Alkaloid and method for synthesizing alkaloid by catalysis of trivalent ferrous porphyrin

Abstract

The present application belongs to the field of organic synthesis technology, and in particular to a method for synthesizing alkaloids by catalysis of alkaloids and ferric porphyrin. The preparation method comprises the steps of: using ferric porphyrin as a catalyst, converting azide compound A into product compound B through ferric nitrogen amination reaction; the chemical structure formula of azide compound A is #imgabs0# the chemical formula of product compound B is #imgabs1#X is selected from C-R5, CO, O, S, SO, SO2, Se or P-R6; n1, n2 are respectively independently positive integers of 1 to 4, and when n1, n2 are greater than 1, multiple R2 are the same or different, and multiple R4 are the same or different; R1, R2, R3, R4, R5 exist independently or at least form a polycyclic ring. Many biologically active alkaloids and their derivatives can be prepared by this method, the synthesis process is simple, the ferric porphyrin catalyst is a cheap metal catalyst, which reduces the synthesis cost and is conducive to industrial production and application.

Description

Technical Field

[0001] The present application belongs to the technical field of organic synthesis, and in particular relates to a method for synthesizing alkaloids by catalyzing alkaloids with ferric iron porphyrin. Background Art

[0002] It is well known that many nitrogen-containing compounds are present in numerous biologically active alkaloids, and these alkaloids have attracted considerable research attention due to their excellent biological activities. However, due to the difficulty in extraction, their preparation is relatively difficult. To this end, chemists have developed a variety of synthetic strategies to prepare some nitrogen-containing compounds. In recent years, carbon-hydrogen bond insertion methods have made great progress in the synthesis of nitrogen-containing compounds. However, relatively little research has been conducted on the catalytic synthesis of complex nitrogen-containing molecules using inexpensive metals. Summary of the Invention

[0003] The purpose of this application is to provide a method for synthesizing alkaloids by catalyzing alkaloids with alkaloids and trivalent iron porphyrin, which aims to solve the problem that the synthesis methods of existing nitrogen-containing compound alkaloids are complex, require the use of precious metals, and are costly.

[0004] To achieve the above application objectives, the technical solutions adopted in this application are as follows:

[0005] In a first aspect, the present application provides a method for synthesizing alkaloids by catalysis of trivalent iron porphyrin, comprising the following steps:

[0006] Using trivalent iron porphyrin as a catalyst, azide compound A is converted into product compound B through iron nitre amination reaction; wherein the chemical structure of the azide compound A is The chemical formula of the corresponding synthesized product compound B is wherein X is selected from C-R5, CO, O, S, SO, SO2, Se or P-R6; n1 and n2 are each independently a positive integer of 1 to 4, and when n1 and n2 are greater than 1, multiple R2s are the same or different, and multiple R4s are the same or different; R1, R2, R3, R4, and R5 exist independently or form at least one polycyclic ring, and R1, R2, R3, R4, R5, and R6 are each independently selected from one of hydrogen, alkyl, substituted alkyl, hydroxyl, methoxy, methyl ester, vinyl, carbonyl, phenyl, substituted phenyl, heterocyclic group, heteroaromatic ring group, carbocyclic group, condensed ring group, and spirocyclic group.

[0007] The first aspect of the present application provides a method for synthesizing alkaloids using trivalent iron porphyrin catalysis. Using trivalent iron porphyrin as a catalyst, an azide compound A is subjected to an iron nitre amination reaction. After the iron porphyrin and the azide substrate are combined, a nitrogen molecule is removed to form an iron nitre intermediate, which undergoes an amination ring-closure reaction to synthesize the product compound B, i.e., an alkaloid, an intermediate of an alkaloid, or a derivative of an alkaloid. This method can be used to prepare many biologically active alkaloids and their derivatives. The synthesis process is simple, and the trivalent iron porphyrin catalyst used is a cheap metal catalyst, which reduces the synthesis cost and is more conducive to industrial production and application.

