Synthesis method of tropisetron

Abstract

The invention relates to the field of medicine synthesis, in particular to a synthesis method of tropisetron. Compared with the traditional method, the synthesis method of tropisetron provided by the invention has the advantages that the synthesis route is more efficient, rapid, environment-friendly and mild, and the selectivity is higher. On the basis of the effect of the Pd monatomic catalyst, the Pd monatomic catalyst has good selectivity on indole serving as an N-H substrate, tropisetron with a substituent group being N-H can be synthesized, and the problem that in the prior art, an N-CH3 substituted tropisetron analogue can only be synthesized by taking 1-methylindole serving as an N-CH3 substrate as a raw material is solved. The yield of the synthesized tropisetron is close to 98%, the purity of the product can reach the medication standard of Chinese pharmacopoeia through a simple purification process, and large-scale industrial production is facilitated. The coordination structure of the Pd monatomic catalyst is optimized, the positive valence state of Pd is kept, a C-H bond at the 3-position of indole can be directly activated, I2 and K2CO3 do not need to be additionally added, and no waste residues are generated after the reaction.

Description

Technical Field

[0001] The present invention relates to the field of drug synthesis, in particular to a method for synthesizing tropisetron. Background Art

[0002] Tropisetron, also known as Tropisetron, is a white solid that is sensitive to light and air. Common formulations include tablets, oral solution, and injection. Tropisetron is an antiemetic and antinausea drug with excellent efficacy in preventing and treating nausea and vomiting caused by cancer chemotherapy.

[0003] Tropisetron is a highly effective and selective 5-HT3 receptor antagonist. It selectively inhibits the excitation of presynaptic 5-HT3 receptors in the peripheral nervous system, thereby blocking the vomiting reflex. This product is a highly selective inhibitor of 5-HT3 receptors in both peripheral neurons and the central nervous system, exerting a central antiemetic effect. It has therapeutic effects on vomiting caused by chemotherapy and radiotherapy.

[0004] Existing synthesis methods generally use indole-3-carboxylic acid as a raw material, which reacts with an acyl chloride reagent such as oxalyl chloride or thionyl chloride to generate an acyl chloride intermediate, indolecarbonyl chloride. Tropine alcohol then reacts with n-butyl lithium or a strong base such as sodium hydroxide or sodium ethoxide to obtain a metal salt of tropine alcohol, which is then reacted with indolecarbonyl chloride to prepare tropisetron.

[0005] Subsequently, a number of improved synthetic methods were introduced. For example, indole-3-carboxylic acid and tropane alcohol are reacted in an inert solvent in the presence of 1,3-dimethyl-2-chloroimidazoline chloride and an organic base at room temperature for 12-24 hours. The reaction is followed by cooling, filtration, and washing to prepare tropisetron. This process does not involve an acylation step, thus avoiding the use of oxalyl chloride, n-butyl lithium, and tetrahydrofuran. However, the preparation of the condensation agent 1,3-dimethyl-2-chloroimidazoline chloride requires the use of the highly toxic phosgene.

[0006] Another example is the direct esterification method: in an inert solvent, indole-3-carboxylic acid and tropane alcohol are directly esterified using an aromatic organic sulfonic acid compound as a catalyst to prepare tropisetron. The reaction temperature is 50-150°C, and the reaction time is 2-35 hours. This process uses a one-step esterification mechanism, but the reaction is heterogeneous, which is not conducive to sufficient reaction progress. It also requires continuous water removal, which is complex. The dehydrating agents used, such as molecular sieves, are difficult to handle. The high reaction temperature may cause the target product to decompose, thereby increasing impurities and reducing purity. Furthermore, post-reaction treatment requires acid-base adjustment, making the process complex and unsuitable for industrial application.

[0007] Another example is the mixed anhydride method: in an inert solvent, indole-3-carboxylic acid is activated to a mixed anhydride using a C2-C4 aliphatic halogenated carboxylic acid as a catalyst and a C2-C4 aliphatic halogenated carboxylic acid anhydride as an activating agent. A tropine solution dissolved in an inert solvent is then added dropwise to initiate a condensation reaction to produce tropisetron. However, C2-C4 aliphatic halogenated carboxylic acids and their anhydrides exhibit a certain degree of chemical activity, making raw material stability and cost a significant challenge in actual production.

