Method for preparing 3-hydroxyl pyrrole indole alkaloid Alline natural product

Abstract

The invention discloses a synthetic method for preparing a 3-hydroxyl pyrrole indole alkaloid Alline natural product, the preparation method takes an o-brominated aniline compound with a chiral sulfinyl prothetic group as a raw material, and the key step in the synthetic route is that arylation series air oxidation is carried out on a site of amide catalyzed by metal palladium; a key oxoindole intermediate containing a hydroxyl quaternary carbon chiral center is prepared, and the 3-hydroxyl pyrrole indole alkaloid Alline natural product is further prepared through subsequent chemical conversion. The preparation method provided by the invention is mild in reaction condition and low in energy consumption, tris (dibenzylideneacetone) dipalladium is used as a catalyst, air is used as a series oxidant, the method is used as a key step, an efficient and universal strategy is developed to synthesize a natural product of 3-hydroxypyrrolindole alkaloid Alline, and the method is suitable for industrial production. The method is beneficial to environmental protection and is beneficial to large-scale preparation of the 3-hydroxyl pyrrole indole alkaloid Alline natural product and analogues thereof.

Description

Technical Field

[0001] The patent of this invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing 3-hydroxypyrroloindole alkaloid Alline natural product. Background Art

[0002] A chiral quaternary carbon center refers to a carbon atom with four different carbon substituents attached to it. Quaternary carbon chiral centers are widely present in drug molecules and natural products. However, due to steric crowding and conformational flexibility, the construction of quaternary carbon chiral centers has always been a huge challenge in organic synthesis. The construction of chiral quaternary carbons is a hot topic in international cutting-edge research. Public data show that among the top 200 small molecule drugs in terms of sales in 2022, about 10% of small molecule drugs contain quaternary carbon chiral centers. 3-Hydroxypyrroloindole alkaloids are a class of natural products with a special structural unit of hexahydropyrrolo[2,3-b]indole (HPI). The 3-Hydroxypyrroloindole alkaloid Alline natural product has a typical quaternary carbon chiral center in its chemical structure. This type of alkaloid includes HPI monomers, dimers and various oligomers. The family is large and has rich and important biological activities, including antioxidant, anticancer and neuroprotective properties. In addition, a series of significant biologically active intermediate compounds can be produced from these basic units of molecular structure. Therefore, in addition to being used as valuable synthetic intermediates, they have also become an important source for many drug discoveries. From a synthetic point of view, the special quaternary carbon at the C3a site of 3-hydroxypyrrolidinole alkaloids and the construction of 3-hydroxypyrrole ring are the difficulties in the synthesis of this type of natural products. The development of efficient methods for constructing quaternary carbon chiral centers will obviously help to synthesize these drugs and their analogs. In recent years, due to the interesting chemical structure, important biological activity and high drug-making rate of 3-hydroxypyrrolidinole alkaloids, they have an important position in the fields of biomedicine and pharmacy, and continue to receive extensive attention from synthetic chemists and pharmacists. The development of new reactions for the efficient synthesis of 3-hydroxypyrrolidinole compounds is particularly important and has always been a hot topic in the field of organic synthetic chemistry, which is of great significance for drug research and development. Therefore, we used o-bromoaniline compounds with chiral sulfinyl auxiliary groups as raw materials. The key step in the synthetic route was palladium-catalyzed arylation of the amide a-position followed by air oxidation to obtain a key oxidized indole intermediate containing a hydroxyl quaternary carbon chiral center. Through subsequent chemical transformation, we further obtained the 3-hydroxypyrroloindole alkaloid Alline natural product, providing sufficient samples for clinical trial research, which has important theoretical and practical significance. Summary of the invention

[0003] The object of the present invention is to provide a method for preparing a natural product of 3-hydroxypyrroloindole alkaloid Alline. The disclosed preparation method uses only metal tris(dibenzylideneacetone)dipalladium as a catalyst and air as a green tandem oxidant, which causes less pollution to the environment, is environmentally friendly, has fewer reaction steps, and has a high yield.

