A method for synthesizing a new honokiol

Abstract

The application provides a synthesis method of new robusta alkaloids. The new robusta alkaloids are prepared from compound 2-4 and compound 3-5 through a process route as follows, compound 2-4 can be prepared from iso-vanillin, and compound 3-5 can be prepared from homoiso-vanillic acid. The application adopts convergent synthesis of new robusta alkaloids, compared with direct synthesis of aporphine alkaloids by using 1-benzyl substituted tetrahydroisoquinoline, the raw material is relatively cheap, and the cost is greatly reduced. Compared with the linear synthesis route, the reaction steps can be obviously reduced, the operation of each step is simple, the yield of most reactions can be controlled at about 80% or even higher, the total reaction yield is improved; the amount of intermediates and raw materials is reduced, and the cost is reduced. The required reaction container is smaller, the flexibility of equipment use is increased; the synthesis cost of intermediates is reduced, the loss is less in the production process, and mass production can be realized.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis, specifically to a method for synthesizing a new litsea alkaloid. Background Technology

[0002] Neo-Litsea alkaloids are alkaloid compounds isolated and identified from the leaves of *Litsea cubeba*. Experiments have shown that they have a certain hypoglycemic effect in vivo, and they have broad application prospects in clinical practice. However, because neo-Litsea alkaloids require extraction from plants, the process is lengthy and the yield is low, resulting in a relatively high price of approximately 40,000 yuan per 10g, which greatly limits the development of related experiments. Currently, there are no reports on the preparation methods of neo-Litsea alkaloids. Although the literature (ChemMedChem, 2018, 13(17), 1817-1832) mentions the synthesis methods of its analogues, the operations are complex, and most of them require column chromatography separation.

[0003] Neolidinine belongs to the apophene alkaloid class. The significant pharmacological effects of apophene alkaloids have attracted widespread attention in organic synthesis; however, their unique benzene ring structure makes direct synthesis challenging. Apophene alkaloids can be synthesized biomimetously using a 1-benzyl-substituted tetrahydroisoquinoline as the basic skeleton; therefore, establishing this core structure is crucial for the synthesis of apophene alkaloids. However, the high cost of 1-benzyl-substituted tetrahydroisoquinoline significantly hinders the synthesis of neolidinine. Therefore, exploring novel synthetic routes is imperative. Developing rational and efficient chemical synthesis methods to rapidly and abundantly obtain neolidinine is of great significance for related research. Summary of the Invention

[0004] The advantages of this invention lie in overcoming the shortcomings of existing technologies and providing a novel method for synthesizing litsea alkaloids. This method offers high synthesis efficiency, simple operation, readily available raw materials, low cost, low equipment requirements, and more flexible operation. It eliminates the multi-step column chromatography described in the literature. The various post-processing methods in this invention (① in the synthesis step of compound 2-3 → compound 2-4, the oxalic acid salt formation method is used in the post-processing of compound 2-4, and the purity after salting is good, avoiding column chromatography separation; ② in the synthesis step of compound 8 → compound 9, the two deprotection reactions are combined into one step, and the purity of methanol-ethyl acetate recrystallization is high) greatly save time and improve synthesis efficiency.

[0005] The first aspect of the present invention is to provide a method for synthesizing a new litsea alkaloid, said new litsea alkaloid being prepared from compounds 2-4 and compounds 3-5 via steps (h)-(m) according to the following process route:

[0006]

[0007] Step (h) involves preparing compound 4 by amidation of compounds 2-4 and 3-5 using an amide condensation agent. The amide condensation agent is an active ester condensation agent, a carbodiimide condensation agent, an onium salt condensation agent, or an organophosphorus condensation agent. When the amide condensation agent is a carbodiimide condensation agent, it is used in combination with 1-hydroxybenzotriazole.

[0008] Preferably, the amide condensing agent in step (h) is a carbodiimide condensing agent, used in combination with 1-hydroxybenzotriazole; preferably, the amide condensing agent is selected from one or a mixture of several of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC).

[0009] Preferably, the specific operation of step (h) is as follows: add compounds 3-5 and 2-4 to the solvent, control the temperature at 20-30°C, stir thoroughly until the system is white and viscous, add HOBt, cool down to below 4°C (preferably to 0°C), add EDC, and then slowly heat up to 20-30°C. After the reaction is complete, purify to obtain compound 4.

[0010] The amounts of compounds 3-5, 2-4, HOBt, and EDC can be reasonably configured by those skilled in the art based on the reaction principle, and do not need to be particularly limited. Considering cost savings and sufficient reaction time, the preferred molar ratio of compounds 2-4, 3-5, HOBt, and EDC is 1:1-1.05:1.1-2:1.05-1.5. For example, in a specific embodiment of the present invention, the molar ratio of compounds 2-4, 3-5, HOBt, and EDC is 1:1.05:1.5:1.2.

[0011] More preferably, the specific operation of step (h) is as follows: add compounds 3-5 and compounds 2-4 to the solvent, control the temperature at 20-30°C, stir thoroughly until the system is white and viscous, add HOBt, cool down to below 4°C, add EDC, and then slowly heat up to 20-30°C. After the reaction is complete, add saturated sodium bicarbonate solution to quench the reaction until there is no exothermic reaction, no bubbles, and no white solid appears. Continue stirring for 0.5-2 hours, filter, and dry the filter cake to obtain compound 4.

[0012] Step (i) involves adding compound 4 and POCl3 into an inert solvent and reacting them at 60-100°C to obtain compound 5.

[0013] The inert solvent used in step (i) is not particularly limited in this invention, and those skilled in the art can make a reasonable selection based on the reaction characteristics of POCl3. Preferably, the inert solvent is one or a mixture of several of acetonitrile, dimethylformamide, DMA, DMI, dimethyl sulfoxide, and hexamethylphosphoric triamine, with acetonitrile being the most preferred.

[0014] The amounts of compound 4 and POCl3 can be reasonably configured by those skilled in the art based on the reaction principle, and there is no need to limit them. From the perspective of cost saving and full reaction, the molar amount of POCl3 can be slightly more than that of compound 4, and the molar ratio of compound 4 to POCl3 is preferably 1:1-1.5. For example, in a specific embodiment of the present invention, the molar ratio of compound 4 to POCl3 is 1:1.2.

[0015] Preferably, step (i) involves adding compound 4 and POCl3 into acetonitrile solvent, heating and refluxing until the reaction is complete, and then purifying to obtain compound 5.

[0016] More preferably, the specific operation of step (i) is as follows: compound 4 and POCl3 are added to acetonitrile solvent, the reaction is carried out at 82°C and stirred until complete, and the solvent is evaporated to obtain a reddish-brown solid, which is compound 5.

[0017] Step (j) involves reducing the imine group of compound 5 with a metal hydride reducing agent to obtain compound 6.

[0018] Preferably, the metal hydride reducing agent in step (j) is lithium aluminum hydride, potassium borohydride, sodium borohydride, lithium borohydride, sodium thioborohydride, or trisec-butyl borohydride.

[0019] Preferably, the specific operation of step (j) is as follows: add compound 5 to a solvent, stir, add a metal hydride reducing agent, and purify to obtain compound 6 after the reaction is complete.