[0008] Therefore, in order to overcome the above problems, it is necessary to change the raw materials and design new synthetic routes, such as the homogeneous Pd-catalyzed carbonylation coupling reaction of indole and tropane (Organic Letters, 2012, 14(16): 4130-4133.). However, the problems of homogeneous Pd catalysts are as follows: (1) I2 must be used first to generate the iodine product, and then Pd 0 The oxidative addition reaction of the catalyst is followed by the addition of K2CO3, which produces KI waste residue. (2) It is not applicable to NH substrates and can only synthesize N-CH3 substituted tropisetron analogs, but not NH tropisetron. (3) When using homogeneous Pd catalysts in drug synthesis processes, special consideration should be given to whether the heavy metal Pd residue in the product complies with the pharmacopoeia regulations. Therefore, the homogeneous catalytic system often uses a post-treatment process of column chromatography to remove the Pd catalyst and achieve the purpose of isolating tropisetron. However, column chromatography is time-consuming and material-intensive, and is not conducive to large-scale drug production.

[0009] In addition, the heterogeneous nanocatalysts such as Pd / C on the market have the defect of slow reaction rate (nanoparticles have a lower reaction rate than single atoms, Chemical reviews, 2020, 120(21): 11986-12043. AppliedCatalysis B: Environmental, 2020, 264: 118502.). The use of catalysts such as Pd / C to catalyze oxidative carbonylation results in a slow esterification rate, low conversion rate, and a large number of by-products, which reduces the quality of tropisetron and makes it difficult to meet the purity requirements of tropisetron compounds in the current pharmacopoeia. Summary of the Invention

[0010] In view of this, the technical problem to be solved by the present invention is to provide a method for synthesizing tropisetron. The synthesis method provided by the present invention can synthesize high-purity tropisetron with high yield, simple method and no waste residue generated after the reaction.

[0011] The present invention provides a method for synthesizing tropisetron, comprising the following steps:

[0012] Indole, carbon monoxide and tropine alcohol react in a solvent in the presence of a Pd single atom catalyst and an oxidant to obtain tropisetron.

[0013] The Pd single-atom catalyst of the present invention comprises a support and Pd single atoms supported on the support; wherein the mass fraction of the Pd single atoms supported on the support is 0.1% to 0.5%, preferably 0.2% to 0.4%, and more preferably 0.3%. The support of the present invention is selected from activated carbon, iron oxide, aluminum oxide, cerium oxide, zirconium oxide, titanium oxide, manganese oxide, or silicon dioxide, and is preferably selected from activated carbon.

[0014] The Pd single-atom catalyst of the present invention is prepared by the following method:

[0015] S1) stirring the EDTA solution containing Pd ions and the support together until the solvent is completely evaporated, and then drying to obtain a precursor of the Pd single atom catalyst;

[0016] S2) calcining the precursor of the Pd single atom catalyst obtained in step S1) to obtain the Pd single atom catalyst.

[0017] The present invention first mixes an EDTA solution containing Pd ions with the support until the solvent evaporates completely, then dries to obtain a precursor of the Pd single-atom catalyst. Specifically, a Pd salt and an EDTA salt are mixed to obtain an EDTA solution containing Pd ions. The support is added to the EDTA solution containing Pd ions and mixed until the solvent evaporates completely, followed by drying to obtain a precursor of the Pd single-atom catalyst. In some embodiments of the present invention, Pd(NO3)2·2H2O and EDTA-2Na are mixed to obtain an EDTA solution containing Pd ions. The support is added to the mixed EDTA solution containing Pd ions and stirred until the solvent evaporates completely, followed by drying to obtain a precursor of the Pd single-atom catalyst. The concentration of the EDTA solution containing Pd ions in the present invention is 5 mg / mL to 15 mg / mL. The amount of the support used in the present invention is 400 mg to 600 mg, preferably 500 mg. The stirring temperature in the present invention is 90°C to 100°C.

[0018] After obtaining the precursor of the Pd single-atom catalyst in the present invention, the obtained precursor of the Pd single-atom catalyst is calcined to obtain the Pd single-atom catalyst. Specifically, the obtained precursor of the Pd single-atom catalyst is calcined under a protective gas atmosphere to obtain the Pd single-atom catalyst. The protective gas atmosphere of the present invention is selected from one or more of nitrogen, helium, neon or argon. The calcination temperature of the present invention is 500°C~700°C, and the calcination time is 2 h~4 h; the calcination heating rate is 4°C / min~6°C / min, preferably 5°C / min.

