the flow control pressure is 107.3kPa, the total flow rate is 42.1mL/min, the column flow rate is 0.68mL/min, and the split ratio is 50.0; the initial temperature of the chromatographic column is 80°C, keep for 2min; 30min; cooling. The modulator is 30°C higher than the furnace temperature and rises synchronously. The modulation period is 4s, and the cold and hot modulation times are 0.8 and 1.2s respectively. The ion source is EI ionization source, the ionization voltage is 70eV, the temperature is 230°C, and the interface temperature is 290°C , using full-scan monitoring, the scan rate is 100 spectra/s, and the scan range is 100-800m/z.

Example 1

Preparation of zinc salt modified hydroxyapatite supported cerium ammonium nitrate catalyst:

First, Ca(NO ₃ ) ₂ .4H ₂ O and diammonium hydrogen phosphate were used as raw materials, and Zn(NO ₃ ) ₂ .6H ₂ O was used as a modifier to prepare zinc salt modified by chemical precipitation under alkaline conditions. Hydroxyapatite; then ion-exchange the zinc salt-modified hydroxyapatite and cerium ammonium nitrate in ethanol aqueous solution to prepare zinc salt-modified hydroxyapatite-loaded cerium ammonium nitrate catalyst.

Concrete preparation process is as follows:

(A) Preparation of zinc salt modified hydroxyapatite:

A-1) 10mmol Ca(NO ₃ ) ₂ .4H ₂ O and 7mmol Zn(NO ₃ ) ₂ .6H ₂ O were dissolved in 50ml water, then added dropwise to 100ml pH=11 ammonia solution and stirred evenly to obtain a calcium-zinc mixture liquid;

A-2) Add 50 ml of diammonium hydrogen phosphate aqueous solution (containing 10 mmol of diammonium hydrogen phosphate) dropwise into ammonia solution with pH=11 and stir evenly to obtain a phosphate solution;

A-3) Heat the calcium-zinc mixed solution to 50-60°C, keep stirring at a speed of 600-800rpm, then add the phosphate solution dropwise to the calcium-zinc mixed solution to form a colloidal precipitate, and the time for adding the phosphate solution Control the dropwise addition between 1-2h, and then reflux for 30-60min;

A-4) The precipitate was cooled to room temperature, centrifuged, washed with water until the washing solution became neutral, and then calcined at 400-450°C to obtain zinc salt-modified hydroxyapatite (abbreviated as Zn/HAP);

(B) Zinc salt modified hydroxyapatite loaded ammonium cerium nitrate process:

B-1) Dissolve 5.0 g of ceric ammonium nitrate and 1.0 g of urea in 200 ml of 90% V ethanol aqueous solution and stir evenly to form a homogeneous mixture;

B-2) Add 50.0 g of zinc salt-modified hydroxyapatite to the homogeneous mixture, heat up to reflux for 6-8 hours;

B-3) After the reaction, cool down to room temperature, centrifuge, wash with water, then collect the filter cake and dry it to constant weight at 60-80°C, then transfer it to a calciner and calcinate at 200-500°C in air atmosphere to obtain zinc salt modification Hydroxyapatite supported cerium ammonium nitrate catalyst;

The zinc salt-modified hydroxyapatite-supported cerium ammonium nitrate catalyst obtained at different calcination temperatures in B-3) is defined as Zn/Ce/HAP/X, where X represents the corresponding calcination temperature.

Example 2

The Zn/Ce/HAP/X prepared by the present invention is used as a catalyst, and its catalytic performance to methyl 6-hydroxyhexanoate is investigated to generate methyl 6-oxohexanoate. The catalytic process is as follows:

Add 10mmol methyl 6-hydroxyhexanoate and catalyst (0.15g, ~10%wt) to 20ml ethanol in a parallel synthesizer, then add 30%wt hydrogen peroxide solution (containing 20mmol hydrogen peroxide, 2.0eq), 20-30 Stir the reaction at ℃ (i.e. reaction at room temperature), detect the catalytic effect of different catalysts by GC-MS, and count the reaction status of the reaction solution after the reaction, including the time taken for the reaction to reach equilibrium, the conversion rate of methyl 6-hydroxyhexanoate and the target product The selectivity of methyl 6-carbonylhexanoate, the results are shown in table 1:

Table 1 Catalytic effects of different catalysts

catalyst 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 above results show that the catalytic activity of hydroxyapatite modified by pure zinc salt is weak, and the conversion rate of methyl 6-hydroxyhexanoate is only 33.9%; after ion exchange with ammonium cerium nitrate, its catalytic activity is greatly enhanced, and with the As the final calcination temperature increases, the catalytic activity continues to increase, but when the calcination temperature is greater than 500°C, the selectivity of the catalyst to the target product is greatly reduced, and there is an over-oxidation by-product of monomethyl orthoadipate; so the final calcination temperature is fixed at 350-400 ℃ is suitable.

Example 3

When determining Zn/Ce/HAP/400 as the catalyst, the reaction solvent, temperature, catalyst dosage, oxidant and its oxidant dosage were further optimized:

In the parallel synthesizer, 10mmol 6-hydroxyhexanoic acid methyl ester, catalyst Zn/Ce/HAP/400 (44mg-440mg, 3.0～30%wt) are added in the 20ml solvent, then add oxidizing agent (molar dosage is substrate 6- 1.5-3.0eq of methyl hydroxyhexanoate), stirring reaction at 0-60°C, GC-MS detection of the catalytic effect of different catalysts, statistics of the reaction of the reaction solution after the end of the reaction, including the time used for the reaction to reach equilibrium, 6- The selectivity of methyl hydroxycaproate conversion and target product 6-oxomethylhexanoate, the results are shown in table 2:

Table 2 List of catalytic system optimization results

Note: DCM means dichloromethane; EA means ethyl acetate; _H2O2 is 30%wt hydrogen peroxide solution; NaClO is 10%wt water solution; t- _BuOOH is 70%wt tert-butyl hydroperoxide Aqueous solution; air means that no oxidant is added, that is, oxidation is carried out by stirring part of the oxygen brought into the air at 25 °C.

The above results show that polar solvents are beneficial to the reaction, and non-polar solvents such as esters, chlorinated hydrocarbons, and benzenes are not easy to react. In polar solvents, acetonitrile and acetone have the best reaction effect; hydrogen peroxide and sodium hypochlorite all have Good oxidation effect, but considering that hydrogen peroxide is oxidized to water, which is more green, so the type of oxidant is hydrogen peroxide; but the present invention can also choose air as the oxidant, the conversion rate is 6.1%, if it can be improved later to increase its conversion rate , the use of air as the oxygen source is more in line with the requirements of green pharmaceutical production; the complete conversion of the substrate can be achieved when the amount of hydrogen peroxide is between 2.0-2.5eq; This oxidation reaction is a weak exothermic reaction, which is beneficial to the reaction at low temperature; in addition, if the temperature is too high, hydrogen peroxide will accelerate decomposition under the catalysis of the catalyst, resulting in low utilization rate of hydrogen peroxide, lower conversion rate of raw materials, and easier production of hydrogen peroxide. by-product.

Example 4

Adopt the reaction condition in sequence 20 in table 2 to carry out scale-up study to reaction, test condition is as follows:

Add substrate 6-hydroxyhexanoic acid methyl ester (146.2g, 1mol), acetonitrile 1.2L, catalyst Zn/Ce/HAP/400 (17.5g, 12%wt) in 1L three-necked jacketed reaction flask, then open stirrer ( IKA overhead stirrer, the stirring paddle is paddle type), and then use high and low temperature circulation pump to control the temperature in the jacketed reaction flask to 0-5°C;

Use a constant pressure dropping funnel to drop a 30%wt hydrogen peroxide solution (2.5mol, 2.5eq) into the reaction bottle between 30-60min; after the addition, keep stirring at 5-10°C for reaction every 1h Sampling was carried out to detect the reaction solution, and the reaction ended after 6 hours (calculated by the area normalization method in the GC, the remaining amount of raw material 6-hydroxyhexanoic acid methyl ester was 0.08%, the target product 6-oxoylhexanoic acid methyl ester was 99.1%, n-hexanedi acid monomethyl ester 0.34%, all the other are unknown impurity); after the reaction finishes, add 2.0mol hydrosulfite and stir