[0020] The solvent used in step (j) is not particularly limited; those skilled in the art can choose it reasonably based on the relevant properties of the metal hydride reducing agent. For example, lithium aluminum hydride decomposes in water, acids, or compounds containing hydroxyl or thiol groups, releasing hydrogen to form the corresponding aluminum salt. Therefore, the reaction must be carried out under anhydrous conditions, and protic solvents containing hydroxyl or thiol groups and solvents that can be reduced (DMF, DMSO, CH2Cl2) cannot be used. Ether solvents are generally used, mainly anhydrous tetrahydrofuran or diethyl ether. Another example is potassium (sodium) boron hydride, which is relatively stable in water and alcohols at room temperature, insoluble in diethyl ether and tetrahydrofuran, but soluble in water, methanol, and ethanol with minimal decomposition. Therefore, alcohols are often chosen as solvents. If the reaction needs to be carried out at a higher temperature, isopropanol, dimethoxyethyl ether, etc., can be used as solvents.

[0021] The amounts of compound 5 and the metal hydride reducing agent can be reasonably configured by those skilled in the art based on the reaction principle, and there is no need for special limitation. From the perspective of cost saving and full reaction, the molar amount of the metal hydride reducing agent can be slightly more than that of compound 5, and the molar ratio of compound 5 to the metal hydride reducing agent is preferably 1:1-2. For example, in a specific embodiment of the present invention, the molar ratio of compound 5 to the metal hydride reducing agent is 1:1.5.

[0022] More preferably, the metal hydride reducing agent is NaBH4, and the specific operation of step (j) is as follows: compound 5 is added to a solvent containing hydroxyl groups, stirred, NaBH4 is added, and after the reaction is complete, compound 6 is obtained by purification.

[0023] More preferably, the specific operation of step (j) is as follows: compound 5 is added to a solvent containing hydroxyl groups, the temperature is controlled at 20℃~30℃, the mixture is stirred evenly, NaBH4 is added, and after the reaction is complete, water is added to quench the reaction until no exothermic phenomenon occurs. The mixture is then evaporated to dryness, filtered, and the filter cake is stirred with a mixed solution of n-hexane and ethanol with a volume ratio of 1:0.8-1.2. The mixture is then filtered, and the filter cake is dried to obtain compound 6.

[0024] Step (k) involves reacting (Boc)₂O with compound 6 at pH 7–11.6 to protect the amino group of compound 6 with Boc, thereby obtaining compound 7.

[0025] The alkali used to adjust the pH in step (k) of the reaction system is not particularly limited in this invention, and those skilled in the art can reasonably choose any alkali commonly used in Boc reactions. Preferably, the alkali used to adjust the pH in the reaction system is one or a mixture of several of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, or diisopropylethylamine.

[0026] In step (k), the amounts of compound 6, (Boc)₂O, and the base can be reasonably configured by those skilled in the art based on the reaction principle, and there is no need for special limitation. Considering cost savings and sufficient reaction time, the molar amount of (Boc)₂O can be slightly more than that of compound 6, and the molar amount of the base can be slightly more than that of (Boc)₂O. The preferred molar ratio of compound 6, (Boc)₂O, and the base is 1:1-2:1-2. For example, in a specific embodiment of the present invention, the molar ratio of compound 6, (Boc)₂O, and the base is 1:1.2:1.3.

[0027] The solvent used in step (k) of the reaction system is not particularly limited in this invention. Those skilled in the art can reasonably select aprotic solvents according to the properties of the Boc reaction. For example, it can be one or a mixture of several of the following: chloromethane, chloroform, dichloromethane, carbon tetrachloride, diethyl ether, tetrahydrofuran, dioxane, acetone, etc.

[0028] Preferably, the specific operation of step (k) is as follows: compound 6 and the base are added to the solvent, stirred evenly, the temperature is controlled at 20℃~30℃, (Boc)2O is added, after the reaction is complete, the mixture is washed with water, washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, washed with dichloromethane, and the solvent is removed to obtain compound 7.

[0029] Step (l) involves adding compound 7, along with catalysts Pd(OAc)2, Ni(dppe)2, and cesium carbonate, to an inert solvent under nitrogen protection and reacting the mixture at 60-100°C to obtain compound 8.

[0030] In step (l), the amounts of compound 7, catalysts Pd(OAc)2, Ni(dppe)2, and cesium carbonate can be reasonably configured by those skilled in the art based on the reaction principle, etc., and do not need to be particularly limited. Preferably, the molar ratio of compound 7, Pd(OAc)2, Ni(dppe)2, and cesium carbonate is 1:0.1-0.5:0.02-0.04:0.08-0.3. For example, in a specific embodiment of the present invention, the molar ratio of compound 7, Pd(OAc)2, Ni(dppe)2, and cesium carbonate is 1:0.2:0.04:0.1.

[0031] Preferably, the specific operation of step (l) is as follows: under nitrogen protection, compound 7, Pd(OAc)2, Ni(dppe)2 and cesium carbonate are added to DMA and reacted at 70-90°C to obtain compound 8.

[0032] More preferably, the specific operation of step (l) is as follows: under nitrogen protection, compound 7, Pd(OAc)2, Ni(dppe)2 5.37g and cesium carbonate are added to DMA and reacted at 70-90℃. After the reaction is complete, the mixture is cooled to 20-30℃, water is added, and then it is extracted with ethyl acetate. After removing the solvent, it is recrystallized to obtain compound 8.

[0033] Step (m) involves removing the benzyl group of compound 8 by palladium-catalyzed hydrogenation, followed by removing the Boc group with hydrochloric acid to obtain compound 9.

[0034] The inert solvent used in step (m) is not particularly limited in this invention, and those skilled in the art can make a reasonable selection based on the reaction characteristics of POCl3. Preferably, the inert solvent is one or a mixture of several of acetonitrile, dimethylformamide, DMA, DMI, dimethyl sulfoxide, and hexamethylphosphoric triamine, with DMA being the most preferred.

[0035] The amounts of compound 8 and Pd / C can be reasonably configured by those skilled in the art based on the reaction principle, and do not require special limitation. Considering cost savings and sufficient reaction, the molar ratio of compound 8 to Pd / C is preferably 1:0.2-1, more preferably 1:0.57. The amount of hydrochloric acid can be reasonably configured by those skilled in the art based on the reaction principle of Boc removal by hydrochloric acid, and does not require special limitation. Considering cost savings and sufficient reaction, the molar amount of HCl in the hydrochloric acid should be equivalent to or slightly more than the amount of Boc groups in the reaction system. Preferably, the molar amount of HCl in the hydrochloric acid is more than 1 times that of compound 8.

[0036] Preferably, the specific operation of step (m) is as follows: compound 8 and Pd / C are added to the solvent, the hydrogen pressure is adjusted to about 0.9 to 1.1 atm, the temperature is controlled at 20°C to 30°C, after the reaction is complete, Pd / C is removed by filtration, the solvent is removed, 0.5-2 mol / L hydrochloric acid is added, after the reaction is complete, compound 9 is obtained by purification.

[0037] More preferably, the specific operation of step (m) is as follows: compound 8 and Pd / C are added to the solvent, the hydrogen pressure is adjusted to about 0.9 to 1.1 atm, the temperature is controlled at 20°C to 30°C, after the reaction is complete, Pd / C is removed by filtration, the solvent is removed, 0.5-2 mol / L hydrochloric acid is added, after the reaction is complete, 5-15% sodium hydroxide solution is added, the pH is adjusted to 9 to 10, and the mixture is extracted with butyl acetate to obtain compound 9.