[0019] The present invention provides a method for synthesizing tropisetron, based on the effect of the Pd single-atom catalyst, which has good selectivity for the NH substrate of indole, and can synthesize tropisetron with NH as the substituent, thereby solving the problem that the prior art can only synthesize N-CH3 substituted tropisetron analogs using the N-CH3 substrate of 1-methylindole as raw material, and the tropisetron synthesized by the present invention has a yield of nearly 98%, a purity that fully complies with the Chinese Pharmacopoeia drug standards, and a simple synthetic method. In addition, the present invention optimizes the coordination structure of the Pd single-atom catalyst, maintains the positive valence state of Pd, can directly activate the C-H bond at the 3-position of indole, does not require the addition of I2 and K2CO3, and no waste residue is generated after the reaction is completed.

[0020] The present invention provides a method for synthesizing tropisetron, which first reacts indole, carbon monoxide, and tropinol in a solvent in the presence of a Pd single-atom catalyst and an oxidant. Specifically, indole, carbon monoxide, tropinol, the Pd single-atom catalyst, and the oxidant are mixed in a solvent, carbon monoxide is introduced into the mixture, and the reaction is carried out by heating.

[0021] The present invention involves reacting indole, carbon monoxide, and tropinol in a solvent in the presence of a Pd single-atom catalyst and an oxidant. The reaction temperature is 20°C to 120°C, and the reaction time is 1 to 12 hours. The carbon monoxide pressure is 1 atm to 10 atm; the molar ratio of indole to tropinol is 1:(1 to 1.5); the amount of the oxidant is 100% to 300% of the amount of indole; the amount of the Pd single-atom catalyst is 30 mg / mmol to 50 mg / mmol, calculated based on the amount of indole; and the amount of the solvent is 2 mL / mmol to 5 mL / mmol, calculated based on the amount of indole. The oxidant is selected from one or more of hydrogen peroxide, oxygen, p-benzoquinone, peracetic acid, 2,2,6,6-tetramethyl-1-piperidine, and tert-butyl hydroperoxide. In one embodiment, the oxidant is selected from 30% hydrogen peroxide. The solvent of the present invention is selected from one or more of water, dimethyl carbonate (DMC), 1,4-dioxane, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), and toluene. Compared with traditional methods, the synthesis method of tropisetron provided by the present invention can use water as a solvent, hydrogen peroxide as an oxidant, and can also be carried out in a carbon monoxide atmosphere at normal pressure. The target product can be synthesized in a single step, making the preparation method faster, more efficient, environmentally friendly, and milder.

[0022] The present invention is under Pd single-atom catalyst and oxidant, after indole, carbon monoxide and tropine alcohol are reacted in a solvent, further comprising: the reaction solution obtained after the reaction is filtered, the filtrate obtained by filtration is desolvated to obtain tropisetron. Specifically, the reaction solution obtained after the reaction is filtered, the solid-phase Pd single-atom catalyst in the reaction solution is removed to obtain filtrate, the filter residue obtained by filtration is washed with dichloromethane to obtain washings, the filtrate and washings are merged, and the solution obtained after merging is dewatered with anhydrous sodium sulfate, the solvent is steamed off and vacuum-dried to obtain tropisetron. The present invention directly filters solid catalyst after the reaction, avoids the pollution of heavy metal Pd to product, and without column chromatography separation, product purity can reach Chinese Pharmacopoeia medication standard, and Pd single-atom catalyst can be recycled, which is more conducive to industrial production than homogeneous catalyst.

[0023] The present invention provides a method for synthesizing tropisetron. Compared with traditional methods, the method for synthesizing tropisetron provided by the present invention has a more efficient, rapid, environmentally friendly, mild, and highly selective synthetic route. Based on the action of the Pd single-atom catalyst, it has good selectivity for the NH substrate indole, enabling the synthesis of tropisetron with NH substituents. This solves the problem that the prior art can only synthesize N-CH substituted tropisetron analogs using 1-methylindole as a raw material. The yield of tropisetron synthesized by the present invention is close to 98%, and the product purity can meet the Chinese Pharmacopoeia drug standards without the need for traditional column chromatography. The high yield and simplified purification process are conducive to large-scale industrial production. In addition, by optimizing the coordination structure of the Pd single-atom catalyst and maintaining the positive valence state of Pd, the present invention can directly activate the C—H bond at the 3-position of indole without the need for the addition of I and KCO, and no waste residue is generated after the reaction. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 This is a high-angle annular dark-field scanning transmission electron microscopy image of the 0.3% Pd / NC single-atom catalyst prepared in Example 1 of the present invention;

