A method for the synthesis of apixaban
By employing a heterogeneous catalytic reaction with a Pd single-atom catalyst in the synthesis of apixaban, the problems of cumbersome separation steps and heavy metal residues in homogeneous catalysts are solved, achieving high-yield and environmentally friendly apixaban synthesis, which is suitable for large-scale industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- GUANGDONG UNIV OF TECH
- Filing Date
- 2025-07-25
- Publication Date
- 2026-05-19
AI Technical Summary
In existing methods for synthesizing apixaban, the homogeneous catalyst and reactants are both in the liquid phase, which leads to cumbersome and inefficient separation steps and the problem of heavy metal residue toxicity.
A heterogeneous catalytic reaction was carried out using a Pd single-atom catalyst under alkaline conditions. The Pd single-atom catalyst was supported on supports such as iron oxide, activated carbon, cerium oxide, or manganese oxide. Apixaban was synthesized via CN coupling reaction. After the reaction was completed, the solid catalyst was removed by filtration.
The synthesis steps were simplified, the yield of apixaban was increased, heavy metal contamination was avoided, and the reaction conditions were mild, making it suitable for large-scale industrial production.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for synthesizing apixaban. Background Technology
[0002] Apixaban is a white solid, sensitive to light and air, that blocks the coagulation cascade, reduces thrombin production, and thus inhibits thrombus formation. Currently, apixaban, as a factor Xa inhibitor, is widely used in the preparation of drugs for the prevention and treatment of thrombosis.
[0003] Currently, apixaban is mostly prepared using homogeneous catalytic reactions. However, since the homogeneous catalyst and reactants are both in the liquid phase, they need to be separated by physical or chemical methods after the reaction, which is cumbersome and inefficient. Traditionally used homogeneous catalysts are heavy metal ions such as copper and palladium ions, which are difficult to completely separate from the products and can easily lead to the heavy metal residue toxicity of the products. Summary of the Invention
[0004] In view of this, the object of the present invention is to provide a method for synthesizing apixaban. This method is simple in procedure, low in cost, and yields apixaban with high selectivity and high yield.
[0005] To achieve this objective, the present invention adopts the following technical solution:
[0006] This invention provides a method for synthesizing apixaban, comprising the following steps:
[0007] Apixaban was obtained by a heterogeneous catalytic reaction of 1-(4-iodophenyl)piperidin-2-one and 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide under alkaline conditions in the presence of a Pd single-atom catalyst.
[0008] Preferably, the Pd single-atom catalyst comprises a support and Pd single atoms supported on the support.
[0009] Preferably, the carrier is selected from one or more of iron oxide, activated carbon, cerium oxide, manganese oxide, or silicon dioxide.
[0010] Preferably, the mass fraction of the Pd single atom loaded on the support is 0.5% to 2%, more preferably 1% to 1.5%, and even more preferably 1.25%.
[0011] Preferably, the Pd single-atom catalyst is prepared by the following method:
[0012] S1: Mix the EDTA solution containing Pd ions with the support, and heat until the solvent is completely evaporated to obtain the precursor of the Pd single-atom catalyst;
[0013] S2: The precursor of the Pd single-atom catalyst obtained in step S1 is calcined to obtain the Pd single-atom catalyst.
[0014] This invention first involves mixing a Pd-ion-containing EDTA solution and the support, then heating appropriately until the solvent completely evaporates to obtain a precursor for a Pd single-atom catalyst. Specifically, a Pd salt and an EDTA salt are mixed to obtain a Pd-ion-containing EDTA solution. The support is then added to the Pd-ion-containing EDTA solution, mixed, and heated appropriately until the solvent completely evaporates. The mixture is then dried to obtain the Pd single-atom catalyst precursor. In some embodiments of this invention, Pd(NO3)2·2H2O and EDTA-2Na are mixed to obtain a Pd-ion-containing EDTA solution. The support is added to the mixed Pd-ion-containing EDTA solution, and the mixture is heated and stirred until the solvent completely evaporates. The mixture is then dried to obtain the Pd single-atom catalyst precursor. The concentration of the Pd-ion-containing EDTA solution in this invention is 5 mg / mL to 15 mg / mL. The amount of the support used in this invention is 400 mg to 600 mg, preferably 500 mg. The mixing temperature in this invention is 85 to 95°C.