[0038] Compound 3-5 is prepared from compound 3-4 via step (g):

[0039]

[0040] (g) Compound 3-4, anhydrous sodium acetate and acetic acid were stirred and dissolved, and liquid bromine was slowly added dropwise until the reaction was complete. The mixture was then purified to obtain compound 3-5.

[0041] In step (g), the amounts of compound 3-4, liquid Br2, and anhydrous sodium acetate can be reasonably configured by those skilled in the art based on the reaction principle, etc., and do not need to be particularly limited. From the perspective of cost saving and full reaction, the molar amount of liquid bromine can be slightly more than that of compound 3-4, and the molar amount of anhydrous sodium acetate can be slightly more than twice that of liquid bromine. The preferred molar ratio of compound 3-4 to liquid Br2 and anhydrous sodium acetate is 1:1-2:2-6. For example, in a specific embodiment of the present invention, the molar ratio of compound 3-4 to liquid Br2 and anhydrous sodium acetate is 1:1.125:3.4.

[0042] Preferably, the specific operation of step (g) is as follows: Compound 3-4, anhydrous sodium acetate and acetic acid are stirred and dissolved, liquid bromine is slowly added dropwise, the temperature is controlled at 20℃~30℃, after the reaction is complete, water is added and stirred, filtered, and the filter residue is dried to obtain compound 3-5.

[0043] Preferably, compounds 3-4 are prepared via steps (d)-(f) according to the following process route:

[0044]

[0045] (d) Compound 3-1 undergoes esterification with ethanol in the presence of concentrated sulfuric acid to give compound 3-2;

[0046] (e) The phenolic hydroxyl group of compound 3-2 was protected with benzyl ether to obtain compound 3-3;

[0047] (f) Hydrolyze the ester bond of compound 3-3 using a water-soluble acid or base to obtain compound 3-4.

[0048] Preferably, step (e) specifically involves adding benzyl chloride, compound 3-2, potassium carbonate, and potassium iodide into acetonitrile, heating under reflux, and after the reaction is complete, purifying to obtain compound 3-3.

[0049] More preferably, step (e) specifically involves adding benzyl chloride, compound 3-2, potassium carbonate, and potassium iodide into acetonitrile, heating under reflux, and after the reaction is complete, filtering, concentrating the filtrate, dissolving it in dichloromethane, washing it with saturated sodium bicarbonate solution to remove the solvent, and obtaining compound 3-3.

[0050] In step (e), the amounts of benzyl chloride, compound 3-2, potassium carbonate, and potassium iodide can be reasonably configured by those skilled in the art based on the reaction principle, and there is no need for special limitation. Considering cost savings and sufficient reaction, the molar amount of benzyl chloride can be slightly more than that of compound 3-2, and the molar amount of potassium carbonate can be slightly more than that of benzyl chloride. The preferred molar ratio of compound 3-2, benzyl chloride, and potassium carbonate is 1:1-2:1.5-4. For example, in a specific embodiment of the present invention, the molar ratio of compound 3-2, benzyl chloride, and potassium carbonate is 1:1.2:2. Preferably, the molar amount of potassium iodide is 1-5% of the total raw materials (the sum of the molar amounts of benzyl chloride, compound 3-2, potassium carbonate, and potassium iodide).

[0051] Preferably, compounds 2-4 are prepared via steps (a)-(c) according to the following process route:

[0052]

[0053] (a) The phenolic hydroxyl group of compound 2-1 was protected with benzyl ether to obtain compound 2-2;

[0054] (b) Compound 2-2 was added to acetic acid along with nitromethane and ammonium acetate, and the mixture was heated under reflux to purify and obtain compound 2-3;

[0055] (c) The nitro group and alkene bond of compound 2-3 are reduced by a metal hydride reducing agent to obtain compound 2-4. Preferably, the metal hydride reducing agent is lithium aluminum hydride, potassium borohydride, sodium borohydride, lithium borohydride, sodium thioborohydride or trisec-butyl borohydride.

[0056] Preferably, the specific operation of step (a) is as follows: benzyl chloride, compound 2-1, potassium carbonate and potassium iodide are added to acetonitrile, heated under reflux, and after the reaction is complete, purified to obtain compound 2-2.

[0057] More preferably, the specific operation of step (a) is as follows: benzyl chloride, compound 2-1, potassium carbonate and potassium iodide are added to acetonitrile, heated to reflux, and after the reaction is complete, extracted with dichloromethane to remove the solvent, cooled, filtered, and the solvent is removed. Dichloromethane is added to dissolve the compound, and the mixture is washed with saturated sodium bicarbonate solution to remove the solvent. Then, n-hexane is added and stirred for 1-4 hours. The filter residue is dried to obtain compound 2-2.

[0058] In step (a), the amounts of benzyl chloride, compound 2-1, potassium carbonate, and potassium iodide can be reasonably configured by those skilled in the art based on the reaction principle, and there is no need for special limitation. Considering cost savings and sufficient reaction, the molar amount of benzyl chloride can be slightly more than that of compound 2-1, and the molar amount of potassium carbonate can be slightly more than that of benzyl chloride. The preferred molar ratio of compound 2-1, benzyl chloride, and potassium carbonate is 1:1-2:1.5-4. For example, in a specific embodiment of the present invention, the molar ratio of compound 2-1, benzyl chloride, and potassium carbonate is 1:1.2:2. Preferably, the molar amount of potassium iodide is 1-5% of the total raw materials (the sum of the molar amounts of benzyl chloride, compound 2-1, potassium carbonate, and potassium iodide).

[0059] In step (b), the amounts of compound 2-2, nitromethane, and ammonium acetate can be reasonably configured by those skilled in the art based on the reaction principle, and there is no need for special limitation. Considering cost savings and sufficient reaction time, the molar amount of ammonium acetate can be slightly more than that of compound 2-2, and the molar amount of nitromethane can be slightly more than that of ammonium acetate. The preferred molar ratio of compound 2-2 to nitromethane and ammonium acetate is 1:1-2:3-6. For example, in a specific embodiment of the present invention, the molar ratio of compound 2-2 to nitromethane and ammonium acetate is 1:1.3:4.

[0060] Preferably, the specific operation of step (b) is as follows: Compound 2-2, nitromethane, and ammonium acetate are added to acetic acid, the temperature is controlled at 118°C, and after the reaction is complete, the mixture is filtered, the filter cake is washed with water until neutral, and the solid is dried to obtain compound 2-3.

[0061] Preferably, the metal hydride reducing agent in step (c) is lithium aluminum hydride, potassium borohydride, sodium borohydride, lithium borohydride, sodium thioborohydride, or trisec-butyl borohydride.

[0062] Preferably, step (c) involves adding compound 2-3 to a solvent, stirring, adding a metal hydride reducing agent, and purifying the mixture after the reaction is complete to obtain compound 2-4.

[0063] The solvent used in step (c) is not particularly limited; those skilled in the art can choose it reasonably based on the relevant properties of the metal hydride reducing agent. For example, lithium aluminum hydride decomposes in water, acids, or compounds containing hydroxyl or thiol groups, releasing hydrogen to form the corresponding aluminum salt. Therefore, the reaction must be carried out under anhydrous conditions, and protic solvents containing hydroxyl or thiol groups and solvents that can be reduced (DMF, DMSO, CH2Cl2) cannot be used. Ether solvents are generally used, mainly anhydrous tetrahydrofuran or diethyl ether. Another example is potassium (sodium) boron hydride, which is relatively stable in water and alcohols at room temperature, insoluble in diethyl ether and tetrahydrofuran, and soluble in water, methanol, and ethanol with minimal decomposition. Therefore, alcohols are often chosen as solvents. If the reaction needs to be carried out at a higher temperature, isopropanol, dimethoxyethyl ether, etc., can be used as solvents.