[0025] Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of the tropisetron product synthesized in Example 1 of the present invention;

[0026] Figure 3 The carbon-1NMR spectrum of the tropisetron product synthesized in Example 1 of the present invention is shown. DETAILED DESCRIPTION

[0027] The invention discloses a synthetic method for tropisetron. Those skilled in the art can learn from the contents of this article and appropriately improve the process parameters to achieve the above. It should be noted that all similar replacements and modifications are obvious to those skilled in the art and are considered to be included in the present invention. The method and application of the present invention have been described through preferred embodiments, and relevant personnel can obviously change or appropriately modify and combine the method and application herein without departing from the content, spirit and scope of the present invention to realize and apply the technology of the present invention.

[0028] The present invention will be further described below with reference to the embodiments:

[0029] Example 1

[0030] The palladium single atom catalyst was prepared as follows:

[0031] Step S1: Pd(NO₃)₂·2H₂O and EDTA-2Na are prepared into a Pd-EDTA solution of a certain concentration. Activated carbon powder is added to the Pd-EDTA solution and stirred until the solvent evaporates completely. The remaining material is then dried to obtain a palladium single-atom catalyst precursor. In step S1, the concentration of the Pd-EDTA solution is 10 mg / mL, the amount of activated carbon powder used is 500 mg, and the stirring temperature is 95°C.

[0032] Step S2: calcining the palladium single-atom catalyst precursor at high temperature to obtain a 0.3% Pd / NC single-atom catalyst. In step S2, the high-temperature calcination atmosphere is nitrogen, the calcination temperature is 600°C, the heating rate is 5°C / min, and the calcination time is 3 hours.

[0033] The structure of the 0.3% Pd / NC single atom catalyst prepared above was tested. Figure 1 As shown, Figure 1 This is a high-angle annular dark field scanning transmission electron microscopy image of the 0.3% Pd / NC single atom catalyst prepared in Example 1 of the present invention, also known as the HAADF-STEM image. Figure 1 It can be clearly seen that the palladium element in the 0.3% Pd / NC single-atom catalyst provided in this application is dispersed on the carbon support in the form of single atoms.

[0034] The performance of the 0.3% Pd / NC single-atom catalyst prepared above was tested. Specifically, the test focused on the catalytic synthesis of tropisetron using indole, carbon monoxide, and tropinol as the reaction raw materials. The synthesis route is as follows:

[0035]

[0036] The specific process of synthesizing tropisetron using palladium single-atom catalyst is as follows:

[0037] To a reaction flask, 117 mg (1 mmol) of indole and 141 mg (1 mmol) of tropane were added, followed by 40 mg of a 0.3% Pd / NC single-atom catalyst, 2 mL of water, and 204 μL of a 30% hydrogen peroxide solution (2 mmol H2O2). The air in the flask was then evacuated and carbon monoxide (1 atm) was introduced. A balloon was attached to the flask and sealed, and a magnetic stirrer was turned on. The reaction was incubated in a water bath at 80°C for 6 h. After the reaction ceased, the reaction solution was filtered to remove the solid-phase catalyst and washed with dichloromethane (20 mL x 2). The filtrate and washings were combined, dehydrated with anhydrous sodium sulfate, filtered again, the solvent evaporated, and dried under vacuum to obtain 0.978 mmol of pure tropisetron with a yield of 97.8%. 1 H NMR and 13 The C NMR data are as follows:

[0038] 1 H NMR (500 MHz, CHLOROFORM-D) δ 10.22 (s, 1H), 8.26 – 8.21 (m, 1H), 7.84 (s, 1H), 7.40 (dd, J = 6.3, 3.0 Hz, 1H), 7.29 – 7.22 (m, 2H), 5.28 (t, J= 5.5 Hz, 1H), 3.21 (s, 2H), 2.34 (s, 3H), 2.32 – 2.25 (m, 2H), 2.18 – 2.06(m, 4H), 1.94 (d, J = 14.0 Hz, 2H);

[0039] 13 C NMR (126 MHz, CHLOROFORM-D) δ 164.83, 136.54, 131.28, 126.11,123.19, 122.01, 121.21, 111.86, 108.89, 66.51, 59.95, 40.20, 36.51, 26.01.

[0040] like Figure 2 and Figure 3 As shown, Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of the tropisetron product synthesized in Example 1 of the present invention. Figure 3 The carbon-1NMR spectrum of the tropisetron product synthesized in Example 1 of the present invention is shown.

