A piperidone alkaloid and analogs thereof, synthetic methods and uses

Abstract

The application provides a synthesis method of active piperidone alkaloid, and the active piperidone alkaloid is Dysidone A. The raw material piperidine is used as a substrate, and the substrate is reacted with p-methoxy benzyl chloride under the condition of N,N-diisopropylethylamine, so that the secondary amine is protected, and the side reaction of sodium hydride and hydrogen on the secondary amine is avoided. Then, the secondary amine is oxidized under the condition of iodine and iodobenzenediacetic acid. Next, the secondary amine is reacted with triethyl phosphine acetic acid ester to obtain an alpha, beta unsaturated ester. Then, the p-methoxy benzyl protection is removed by using ammonium cerium nitrate in a mild and efficient manner. Finally, the ester is reduced into an alcohol by using diisobutylaluminum hydride. The piperidone alkaloid or the like is obtained through five reaction steps. The synthesis process is simple, the raw material is cheap and easy to obtain, the cost is low, the reaction condition is relatively mild, the purity is high, and the method has good economic and social benefits.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, and specifically relates to a piperidone alkaloid and its analogues, their synthesis methods and applications. Background Technology

[0002] Marine life accounts for about 87% of the total biomass on Earth. Due to the high salinity, high pressure, lack of oxygen, and lack of light in the ocean, as well as the intense competitive pressure, marine organisms have a wide range of biological activities. Therefore, the ocean is a huge natural treasure trove of medicines, especially alkaloids. These are a class of basic secondary metabolites containing amide groups and other complex carbon skeleton ring structures, synthesized from different amino acids or their direct derivatives.

[0003] Piperidine, chemically known as aziridine or hexahydropyridine, is a non-aromatic, saturated six-membered nitrogen heterocyclic compound, unlike pyridine. It is a colorless liquid with a peppery odor, a boiling point of 106°C, and is soluble in water, ethanol, and ether. Its basicity is much greater than that of pyridine; its aqueous solution is a strong base, corrosive, and moderately toxic. It reacts with acids to form salts and can explode or burn upon contact with open flames or high heat. It reacts violently with oxidizers and must be stored in a cool, well-ventilated place. Piperidine is an important nitrogen heterocyclic organic intermediate. Currently, it is only produced on a small scale in China. The main synthetic route involves hydrogenating pyridine as a starting material in the presence of platinum oxide or Raney Ni catalyst. There are also reports from abroad of preparing pyridine through electrolytic reduction.

[0004] Piperidinones and their derivatives are very important piperidine homologues. The carbonyl group and the methylene group at the ortho position in the piperidinone structure can be used to initiate many organic reactions, leading to the derivation of many practical pharmaceutical, pesticide, and chemical intermediates. In particular, N-substituted-4-piperidinone compounds are important synthetic intermediates for the preparation of various alkaloids and drugs, playing an increasingly important role in drug synthesis. Its derivatives have been found to possess antidepressant, antiarrhythmic, antithrombotic, antispasmodic, sedative, and cholesterol-lowering activities. Furthermore, N-substituted 4-piperidinone compounds are important intermediates for many neurological drugs and are currently widely used for analgesia, antiarrhythmia, M-series muscarinic antagonists, and central nervous system 5HT1A receptor antagonists, such as pethidine, the first analgesic synthesized in 1939, and the widely used tannic acid analgesics with high therapeutic index and good safety profile. In addition, Jonathan et al. synthesized a series of 3,5-di(aryl)-4-piperidinones and their N-substituted acrylamide derivatives. Bioactivity tests showed that many of these compounds exhibited cytotoxic activity against murine leukemia cells P388, human leukemia cells L1210, and human Molt 4 / C8 and CEM tumors. Their mechanism of action is to inhibit the biosynthesis of DNA, RNA, and proteins in tumor cells, and there is hope that highly effective anticancer drugs can be screened from them. Summary of the Invention

[0005] This invention provides a method for synthesizing an active piperidinone alkaloid, wherein the active piperidinone alkaloid is Dysidone A, and its structure is shown in formula (I):

[0006]

[0007] Its preparation method includes the following steps:

[0008] Protection of S1 secondary amine: Piperidine was reacted with p-methoxybenzyl chloride in the presence of N,N-diisopropylethylamine to give 1-(4-methoxybenzyl)piperidine;

[0009] Oxidation of piperidinone derivatives in S2: The product 1-(4-methoxybenzyl)piperidine obtained in S1 was reacted with iodine and iodophenyl diacetic acid to give 1-(4-methoxybenzyl)piperidine-2,3-dione.