[0008] In a second aspect, the present application provides an alkaloid, which is prepared by the above method, and the chemical formula of the alkaloid is wherein X is selected from C-R5, CO, O, S, SO, SO2, Se or P-R6; n1 and n2 are each independently a positive integer of 1 to 4, and when n1 and n2 are greater than 1, multiple R2s are the same or different, and multiple R4s are the same or different; R1, R2, R3, R4, and R5 exist independently or form at least one polycyclic ring, and R1, R2, R3, R4, R5, and R6 are each independently selected from one of hydrogen, alkyl, substituted alkyl, hydroxyl, methoxy, methyl ester, vinyl, carbonyl, phenyl, substituted phenyl, heterocyclic group, heteroaromatic ring group, carbocyclic group, condensed ring group, and spirocyclic group.

[0009] The alkaloids provided in the second aspect of this application are prepared by the above-mentioned method, have a simple synthesis process, and employ a trivalent iron porphyrin catalyst, which is an inexpensive metal catalyst, thereby reducing the synthesis cost. These alkaloids have a diverse production process and can form alkaloids of different structures. These alkaloids are biologically active and can be used directly or as intermediates to synthesize other active substances, thus having a wide range of applications. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the following briefly introduces the drawings required for use in the embodiments or descriptions of the prior art. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without any creative work.

[0011] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of the product compound B-1a provided in the examples of the present application;

[0012] Figure 2 is the carbon NMR spectrum of the product compound B-1a provided in the examples of the present application;

[0013] Figure 3 is the hydrogen nuclear magnetic resonance spectrum of the product compound B-1b provided in the examples of the present application;

[0014] Figure 4 is the carbon NMR spectrum of the product compound B-1b provided in the examples of the present application;

[0015] Figure 5 is the hydrogen nuclear magnetic resonance spectrum of the product compound B-2 provided in the examples of the present application;

[0016] Figure 6 is the carbon NMR spectrum of the product compound B-2 provided in the examples of the present application;

[0017] Figure 7 This is the hydrogen nuclear magnetic resonance spectrum of the product compound B-2-1 provided in the examples of the present application;

[0018] Figure 8 This is the carbon NMR spectrum of the product compound B-2-1 provided in the examples of the present application;

[0019] Figure 9 This is the hydrogen nuclear magnetic resonance spectrum of the product compound B-3 provided in the examples of the present application;

[0020] Figure 10 This is the carbon NMR spectrum of the product compound B-3 provided in the examples of the present application;

[0021] Figure 11 is the hydrogen nuclear magnetic resonance spectrum of the product compound B-4 provided in the examples of the present application;

[0022] Figure 12 is the hydrogen nuclear magnetic resonance spectrum of the product compound B-4 provided in the examples of the present application;

[0023] Figure 13 This is the carbon NMR spectrum of the product compound B-4-1 provided in the examples of the present application;

[0024] Figure 14 This is the carbon NMR spectrum of the product compound B-4-1 provided in the examples of the present application;

[0025] Figure 15 This is the carbon NMR spectrum of the product compound B-5 provided in the examples of the present application;

[0026] Figure 16 This is the carbon NMR spectrum of the product compound B-5 provided in the examples of the present application;

[0027] Figure 17 is the carbon NMR spectrum of the product compound B-6 provided in the examples of the present application;

[0028] Figure 18 is the carbon NMR spectrum of the product compound B-6 provided in the examples of the present application;

[0029] Figure 19 is the carbon NMR spectrum of the product compound B-7b provided in the examples of the present application;

[0030] Figure 20 is the carbon NMR spectrum of the product compound B-7b provided in the examples of the present application;

[0031] Figure 21 This is the carbon NMR spectrum of the product compound B-7-1 provided in the examples of this application;

[0032] Figure 22 This is the carbon NMR spectrum of the product compound B-7-1 provided in the examples of this application. DETAILED DESCRIPTION

[0033] In order to make the technical problems, technical solutions and beneficial effects to be solved by this application more clearly understood, the present application is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain this application and are not intended to limit this application.

[0034] In this application, the term "and / or" describes the relationship between associated objects, indicating that three possible relationships exist. For example, A and / or B can represent: A exists alone, A and B exist simultaneously, and B exists alone. A and B can be singular or plural. The character " / " generally indicates that the associated objects are in an "or" relationship.