[0015] In this invention, after obtaining the precursor of the Pd single-atom catalyst, the precursor is calcined to obtain the Pd single-atom catalyst. Specifically, the precursor is calcined under a nitrogen atmosphere to obtain the Pd single-atom catalyst. The calcination temperature is 300–500°C, the calcination time is 2–4 hours, and the heating rate is 4–6°C / min, preferably 5°C / min.
[0016] Preferably, the ratio of the Pd single-atom catalyst to 1-(4-iodophenyl)piperidin-2-one is (30-50) mg: 1 mmol.
[0017] Preferably, the molar ratio of 1-(4-iodophenyl)piperidin-2-one and 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide is 1:(0.9 to 1.1).
[0018] Preferably, the alkaline conditions are provided by an alkaline substance.
[0019] Preferably, the alkaline substance is selected from any one or more of potassium carbonate, sodium bicarbonate, triethylamine, diisopropylethylamine, or diisopropylaminolithium.
[0020] Preferably, the molar ratio of the alkaline substance to 1-(4-iodophenyl)piperidin-2-one is (1-3):1.
[0021] Preferably, the heterogeneous catalytic reaction is carried out in the presence of a solvent selected from one or more of water, N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, or dimethyl sulfoxide.
[0022] Preferably, the volume ratio of the solvent to 1-(4-iodophenyl)piperidin-2-one is (2-5) mL: 1 mmol.
[0023] Preferably, the temperature of the heterogeneous catalytic reaction is 10–75°C, and the reaction time is 1–12 h.
[0024] Preferably, the heterogeneous catalytic reaction is carried out in an inert atmosphere at a pressure of 1 to 10 atm.
[0025] Preferably, the heterogeneous catalytic reaction further includes steps of filtration, washing, and drying after completion.
[0026] Preferably, the yield of the apixaban is above 94%.
[0027] Compared with the prior art, the beneficial effects of the present invention are as follows:
[0028] This invention provides a method for synthesizing apixaban, which employs a heterogeneous Pd single-atom catalyst to catalyze a CN coupling reaction between 1-(4-iodophenyl)piperidin-2-one and 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide to obtain apixaban. This method is not only simple to operate, but also utilizes a Pd single-atom catalyst with high selectivity for NH substrates, achieving an apixaban yield of over 94%.
[0029] Furthermore, compared with traditional methods, the synthesis method provided by this invention can use water as a solvent, can react under normal pressure, and directly synthesizes the target product in one step using a Pd single-atom catalyst, which is faster, more efficient, and more environmentally friendly and mild.
[0030] Furthermore, this synthesis method removes the solid Pd single-atom catalyst by filtration, avoiding contamination of the product by the heavy metal Pd in the homogeneous catalyst. The subsequent processing is simple, requiring no complex column chromatography to separate and purify the product. Moreover, the filtered solid catalyst can be reused, offering significant economic benefits for large-scale industrial production. Attached Figure Description
[0031] Figure 1 HAADF-STEM image of the palladium single-atom catalyst provided in Example 1;
[0032] Figure 2 This is a schematic diagram of the synthetic route for the synthesis of apixaban compounds using a palladium single-atom catalyst provided in Example 1;
[0033] Figure 3 The 1H NMR spectrum of the apixaban compound synthesized in Example 1 is shown below.
[0034] Figure 4 The carbon NMR spectrum of the apixaban compound synthesized in Example 1 is shown below.
[0035] Figure 5 A schematic diagram of the synthetic route for the synthesis of apixaban compounds catalyzed by the homogeneous palladium acetate catalyst provided in Comparative Example 1;
[0036] Figure 6 A schematic diagram of the synthetic route for the synthesis of apixaban compounds catalyzed by the heterogeneous palladium nanocatalyst provided for Comparative Example 2. Detailed Implementation
[0037] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.