[0010] S3 CC bond connection: The product obtained in S2, 1-(4-methoxybenzyl)piperidine-2,3-dione, was reacted with triethylphosphonoacetate to give (Z)-2-(1-(4-methoxybenzyl)-2-oxoperidine-3-ylidene)ethyl acetate;

[0011] S4 Removal of methoxybenzyl group: The ethyl (Z)-2-(1-(4-methoxybenzyl)-2-oxopiperidin-3-ylidene)acetate obtained from S3 was reacted with cerium ammonium nitrate to remove the protection of the methoxybenzyl group, yielding ethyl (Z)-2-(2-oxopiperidin-3-ylidene)acetate.

[0012] S5 ester reduction: The (Z)-2-(2-oxopiperidin-3-ethylene)ethyl acetate obtained from S4 was reacted with diisobutylaluminum hydride to give the final product (Z)-3-(2-hydroxyethylidene)piperidin-2-one;

[0013] Furthermore, in S1, the molar ratio of p-methoxybenzyl chloride, piperidine, and N,N-diisopropylethylamine is 0.5–2:0.5–2:1–1.8; furthermore, in S1, the molar ratio of p-methoxybenzyl chloride, piperidine, and N,N-diisopropylethylamine is 1.1:1.0:1.5;

[0014] Furthermore, in S1, the reaction is carried out in the solvent dichloromethane (i.e., DCM);

[0015] Furthermore, in S1, the p-methoxybenzyl chloride is added dropwise; even further, in S1, the dropwise addition temperature is 0°C.

[0016] Furthermore, the specific steps of S1 include the following steps: dissolving piperidine and N,N-diisopropylethylamine in dichloromethane, adding p-methoxybenzyl chloride dropwise under ice bath conditions, and then reacting overnight at room temperature. After the reaction is completed, the resulting reaction solution is purified to obtain 1-(4-methoxybenzyl)piperidine.

[0017] Furthermore, in S1, the purification refers to washing the obtained reaction solution with saturated brine, extracting the aqueous layer three times with dichloromethane, combining the organic phases and drying them, and then separating and purifying them by column chromatography. The elution conditions are a volume ratio of petroleum ether to ethyl acetate of 15:1, which yields the target product.

[0018] Further, in step S2, the product 1-(4-methoxybenzyl)piperidine from step S1, along with iodophenyl diacetic acid and iodine, is dissolved in dry tetrahydrofuran. The molar ratio of 1-(4-methoxybenzyl)piperidine, iodophenyl diacetic acid, and iodine is 0.5–2:1.0–3.0:1.0–3.0. After stirring for 30–60 min, an equimolar amount of iodophenyl diacetic acid is added to the mixture. The reaction is continued for 10–15 h, followed by quenching with saturated sodium thiosulfate solution. After quenching, the resulting reaction solution is purified to obtain 1-(4-methoxybenzyl)piperidine-2,3-dione. Preferably, the molar ratio of 1-(4-methoxybenzyl)piperidine, iodophenyl diacetic acid, and iodine is 1.0:2.0:2.0. Preferably, the stirring time is 50 min. Preferably, the stirring time is continued for 12 h.

[0019] The product 1-(4-methoxybenzyl)piperidine, along with iodophenyl diacetic acid and iodine, from S1 are dissolved in dry tetrahydrofuran. The molar ratio of 1-(4-methoxybenzyl)piperidine, iodophenyl diacetic acid, and iodine is 0.5–2:1.0–3.0:1.0–3.0. After stirring for a period of time, an equimolar amount of iodophenyl diacetic acid is added to the mixture. The reaction is continued for a period of time, and then quenched with saturated sodium thiosulfate solution. After quenching, the resulting reaction solution is purified to obtain 1-(4-methoxybenzyl)piperidine-2,3-dione. Preferably, in S2, the molar ratio of 1-(4-methoxybenzyl)piperidine, iodophenyl diacetic acid, and iodine is 1.0:2.0:2.0.