[0035] In this application, "at least one" means one or more, and "plurality" means two or more. "At least one of the following" or similar expressions refers to any combination of these items, including any combination of single items or plural items. For example, "at least one of a, b or c", or "at least one of a, b and c" can all mean: a, b, c, ab (i.e., a and b), ac, bc, or abc, where a, b, c can be single or multiple.

[0036] It should be understood that in the various embodiments of the present application, the size of the serial numbers of the above-mentioned processes does not mean the order of execution. Some or all of the steps can be executed in parallel or sequentially. The execution order of each process should be determined by its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of the present application.

[0037] The terms used in the embodiments of the present application are only for the purpose of describing specific embodiments and are not intended to limit the present application. The singular forms "a", "an" and "the" used in the embodiments of the present application and the appended claims are also intended to include plural forms unless the context clearly indicates otherwise.

[0038] The weights of the relevant components mentioned in the examples of this specification may not only refer to the specific content of each component, but also represent the weight ratio between the components. Therefore, as long as the content of the relevant components in the examples of this specification is proportionally enlarged or reduced according to the examples of this specification, it is within the scope disclosed in the examples of this specification. Specifically, the mass in the examples of this specification may be μg, mg, g, kg, etc., which are mass units known in the chemical industry.

[0039] The terms "first" and "second" are used solely for descriptive purposes to distinguish objects, such as substances, from one another and should not be understood to indicate or imply relative importance or to implicitly specify the quantity of the technical features being referred to. For example, without departing from the scope of the embodiments of this application, a first XX may also be referred to as a second XX, and similarly, a second XX may also be referred to as a first XX. Thus, features defined as "first" or "second" may explicitly or implicitly include one or more of such features.

[0040] A first aspect of the present invention provides a method for synthesizing alkaloids by catalysis of trivalent iron porphyrin, comprising the following steps:

[0041] S10. Using trivalent iron porphyrin as a catalyst, azide compound A is converted into product compound B through an iron nitre amination reaction; wherein the chemical structure of azide compound A is The chemical formula of the corresponding synthesized product compound B is wherein X is selected from C-R5, CO, O, S, SO, SO2, Se or P-R6; n1 and n2 are each independently a positive integer of 1 to 4, and when n1 and n2 are greater than 1, multiple R2s are the same or different, and multiple R4s are the same or different; R1, R2, R3, R4, and R5 exist independently or form at least one polycyclic ring, and R1, R2, R3, R4, R5, and R6 are each independently selected from one of hydrogen, alkyl, substituted alkyl, hydroxyl, methoxy, methyl ester, vinyl, carbonyl, phenyl, substituted phenyl, heterocyclic group, heteroaromatic ring group, carbocyclic group, condensed ring group, and spirocyclic group.

[0042] The first aspect of the present invention provides a method for synthesizing alkaloids using ferric porphyrin as a catalyst. Azide compound A is subjected to an iron nitre amination reaction using ferric porphyrin as a catalyst. After the iron porphyrin and the azide substrate are combined, a nitrogen molecule is removed to form an iron nitre intermediate, which undergoes an amination ring-closure reaction to synthesize product compound B, i.e., an alkaloid, an alkaloid intermediate, or an alkaloid derivative. This method can be used to prepare many biologically active alkaloids and their derivatives. The synthesis process is simple, and the ferric porphyrin catalyst used is an inexpensive metal catalyst, which reduces the synthesis cost and is more conducive to industrial production and application.

[0043] In some possible implementations, the ferric porphyrin is [Fe III (TDCPP)(IMe)2]I, wherein the ligand H2TDCPP is tetrakis(2,6-dichlorophenyl)porphyrin and the ligand IMe is 1,3-dimethylimidazol-2-ylidene. The catalyst uses iron ions as the intermediate active metal, which is inexpensive and readily available, and trivalent ferrous porphyrin is simple and easy to obtain. Using this trivalent ferrous porphyrin as a catalyst not only effectively catalyzes the iron-nitrogen amination reaction of azide compounds to efficiently synthesize alkaloids and their derivatives, but also has a low catalyst cost, which can effectively reduce the preparation cost of alkaloids and is more conducive to industrial production and application.