[0038] This invention provides a method for synthesizing apixaban, comprising the following steps:
[0039] Apixaban was obtained by a heterogeneous catalytic reaction of 1-(4-iodophenyl)piperidin-2-one and 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide under alkaline conditions in the presence of a Pd single-atom catalyst.
[0040] According to the present invention, the reaction raw materials are first provided as follows: 1-(4-iodophenyl)piperidin-2-one and 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, which can be prepared by means well known in the art.
[0041] In this invention, the molar ratio of 1-(4-iodophenyl)piperidin-2-one and 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide is 1:(0.9 to 1.1).
[0042] In some embodiments of the present invention, it is preferable to first add 1-(4-iodophenyl)piperidin-2-one and 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide to the reaction flask, followed by the addition of a Pd single-atom catalyst, solvent, and alkaline substance. Then, the air in the reaction flask is purged and an inert atmosphere is introduced. A balloon is attached to the mouth of the flask and sealed. The magnetic stirrer is turned on, and the reaction is carried out in a water bath at 10–75°C for 1–12 h, preferably at 25–70°C for 8–10 h.
[0043] In this invention, the Pd single-atom catalyst comprises a support and Pd single atoms supported on the support. The support is selected from any one or more of iron oxide, activated carbon, cerium oxide, manganese oxide, or silicon dioxide, preferably iron oxide.
[0044] In this invention, the ratio of the above-mentioned Pd single-atom catalyst to 1-(4-iodophenyl)piperidin-2-one is (30-50) mg:1 mmol, such as 30 mg:1 mmol, 35 mg:1 mmol, 40 mg:1 mmol, 45 mg:1 mmol or 50 mg:1 mmol, etc.
[0045] In this invention, the alkaline substance is selected from any one or more of potassium carbonate, sodium bicarbonate, triethylamine, diisopropylethylamine or diisopropylaminolithium, preferably potassium carbonate; the molar ratio of the alkaline substance and 1-(4-iodophenyl)piperidin-2-one is (1-3):1, such as 1:1, 1.5:1, 2:1, 2.5:1 or 3:1, etc.
[0046] In this invention, the solvent is selected from any one or more of water, N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, or dimethyl sulfoxide, preferably water, to meet the requirements of environmental protection and greenness. The volume ratio of the solvent to 1-(4-iodophenyl)piperidin-2-one is (2-5) mL:1 mmol, such as 2 mL:1 mmol, 3 mL:1 mmol, 4 mL:1 mmol, or 5 mL:1 mmol, etc.
[0047] In this invention, the inert atmosphere can be any atmosphere known to those skilled in the art, and the pressure of the inert atmosphere is 1 to 10 atm, such as 1 atm, 3 atm, 5 atm, 8 atm or 10 atm, etc.
[0048] In this invention, the reaction is further complicated by steps of filtration, washing and drying.
[0049] In some embodiments of the present invention, after the reaction is stopped, the reaction solution is filtered to remove the solid Pd single-atom catalyst, washed with dichloromethane, the filtrate and washing solution are combined, anhydrous sodium sulfate is added to remove water, filtered again, the solvent is evaporated and dried to obtain pure apixaban compound.
[0050] This invention prepares apixaban compounds using a heterogeneous synthesis method, resulting in a significantly improved yield of apixaban compounds, reaching over 94%. Furthermore, the obtained apixaban compounds were subjected to 1H and 1C NMR spectroscopy, and the spectral results indicate that the apixaban compounds have high purity.
[0051] In summary, compared with existing methods, the heterogeneous synthesis method described above offers higher reaction efficiency, a more environmentally friendly synthetic route, milder reaction conditions, and higher reaction selectivity. The obtained apixaban does not require column chromatography purification, and the purity of the compound meets the standards for use in the Chinese Pharmacopoeia. Therefore, this synthetic method simplifies the synthetic steps, reduces time costs, and is beneficial for large-scale production.
[0052] To further illustrate the present invention, the following embodiments provide a detailed description. The experimental materials used in the following embodiments of the present invention are commercially available products.