[0020] Furthermore, in S2, the purification refers to extraction three times with ethyl acetate and saturated brine, combining the organic phases and drying them, followed by column chromatography separation and purification. The elution conditions are a volume ratio of petroleum ether to ethyl acetate of 5:1, which yields the target product.

[0021] Further, in S3, the molar ratio of the product 1-(4-methoxybenzyl)piperidine-2,3-dione obtained in S2 to triethylphosphonoacetate is 0.8-1.5:1-2; preferably, the molar ratio of the product 1-(4-methoxybenzyl)piperidine-2,3-dione obtained in S2 to triethylphosphonoacetate is 1:1.5.

[0022] Furthermore, S3 specifically includes the following steps: at room temperature, add alkali to tetrahydrofuran, cool to -10 to 10°C, then add triethylphosphonoacetate dropwise, stir for 10 to 30 minutes, then add 1-(4-methoxybenzyl)piperidine-2,3-dione dissolved in tetrahydrofuran dropwise, then raise the temperature to room temperature and react until the reactants have reacted completely, finally quench with water, and purify the resulting reaction solution to obtain (Z)-2-(1-(4-methoxybenzyl)-2-oxopiperidine-3-ylidene)ethyl acetate; preferably, cool to 0°C;

[0023] More preferably, in S3, the alkali is sodium hydride (i.e., NaH);

[0024] More preferably, in S3, the tetrahydrofuran is anhydrous tetrahydrofuran;

[0025] More preferably, in S3, the molar ratio of 1-(4-methoxybenzyl)piperidine-2,3-dione, triethylphosphonoacetate, and sodium hydride is 0.8–1.5:1–2:1–2; preferably, the molar ratio of 1-(4-methoxybenzyl)piperidine-2,3-dione, triethylphosphonoacetate, and sodium hydride is 1.0:1.5:1.5.

[0026] More preferably, in S3, the purification refers to extracting the reaction solution three times with dichloromethane (DCM) and saturated brine, combining the organic phases and drying them, and then separating and purifying them by column chromatography. The elution conditions are a volume ratio of petroleum ether to ethyl acetate of 1:1, thus obtaining the target product.

[0027] Furthermore, in S4, the molar ratio of ethyl (Z)-2-(1-(4-methoxybenzyl)-2-oxopiridine-3-ylidene)acetate to ceric ammonium nitrate is 1:1 to 2; more preferably, the molar ratio of ethyl (Z)-2-(1-(4-methoxybenzyl)-2-oxopiridine-3-ylidene)acetate to ceric ammonium nitrate is 1:1.3;

[0028] Furthermore, S4 specifically includes the following steps: dissolving ethyl (Z)-2-(1-(4-methoxybenzyl)-2-oxopiridine-3-ylidene)acetate in a mixed solvent, adding cerium ammonium nitrate, quenching with brine after the reaction is complete, and purifying the reaction solution to obtain ethyl (Z)-2-(2-oxopiridine-3-ylidene)acetate;

[0029] Furthermore, in S4, the mixed solvent is a mixture of tert-butanol and water, with a volume ratio of 3 to 6:1; more preferably, the mixed solvent is a mixture of tert-butanol and water, with a volume ratio of 4:1.

[0030] Furthermore, in S4, purification refers to extracting the reaction solution three times with ethyl acetate and saturated brine, combining the organic phases and drying them, and then separating and purifying them by column chromatography. The elution conditions are a volume ratio of petroleum ether to ethyl acetate of 0:100, which yields the target product.

[0031] Further, in S5, the molar ratio of (Z)-2-(2-oxopiperidin-3-ylidene)ethyl acetate to diisobutylaluminum hydride is 1.0:2 to 3; more preferably, in S5, the molar ratio of (Z)-2-(2-oxopiperidin-3-ylidene)ethyl acetate to diisobutylaluminum hydride is 1.0:2.2;

[0032] Furthermore, S5 specifically includes the following steps: dissolving the product of S4, (Z)-2-(2-oxopiperidin-3-ylidene)ethyl acetate, in an organic solvent, cooling to -80 to -70°C under nitrogen conditions, then adding diisobutylaluminum hydride dissolved in the organic solvent dropwise to the reaction solution and reacting for a period of time, then raising to room temperature, and adding water, sodium hydroxide, and water in sequence, with each addition spaced 10 to 20 seconds apart. After the addition is completed, purifying the resulting reaction solution yields the product.