[0041] Example 2

[0042] A palladium single-atom catalyst was prepared in the same manner as in Example 1, except that activated carbon was replaced with CeO2, and finally a 0.3% Pd / CeO2 single-atom catalyst was obtained.

[0043] Tropisetron was synthesized using a palladium single-atom catalyst according to the synthetic route of Example 1. The specific process is as follows:

[0044] First, 117 mg (1 mmol) of indole and 141 mg (1 mmol) of tropine were added to the reaction flask, followed by 40 mg of 0.3% Pd / CeO2 single-atom catalyst, 2 mL of water, and 204 μL of 30% hydrogen peroxide solution (2 mmol H2O2). The air in the reaction flask was then evacuated and carbon monoxide (1 atm) was introduced. A balloon was connected to the flask mouth and sealed. The magnetic stirrer was turned on and the reaction was carried out in a water bath at 80°C for 6 h. After the reaction was stopped, the reaction solution was filtered to remove the solid-phase catalyst and washed with dichloromethane (20 mL×2). The filtrate and washing solution were combined, anhydrous sodium sulfate was added to remove water, the reaction was filtered again, the solvent was evaporated, and the reaction was dried in vacuo to obtain 0.951 mmol of pure tropisetron compound with a yield of up to 95.1%.

[0045] Example 3

[0046] The 0.3% Pd / NC single-atom catalyst prepared in Example 1 was used to catalyze the synthesis of tropisetron using a palladium single-atom catalyst according to the synthesis route of Example 1. The specific process is as follows:

[0047] To a reaction flask, 117 mg (1 mmol) of indole and 141 mg (1 mmol) of tropine were added, followed by 40 mg of 0.3% Pd / NC single-atom catalyst, 2 mL of water, and 180 mg (1 mmol) of tert-butyl hydroperoxide. The flask was then evacuated and filled with carbon monoxide (1 atm). A balloon was attached to the flask and sealed securely. A magnetic stirrer was then activated and the reaction was continued in a water bath at 80°C for 6 h. After the reaction was terminated, the solid-phase catalyst was removed by filtration and washed with dichloromethane (20 mL x 2). The filtrate and washings were combined, dehydrated with anhydrous sodium sulfate, filtered again, the solvent evaporated, and dried under vacuum to obtain 0.965 mmol of pure tropisetron in a 96.5% yield.

[0048] Example 4

[0049] The 0.3% Pd / NC single-atom catalyst prepared in Example 1 was used to synthesize tropisetron using the palladium single-atom catalyst according to the synthesis route of Example 1. The specific process is as follows:

[0050] To a reaction flask, 117 mg (1 mmol) of indole and 141 mg (1 mmol) of tropine were added, followed by 40 mg of a 0.3% Pd / NC single-atom catalyst, 2 mL of toluene, and 204 μL of a 60% hydrogen peroxide solution (2 mmol H2O2). The air in the flask was evacuated and carbon monoxide (1 atm) was introduced. A balloon was attached to the flask and sealed securely. A magnetic stirrer was activated and the reaction was incubated in an 80°C waterbath for 6 h. After the reaction was terminated, the solid-phase catalyst was removed by filtration and washed with dichloromethane (20 mL x 2). The filtrate and washings were combined, dehydrated with anhydrous sodium sulfate, filtered again, the solvent evaporated, and dried under vacuum to yield 0.964 mmol of pure tropisetron in a 96.4% yield.

[0051] Comparative Example 1

[0052] The performance of the homogeneous (CH3COO)2Pd catalyst was tested. Specifically, the test focused on the catalytic synthesis of tropisetron using indole, carbon monoxide, and tropinol as the raw materials. The synthesis route is as follows:

[0053]

[0054] The specific process of catalytic synthesis of tropisetron by homogeneous (CH3COO)2Pd catalyst is as follows:

[0055] To a reaction flask, 117 mg (1 mmol) of indole and 141 mg (1 mmol) of tropine were added, followed by 4 mL of 5 mmol / mL (CH3COO)2Pd catalyst, 2 mL of water, and 204 μL of 30% hydrogen peroxide solution (2 mmol H2O2). The air in the flask was evacuated and carbon monoxide (1 atm) was introduced. A balloon was attached to the flask and sealed securely. A magnetic stirrer was then activated and the reaction was incubated in an 80°C water bath for 6 h. After the reaction ceased, the organic phase was washed with dichloromethane and separated by column chromatography to obtain an organic solution of tropisetron. The solvent was then removed by rotary evaporation and dried under vacuum to yield 0.05 mmol of pure tropisetron, a yield of only 5%.