[0004] To achieve the above object, the present invention provides the following technical solutions: A method for preparing a 3-hydroxypyrroloindole alkaloid Alline natural product, characterized in that it comprises the following steps: S1. Tris(dibenzylideneacetone)dipalladium, triphenylphosphine and a chiral sulfenamide compound are mixed, and degassed three times under the protection of high-purity nitrogen, anhydrous toluene is added, and lithium bis(trimethylsilylamide) is added under stirring at room temperature, and then degassed three times, and heated to react for 5 hours under the protection of high-purity inert gas, and then placed in an air atmosphere in an ice-water bath to continue the reaction for 5 hours, and after purification, an oxidized indole compound containing a hydroxyl quaternary carbon chiral center is obtained; wherein, the molecular structure 2 of the oxidized indole compound containing a hydroxyl quaternary carbon chiral center is: ; S2, dissolving the oxidized indole compound containing a hydroxyl quaternary carbon chiral center in an anhydrous solvent, then adding a dilute hydrochloric acid solution under the reaction conditions of an ice-water bath for 5 hours to remove the tert-butylsulfinyl group, and obtaining the oxidized indole compound containing a hydroxyl quaternary carbon chiral center after purification; wherein the molecular structure 3 of the oxidized indole compound containing a hydroxyl quaternary carbon chiral center is: ; S3, dissolving the oxidized indole compound containing a hydroxyl quaternary carbon chiral center in an anhydrous solvent, degassing 3 times under the protection of high-purity nitrogen, then adding a reducing agent to react for 1 hour under the reaction conditions of an ice-water bath, then heating to room temperature to react for 2 hours, and then placing the reaction under the heating conditions of an oil bath, continuing the reaction for 10 to 15 hours, and obtaining a 3-hydroxypyrrolidinole compound after purification; wherein, the molecular structure 4 of the 3-hydroxypyrrolidinole compound is: ; S4, first prepare a reducing agent, then add anhydrous tetrahydrofuran to the 3-hydroxypyrrolidinole compound, degas 3 times under high-purity nitrogen protection, cool to -40°C, slowly add the reducing agent until the green color remains, then react at a low temperature of -40°C for 2 hours, then place the reaction at room temperature, continue to react for 12 hours, and obtain a 3-hydroxypyrrolidinole alkaloid Alline natural product after purification; wherein, the molecular structure 5 of the 3-hydroxypyrrolidinole alkaloid Alline natural product is: ; Preferably, according to the present invention, the solvent in S1 is anhydrous toluene, the heating temperature is 80° C., the heating reaction time is 5 hours, the high-purity inert gas is high-purity nitrogen, and air is used as a series oxidant.

[0005] Preferably according to the present invention, the anhydrous solvent in S2 is anhydrous methanol solvent, and the concentration of the hydrochloric acid solution is 1-3 mol / L.

[0006] Preferably according to the present invention, the anhydrous solvent in S3 is anhydrous tetrahydrofuran solvent, and the reducing agent is lithium aluminum hydride solution.

[0007] Preferably, according to the present invention, the reducing agent in S4 is a sodium naphthalene solution, and its preparation method specifically comprises: weighing naphthalene, metallic sodium, and anhydrous tetrahydrofuran into a container, then degassing 3 times under the protection of high-purity nitrogen, and then placing the container in an ultrasonic instrument for ultrasonic stirring and reaction for 15 minutes, and then stirring and reacting at room temperature for 1 hour, until the solution turns dark green and is stored for later use.

[0008] Preferably, according to the present invention, the purification method included in S1 to S4 is: concentrating the crude product initially obtained in each step, followed by chromatography separation and purification, and finally obtaining a compound with high purity.

[0009] The beneficial technical effects of the present invention are as follows: 1. The preparation method provided by the present invention has mild reaction conditions, uses metal tris(dibenzylideneacetone)dipalladium as a catalyst, uses air as a green oxidant, has low energy consumption, is beneficial to environmental protection, and is conducive to the large-scale preparation of 3-hydroxypyrroloindole alkaloid Alline natural products and their analogs; 2. The preparation method provided by the present invention has good atom economy and high product yield; 3. The preparation method provided by the present invention has a short synthetic route and a relatively simple reaction operation process. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] In order to more clearly illustrate the technical solution of the embodiment of the present invention, the drawings required for describing the embodiment are briefly introduced below. Those skilled in the art can also obtain other drawings based on these drawings without paying any creative work.

[0011] Figure 1 It is a schematic diagram of the preparation process of the present invention; DETAILED DESCRIPTION

[0012] The following will be combined with the accompanying drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0013] In order to synthesize 3-hydroxypyrroloindole alkaloid Alline natural product and its analogs in large quantities, and provide sufficient samples for clinical trial research.