[0033] Furthermore, in S5, the organic solvent is selected from either anhydrous dichloromethane (DCM) or anhydrous tetrahydrofuran (THF).

[0034] Furthermore, in step S5, the concentration of sodium hydroxide is 0.5–2 mol / L; more preferably, in step S5, the concentration of sodium hydroxide is 1 mol / L.

[0035] Furthermore, in S5, the purification refers to extraction with dichloromethane (DCM) 1 to 3 times, combining the extracted organic phases and drying them, followed by HPLC separation and purification. The mobile phase used is methanol:water with a volume ratio of 20:80, thus obtaining the target product.

[0036] Beneficial effects

[0037] (1) This invention uses piperidine as a substrate and reacts with p-methoxybenzyl chloride under the conditions of N,N-diisopropylethylamine to protect the secondary amine and avoid side reactions between sodium hydride and the hydrogen on the secondary amine. Then, it is oxidized under the conditions of iodine and iodophenyl diacetic acid. Next, it reacts with triethylphosphonoacetate to obtain an α,β-unsaturated ester. Then, the protection of the p-methoxybenzyl group is removed by cerium ammonium nitrate in a mild and efficient manner. Finally, the ester is reduced to an alcohol by diisobutylaluminum hydride. Finally, piperidinone alkaloids or their analogues are obtained through five steps. The synthesis process is simple, the raw materials are cheap and readily available, the cost is low, the reaction conditions are relatively mild, and the purity is high.

[0038] (2) The present invention employs optimal process conditions to achieve the optimal yield and the shortest reaction time for each step of the reaction. Attached Figure Description

[0039] Figure 1 A detailed flowchart of the synthetic reaction route for piperidone compounds.

[0040] Figure 2 This is a schematic diagram of the specific synthetic reaction route of the piperidinone compounds in Example 1.

[0041] Figure 3 Mass spectra of piperidinone compounds in Example 1

[0042] Figure 4 For the piperidinone compounds in Example 1 1 H-NMR spectrum

[0043] Figure 5 For the piperidinone compounds in Example 1 13 C-NMR spectrum

[0044] Figure 6 The ultraviolet spectrum of the piperidinone compounds in Example 1

[0045] Figure 7 Infrared spectra of piperidinone compounds in Example 1 Detailed Implementation Plan

[0046] The present invention will now be described in further detail with reference to examples and accompanying drawings, but the implementation methods of the present invention are not limited thereto.

[0047] Unless otherwise specified, all reagents used in the examples are commercially available.

[0048] Example 1:

[0049] Protection of S1 secondary amine: In a 100 mL round-bottom flask and a 250 mL round-bottom flask, 5.1 g of piperidine and 3.88 g of N,N-diisopropylethylamine were dissolved in 80 mL of dichloromethane. 3.13 g of p-methoxybenzyl chloride was added dropwise under ice bath conditions, and the mixture was then allowed to react overnight at room temperature. After the reaction was complete, the reaction solution was washed with saturated brine, and the aqueous layer was extracted twice with dichloromethane. The organic phases were combined and dried, and then separated by column chromatography to obtain 1-(4-methoxybenzyl)piperidine. The 1H and 1C NMR spectra are shown below, indicating that 1-(4-methoxybenzyl)piperidine was successfully synthesized in this step. The yield of this step was 90.9%.

[0050] NMR data for 1-(4-methoxybenzyl)piperidine: 1 H NMR (300M, CDCl3): δ7.22(d,J=8.6Hz,2H),6.84(d,J=8.6Hz,2H),3.80(s,3H),3.41(s,2H),2.35(s,4H),1.56(m,4H),1.47-1.30(m,2H). 13 C NMR (75MHz, CDCl3): δ158.5, 130.5, 130.4, 113.4, 63.2, 55.2, 54.3, 26.0, 24.4.

[0051] Oxidation of S2 piperidinone derivatives: In a 250 mL round-bottom flask, 0.25 g of the product obtained in S1, 0.77 g of iodophenyldiacetic acid, and 0.61 g of elemental iodine were dissolved in 80 mL of tetrahydrofuran (THF). After reacting at room temperature for 6 hours, 0.39 g of iodophenyldiacetic acid was added, and the reaction was continued for another 12 hours. The reaction was then quenched with 48 mL of saturated sodium thiosulfate. The reaction solution was extracted three times with ethyl acetate, the organic phases were combined and dried, and then separated by column chromatography to obtain 1-(4-methoxybenzyl)piperidine-2,3-dione. The 1H and 1C NMR spectra are shown below, indicating that 1-(4-methoxybenzyl)piperidine-2,3-dione was successfully synthesized in this step, with a yield of 45.6%.