[0064] The amounts of compounds 2-3 and the metal hydride reducing agent can be reasonably configured by those skilled in the art based on the reaction principle, and there is no need for special limitation. Considering cost savings and sufficient reaction, the molar amount of the metal hydride reducing agent can be slightly more than that of compound 2-3. The preferred molar ratio of compound 2-3 to the metal hydride reducing agent is 1:2-6. For example, in a specific embodiment of the present invention, the molar ratio of compound 2-3 to the metal hydride reducing agent is 1:4.

[0065] Preferably, step (c) involves adding compound 2-3 to a solvent, stirring, adding a metal hydride reducing agent, and purifying the mixture after the reaction is complete to obtain compound 2-4.

[0066] More preferably, the metal hydride reducing agent is lithium aluminum hydride, and the specific operation of step (c) is as follows: under nitrogen protection, lithium aluminum hydride is added to anhydrous tetrahydrofuran or diethyl ether, the temperature is controlled at 20-30°C, and an anhydrous tetrahydrofuran or diethyl ether solution containing compounds 2-3 is slowly added dropwise. After the reaction is complete, the mixture is purified to obtain compounds 2-4.

[0067] More preferably, step (c) is specifically performed as follows: under nitrogen protection, anhydrous tetrahydrofuran or diethyl ether is cooled to 0°C, lithium aluminum hydride is added, stirred, and heated to 20-30°C. Anhydrous tetrahydrofuran or diethyl ether solution containing compounds 2-3 is slowly added dropwise. After the reaction is complete, water is slowly added dropwise to the reaction solution to destroy the reducing agent. Ethyl acetate is added, and 10-20% sodium hydroxide is used to adjust the pH to 12-13. The organic layer is washed with water until neutral, and the solvent is removed to obtain compounds 2-4.

[0068] A second aspect of the present invention is to provide a novel litsea alkaloid prepared using the synthetic method described in the first aspect of the present invention.

[0069] This invention employs a convergent synthesis method for novel litsea alkaloids. Compared to the direct synthesis of apophene alkaloids using 1-benzyl-substituted tetrahydroisoquinoline, this method uses cheaper raw materials, significantly reducing costs. Furthermore, compared to linear synthetic routes, it significantly reduces reaction steps, simplifies each step, and allows for controllable yields of most reactions at around 80% or even higher, thus increasing the overall reaction yield. It also reduces the amount of intermediates and raw materials used, lowering costs. The required reaction vessel is smaller, increasing equipment flexibility; it reduces the synthesis cost of intermediates; and it minimizes losses in case of errors during production, enabling large-scale production. Attached Figure Description

[0070] Figure 1 The process flow for the synthesis of neo-Litsea alkaloids.

[0071] Figure 2 The hydrogen spectra of compounds 2-4 are shown.

[0072] Figure 3 The carbon spectra of compounds 2-4 are shown.

[0073] Figure 4 The hydrogen spectra of compounds 3-5 are shown.

[0074] Figure 5 These are the carbon spectra of compounds 3-5.

[0075] Figure 6 This is the hydrogen spectrum of compound 5.

[0076] Figure 7 This is the carbon spectrum of compound 5.

[0077] Figure 8 This is the hydrogen spectrum of neo-Litsea alkaloid.

[0078] Figure 9 This is the carbon spectrum of neolidinone. Detailed Implementation

[0079] The present invention will be further described below with reference to the accompanying drawings and specific embodiments to better understand the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0080] Synthesis of intermediates 2-4 in Example 1

[0081] The specific process flow for intermediates 2-4 is as follows:

[0082]

[0083] (a) Synthesis of compound 2-2

[0084] Compound 2-1 102.50g 152.15 1 benzyl chloride 102.33g 126.58 1.2 Potassium carbonate 186.22g 138.21 2 Potassium iodide 2.56g Acetonitrile 500ml

[0085] In a three-necked flask, compound 2-1102.50 g, benzyl chloride 102.33 g, potassium carbonate 186.22 g, potassium iodide 2.56 g, and acetonitrile 500 ml were added. The mixture was stirred at 82 °C for 2 hours. The reaction was confirmed to be complete by TLC (n-hexane:ethyl acetate = 3:1). The mixture was cooled to 20–30 °C, filtered, and the filtrate was distilled under reduced pressure at 50 °C to obtain a red oily substance. This substance was dissolved in 600 ml of dichloromethane, washed twice with 200 ml of saturated sodium bicarbonate solution, washed twice with 200 ml of saturated brine, dried over 100 g of anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure at 50 °C. After evaporation to dryness, the mixture was cooled to 20–30 °C, and a large amount of pale yellow solid precipitated. This solid was added to 600 ml of n-hexane and stirred for 2 hours. The mixture was filtered, and the filter cake was air-dried to obtain compound 2-2135.46 g, with a yield of 83%.

[0086] (b) Synthesis of compounds 2-3

[0087] Compound 2-2 135.46g 242.27 1 ammonium acetate 56.01g 77.08 1.3 Nitromethane 136.52g 61.04 4 Acetic acid 700ml

[0088] In a three-necked flask, 135.46 g of compound 2-2, 56.01 g of ammonium acetate, 136.52 g of nitromethane, and 700 ml of acetic acid were added. The mixture was stirred at 118 °C for 4 hours. The reaction was monitored by TLC (dichloromethane) until complete. The mixture was then cooled to 20–30 °C, filtered, and the filter cake was washed with water until neutral to obtain a bright yellow powder, which was 141.97 g of compound 2-3, with a yield of 89%.

[0089] (c) Synthesis of compounds 2-4

[0090] Compounds 2-3 141.97g 285.30 1 Lithium aluminum hydroxide 75.54g 37.95 4 THF 2100ml

[0091] Under nitrogen protection, 700 ml of THF was added to a three-necked flask, and the temperature was lowered to 0°C. 75.54 g of lithium aluminum hydride was added and stirred until the temperature rose to 20–30°C. A mixed solution of 1400 ml of THF and compound 2-3141.97 g was slowly added dropwise to the reaction mixture. After the addition was complete, the temperature was maintained at 25–30°C for 0.5–1 h. 300 ml of purified water was slowly added dropwise, followed by 1000 ml of dichloromethane. The pH was adjusted to 12–13 with 15% sodium hydroxide. The organic layer was washed with water until neutral, then washed twice with 300 ml of saturated brine. The mixture was dried over 200 g of anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure at 50°C to obtain 1.8 g of a reddish-brown oily substance, 2-4131.8 g. 600 ml of methanol was added to the residue and stirred to dissolve it. 46.13 g of anhydrous oxalic acid was added, and the temperature was maintained at 45°C. After complete dissolution, 1200 ml of oxalic acid was added to the residue. 1 ml of ethyl acetate was added, and a large amount of white solid precipitated. The reaction was stirred for 2 hours, cooled to 20-30°C, filtered, and the filter cake was air-dried to obtain 103.8 g of white solid 2-4 oxalate. 30% sodium hydroxide solution was added and the pH was adjusted to 12-13. 600 ml of dichloromethane was added for extraction 2-3 times. The organic layers were combined and washed with water until the pH reached 8-9. The organic layers were washed with 200 ml of saturated brine, dried with 100 g of anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure at 50°C to obtain 92.20 g of reddish-brown oil, which is compound 2-4, with a yield of 72%.