[0014] The inventors provide a method for preparing 3-hydroxypyrroloindole alkaloid Alline natural product and its analogs, comprising the following steps: 1. A method for preparing a 3-hydroxypyrroloindole alkaloid Alline natural product, characterized in that it comprises the following steps: S1. Tris(dibenzylideneacetone)dipalladium, triphenylphosphine and a chiral sulfenamide compound are mixed, and degassed three times under the protection of high-purity nitrogen, anhydrous toluene is added, and lithium bis(trimethylsilylamide) is added under stirring at room temperature, and then degassed three times, and heated to react for 5 hours under the protection of high-purity inert gas, and then placed in an ice-water bath under an atmosphere of air to continue the reaction for 5 hours, and after purification, an oxidized indole compound containing a hydroxyl quaternary carbon chiral center is obtained; Furthermore, the solvent in S1 is anhydrous toluene, the heating temperature is 80° C., the heating reaction time is 5 hours, the high-purity inert gas is high-purity nitrogen, and air is used as a series oxidant.

[0015] S2, dissolving the oxidized indole compound containing a hydroxyl quaternary carbon chiral center in an anhydrous solvent, then adding a dilute hydrochloric acid solution in an ice-water bath for 5 hours to remove the tert-butylsulfinyl group, and obtaining the oxidized indole compound containing a hydroxyl quaternary carbon chiral center after purification; Furthermore, the anhydrous solvent in S2 is anhydrous methanol solvent, and the concentration of the hydrochloric acid solution is 1~3 mol / L.

[0016] S3, dissolving the oxidized indole compound containing a hydroxyl quaternary carbon chiral center in an anhydrous solvent, degassing 3 times under the protection of high-purity nitrogen, then adding a reducing agent to react for 1 hour under the reaction conditions of an ice-water bath, then heating to room temperature to react for 2 hours, and then placing the reaction under the heating conditions of an oil bath, continuing the reaction for 10 to 15 hours, and obtaining a 3-hydroxypyrroloindole compound after purification; Furthermore, the anhydrous solvent in S3 is anhydrous tetrahydrofuran solvent, and the reducing agent is lithium aluminum hydride solution.

[0017] Furthermore, the reducing agent in S4 is a sodium naphthalene solution, and its preparation method specifically includes: weighing naphthalene, metallic sodium, and anhydrous tetrahydrofuran into a container, then degassing 3 times under the protection of high-purity nitrogen, and then placing the container in an ultrasonic instrument for ultrasonic stirring and reaction for 15 minutes, and then stirring and reacting at room temperature for 1 hour until the solution turns dark green and is stored for later use.

[0018] S4, first prepare a reducing agent, then add anhydrous tetrahydrofuran to the 3-hydroxypyrrolidinole compound, degas 3 times under high-purity nitrogen protection, cool to -40°C, slowly add the reducing agent until the green color remains, then react at a low temperature of -40°C for 2 hours, then place the reaction at room temperature, continue to react for 12 hours, and obtain the 3-hydroxypyrrolidinole alkaloid Alline natural product after purification; Furthermore, the purification method included in S1 to S4 is: concentrating the crude product initially obtained in each step, followed by chromatography separation and purification, and finally obtaining a compound with high purity.

[0019] The preparation method provided by the invention has mild reaction conditions, low cost, low energy consumption, is beneficial to environmental protection and is conducive to the mass preparation of 3-hydroxypyrroloindole alkaloid Alline natural products and analogs thereof.

[0020] In the process of studying and preparing 3-hydroxypyrroloindole alkaloid Alline natural product and its analogs, the inventors also made the following specific examples: Example