[0052] NMR data for 1-(4-methoxybenzyl)piperidine-2,3-dione: 1H NMR (300M, CDCl3): δ7.15 (d, J = 8.7Hz, 2H), 6.78 (d, J = 8.7Hz, 2H), 4.53 (s, 2H) ,3.71(s,3H),3.38(t,J=6.0Hz,2H),2.63(t,J=6.9Hz,2H),2.08-2.00(m,2H); 13 C NMR (75MHz, CDCl3): δ191.7,159.2,157.7,129.7,127.6,114.0,55.1,50.3,46.4,38.4,21.5.

[0053] S3C-C bond connection: In a 50 mL round-bottom flask, 0.128 g of sodium hydride (NaH, 3.2 mmol) was dissolved in 10 mL of dry tetrahydrofuran (THF), cooled to 0 °C, and then 0.51 g of triethylphosphonoacetate was added dropwise. After 15 minutes, 0.33 g of the product obtained from S2, 1-(4-methoxybenzyl)piperidine-2,3-dione, was dissolved in 2 mL of anhydrous tetrahydrofuran (THF) and added dropwise to the reaction solution. The mixture was then heated to room temperature, and the reaction was monitored by thin-layer chromatography (TLC). After the reaction was complete, the mixture was extracted three times with dichloromethane (DCM) and water. The organic phases were combined and dried, and then separated by column chromatography to obtain (Z)-2-(1-(4-methoxybenzyl)-2-oxopiperidine-3-yl)ethyl acetate. The 1H and 1C NMR spectra are shown below, indicating that this step successfully synthesized (Z)-2-(1-(4-methoxybenzyl)-2-oxopiperidin-3-ylidene)ethyl acetate; the yield of this step was 76.0%.

[0054] NMR data for ethyl (Z)-2-(1-(4-methoxybenzyl)-2-oxopiperidin-3-ylidene)acetate: 1 H NMR (300MHz, CDCl3): δ7.06 (d, J = 8.7Hz, 2H), 6.69 (d, J = 8.7Hz, 2H), 5.85 (s, 1H), 4.41 (s, 2H), 4.16 (q, J = 7. 2Hz,2H),3.63(s,3H),3.10(t,J=6.0Hz,2H),3.39(t,J=6.0Hz,2H),1.75-1.67(m,2H),1.20(t,J=7.1,3H); 13 C NMR (75MHz, CDCl3): δ167.6,161.8,158.6,135.2,129.2,128.4,128.5,113.5,60.4,54.8,49.2,46.5,29.7,22.2,13.7.

[0055] De-methoxybenzyl group removal by S4: In a 50 mL round-bottom flask, 0.22 g of the product obtained by S4, ethyl (Z)-2-(1-(4-methoxybenzyl)-2-oxopiridine-3-yl)acetate, was dissolved in 10 mL of a mixture of tert-butanol and water (volume ratio 4:1). Then, 0.33 g of cerium ammonium nitrate was added, and the reaction was carried out for 1 h. After extraction with 10 wt% sodium chloride solution and ethyl acetate, the aqueous layer was washed three times with ethyl acetate. The organic phases were combined and dried, and then separated by column chromatography to obtain ethyl (Z)-2-(2-oxopiridine-3-yl)acetate. The 1H and 1C NMR spectra are shown below, indicating that ethyl (Z)-2-(2-oxopiridine-3-yl)acetate was successfully synthesized in this step; the yield of this step was 43.0%.

[0056] NMR data for ethyl (Z)-2-(2-oxopiperidin-3-yl)acetate: 1 H NMR (300M, CDCl3): δ6.86 (s, 1H), 5.97 (s, 1H), 4.23 (q, J = 7.2Hz, 2H), 3.35 -3.30(m,2H),2.56-2.52(m,2H),1.92-1.83(m,2H),1.29(t,J=7.1Hz,3H); 13 C NMR (75MHz, CDCl3): δ168.0,164.1,134.7,127.4,60.9,42.1,29.8,22.6,13.9.