[0056] Comparative Example 2

[0057] The performance of the 10% nano-Pd / C catalyst was tested. Specifically, the test focused on the catalytic synthesis of tropisetron using indole, carbon monoxide, and tropinol as the raw materials. The synthesis route is as follows:

[0058]

[0059] The process of synthesizing tropisetron using 10% nano-Pd / C catalyst includes:

[0060] To a reaction flask, 117 mg (1 mmol) of indole and 141 mg (1 mmol) of tropine were added, followed by 40 mg of 10% nano-Pd / C catalyst, 2 mL of water, and 204 μL of 30% hydrogen peroxide solution (2 mmol H2O2). The air in the flask was evacuated and carbon monoxide (1 atm) was introduced. A balloon was attached to the flask and sealed securely. A magnetic stirrer was then activated and the reaction was incubated in an 80°C waterbath for 6 h. After the reaction ceased, the solid-phase catalyst was removed by filtration and washed with dichloromethane (20 mL x 4). The filtrate and washings were combined, dehydrated with anhydrous sodium sulfate, filtered again, the solvent evaporated, and dried under vacuum to yield 0.386 mmol of pure tropisetron, with a yield of only 38.6%.

[0061] By the contrast of above-mentioned example, it can be found that in embodiment 1~4, the productive rate of using palladium single-atom catalyst catalytic synthesis of tropisetron is all higher than 95%.Use (CH3COO)2During Pd homogeneous catalyst, the productive rate of tropisetron only has 5%.In addition, when using 10%Pd / C heterogeneous nanocatalyst, the consumption of dichloromethane washings obviously increases, and the productive rate of tropisetron only has 38.6%.

[0062] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any technician familiar with the technical field, within the technical scope disclosed by the present invention, who makes equivalent replacements or changes based on the technical solution and inventive concept of the present invention, should be covered by the scope of protection of the present invention.

Claims

1. A method for synthesizing tropisetron, characterized in that: The following steps are involved: Indole, carbon monoxide and tropine alcohol react in a solvent in the presence of a Pd single atom catalyst and an oxidant to obtain tropisetron.

2. The synthesis method according to claim 1, wherein The Pd single-atom catalyst includes a carrier and Pd single atoms supported on the carrier; The mass fraction of the Pd single atom loaded on the carrier is 0.1% to 0.5%.

3. The synthesis method according to claim 2, characterized in that The carrier is selected from activated carbon, iron oxide, aluminum oxide, cerium oxide, zirconium oxide, titanium oxide, manganese oxide or silicon dioxide.

4. The synthesis method according to claim 2, characterized in that The Pd single-atom catalyst is prepared by the following method: S1) stirring the EDTA solution containing Pd ions and the support together until the solvent is completely evaporated, and then drying to obtain a 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.

5. The synthesis method according to claim 4, characterized in that In step S1), the concentration of the EDTA solution containing Pd ions is 5 mg / mL to 15 mg / mL.

6. The synthesis method according to claim 4, characterized in that In step S1), the stirring temperature is 90°C to 100°C; In step S2), the calcination is performed in a protective gas atmosphere at a temperature of 500° C. to 700° C. and for a time of 2 h to 4 h.

7. The synthesis method according to claim 1, characterized in that The carbon monoxide pressure is 1 atm to 10 atm; The molar ratio of indole to tropine is 1:(1-1.5); The amount of the oxidant is 100% to 300% of the amount of the indole substance; The amount of the Pd single atom catalyst used is 30 mg / mmol to 50 mg / mmol based on the amount of the indole substance; The amount of the solvent used is 2 mL / mmol to 5 mL / mmol based on the amount of the indole substance.

8. The synthesis method according to claim 1, characterized in that The oxidant is selected from one or more of hydrogen peroxide, oxygen, p-benzodiquinone, peracetic acid, 2,2,6,6-tetramethyl-1-piperidine and tert-butyl hydroperoxide; The solvent is selected from one or more of water, dimethyl carbonate, 1,4-dioxane, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide and toluene.

9. The synthesis method according to claim 1, characterized in that The reaction temperature is 20° C. to 120° C., and the reaction time is 1 h to 12 h.

10. The synthesis method according to claim 1, characterized in that After the reaction, the method further comprises: filtering the reaction solution obtained after the reaction, and removing the solvent from the filtrate obtained by filtration to obtain tropisetron.

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