[0021] A method for preparing a 3-hydroxypyrroloindole alkaloid Alline natural product (preparation process as shown in Figure 1 shown): (1) Synthesis of compound 2, the reaction formula is as follows: ; Tris(dibenzylideneacetone)dipalladium [Pd2(dba)3, 57 mg, 0.0625mmol], triphenylphosphine (39 mg, 0.15 mmol) and compound 1 (1.16 g, 2.5 mmol) were weighed into a 50 mL double-necked round-bottom flask, degassed 3 times under high-purity nitrogen protection, then 35 mL of anhydrous toluene was added, and lithium bis(trimethylsilylamide) (1.0 M in THF, 5.0mL, 5.0 mmol, 2.0 equiv) was added under stirring at room temperature, and then degassed 3 times, and then heated in an oil bath at 80°C for 5 hours. High-purity nitrogen protection was required throughout the reaction process. Then stop heating, return to room temperature, cool to 0 °C, and then open the reaction to the air atmosphere and continue the reaction for 5 hours. Post-treatment: add saturated ammonium chloride solution (10 mL) and stir for 30 minutes, then add water (10 mL) to dilute, extract with ethyl acetate (3 ´ 20 mL), dry over anhydrous sodium sulfate, concentrate the filtrate under reduced pressure, and chromatograph on a silica gel column (petroleum ether 60-90 ºC: ethyl acetate = 2:1) to obtain a light yellow liquid compound 2 (850 mg, 85%).

[0022] The characterization data of compound 2 are as follows: 1 H-NMR (300 MHz, CDCl3), δ (ppm): 7.38 – 7.02 (m, 7H), 6.91 (t, J =7.5 Hz, 1H), 6.92 (d, J = 7.5 Hz, 1H), 6.58 (d, J = 7.8 Hz, 1H), 4.80 (d, J =15.9 Hz, 1H), 4.66 (dd, J = 15.6, 3.0 Hz, 1H), 4.54 (d, 14.7 Hz, 1H), 3.02 –2.88 (m, 2H), 2.45 (s, 1.5H), 2.44 (s, 1.5H), 2.18 – 2.10 (m, 2H), 0.97 (s,4.5H), 0.94 (s, 4.5H). 13 C-NMR (75 MHz, CDCl3), δ (ppm): 177.85, 142.22,135.50, 130.05, 129.63, 128.85, 128.40, 127.72, 127.27, 123.99, 123.24,109.63, 75.07, 58.16, 48.46, 43.79, 36.72, 33.39, 33.04, 23.37. HRMS (ESI-TOF) m / z [M+H] + Calculate for C 22 H 29 N2O3S: 401.1894, found 401.1894. (2) Synthesis of compound 3, the reaction formula is as follows: ; In a 50 mL double-necked round-bottom flask, add the oxidized indole compound 2 (800 mg, 2.0 mmol), then add 30 mL of anhydrous methanol solvent to dissolve, add dilute hydrochloric acid (2 mmol / mL, 2.0 mL, 4.0 mmol, 2.0 equiv) under ice-water bath conditions, and then continue to react for 5 hours under ice-water bath conditions. Post-treatment: add saturated sodium bicarbonate solution until the pH of the solution is >7, then evaporate most of the organic solvent, extract with ethyl acetate (3 ´ 50 mL), dry with anhydrous sodium sulfate, concentrate the filtrate under reduced pressure, and chromatograph on a silica gel column (dichloromethane: methanol: ammonia water = 200:10:1) to obtain a light yellow liquid compound 3 (527 mg, 89%).

[0023] The characterization data of compound 3 are as follows: 1 H-NMR (300 MHz, CDCl3), δ (ppm): 7.38 (d, J = 6.9 Hz, 1H), 7.3-7.20(m, 5H), 7.15 (t, J = 7.8 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.67(d, J = 7.5Hz, 1H), 4.96 (d, J = 15.6 Hz, 1H), 4.81 (brs , 2H), 4.76 (d, J = 15.6 Hz,1H), 3.51-3.42 (m, 1H), 2.94 – 2.87 (m, 1H), 2.51 (s, 3H), 2.15 – 2.06 (m,1H), 1.90 – 1.82 (m, 1H), 1.18 (s, 1H). 13 C-NMR (75 MHz, CDCl3), δ (ppm):178.69, 141.87, 135.88, 132.09, 129.10, 128.80, 128.41, 127.59, 127.25,123.72, 122.92, 109.24, 75.71, 46.71, 43.60, 35.91, 35.07, 21.54. HRMS (ESI-TOF) m / z [M+H] + Calculate for C 18 H 21N2O2: 297.1598, found 297.1596. (3) Synthesis of compound 4, the reaction formula is as follows: ; Compound 3 (296 mg, 1.0 mmol) was weighed into a double-necked round-bottom flask and dissolved in 5 mL of anhydrous tetrahydrofuran. The mixture was degassed three times under high-purity nitrogen protection, and then LiAlH4 solution (2.5 M in Toluene, 1.2 mL, 3.0 equiv) was added at 0°C. The reaction was continued for 1 h, and then the temperature was raised to room temperature for 2 h, and then the reaction was heated in an oil bath at 80 °C for 12 h. Post-treatment: The reaction was cooled to 0°C, saturated sodium potassium tartrate solution (10 mL) was slowly added, and then the mixture was returned to room temperature and stirred vigorously for 2 h, 5 mL of water was added for dilution, and then extracted with ethyl acetate (3 ´ 30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and evaporated to dryness under reduced pressure, and then chromatographed on a silica gel column (petroleum ether 60-90 ºC: ethyl acetate = 1: 4) to obtain compound 4 (199 mg, 71%) as a white foamy solid.