Remove the catalyst Zn/Ce/HAP/400 by filtration to obtain the filtrate, concentrate the filtrate at 40-45°C until the remaining amount is 600-700ml, then add 1L of purified water and stir evenly, then extract with n-heptane (1.5LX3), and combine three times The n-heptane extract was distilled under reduced pressure at a temperature of 80°C and a pressure of 0.2mmHg to obtain 129.03g of methyl 6-oxohexanoate, with a yield of 89.5%; GC purity of 99.68%; 1H-NMR (300MHz, CDCl ₃ ) δ: 1.60-1.68 (4H, -CH ₂ ), 2.33 (2H, -CH ₂ CO ₂ ), 2.45 (2H, -CH ₂ =O), 3.65 (3H, -CH ₃ O), 9.86 (1H ,-CHO).

Example 5

The Zn/Ce/HAP/400 separated by filtration in Example 4 was washed with acetonitrile ultrasonically and then dried at 50-60°C to a constant weight for recovery (every recovery was performed with acetonitrile ultrasonically washed and then dried at 50-60°C To constant weight), investigate the change of catalytic performance with the number of times of use, the catalytic process is carried out according to the reaction conditions in sequence 20 in embodiment 2 (test scale is substrate 6-hydroxycaproic acid methyl ester 10mmol), reaction situation is as shown in table 3 Show:

Table 3 The change table of catalytic performance with the number of recycling

Apply times 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 results show that with the increase of the number of mechanical applications, the conversion rate of the raw materials continues to decline, but the selectivity of the target product does not change; when the recovery process is applied for the fourth time, the conversion rate drops significantly, and the next reaction cannot be carried out after the fifth time.

Example 6

The zinc salt-modified hydroxyapatite-supported cerium ammonium nitrate catalyst prepared by the present invention is a heterogeneous catalyst, and the decline in catalytic activity of heterogeneous catalysts is usually caused by catalyst morphology (pore size, particle size), chemical composition or carbon deposition (catalyst active sites are blocked) Small organic molecules are deposited, so the active sites are shielded) and other factors lead to catalyst deactivation.

In order to solve the problem of catalyst deactivation, the present invention has tried the following schemes to activate the Zn/Ce/HAP/400 catalyst after 5 times of recycling as the research object:

1. High temperature calcination

Ultrasonicate the recovered Zn/Ce/HAP/400 catalyst in acetonitrile at 40°C for 2-3h, filter it, and calcinate it at different temperatures for 1-2h under a nitrogen atmosphere to obtain the activated catalyst. Catalyze 6-hydroxyhexanoic acid methyl ester (the reaction condition of sequence 20 in embodiment 2 table 2), the catalyst catalytic performance that different calcining temperature obtains is as shown in table 4:

Table 4 Effects of different calcination temperatures on catalyst activation

Calcination temperature/℃ 100 200 300 400 500 600 700 Conversion rate 89.2 90.9 92.8 86.1 65.2 60.2 56.7

The above results show that with the continuous increase of the calcination activation temperature, the activity of the catalyst is partially revived, but the highest catalytic activity can only reach 92.8% when activated by simple high-temperature calcination activation.

2. Oxidation/calcination activation

Considering that if the active site of the catalyst is shielded by organic small molecules such as methyl 6-hydroxyhexanoate or methyl 6-carbonylhexanoate, a stronger oxidant can be considered to oxidize the small organic molecules blocked in the catalyst pores into acid , and then use alkali ultrasonic to remove small molecules, and finally activate the catalyst activity by high-temperature calcination. The specific steps are as follows:

Place 1.0 g of the recovered Zn/Ce/HAP/400 catalyst in 10 ml of 0.1 mol/L hydrogen peroxide for 2-3 hours for oxidation treatment, then filter and place the filter cake in 10 ml of 0.1 mol/L potassium hydroxide aqueous solution Ultrasound at 40-50°C for 20-30min, filter, wash with water until the washing liquid becomes neutral, collect the filter cake and calcinate at 300°C for 1h to obtain the activated catalyst; adopt the activated catalyst according to the optimum process conditions (Table 2 of Example 2 2 in Sequence 20) to carry out the catalytic reaction, the conversion rate has reached 99.8%, and the selectivity is 99.2%, which has almost reached the catalytic performance of a fresh catalyst, that is, the catalyst can be activated by this method, thereby reducing the catalytic performance. cost.