[0092] Compounds 2-4 were identified, and their proton and carbon spectra are shown below. Figure 2 and Figure 3 As shown.

[0093] 1 H-NMR (400MHz, CDCl3): δ7.2-7.4(m,-PhH,5H),6.74(d,J=8.0Hz,-ArH,1H),6.69(d,J=2.0Hz,-ArH,1H),6.66(dd,J=2.0,8.0Hz,-ArH,1H),5.06(s,-OCH 2, 2H), 3.76(s,-OCH) 3, 3H), 2.79(t,J=6.9Hz,-CH2,2H), 2.56(t,J=6.9Hz,-CH2,2H).

[0094] 13 C-NMR (100MHz, CDCl3): δ148.30,148.09,137.28,132.27,128.58,127.90,127.48,121.56,115.14,112.10,71.07,56.10,43.47,39.16.

[0095] The reaction was expanded according to the above procedure to obtain a sufficient amount of compounds 2-4 for subsequent operations.

[0096] Synthesis of intermediates 3-5 in Example 2

[0097] The specific process flow for intermediate 3-5 is as follows:

[0098]

[0099] (d) Synthesis of compound 3-2

[0100] Compound 3-1 210.37g 182.17 1 ethanol 1200ml concentrated sulfuric acid 10ml

[0101] 10.37 g of compound 3-12 and 1200 ml of ethanol were added to a three-necked flask. 10 ml of concentrated sulfuric acid was slowly added, and the reaction was stirred at 78 °C. The reaction was monitored by TLC (n-hexane:ethyl acetate = 1:2) to ensure complete reaction. The solvent was removed by vacuum distillation at 50 °C, yielding a purplish-red oily substance. This substance was dissolved in 1000 ml of ethyl acetate and adjusted to pH 8-9 with saturated sodium bicarbonate solution. The mixture was separated, and the organic layer was washed twice with 300 ml of 15% saline solution and dehydrated twice with 300 ml of saturated saline solution. The solution was dried over 200 g of anhydrous sodium sulfate, filtered, and the filtrate was distilled under vacuum at 50 °C to yield 218.50 g of a reddish-brown oily substance, which was compound 3-2, with a yield of 90%.

[0102] (e) Synthesis of compound 3-3

[0103]

[0104]

[0105] In a three-necked flask, 18.50 g of compound 3-22, 157.87 g of benzyl chloride, 287.29 g of potassium carbonate, 5.5 g of potassium iodide, and 1200 ml of acetonitrile were added. The mixture was stirred at 82 °C for 3 hours. The reaction was monitored by TLC (n-hexane:ethyl acetate = 4:1) to ensure complete reaction. The mixture was cooled to 20–30 °C, filtered, and the filtrate was distilled under reduced pressure at 50 °C. The filtrate was dissolved in 1000 ml of dichloromethane, washed 2–3 times with 300 ml of saturated sodium bicarbonate solution, washed with 300 ml of saturated brine, dried over 300 g of anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure at 50 °C to obtain a pale yellow solid, namely 55.97 g of compound 3-32, with a yield of 82%.

[0106] (f) Synthesis of compounds 3-4

[0107] Compound 3-3 255.97g 300.35 1 NaOH 68.18g 40.00 2 ethanol 1300ml

[0108] In a three-necked flask, 255.97 g of compound 3-3, 1300 ml of ethanol, and 20% NaOH solution were added. The mixture was stirred at 78°C for 3 hours. The reaction was monitored by TLC (after sampling, a large amount of water and a small amount of ethyl acetate were added, and the organic layer was spotted onto the TLC plate) (hexane:ethyl acetate = 4:1). After the reaction was complete, the mixture was evaporated to dryness, and 1500 ml of dichloromethane was added. The pH was adjusted to 2-3 with 10% HCl. At this point, a large amount of pale yellow solid appeared. The mixture was filtered, and the filter cake was washed with water until neutral. The filter cake was then air-dried to obtain 215.82 g of pale yellow powder, which was compound 3-4, with a yield of 93%.

[0109] (g) Synthesis of compounds 3-5

[0110] Compounds 3-4 215.82g 272.30 1 <![CDATA[liquid Br₂]]> 142.44g 159.81 1.125 Anhydrous sodium acetate 220.97g 82.03 3.4 Acetic acid 1300ml

[0111] In a three-necked flask, compound 3-4 was added to a volume of 15.82 g, along with 220.97 g of anhydrous sodium acetate and 1300 ml of acetic acid. The mixture was stirred until dissolved. Br2 was slowly added to a volume of 142.44 g, and the reaction was carried out at 20-30°C with stirring. The reaction was monitored by TLC (hexane:ethyl acetate = 2:1) to ensure complete reaction. 1000 ml of water was added and the mixture was stirred for 1 hour. The mixture was then filtered, and the filter cake was stirred again with 1000 ml of water for 1 hour. After filtration, the filter cake was air-dried overnight to obtain compound 3-5, which had a yield of 61%.

[0112] Compounds 3-5 were identified, and their proton and carbon spectra are as follows: Figure 4 and Figure 5 As shown.

[0113] 1 H-NMR (400MHz, CDCl3): δ7.2-7.5(m,-PhH,5H),7.05(s,-ArH,1H),6.82(s,-ArH,1H),5.09(s,-OCH 2, 2H),3.84(s,-OCH3,3H),3.70(s,-CH2,2H).

[0114] 13 C-NMR (100MHz, CDCl3): δ176.87,149.80,147.63,136.56,128.71,128.18,127.56,125.25,116.74,116.04,115.80,71.39,56.32,40.85.

[0115] The reaction was expanded according to the above procedure to obtain a sufficient amount of compounds 3-5 for subsequent operations.

[0116] Example 3 Synthesis of Neo-Litsea alkaloid

[0117] The specific process flow for neo-Litsea cubeba alkaloids is as follows:

[0118]

[0119] (h) Synthesis of Compound 4

[0120] Compounds 2-4 92.20g 257.33 1 Compounds 3-5 131.65g 351.19 1.05 DMF (N,N-dimethylformamide) 2000ml HOBt (1-hydroxybenzotriazole) 72.87g 135.13 1.5 EDC (1-Ethyl-(3-dimethylaminopropyl)carbodiimide) 82.13g 191.70 1.2

[0121] In a three-necked flask, 131.65 g of compound 3-5, 292.20 g of compound 2-4, and 2000 ml of DMF were added. The temperature was controlled at 20°C–30°C, and the mixture was stirred for 30 minutes until it became a white, viscous substance. 72.87 g of HOBt was added, and the temperature was lowered to 0°C. 82.13 g of EDC was added, and the temperature was slowly raised to 20°C–30°C with stirring for 4 hours. The reaction was monitored by TLC (dichloromethane:methanol = 20:1) to ensure complete reaction. The reaction was quenched with saturated sodium bicarbonate solution (until no exothermic reaction, no bubbles, and no white solid appeared). Stirring was continued for 1 hour. The mixture was filtered, and the filter cake was repeatedly washed with water to remove HOBt. The mixture was then filtered again and air-dried to obtain 4198.88 g of a white solid compound, with a yield of 94%.