[0024] The characterization data of compound 4 are as follows: 1 H-NMR (300 MHz, CDCl3), δ (ppm): 7.34 – 7.22 (m, 6H), 7.12 –7.07 (m,1H), 6.75 (t, J = 7.2 Hz, 1H), 6.36 (d, J = 7.8Hz, 1H), 4.51(d, J = 16.5 Hz,1H), 4.41 (s, 1H), 4.38 (d, J = 16.5 Hz, 2H), 2.85 – 2.68 (m, 2H), 2.39 (s, 3H), 2.33 – 2.18 (m, 2H). 13 C-NMR (75 MHz, CDCl3), δ (ppm): 151.66, 138.84,132.43, 129.89, 128.71, 127.08, 123.45, 118.58, 108.36, 96.82, 88.43, 53.80,52.97, 40.76, 38.54. HRMS (ESI-TOF) m / z [M+H] + Calculate for C 18 H21 N2O: 281.1649, found 281.1648. (4) Synthesis of 3-hydroxypyrroloindole alkaloid Alline natural product, the reaction formula is as follows: ; Step 1: Preparation of Na / Naphthalene: Naphthalene (7.7 mmol, 0.99 g), sodium metal (6.5 mmol, 148 mg), and anhydrous tetrahydrofuran (10 mL) were weighed into a 25 mL two-necked round-bottom flask, and the mixture was degassed three times under the protection of high-purity nitrogen. The two-necked round-bottom flask was then placed in an ultrasonicator for ultrasonic stirring and reaction for 15 minutes, and then stirred at room temperature for reaction for 1 hour, and the solution turned dark green.

[0025] Step 2: Substrate 5 (0.2 mmol, 56 mg) was weighed into a 25 mL double-necked round-bottom flask, anhydrous tetrahydrofuran (4 mL) was added, and the mixture was degassed 3 times under the protection of high-purity nitrogen. The mixture was cooled to -40 °C, and sodium naphthalene solution was slowly added until the green color remained. The mixture was reacted for 2 hours at a low temperature of -40 °C, and then the reaction was placed at room temperature and continued to react for 12 hours. Post-treatment: 2 mL of saturated ammonium chloride solution was added and stirred for 10 minutes, then diluted with water, and then ethyl acetate (3×20 mL) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and dried by column chromatography (dichloromethane: methanol: ammonia water = 100:50: 1) to obtain a white solid product (30 mg, 80%).

[0026] The characterization data of the natural product 3-hydroxypyrroloindole alkaloid Alline are as follows: 1 H-NMR (300 MHz, CDCl3), δ (ppm): 7.29 (d, J = 7.2 Hz, 1H), 7.16 –7.08 (m, 1H), 6.80 (t, J = 7.5Hz, 1H), 6.63 (d, J = 7.8Hz, 1H), 4.52 (brs,1H), 2.87 – 2.76 (m, 1H), 2.66 – 2.56 (m, 1H), 2.44 (s, 3H), 2.39 – 2.18 (m,2H). 13C-NMR (75 MHz, CDCl3), δ (ppm): 150.03, 132.66, 129.81, 123.94, 119.74,110.54, 90.34, 89.46, 52.43, 40.66, 37.26. HRMS (ESI-TOF) m / z [M+H] + calcdfor C 11 H 15 N2O: 191.1179, found 191.1180. It can be seen from the above examples that the preparation method provided by the present invention has a high product yield, a short synthesis route, a simple reaction operation process, and good atom economy.