[0044] In some possible implementations, the steps of the iron nitride amination reaction include: dissolving trivalent iron porphyrin, azide compound A and an amino protective agent in an organic solvent, reacting in an inert atmosphere at a temperature of 100-200°C for 0.5-1 hour, allowing the iron porphyrin and the azide substrate to combine, removing a nitrogen molecule to form an iron nitride intermediate, performing an amination ring-closure reaction, and isolating the product compound B. Among them, the amino protective agent contains a group that can react with the amino group, so that the generated product can exist stably under the reaction conditions of reflux, thereby improving the product purity and yield. In some specific embodiments, the reaction temperature can be 100-120°C, 120-150°C, 150-180°C, 180-200°C, etc., and the inert atmosphere conditions can be at least one of nitrogen, argon, and helium.

[0045] In some possible implementations, the molar ratio of the ferric porphyrin, the azide compound A, and the amino protecting agent is (0.02-0.06):1:(1-3), which can fully catalyze the iron-nitrogen amination reaction of the azide compound A to form the product compound B.

[0046] In some specific embodiments, thin layer chromatography is used to judge the progress of the reaction. After the reactants are completely consumed, the reaction mixture is concentrated under reduced pressure and the residue is removed by silica gel flash column chromatography to obtain a purified product.

[0047] In some possible implementations, the amino-protecting agent includes at least one of di-tert-butyl dicarbonate, methyl chloroformate, ethyl chloroformate, phenyl chloroformate, benzyl chloroformate, benzyl chloroformate, benzenesulfonic anhydride, acetic anhydride, trifluoroacetic anhydride, and trifluoromethanesulfonic anhydride; and contains a group capable of reacting with an amino group, thereby ensuring the stability of the resulting product under reflux reaction conditions and improving product purity and yield. In some specific embodiments, the amino-protecting agent is di-tert-butyl dicarbonate.

[0048] In some possible implementations, the organic solvent includes at least one of toluene, chlorobenzene, fluorobenzene, trifluoromethylbenzene, dioxane, N,N-dimethylformamide, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and methyl tert-butyl ether; these organic solvents have good solubility for trivalent iron porphyrin, azide compound A, and amino protective agent, which is conducive to the iron-nitrogen amination reaction of each raw material component to synthesize the product compound B.

[0049] In some possible implementations, the general chemical formula of the product compound B is Wherein, X is selected from C-R5, CO, O, S, SO, SO2, Se, or P-R6; that is, X in the product compound B can be either a carbon group or a heteroatom group. n1 and n2 are each independently a positive integer from 1 to 4, forming a five-membered ring when n is 1, and forming a polycyclic ring when n is 2 to 4. Furthermore, when n1 and n2 are greater than 1, multiple R2s may be the same or different, and multiple R4s may be the same or different; that is, when R2 and R4 have multiple carbon positions, the substituents at different carbon positions may be the same or different.

[0050] In some possible implementations, R1, R2, R3, R4, and R5 exist independently, or at least form a polycyclic ring. When adjacent substituents form a ring, the ring formed is a cyclic ring, similar to When the alternate substituents form a ring, the ring formed is a bridged ring, similar to In some possible implementations, R1, R2, R3, R4, and R5 form at least one polycyclic ring, which includes a five-membered ring, a six-membered ring, a seven-membered ring, an eight-membered ring, a spiro ring, or a fused ring.

[0051] In some possible implementations, the five-membered ring, six-membered ring, seven-membered ring, and eight-membered ring are saturated or unsaturated rings; wherein the unsaturated ring has one or more olefinic bonds.

[0052] In some possible implementations, the five-membered ring, the six-membered ring, the seven-membered ring, and the eight-membered ring are carbocyclic groups or heterocyclic groups.