[0122] (i) Synthesis of compound 5

[0123] Compound 4 198.88g 590.50 1 <![CDATA[POCl3]]> 59.50g 153.33 1.2 Acetonitrile 4000ml

[0124] Compound 4198.88 g, acetonitrile 4000 ml, and POCl 359.50 g were added to a three-necked flask. The mixture was stirred at 82 °C for 4 hours. The reaction was monitored by TLC (dichloromethane:methanol = 20:1) to ensure complete reaction. The solvent was evaporated to dryness, yielding 98.1 g of a reddish-brown solid, which was compound 5179.32 g, with a yield of 93%.

[0125] Compound 5 was identified, and its proton and carbon spectra are as follows: Figure 6 and Figure 7 As shown.

[0126] 1 H-NMR (400MHz, CDCl3): δ7.1-7.5(m,-PhH,10H),7.03(s,-ArH,1H),6.90(s,-ArH,1H),6.79(s,-ArH,1H),6.62(s,-ArH,1H),5.15(s,-OCH 2, ,2H),5.00(s,-OCH2,2H),4.04(s,-CH 2, 2H), 3.82(s,-OCH 3, 3H), 3.79(s,-OCH) 3, 3H)3.59(t,J=8.0Hz,-CH2,2H),2.43(t,J=8.0Hz,-CH2,2H).

[0127] 13 C-NMR (100MHz, CDCl3): δ165.65,150.04,148.98,147.99,147.70,136.71,136.68,131.47,129.43,128.76,128.54,128.13, 127.88,127.28,127.16,121.61,115.78,114.87,114.69,112.31,109.75,70.97,70.85,56.38,56.27,47.21,42.05,25.68.

[0128] The reaction was expanded according to the above procedure to obtain a sufficient amount of compound 5 for subsequent operations.

[0129] (j) Synthesis of Compound 6

[0130] Compound 5 179.32g 572.49 1 <![CDATA[NaBH4]]> 17.95g 37.83 1.5 ethanol 2000ml

[0131] 5179.32 g of the compound and 2000 ml of ethanol were added to a three-necked flask. The temperature was controlled at 20℃~30℃, and the mixture was stirred until homogeneous. 17.95 g of NaBH4 was added, and a large number of bubbles were generated. The mixture was stirred for 4 hours, and the reaction was monitored by TLC (dichloromethane:methanol = 10:1) to ensure complete reaction. The reaction was quenched with water until no exothermic phenomenon occurred. The ethanol was evaporated to dryness, and the mixture was filtered. The filter cake was stirred with 1000 ml of n-hexane and 1000 ml of ethanol for 3 hours, filtered, and the filter cake was air-dried to obtain 6163.75 g of white solid compound, with a yield of 91%.

[0132] (k) Synthesis of Compound 7

[0133] 6 163.75g 574.50 1 <![CDATA[(Boc)2O]]> 74.52g 218.25 1.2 0.93 Triethylamine 37.42g 101.19 1.3 0.73 dichloromethane 1000ml

[0134] In a three-necked flask, 1000 ml of dichloromethane, 37.42 g of triethylamine, and 6163.75 g of compound 6163 were added and stirred until homogeneous. The reaction was carried out at a controlled temperature of 20-30°C. 74.52 g of (Boc)₂O was added, and the mixture was stirred for 2-3 hours. A sample was taken (with a large amount of water and a small amount of dichloromethane added, impurities were washed away with water, and the dichloromethane layer was collected) and subjected to TLC (dichloromethane). The mixture was developed twice (dichloromethane:methanol = 10:1) to monitor for complete reaction. The reaction solution was washed 2-3 times with 500 ml of water, and the organic layer was washed with 300 ml of saturated sodium chloride solution. The mixture was dried with 200 g of anhydrous sodium sulfate for 2 hours, filtered, washed with 200 ml of dichloromethane, and the solvent was removed by vacuum distillation at 50°C to obtain a pale yellow solid compound 7171.14 g, with a yield of 89%.

[0135] (l) Synthesis of compound 8

[0136] 7 171.14g 674.62 1 DMA (N,N-dimethylacetamide) 1500ml <![CDATA[Pd(OAc)2]]> 11.48g 224.49 0.2 <![CDATA[Ni(DPPE)Cl2]]> 5.36g 528.04 0.04 cesium carbonate 8.27g 325.82 0.1

[0137] Under nitrogen protection, compound 7171.14 g, DMA 1500 ml, Pd(OAc)2 11.48 g, Ni(dppe)2 5.37 g, and cesium carbonate 7.97 g were added to a three-necked flask. The temperature was controlled at 80 °C, and the mixture was stirred for 10 hours. After cooling to 20 °C–30 °C, 1000 ml of purified water was added, and the mixture was extracted with 500 ml of ethyl acetate three times. The organic phases were combined, washed with 180 ml of saturated sodium chloride solution, dried over 200 g of anhydrous sodium sulfate for 2 hours, filtered, washed with 500 ml of ethyl acetate, and the solvent was removed by vacuum distillation at 50 °C. The mixture was recrystallized from ethyl acetate / isopropanol (volume ratio 1:2) to give compound 8115.72 g as a white solid, with a yield of 79.4%.

[0138] (m) Synthesis of Compound 9 (Neostemanine)

[0139]

[0140]

[0141] In a three-necked flask, 5.72 g of compound 811, 600 ml of isopropanol and 11.57 g of Pd / C were added. The mixture was purged with nitrogen three times and hydrogen three times, adjusting the hydrogen pressure to approximately 0.9–1.1 atm. The temperature was controlled at 20–30°C, and the mixture was stirred for 2.0–3.0 hours. The Pd / C was filtered off, and the filter cake was washed with 120 ml of isopropanol. The solvent was removed by vacuum distillation at 40°C. The residue was added to 360 ml of 1 mol / L hydrochloric acid, and the mixture was stirred at 20–30°C for 1 hour. 10% sodium hydroxide was added dropwise to adjust the pH to 9–10. The mixture was extracted with 360 ml of butyl acetate (3 times). The extract was washed with 120 ml of saturated sodium chloride solution, dried with 200 g of anhydrous sodium sulfate for 2 hours, filtered, washed with 50 ml of butyl acetate, and the solvent was removed by vacuum distillation at 50°C. The mixture was recrystallized from methanol-ethyl acetate (1:3 v / v) to give 952.2 g of compound, with a yield of 82.7%.

[0142] HPLC and NMR analysis showed a purity greater than 95%, indicating a crystalline powder with a positive result for potassium bismuth iodide. The 1H and 1C NMR spectra are as follows:

[0143] 1H-NMR(600MHz,CD3OD)δ:7.96(1H,s,H-11),6.73(1H,s,H-8),6.53(1H,s,H-3),3.86(3H,s,10-OCH3),3.56(3H,s,1-OCH3 ),3.00(2H,m,H-7a,4b),2.90(1H,m,H-5a),2.64(1H,m,H-6a),2.51(3H,s,N-CH3),2.47(1H,m,H-5b),2.43(1H,m,H-7b).

[0144] 13 C-NMR(150MHz,CD3OD)δ:151.2(C-2),148.3(C-10),147.7(C-9),144.9(C-1),131.2(C-7a),130.5(C-3a),128.0(C-1a),127.1(C-1b),125.3( C-11a),116.4(C-8),115.5(C-3),113.3(C-11),64.5(C-6a),54.8(C-5 ),60.8(1-OCH3),57.1(10-OCH3),44.4(N-CH3),35.4(C-7),29.8(C-4).