[0053] Example 1
[0054] In this embodiment, a 1.25 wt% Pd / Fe2O3 single-atom catalyst was prepared according to the following method, and its structure and performance were tested.
[0055] Step S1: Prepare a 100 mL Pd-EDTA solution of a specific concentration using 675 mg Pd(NO3)2·2H2O and 852 mg EDTA-2Na. Add the Pd-EDTA solution to Fe2O3 powder, then add a certain amount of purified water to cover the solid. Stir until the solvent is completely evaporated, and dry to obtain the precursor of the palladium single-atom catalyst. In Step S1, the concentration of the Pd-EDTA solution is 10 mg / mL, the volume of Pd-EDTA solution is 0.63 mL, the volume of Fe2O3 powder is 500 mg, and the stirring temperature is 90 °C.
[0056] Step S2: The precursor of the palladium single-atom catalyst was calcined at high temperature under nitrogen to obtain a 1.25 wt% Pd / Fe2O3 single-atom catalyst. The calcination temperature was 400 °C, the heating rate was 5 °C / min, and the time was 3 h.
[0057] The electron micrograph of the palladium single-atom catalyst is attached. Figure 1 As shown, from Figure 1It is evident that the palladium element in the 1.25wt% Pd / Fe2O3 single-atom catalyst provided in this application is dispersed in single-atom form on the iron oxide support.
[0058] Performance testing of 1.25 wt% Pd / Fe2O3 single-atom catalyst: Apixaban was synthesized using 1-(4-iodophenyl)piperidin-2-one and 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide as reactants. The synthetic route is shown in the attached figure. Figure 2 As shown. The specific synthesis steps include:
[0059] First, 301 mg (1 mmol) of 1-(4-iodophenyl)piperidin-2-one and 286 mg (1 mmol) of 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide were added to the reaction flask. Then, 40 mg of 1.25 wt% Pd / Fe₂O₃ catalyst, 2 mL of water, and 3 mmol of potassium carbonate were added. The air in the reaction flask was then purged and nitrogen gas was introduced. A balloon was attached to the flask opening and the flask was sealed. A magnetic stirrer was turned on, and the reaction was carried out in a water bath at 70 °C for 8 h. After the reaction was stopped, the reaction solution was filtered to remove the solid catalyst. The solution was washed with dichloromethane (20 mL × 2). The filtrate and washings were combined, and anhydrous sodium sulfate was added to remove water. The solution was filtered again, the solvent was evaporated, and the solution was dried to obtain 0.968 mmol of pure apixaban compound, with a yield of 96.8%. The 1H and 1C NMR spectra of the apixaban compound are shown below. Figures 3-4 As shown, 1 H NMR and 13 The C NMR data are as follows:
[0060] 1 H NMR(500MHz, CDCl3)δ7.72(s,1H),7.50–7.45(m,2H),7.44(s,1H),7.34–7.28(m,2H),7.27–7.21(m,2H),6.99–6.93(m,2H) ,4.01(t,J=6.6Hz,2H),3.76(s,3H),3.55(t,J=5.6Hz,2H),3.17(t,J=6.6Hz,2H),2.35(t,J=6.4Hz,2H),1.89–1.71(m,4H).
[0061] 13C NMR (126MHz, CDCl3) δ169.39,163.73,159.64,157.16,142.00,141.88,140.33,133.49,133.0 8,127.35,126.85,126.52,125.78,113.91,56.00,51.45,51.36,33.12,23.53,21.57,21.44.
[0062] Example 2
[0063] In this embodiment, a palladium single-atom catalyst was prepared using the same method as in Example 1, except that Fe2O3 was replaced with CeO2, resulting in a 1.25wt% Pd / CeO2 single-atom catalyst, which was then subjected to structural and performance testing.