[0057] Reduction of S5 ester group: 0.0754 g of the product obtained from S4 was added to a 100 mL round-bottom flask with a side arm. The air in the reaction flask was evacuated and nitrogen was applied for protection. 3 mL of anhydrous dichloromethane (DCM) was added, followed by 1 mL of diisobutylaluminum hydride dissolved in 1 mL of anhydrous dichloromethane (DCM). The reaction was cooled to -78 °C and allowed to proceed to room temperature. Water, 1 M sodium hydroxide, and water were added sequentially, with each addition occurring 17 seconds apart. The mixture was then poured into a separatory funnel. The aqueous layer was extracted three times with dichloromethane (DCM). The organic phases were combined and dried, and then separated by column chromatography to obtain the final target product, piperidinone alkaloids. The 1H and 1C NMR spectra are shown below, indicating that the final target product, piperidinone alkaloids, was successfully synthesized in this step. The yield of this step was 78.0%.

[0058] Piperidone alkaloid NMR data: 1 H NMR (300M, CDCl3): δ6.19(m,1H),5.98(brs,1H),4.33(d,J=6.1Hz,2H),3.38(m,2H),2.53(m,2H),1.88(m,2H); 13C NMR (75MHz, CDCl3): δ167.1,141.6,130.8,59.4,42.7,31.9,22.9.

[0059] Example 2: Activity data of piperidone alkaloids

[0060] Dysidone is a neopiperidinone alkaloid isolated from the secondary metabolites of the sponge *Dysidea* sp. collected in Xuwen County, Zhanjiang City, my country. The compound was used at a concentration of 100 μM to treat mouse mononuclear macrophage leukemia cells (RAW264.7), with the inducible nitric oxide synthase inhibitor SMT as a positive control. The inhibitory effect of dysidone A on NO was observed. The results showed that the compound has a certain degree of activity in inhibiting NO, with an IC50 value of [missing value]. 50 The value is 378.27 μM. However, since the amount extracted from nature is very small, the prospect of using synthetic methods to replace extraction and separation is very promising and feasible.

[0061] The above examples are preferred embodiments of the present invention, but the implementation of the present invention is not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention should be considered equivalent substitutions and are included within the protection scope of the present invention.

Claims

1. A method for synthesizing active piperidone alkaloids, characterized in that, The active piperidinone alkaloid is Dysidone A, whose structure is shown in formula (I): (I) Its preparation method includes the following steps: Protection of S1 secondary amines: using piperidine as a substrate, in N , N In the presence of diisopropylethylamine, it reacts with p-methoxybenzyl chloride to give 1-(4-methoxybenzyl)piperidine; Oxidation of piperidinone derivatives in S2: The product 1-(4-methoxybenzyl)piperidine obtained in S1 was reacted with elemental iodine and iodophenyl diacetic acid to give 1-(4-methoxybenzyl)piperidine-2,3-dione; S3 CC bond connection: The product obtained in S2, 1-(4-methoxybenzyl)piperidine-2,3-dione, was reacted with triethylphosphonoacetate to give (Z)-2-(1-(4-methoxybenzyl)-2-oxoperidine-3-ylidene)ethyl acetate; S4 Removal of methoxybenzyl group: The ethyl (Z)-2-(1-(4-methoxybenzyl)-2-oxopiperidin-3-ylidene)acetate obtained from S3 was reacted with cerium ammonium nitrate to remove the protection of the methoxybenzyl group, yielding ethyl (Z)-2-(2-oxopiperidin-3-ylidene)acetate. S5 ester reduction: The (Z)-2-(2-oxopiperidin-3-yl)ethyl acetate obtained from S4 was reacted with diisobutylaluminum hydride to give the final product (Z)-3-(2-hydroxyethylidene)piperidin-2-one.

2. The method for synthesizing active piperidinone alkaloids according to claim 1, characterized in that, In S1, p-methoxybenzyl chloride, piperidine, and N , N The molar ratio of diisopropylethylamine is 0.5~2:0.5~2:1~1.

8.

3. The method for synthesizing active piperidinone alkaloids according to claim 2, characterized in that, In S1, p-methoxybenzyl chloride, piperidine, and N , N The molar ratio of diisopropylethylamine is 1.1:1.0:1.

5.