[0053] In some possible implementations, the five-membered ring, six-membered ring, seven-membered ring, and eight-membered ring contain at least one substituent; the substituents include hydroxyl, methoxy, carboxyl, vinyl, carbonyl, heterocyclic group, carbocyclic group, condensed ring group, and spirocyclic group.

[0054] In the above embodiments of the present application, the terms "fused bicyclic ring," "fused ring," "fused bicyclic group," and "fused cyclic group" are used interchangeably to refer to a monovalent or polyvalent saturated or partially unsaturated bridged ring system, wherein a bridged ring system refers to a non-aromatic bicyclic ring system. Such a system may include independent or conjugated unsaturated systems, but its core structure does not include aromatic rings or heteroaromatic rings (although aromatic groups may be substituents thereon).

[0055] The terms "spirocyclyl," "spirocycle," "spirobicyclyl," or "spirobicycle" are used interchangeably and refer to a monovalent or multivalent saturated or partially unsaturated ring system in which one ring originates from a specific ring carbon atom of another ring. For example, a saturated bridged ring system (rings B and B') is called a "fused bicyclic," while rings A and B share a carbon atom in two saturated ring systems and are called "spirocycles" or "spirobicycles." Each ring in a fused bicyclic and spirobicyclyl group can be a carbocyclyl or a heterocyclyl, and each ring is optionally substituted with one or more substituents described herein.

[0056] The terms "heterocyclyl" and "heterocycle" are used interchangeably and refer to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring containing 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise indicated, a heterocyclyl group can be a carbon group or a nitrogen group, and a -CH2- group can optionally be replaced by a -C(O)- group. The sulfur atom of the ring can optionally be oxidized to an S-oxide. The nitrogen atom of the ring can optionally be oxidized to an N-oxide. Examples of heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine Base, diazepine Base, thiazolin Examples of heterocyclic groups in which the -CH2- group is replaced by -C(O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinyl, 3,5-dioxopiperidinyl, and pyrimidinedione. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl. The heterocyclic group may be optionally substituted with one or more substituents described herein.

[0057] In some possible implementations, the heterocyclic radical is a 4-8 atom heterocyclic radical, meaning a saturated or partially unsaturated monocyclic ring containing 4-8 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise indicated, the 4-8 atom heterocyclic radical may be a carbon radical or a nitrogen radical, and the -CH2- group may optionally be replaced by -C(O)-. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups of 4 to 8 atoms include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepanyl, Base, diazepine Base, thiazolin Examples of heterocyclic groups in which the -CH2- group is replaced by -C(O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidonyl, 3,5-dioxopiperidinyl, and pyrimidinedione. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl. Heterocyclic groups composed of 4 to 8 atoms may be optionally substituted with one or more substituents described herein.

[0058] In some possible implementations, the azide compound A comprises

[0059] That is, when the azide compound is A-1, the product compound B-1 is synthesized by an iron-nitrene amination reaction; when the azide compound is A-2, the product compound B-2 is synthesized by an iron-nitrene amination reaction; when the azide compound is A-3, the product compound B-3 is synthesized by an iron-nitrene amination reaction; when the azide compound is A-4, the product compound B-4 is synthesized by an iron-nitrene amination reaction; when the azide compound is A-5, the product compound B-5 is synthesized by an iron-nitrene amination reaction; when the azide compound is A-6, the product compound B-6 is synthesized by an iron-nitrene amination reaction; when the azide compound is A-7, the product compound B-7 is synthesized by an iron-nitrene amination reaction.

[0060] In some possible implementations, the steps of preparing the product compound B-1 include: using 6-(2-bromoethyl)benzo[d][1,3]dioxetane-5-carbaldehyde as a raw material, sequentially performing a Wittig reaction, a nucleophilic substitution reaction, a catalytic hydrogenation reduction reaction, and an azide transfer reaction to obtain an azide compound A-1; dissolving the azide compound A-1 and an amino protecting agent in an organic solvent, reacting in an inert atmosphere at a temperature of 100 to 200°C for 0.5 to 1 hour, and isolating to obtain the product compound B-1.