[0145] The above data is consistent with the literature reports, therefore it was identified as neo-Litsea alkaloid.

[0146] The specific embodiments of the present invention have been described in detail above, but they are only examples, and the present invention is not limited to the specific embodiments described above. For those skilled in the art, any equivalent modifications and substitutions to this utility model are also within the scope of the present invention. Therefore, all equivalent changes and modifications made without departing from the spirit and scope of the present invention should be covered within the scope of the present invention.

Claims

1. A method for synthesizing a new litsea alkaloid, characterized in that, The neo-Lithocarpine alkaloid is prepared from compounds 2-4 and 3-5 via steps (h)-(m) according to the following process route: (h) Compound 4 is prepared by amidation of compounds 2-4 and 3-5 with an amide condensation agent, wherein the amide condensation agent is an active ester condensation agent, a carbodiimide condensation agent, an onium salt condensation agent or an organophosphorus condensation agent. When the amide condensation agent is a carbodiimide condensation agent, it is used in combination with 1-hydroxybenzotriazole. (i) Compound 4 and POCl3 were added to an inert solvent and reacted at 60-100 °C to obtain compound 5; (j) The imine group of compound 5 was reduced by a metal hydride reducing agent to obtain compound 6; (k) Compound 6 was reacted with (Boc)2O at pH 7 to 11.6 to protect the amino group of compound 6 with Boc, thus obtaining compound 7; (l) Under nitrogen protection, compound 7, along with catalysts Pd(OAc)2, Ni(dppe)2 and cesium carbonate, were added to an inert solvent and reacted at 60-100 °C to obtain compound 8; (m) The benzyl group of compound 8 was removed by palladium on carbon catalytic hydrogenation, and the Boc group was removed by hydrochloric acid to obtain compound 9.

2. The synthesis method according to claim 1, characterized in that, The amide condensing agent mentioned in step (h) is a carbodiimide condensing agent, used in combination with 1-hydroxybenzotriazole; The inert solvent mentioned in step (i) is one or a mixture of several of acetonitrile, dimethylformamide, DMA, DMI, dimethyl sulfoxide, and hexamethylphosphoric triamine; The metal hydride reducing agent mentioned in step (j) is lithium aluminum hydride, potassium borohydride, sodium borohydride, lithium borohydride, sodium thioborohydride, or trisec-butyl borohydride. The base used to adjust the pH in step (k) of the reaction system is one or a mixture of several of the following: potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, or diisopropylethylamine; The inert solvent mentioned in step (l) is one or a mixture of several of acetonitrile, dimethylformamide, DMA, DMI, dimethyl sulfoxide, and hexamethylphosphoric triamine.

3. The synthesis method according to claim 2, characterized in that, The amide condensing agent in step (h) is selected from one or a mixture of several of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC); the inert solvent in step (i) is acetonitrile; and the inert solvent in step (l) is DMA.

4. The synthesis method according to claim 1 or 2, characterized in that, The specific operation of step (h) is as follows: add compounds 3-5 and 2-4 to the solvent, control the temperature at 20-30℃, stir thoroughly until the system is white and viscous, add HOBt, cool down to below 4℃, add EDC, and then slowly heat up to 20-30℃. After the reaction is complete, purify to obtain compound 4. The specific operation of step (i) is as follows: compound 4 and POCl3 are added to acetonitrile solvent, heated under reflux until the reaction is complete, and then purified to obtain compound 5; The specific operation of step (j) is as follows: add compound 5 to the solvent, stir, add metal hydride reducing agent, and purify to obtain compound 6 after the reaction is complete; The specific operation of step (k) is as follows: add compound 6 and base to solvent, stir evenly, control the temperature at 20℃~30℃, add (Boc)2O, after the reaction is complete, wash with water, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter, wash with dichloromethane, remove solvent, and obtain compound 7. The specific operation of step (l) is as follows: under nitrogen protection, compound 7, Pd(OAc)2, Ni(dppe)2 and cesium carbonate are added to DMA and reacted at 70-90℃ to obtain compound 8; The specific operation of step (m) is as follows: add compound 8 and Pd / C to the solvent, adjust the hydrogen pressure to 0.9~1.1 atm, control the temperature to 20℃~30℃, after the reaction is complete, filter to remove Pd / C, then remove the solvent, add 0.5-2 mol / L hydrochloric acid, after the reaction is complete, purify to obtain compound 9.

5. The synthesis method according to claim 4, characterized in that, The specific operation of step (h) is as follows: Compounds 3-5 and 2-4 are added to the solvent, the temperature is controlled at 20-30℃, and the mixture is stirred thoroughly until the system becomes a white viscous substance. HOBt is added, the temperature is lowered to below 4℃, EDC is added, and then the temperature is slowly raised to 20-30℃. After the reaction is complete, saturated sodium bicarbonate solution is added to quench the reaction until no heat is released, no bubbles appear, and no white solid appears. Stirring is continued for 0.5-2 hours. The mixture is filtered, and the filter cake is dried to obtain compound 4. The molar ratio of compounds 2-4, 3-5, HOBt, and EDC is 1:1-1.05:1.1-2:1.05-1.

5. The specific operation of step (i) is as follows: Compound 4 and POCl3 are added to acetonitrile solvent, the reaction is carried out at 82℃ and stirred until complete, the solvent is evaporated to obtain a reddish-brown solid, which is compound 5; the molar ratio of compound 4 and POCl3 is 1:1-1.

5. The metal hydride reducing agent in step (j) is NaBH4. The specific operation of step (j) is as follows: compound 5 is added to a solvent containing hydroxyl groups, stirred, NaBH4 is added, and after the reaction is complete, compound 6 is obtained by purification; the molar ratio of compound 5 to metal hydride reducing agent is 1:1-2. In step (k), the molar ratio of compound 6, (Boc)₂O, and the base is 1:1-2:1-2. The specific operation of step (l) is as follows: Under nitrogen protection, compound 7, Pd(OAc)2, Ni(dppe)2 5.37g and cesium carbonate are added to DMA, and the reaction is carried out at 70-90℃. After the reaction is complete, it is cooled to 20-30℃, water is added, and then extracted with ethyl acetate. After removing the solvent, it is recrystallized to obtain compound 8. The molar ratio of compound 7, Pd(OAc)2, Ni(dppe)2 and cesium carbonate is 1:0.1-0.5:0.02-0.04:0.08-0.

3. The specific operation of step (m) is as follows: Compound 8 and Pd / C are added to the solvent, the hydrogen pressure is adjusted to 0.9~1.1 atm, the temperature is controlled at 20℃~30℃, after the reaction is complete, Pd / C is removed by filtration, the solvent is removed, 0.5-2 mol / L hydrochloric acid is added, after the reaction is complete, 5-15% sodium hydroxide solution is added, the pH is adjusted to 9~10, and butyl acetate is used for extraction to obtain compound 9; the molar ratio of compound 8 to Pd / C is 1:0.2-1, and the molar amount of HCl in the hydrochloric acid is more than 1 times that of compound 8.

6. The synthesis method according to claim 5, characterized in that, In step (h), the molar ratio of compounds 2-4, 3-5, HOBt, and EDC is 1:1.05:1.5:1.