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

Claims (9)

1. A preparation method for a zinc salt modified hydroxyapatite loaded cerium ammonium nitrate catalyst, characterized in that: the zinc salt modified hydroxyapatite loaded cerium ammonium nitrate catalyst is modified by zinc salts of hydroxyapatite and cerium nitrate Ammonium is obtained by ion exchange in ethanol aqueous solution; the zinc salt-modified hydroxyapatite is made of Ca(NO ₃ ) ₂ .4H ₂ O and diammonium hydrogen phosphate as raw materials, Zn(NO ₃ ) ₂ .6H ₂ O is a modifier, which is prepared by chemical precipitation under alkaline conditions. 2. preparation method according to claim 1, is characterized in that: specifically comprise the following steps: (A) Preparation of zinc salt modified hydroxyapatite: A-1) Ca(NO ₃ ) ₂ .4H ₂ O and Zn(NO ₃ ) ₂ .6H ₂ O were dissolved in water, then added dropwise to ammonia solution with pH=11 and stirred evenly to obtain a calcium-zinc mixture; A-2) Add the aqueous solution of diammonium hydrogen phosphate dropwise to the ammonia solution with pH=11 and stir evenly to obtain a phosphate solution; A-3) Heat the calcium-zinc mixed solution to 50-60°C, keep stirring at a speed of 600-800rpm, then add the phosphate solution dropwise to the calcium-zinc mixed solution to form a colloidal precipitate, and the time for adding the phosphate solution Control the dropwise addition between 1-2h, and reflux reaction for 30-60min after the dropwise addition; A-4) The precipitate was cooled to room temperature, centrifuged, washed with water until the washing solution became neutral, and then calcined at 400-450°C to obtain zinc salt-modified hydroxyapatite; (B) Zinc salt modified hydroxyapatite loaded ammonium cerium nitrate process: B-1) dissolving ceric ammonium nitrate and urea in 90% V ethanol aqueous solution and stirring evenly to form a homogeneous mixed solution; B-2) Add zinc salt-modified hydroxyapatite to the homogeneous mixture, heat up to reflux for 6-8 hours; B-3) After the reaction, cool down to room temperature, centrifuge, wash with water, collect the filter cake and dry it to constant weight at 60-80°C, then transfer to a calciner and calcinate at 200-500°C in an air atmosphere to obtain zinc salt-modified hydroxyl Apatite supported cerium ammonium nitrate catalyst. 3. The preparation method according to claim 2, characterized in that: calculated according to the molar ratio, the molar number of Ca(NO ₃ ) ₂ .4H ₂ O and Zn(NO ₃ ) ₂ .6H ₂ O in step (A) The ratio of the sum to the moles of diammonium hydrogen phosphate is 1.7:1. 4. The preparation method according to claim 2, characterized in that: in step (B), calculated according to the weight ratio, cerium ammonium nitrate: urea: zinc salt modified hydroxyapatite=3-5:1:50-60 . 5 . The preparation method according to claim 2 , characterized in that: in step B-3), the cerium ammonium nitrate catalyst supported on hydroxyapatite is obtained by calcining under air atmosphere at 350-400° C. to obtain zinc salt modified hydroxyapatite. 6. A use of the zinc salt modified hydroxyapatite supported cerium ammonium nitrate catalyst according to any one of claims 1-5, characterized in that: in the presence of a solvent and an oxidizing agent, it is used to catalyze 6-hydroxyhexanoic acid methyl The ester produces methyl 6-carbonylhexanoate. 7. purposes according to claim 6, is characterized in that: described solvent is acetonitrile, ethanol, acetone or Virahol. 8. The use according to claim 6, characterized in that: the oxidizing agent is hydrogen peroxide, sodium hypochlorite or tert-butyl hydroperoxide. 9. The use according to claim 6, characterized in that: the amount of the zinc salt-modified hydroxyapatite-supported cerium ammonium nitrate catalyst is 5-20% of the weight of methyl 6-hydroxyhexanoate.