[0061] In some specific embodiments, the process route for synthesizing the product compound B-1 is:

[0062]

[0063] Among them, 6-(2-bromoethyl)benzo[d][1,3]dioxetane-5-carbaldehyde was purchased commercially or synthesized according to the documented method.

[0064] The reaction type for synthesizing compounds A1 and A2 is a Wittig reaction, which involves the reaction of a hydrocarbon bromide with triphenylphosphine to form a ylide reagent, which then reacts with an aldehyde to produce an olefin. In some specific embodiments, the preparation steps for compounds A1 and A2 include: injecting a hexane solution of n-butyllithium (0.62 mL, 2.50 mol / L) into a Wittig reagent (1.56 mmol) dissolved in anhydrous tetrahydrofuran under an ice-water bath and argon atmosphere. The resulting mixture is stirred for 1 hour, followed by the addition of 6-(2-bromoethyl)benzo[d][1,3]dioxetane-5-carbaldehyde (1.30 mmol) dissolved in anhydrous tetrahydrofuran. The reaction mixture is then stirred at room temperature for 12 hours and then poured into ice water. The reaction mixture is extracted with dichloromethane, and the combined organic layers are washed sequentially with saturated sodium bicarbonate solution (2 × 30 mL), water (3 × 30 mL), and brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, crude products A1 and A2 were obtained. The by-products had no effect on the next reaction and could be used directly in the next step without purification.

[0065] Among them, the reaction type for synthesizing compounds B1 and B2 is a nucleophilic substitution reaction, and the reaction principle is to use N3 -The nucleophile NaN3 replaces the removable halogen bromine. In some specific embodiments, the preparation steps of compounds B1 and B2 include: under an argon atmosphere, adding sodium azide (98 mg, 1.50 mmol) to a solution of A1 and A2 (1.00 mmol) dissolved in dimethylformamide. The reaction mixture is stirred at 80°C (oil bath) overnight. Water is added to the reaction mixture, and the crude product is extracted with diethyl ether (10 mL × 3). The combined organic layers are washed with water (10.0 mL × 4), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to obtain B1 with a yield of 51% and B2 with a yield of 43%. (E)-5-(2-azidoethyl)-6-phenylvinylbenzo[d][1,3]diazole (B1) (trans:cis = 1:0.9). 1 HNMR(500MHz, CDCl3)δ7.53(cis,d,J=7.2Hz,2H),7.41(trans,t,J=7.7Hz,2H),7.33–7.15(cis or trans,m,4H);6.94(trans,d,J=16.0Hz,1H),6.77(trans,s,1H),6.74(cis,s,1H),6.68(trans,s,1H),6.63(cis,s,1H),6.63(cis,d,J=1.9Hz,1H),6 .00(cis,s,2H),5.95(trans,s,2H),3.48(cis,t,J=7.4Hz,2H),3.42(trans,t,J=7.3Hz,2H),3.00(cis,t,J=7.4Hz,2H),2.86(trans,t,J=7.3Hz,2H). 13 C NMR (126MHz, CDCl3) δ147.48(cis),147.20(cis),147.16,146.56,137.45(cis),136.45,131. 26,130.38,130.11(cis),129.70,129.58(cis),129.49(cis),129.00,128.80(cis),128.31, 128.22,127.71(cis),127.38,126.49(cis),125.10(cis),110.11(cis),109.96,109.60,105 .83(cis),101.23(cis),101.08,52.18(cis),51.77,33.09,32.90(cis).HRMS(ESI)m / z:calcd for C 17 H 16 NO2([M–N2+H]+ )266.1176, found266.1180. (E)-5-(2-Azidoethyl)-6-(but-1-en-1-yl)benzo[d][1,3]dioxadiene (B2) (trans:cis = 0.6:1). 1 H NMR(500MHz,CDCl3)δ6.96(trans,s,1H),6.72(cis,s,1H),6.70(cis,s,1H),6.66(trans,s,1H),6.52(trans,dt,J=15.3,1.7Hz, 1H),6.39(cis,dt,J=11.3,1.7Hz,1H),6.07(trans,dt,J=15.5,6.6Hz,1H),5.96(cis,s,2H),5.94(trans,s,2H),5.72(cis,dt,J =11.3,7.4Hz,2H),3.42(trans,t,J=7.5Hz,2H),3.38(cis,t,J=7.4Hz,2H),2.90(trans,t,J=7.5Hz,2H),2.83(cis,t,J=7.4Hz,2 H), 2.27(trans,pd,J=7.5,1.7Hz,2H), 2.17(cis,pd,J=7.5,1.5Hz,2H), 1.13(trans,t,J=7.5Hz,3H), 1.04(cis,t,J=7.5Hz,3H). 13 C NMR(126MHz, CDCl3)δ146.93,146.72,146.57(cis),146.08(cis),135.40(cis),133.77,130.79,130.20(cis),129.46(cis),128.26,126.34(cis),125.40 ,109.84(cis),109.79,109.71(cis),106.15,101.00,51.92,51.70(cis),32.93(cis),32.71,26.31,21.75(cis),14.25(cis),13.84.HRMS(ESI)m / z:calcd for C 13 H 16 NO2([M–N2+H] + )218.1176,found218.1171.