[0064] 301 mg (1 mmol) of 1-(4-iodophenyl)piperidin-2-one and 286 mg (1 mmol) of 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide were added to a reaction flask, along with 40 mg of 1.25% wt% Pd / CeO2 catalyst, 2 mL of water, and 3 mmol of potassium carbonate. The air in the reaction flask was then purged and nitrogen gas was introduced. A balloon was attached to the mouth of the flask and sealed. The magnetic stirrer was turned on, and the reaction was carried out in a water bath at 70 °C for 8 h. After the reaction was stopped, the reaction solution was filtered to remove the solid catalyst. The solution was washed with dichloromethane (20 mL × 2). The filtrate and washing solution were combined, and anhydrous sodium sulfate was added to remove water. The solution was filtered again, the solvent was evaporated, and the solution was dried to obtain 0.955 mmol of pure apixaban compound, with a yield of up to 95.5%.
[0065] Example 3
[0066] 301 mg (1 mmol) of 1-(4-iodophenyl)piperidin-2-one and 286 mg (1 mmol) of 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide were added to a reaction flask, followed by 40 mg of 1.25% wt% Pd / Fe2O3 catalyst (preparation reference: Example 1), 2 mL of water, and 303 mg of triethylamine. The air in the reaction flask was then purged and nitrogen gas was introduced. A balloon was attached to the flask opening and the flask was sealed. A magnetic stirrer was turned on, and the reaction was carried out in a water bath at 70 °C for 8 h. After the reaction was stopped, the reaction solution was filtered to remove the solid catalyst. The solution was washed with dichloromethane (20 mL × 2), and the filtrate and washings were combined. Anhydrous sodium sulfate was added to remove water, and the solution was filtered again. The solvent was evaporated and the solution was dried to obtain 0.952 mmol of pure apixaban compound, with a yield of up to 95.2%.
[0067] Example 4
[0068] 301 mg (1 mmol) of 1-(4-iodophenyl)piperidin-2-one and 286 mg (1 mmol) of 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide were added to a reaction flask, followed by 40 mg of 1.25% wt% Pd / Fe2O3 catalyst (preparation as per Example 1), 2 mL of water, and 1 mmol of potassium carbonate. The air in the reaction flask was then purged and nitrogen gas was introduced. A balloon was attached to the flask opening and the flask was sealed. A magnetic stirrer was turned on, and the reaction was carried out in a water bath at 70 °C for 8 h. After the reaction was stopped, the reaction solution was filtered to remove the solid catalyst. The solution was washed with dichloromethane (20 mL × 2), and the filtrate and washings were combined. Anhydrous sodium sulfate was added to remove water, and the solution was filtered again. The solvent was evaporated and the solution was dried to obtain 0.947 mmol of pure apixaban compound, with a yield of 94.7%.
[0069] Comparative Example 1
[0070] This comparative example demonstrates the performance of a homogeneous (CH3COO)2Pd catalyst. Using 1-(4-iodophenyl)piperidin-2-one and 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide as reactants, apixaban was synthesized via a catalytic route shown in the attached figure. Figure 5 As shown. The specific synthesis process includes:
[0071] 301 mg (1 mmol) of 1-(4-iodophenyl)piperidin-2-one and 286 mg (1 mmol) of 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide were added to a reaction flask, followed by 4 mL of 5 mmol / mL (CH3COO)2Pd catalyst, 2 mL of water, and 3 mmol of potassium carbonate. The air in the flask was then purged and nitrogen gas was introduced. A balloon was attached to the flask opening and the flask was sealed. A magnetic stirrer was turned on, and the reaction was carried out in a water bath at 70 °C for 8 h. After the reaction was stopped, the organic phase was washed with dichloromethane, and the organic solution of apixaban was obtained by column chromatography. The solvent was removed by rotary evaporation and the solution was dried to obtain 0.053 mmol of pure apixaban compound, with a yield of only 5.3%.