2. In step (i), the molar ratio of compound 4 to POCl3 is 1:1.2; The specific operation of step (j) is as follows: Compound 5 is added to a solvent containing hydroxyl groups, the temperature is controlled at 20℃~30℃, the mixture is stirred evenly, NaBH4 is added, and after the reaction is complete, water is added to quench the reaction until no exothermic phenomenon occurs. The mixture is then evaporated to dryness, filtered, and the filter cake is stirred with a mixed solution of n-hexane and ethanol with a volume ratio of 1:0.8-1.

2. The mixture is then filtered, the filter cake is dried, and compound 6 is obtained. The molar ratio of compound 5 to the metal hydride reducing agent is 1:1.

5. In step (k), the molar ratio of compound 6, (Boc)₂O, and the base is 1:1.2:1.3; In step (l), the molar ratio of compound 7, Pd(OAc)2, Ni(dppe)2 and cesium carbonate is 1:0.2:0.04:0.1; In step (m), the molar ratio of compound 8 to Pd / C is 1:0.

57.

7. The synthesis method according to claim 1, characterized in that, Compounds 3-5 were prepared from compounds 3-4 via step (g): (g) Compound 3-4, anhydrous sodium acetate and acetic acid were stirred and dissolved, and liquid bromine was slowly added dropwise. The reaction was completed and purified to obtain compound 3-5.

8. The synthesis method according to claim 7, characterized in that, The specific operation of step (g) is as follows: Compound 3-4, anhydrous sodium acetate and acetic acid are stirred and dissolved, liquid bromine is slowly added dropwise, the temperature is controlled at 20℃~30℃, after the reaction is complete, water is added and stirred, filtered, and the filter residue is dried to obtain compound 3-5.

9. The synthesis method according to claim 7, characterized in that, The molar ratio of compounds 3-4 to liquid Br2 and anhydrous sodium acetate is 1:1-2:2-6.

10. The synthesis method according to claim 9, characterized in that, The molar ratio of compounds 3-4 to liquid Br2 and anhydrous sodium acetate is 1:1.125:3.

4.

11. The synthesis method according to claim 7, characterized in that, Compounds 3-4 were prepared via steps (d)-(f) according to the following process route: (d) Compound 3-1 undergoes esterification with ethanol in the presence of concentrated sulfuric acid to give compound 3-2; (e) The phenolic hydroxyl group of compound 3-2 was protected with benzyl ether to obtain compound 3-3; (f) Hydrolyze the ester bond of compound 3-3 using a water-soluble acid or base to obtain compound 3-4.

12. The synthesis method according to claim 11, characterized in that, Step (e) involves adding benzyl chloride, compound 3-2, potassium carbonate, and potassium iodide to acetonitrile, heating under reflux, and purifying after complete reaction to obtain compound 3-3.

13. The synthesis method according to claim 12, characterized in that, Step (e) is specifically performed as follows: benzyl chloride, compound 3-2, potassium carbonate, and potassium iodide are added to acetonitrile, heated under reflux, and after the reaction is complete, filtered, the filtrate is concentrated, dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, and the solvent is removed to obtain compound 3-3; the molar ratio of compound 3-2, benzyl chloride, and potassium carbonate is 1:1-2:1.5-4; the molar amount of potassium iodide is 1-5% of the total molar amounts of benzyl chloride, compound 3-2, potassium carbonate, and potassium iodide.

14. The synthesis method according to claim 13, characterized in that, The molar ratio of compound 3-2, benzyl chloride, and potassium carbonate is 1:1.2:

2.

15. The synthesis method according to claim 1, characterized in that, Compounds 2-4 were prepared via steps (a)-(c) according to the following process route: (a) The phenolic hydroxyl group of compound 2-1 was protected with benzyl ether to obtain compound 2-2; (b) Compound 2-2, along with nitromethane and ammonium acetate, was added to acetic acid, heated to reflux, and purified to obtain compound 2-3; (c) The nitro group and alkene bond of compound 2-3 were reduced by a metal hydride reducing agent to obtain compound 2-4.

16. The synthesis method according to claim 15, characterized in that, The metal hydride reducing agent in step (c) is lithium aluminum hydride, potassium borohydride, sodium borohydride, lithium borohydride, sodium thioborohydride, or trisec-butyl borohydride.

17. The synthesis method according to claim 15, characterized in that, The specific operation of step (a) is as follows: benzyl chloride, compound 2-1, potassium carbonate and potassium iodide are added to acetonitrile, heated to reflux, and after the reaction is complete, purified to obtain compound 2-2; The specific operation of step (b) is as follows: Compound 2-2, nitromethane, and ammonium acetate are added to acetic acid, the temperature is controlled at 118℃, after the reaction is complete, the mixture is filtered, the filter cake is washed with water until neutral, and the solid is dried to obtain compound 2-3; The specific operation of step (c) is as follows: Compound 2-3 is added to a solvent, stirred, a metal hydride reducing agent is added, and after the reaction is complete, the mixture is purified to obtain compound 2-4.

18. The synthesis method according to claim 17, characterized in that, The specific operation of step (a) is as follows: benzyl chloride, compound 2-1, potassium carbonate, and potassium iodide are added to acetonitrile, heated to reflux, and after the reaction is complete, extracted with dichloromethane to remove the solvent. After cooling, the mixture is filtered to remove the solvent, dissolved in dichloromethane, washed with saturated sodium bicarbonate solution to remove the solvent, and then hexane is added and stirred for 1-4 hours. The filter residue is dried to obtain compound 2-2. The molar ratio of compound 2-1, benzyl chloride, and potassium carbonate is 1:1-2:1.5-4, and the molar amount of potassium iodide is 1-5% of the total molar amounts of benzyl chloride, compound 2-1, potassium carbonate, and potassium iodide. In step (b), the molar ratio of compound 2-2 to nitromethane and ammonium acetate is 1:1-2:3-6; The metal hydride reducing agent in step (c) is lithium aluminum hydride. The specific operation of step (c) is as follows: under nitrogen protection, lithium aluminum hydride is added to anhydrous tetrahydrofuran or diethyl ether, the temperature is controlled at 20-30℃, and an anhydrous tetrahydrofuran or diethyl ether solution containing compounds 2-3 is slowly added dropwise. After the reaction is complete, the mixture is purified to obtain compounds 2-4. The molar ratio of compounds 2-3 to the metal hydride reducing agent is 1:2-6.

19. The synthesis method according to claim 18, characterized in that, In step (a), the molar ratio of compound 2-1, benzyl chloride, and potassium carbonate is 1:1.2:2; In step (b), the molar ratio of compound 2-2 to nitromethane and ammonium acetate is 1:1.3:

4. The specific operation of step (c) is as follows: Under nitrogen protection, anhydrous tetrahydrofuran or diethyl ether is cooled to 0°C, lithium aluminum hydride is added, stirred, and heated to 20-30°C. Anhydrous tetrahydrofuran or diethyl ether solution containing compounds 2-3 is slowly added dropwise. After the reaction is complete, water is slowly added dropwise to the reaction solution to destroy the reducing agent. Ethyl acetate is added, and 10-20% sodium hydroxide is used to adjust the pH to 12-13. The organic layer is washed with water until neutral, and the solvent is removed to obtain compounds 2-4. The molar ratio of compounds 2-3 to the metal hydride reducing agent is 1:4.

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