[0027] It will be apparent to those skilled in the art that the invention is not limited to the details of the exemplary embodiments described above and that the invention can be implemented in other specific forms without departing from the spirit or essential features of the invention. Therefore, the embodiments should be considered exemplary and non-limiting in all respects, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations falling within the meaning and scope of the equivalent elements of the claims be included in the invention. Any reference numeral in a claim should not be considered as limiting the claim to which it relates.

[0028] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. A method for preparing a 3-hydroxypyrroloindole alkaloid Alline natural product, characterized in that: The following steps are involved: S1. Tris(dibenzylideneacetone)dipalladium, triphenylphosphine and a chiral sulfenamide compound are mixed, and degassed three times under the protection of high-purity nitrogen, anhydrous toluene is added, and lithium bis(trimethylsilylamide) is added under stirring at room temperature, and then degassed three times, and heated to react for 5 hours under the protection of high-purity inert gas, and then placed in an air atmosphere in an ice-water bath to continue the reaction for 5 hours, and after purification, an oxidized indole compound containing a hydroxyl quaternary carbon chiral center is obtained; wherein, the molecular structure 2 of the oxidized indole compound containing a hydroxyl quaternary carbon chiral center is: ; S2, dissolving the oxidized indole compound containing a hydroxyl quaternary carbon chiral center in an anhydrous solvent, then adding a dilute hydrochloric acid solution under the reaction conditions of an ice-water bath for 5 hours to remove the tert-butylsulfinyl group, and obtaining the oxidized indole compound containing a hydroxyl quaternary carbon chiral center after purification; wherein the molecular structure 3 of the oxidized indole compound containing a hydroxyl quaternary carbon chiral center is: ; S3, dissolving the oxidized indole compound containing a hydroxyl quaternary carbon chiral center in an anhydrous solvent, degassing 3 times under the protection of high-purity nitrogen, then adding a reducing agent to react for 1 hour under the reaction conditions of an ice-water bath, then heating to room temperature to react for 2 hours, and then placing the reaction under the heating conditions of an oil bath, continuing the reaction for 10 to 15 hours, and obtaining a 3-hydroxypyrrolidinole compound after purification; wherein, the molecular structure 4 of the 3-hydroxypyrrolidinole compound is: ; S4, first prepare a reducing agent, then add anhydrous tetrahydrofuran to the 3-hydroxypyrrolidinole compound, degas 3 times under high-purity nitrogen protection, cool to -40°C, slowly add the reducing agent until the green color remains, then react at a low temperature of -40°C for 2 hours, then place the reaction at room temperature, continue to react for 12 hours, and obtain a 3-hydroxypyrrolidinole alkaloid Alline natural product after purification; wherein, the molecular structure 5 of the 3-hydroxypyrrolidinole alkaloid Alline natural product is: 。 2. A method for preparing a 3-hydroxypyrroloindole alkaloid Alline natural product according to claim 1, characterized in that: The solvent in S1 is anhydrous toluene, the heating temperature is 80° C., the heating reaction time is 5 hours, the high-purity inert gas is high-purity nitrogen, and air is used as a series oxidant.

3. A method for preparing a 3-hydroxypyrroloindole alkaloid Alline natural product according to claim 1, characterized in that: The anhydrous solvent in S2 is anhydrous methanol solvent, and the concentration of the hydrochloric acid solution is 1-3 mol / L.

4. A method for preparing a 3-hydroxypyrroloindole alkaloid Alline natural product according to claim 1, characterized in that: The anhydrous solvent in S3 is anhydrous tetrahydrofuran solvent, and the reducing agent is lithium aluminum hydride solution.

5. A method for preparing a 3-hydroxypyrroloindole alkaloid Alline natural product according to claim 1, characterized in that: The reducing agent in S4 is a sodium naphthalene solution, and its preparation method specifically includes: weighing naphthalene, metallic sodium, and anhydrous tetrahydrofuran into a container, then degassing 3 times under the protection of high-purity nitrogen, and then placing the container in an ultrasonic instrument for ultrasonic stirring and reaction for 15 minutes, and then stirring and reacting at room temperature for 1 hour until the solution turns dark green and is stored for later use.

6. A method for preparing a 3-hydroxypyrroloindole alkaloid Alline natural product according to claim 1, characterized in that: The purification method included in S1 to S4 is: concentrating the crude product initially obtained in each step, followed by chromatography separation and purification, and finally obtaining a compound with high purity.

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