4. The method for synthesizing active piperidinone alkaloids according to claim 2 or 3, characterized in that, S1 specific steps include the following steps: mixing piperidine and... N , N - Diisopropylethylamine was dissolved in dichloromethane, and p-methoxybenzyl chloride was added dropwise under ice bath conditions. The reaction was carried out overnight at room temperature. After the reaction was completed, the resulting reaction solution was purified to obtain 1-(4-methoxybenzyl)piperidine.

5. The method for synthesizing active piperidinone alkaloids according to claim 4, characterized in that, In S1, the purification refers to washing the obtained reaction solution with saturated brine, extracting the aqueous layer three times with dichloromethane, combining the organic phases and drying them, and then separating and purifying them by column chromatography. The elution conditions are a volume ratio of petroleum ether to ethyl acetate of 15:1, which yields the target product.

6. The method for synthesizing active piperidinone alkaloids according to claim 1, characterized in that, In S2, the molar ratio of 1-(4-methoxybenzyl)piperidine, iodophenyl diacetic acid and iodine is 0.5~2:2.0~6.0:1.0~3.

0.

7. The method for synthesizing active piperidinone alkaloids according to claim 6, characterized in that, Preferably, in S2, the molar ratio of 1-(4-methoxybenzyl)piperidine, iodophenyldiacetic acid and iodine is 1.0:4.0:2.

0.

8. The method for synthesizing active piperidinone alkaloids according to claim 6 or 7, characterized in that, The specific steps of S2 include dissolving the product 1-(4-methoxybenzyl)piperidine from S1, along with iodophenyl diacetic acid and iodine, in dry tetrahydrofuran. The molar ratio of 1-(4-methoxybenzyl)piperidine, iodophenyl diacetic acid, and iodine is 0.5~2:1.0~3.0:1.0~3.

0. After stirring for 30~60 min, an equimolar amount of iodophenyl diacetic acid is added to the mixture. Stirring is continued for 10~15 h, followed by quenching with saturated sodium thiosulfate solution. After quenching, the resulting reaction solution is purified to obtain 1-(4-methoxybenzyl)piperidine-2,3-dione.

9. The method for synthesizing active piperidinone alkaloids according to claim 8, characterized in that, In S2, the molar ratio of 1-(4-methoxybenzyl)piperidine, iodophenyldiacetic acid, and iodine is 1.0: 2.0: 2.

0.

10. The method for synthesizing active piperidinone alkaloids according to claim 8, characterized in that, In S2, the stirring time is 50 min.

11. The method for synthesizing active piperidinone alkaloids according to claim 8, characterized in that, In S2, the stirring time is 12 hours.

12. The method for synthesizing active piperidinone alkaloids according to claim 8, characterized in that, In S2, the purification refers to extraction three times with ethyl acetate and saturated brine, combining the organic phases and drying them, followed by column chromatography separation and purification. The elution conditions are a volume ratio of petroleum ether to ethyl acetate of 5:1, which yields the target product.

13. The method for synthesizing active piperidinone alkaloids according to claim 1, characterized in that, In S3, the molar ratio of 1-(4-methoxybenzyl)piperidine-2,3-dione to triethylphosphonoacetate is 0.8~1.5:1~2.

14. The method for synthesizing the active piperidinone alkaloids according to claim 13, characterized in that, In S3, the molar ratio of 1-(4-methoxybenzyl)piperidine-2,3-dione to triethylphosphonoacetate is 1:1.

5.

15. The method for synthesizing the active piperidinone alkaloids according to claim 13 or 14, characterized in that, S3 specifically includes the following steps: At room temperature, add alkali to tetrahydrofuran, cool to -10~10℃, then add triethylphosphonoacetate dropwise, stir for 10~30 min, then add 1-(4-methoxybenzyl)piperidine-2,3-dione dropwise dissolved in tetrahydrofuran, then raise the temperature to room temperature and react until the raw materials have reacted completely, finally quench with water, and after quenching the reaction, purify the resulting reaction solution to obtain (Z)-2-(1-(4-methoxybenzyl)-2-oxopiperidine-3-ylidene)ethyl acetate.

16. The method for synthesizing active piperidinone alkaloids according to claim 15, characterized in that, In S3, the base is sodium hydride (i.e., NaH).

17. The method for synthesizing active piperidinone alkaloids according to claim 15, characterized in that, In S3, the tetrahydrofuran is anhydrous tetrahydrofuran.