[0072] Comparative Example 2
[0073] Comparative Example 2 tested the performance of a 10 wt% nano-Pd / Fe2O3 heterogeneous catalyst. Using 1-(4-iodophenyl)piperidin-2-one and 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide as reactants, apixaban was synthesized via a catalytic route shown in the attached figure. Figure 6 As shown. The specific synthesis process includes:
[0074] 301 mg (1 mmol) of 1-(4-iodophenyl)piperidin-2-one and 286 mg (1 mmol) of 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide were added to a reaction flask, followed by 40 mg of 10 wt% nano-Pd / Fe2O3 catalyst, 2 mL of water, and 3 mmol of potassium carbonate. The air in the flask was then purged and nitrogen gas was introduced. A balloon was attached to the flask opening and the flask was sealed. A magnetic stirrer was turned on, and the reaction was carried out in a water bath at 70 °C for 8 h. After the reaction was stopped, the reaction solution was filtered to remove the solid catalyst, washed with dichloromethane (20 mL × 4), and the filtrate and washings were combined. Anhydrous sodium sulfate was added to remove water, and the mixture was filtered again. The solvent was evaporated and the solution was dried to obtain 0.127 mmol of pure apixaban compound, with a yield of only 12.7%.
[0075] Through the above comparison, it can be found that in Examples 1-4, the yields of apixaban compounds synthesized using palladium single-atom catalysts were all higher than 94.0%. In Comparative Example 1, when using a homogeneous (CH3COO)2Pd catalyst, the Pd catalyst needed to be removed by column chromatography to obtain the apixaban organic solution, a cumbersome and complex process, and the yield of apixaban was only 5.3%. In Comparative Example 2, when using a 10wt% Pd / Fe2O3 heterogeneous nanocatalyst, the amount of dichloromethane washing solution needed to be increased, and the yield of apixaban was only 12.7%.
[0076] The above description of the disclosed embodiments enables those skilled in the art to make or use the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the invention is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims
1. A method for synthesizing apixaban, characterized in that, Includes the following steps: Using 1-(4-iodophenyl)piperidin-2-one and 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide as reactants, a heterogeneous catalytic reaction was carried out under alkaline conditions in the presence of a Pd single-atom catalyst to obtain apixaban; The Pd single-atom catalyst includes a support and Pd single atoms supported on the support; The carrier is selected from any one or more of iron oxide, activated carbon, cerium oxide, manganese oxide, or silicon dioxide; The mass fraction of the Pd single atom load on the support is 0.5% to 2%; The Pd single-atom catalyst was prepared by the following method: S1: Mix the EDTA solution containing Pd ions with the support, and heat until the solvent is completely evaporated to obtain the precursor of the Pd single-atom catalyst; S2: Calcining the precursor of the Pd single-atom catalyst obtained in step S1 to obtain the Pd single-atom catalyst. In step S1, the concentration of the EDTA solution containing Pd ions is 5 mg / mL to 15 mg / mL; In step S1, the temperature is raised to 85~95℃; In step S2, the calcination temperature is 300℃~500℃, and the calcination time is 2 h~4 h.
2. The synthesis method according to claim 1, characterized in that, The ratio of the Pd single-atom catalyst to 1-(4-iodophenyl)piperidin-2-one is (30~50) mg:1 mmol.
3. The synthesis method according to claim 1 or 2, characterized in that, The molar ratio of 1-(4-iodophenyl)piperidin-2-one and 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide is 1:(0.9~1.1).
4. The synthesis method according to claim 1, characterized in that, The alkaline conditions are provided by an alkaline substance; The alkaline substance is selected from any one or more of potassium carbonate, sodium bicarbonate, triethylamine, diisopropylethylamine, or diisopropylaminolithium. The molar ratio of the alkaline substance to 1-(4-iodophenyl)piperidin-2-one is (1~3):
1.
5. The synthesis method according to claim 1, characterized in that, The heterogeneous catalytic reaction is carried out in the presence of a solvent selected from one or more of water, N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, or dimethyl sulfoxide. The volume ratio of the solvent to 1-(4-iodophenyl)piperidin-2-one is (2~5) mL:1 mmol.
6. The synthesis method according to claim 1, characterized in that, The temperature of the heterogeneous catalytic reaction is 10~75℃, and the reaction time is 1~12 h; The heterogeneous catalytic reaction is carried out in an inert atmosphere at a pressure of 1 to 10 atm.
7. The synthesis method according to claim 1, characterized in that, The heterogeneous catalytic reaction also includes steps of filtration, washing, and drying after completion.
8. The synthesis method according to claim 1, characterized in that, The yield of the apixaban is over 94%.