18. The method for synthesizing active piperidinone alkaloids according to claim 15, characterized in that, In S3, the purification refers to extracting the reaction solution three times with dichloromethane (DCM) and saturated brine, combining the organic phases and drying them, and then performing column chromatography with the elution conditions being a volume ratio of petroleum ether to ethyl acetate of 1:

1. The target product is obtained after separation and purification.

19. The method for synthesizing the active piperidinone alkaloids according to claim 15, characterized in that, In S3, it is cooled to 0 °C.

20. The method for synthesizing active piperidinone alkaloids according to claim 1, characterized in that, In S4, the molar ratio of (Z)-2-(1-(4-methoxybenzyl)-2-oxopiperidin-3-yl)ethyl acetate to cerium ammonium nitrate is 1:1~2.

21. The method for synthesizing active piperidinone alkaloids according to claim 20, characterized in that, In S4, the molar ratio of (Z)-2-(1-(4-methoxybenzyl)-2-oxopiperidin-3-ylidene)ethyl acetate and cerium ammonium nitrate is 1:1.

3.

22. The method for synthesizing active piperidinone alkaloids according to claim 20 or 21, characterized in that, S4 specifically includes the following steps: dissolving ethyl (Z)-2-(1-(4-methoxybenzyl)-2-oxopiridine-3-yl)acetate in a mixed solvent, adding cerium ammonium nitrate, quenching with saturated brine after the reaction is complete, and purifying the reaction solution to obtain ethyl (Z)-2-(2-oxopiridine-3-yl)acetate.

23. The method for synthesizing active piperidinone alkaloids according to claim 22, characterized in that, In S4, the mixed solvent is a mixture of tert-butanol and water, with a volume ratio of 3 to 6:

1.

24. The method for synthesizing active piperidinone alkaloids according to claim 22, characterized in that, In S4, the mixed solvent is a mixture of tert-butanol and water in a volume ratio of 4:

1.

25. The method for synthesizing active piperidinone alkaloids according to claim 22, characterized in that, In S4, purification refers to extracting the reaction solution three times with ethyl acetate and saturated brine, combining the organic phases and drying them, and then separating and purifying them by column chromatography. The elution conditions are a volume ratio of petroleum ether to ethyl acetate of 0:100, which yields the target product.

26. The method for synthesizing active piperidinone alkaloids according to claim 1, characterized in that, In S5, the molar ratio of (Z)-2-(2-oxopiperidin-3-yl)ethyl acetate and diisobutylaluminum hydride is 1.0:2~3.

27. The method for synthesizing active piperidinone alkaloids according to claim 26, characterized in that, In S5, the molar ratio of (Z)-2-(2-oxopiperidin-3-yl)ethyl acetate and diisobutylaluminum hydride is 1.0:2.

2.

28. The method for synthesizing active piperidinone alkaloids according to claim 26 or 27, characterized in that, S5 specifically includes the following steps: dissolve the product of S4, (Z)-2-(2-oxopiperidin-3-yl)ethyl acetate, in an organic solvent, cool it to -80~-70℃ under nitrogen conditions, then dissolve diisobutylaluminum hydride in an organic solvent and drop it into the reaction solution for a period of time, then raise it to room temperature, and add water, sodium hydroxide, and water in sequence, with an interval of 10~20 seconds between each drop. After the drop addition is completed, purify the resulting reaction solution to obtain the product.

29. The method for synthesizing active piperidinone alkaloids according to claim 28, characterized in that, In S5, the organic solvent is selected from either anhydrous dichloromethane (DCM) or anhydrous tetrahydrofuran (THF).

30. The method for synthesizing active piperidinone alkaloids according to claim 28, characterized in that, In S5, the concentration of sodium hydroxide is 0.5~2 mol / L.

31. The method for synthesizing active piperidinone alkaloids according to claim 28, characterized in that, In S5, the concentration of sodium hydroxide is 1 mol / L.

32. The method for synthesizing active piperidinone alkaloids according to claim 28, characterized in that, In S5, the purification refers to extraction with dichloromethane (DCM) 1 to 3 times, combining the extracted organic phases and drying them, followed by separation and purification by HPLC. The mobile phase used is methanol:water with a volume ratio of 20:80, which yields the target product.

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