[0066] The steps for synthesizing azide compounds A-1a and A-1b include: first, activating hydrogen by catalytic hydrogenation reduction reaction using hydrogen gas combined with palladium carbon to form free hydrogen, and then performing a reduction reaction to obtain crude product C; and then performing an azide transfer reaction to synthesize azide compounds A-1a and A-1b. In some specific embodiments, the preparation steps of azide compounds A-1a and A-1b include: injecting ethanol (15.0 mL) into a round-bottom flask containing compound B (0.80 mmol) and Pd / C (0.12 mmol, 10 wt%) under a hydrogen atmosphere (1 atm). The resulting mixture is stirred at room temperature for 12 hours. Thereafter, the mixture is filtered and washed with dichloromethane. The filtrate is concentrated under reduced pressure, and the crude product C is directly used in the next step. Under a nitrogen atmosphere, 1H-imidazole-1-sulfonyl azide (0.96 mmol), potassium carbonate (1.44 mmol), and anhydrous copper sulfate (0.04 mmol) were added to a solution of C in methanol (8.0 mL). The resulting mixture was then stirred at room temperature overnight. After concentration under reduced pressure, the residue was purified by silica gel flash column chromatography to provide A-1a in 55% yield and A-1b in 51% yield. 5-(2-Azidoethyl)-6-phenylethylbenzo[d][1,3]diazole (A-1a). 1 H NMR (500MHz, CDCl3) δ7.32(t,J=7.4Hz,2H),7.24(t,J=7.4Hz,1H),7.19(d,J=8.0Hz,2H),6.7 2(s,1H),6.67(s,1H),5.95(s,2H),3.34(t,J=7.5Hz,2H),2.87(s,4H),2.77(t,J=7.5Hz,2H). 13 C NMR (126MHz, CDCl3) δ146.54,145.99,141.38,133.18,128.64,128.50,128.46,1 26.17,109.57,109.55,100.92,52.19,37.96,34.65,31.92.HRMS(ESI)m / z:calcd for C 17 H 18 NO2([M–N2+H] + )268.1332,found268.1335.5-(2-Azidoethyl)-6-butylbenzo[d][1,3]diazole (A-1b). 1H NMR (500MHz, CDCl3) δ6.67(s,1H),6.65(s,1H),5.90(s,2H),3.42(t,J=7.5Hz,2H),2.83(t,J =7.5Hz,2H),2.55–2.51(m,2H),1.56–1.49(m,2H),1.43–1.35(m,2H),0.95(t,J=7.3Hz,3H). 13 C NMR(101MHz, CDCl3)δ146.42,145.72,134.41,128.28,109.56,109.51,100.82,52.32,33.79,32.35,32.01,22.65,14.03.HRMS(ESI)m / z:calcd for C 13 H 18 NO2([M–N2+H] + )220.1332,found220.1335.

[0067] Among them, the reaction type of the synthetic product compounds B-1a and B-1b is an iron nitride amination reaction. The reaction principle is that after the iron porphyrin and the azide substrate are combined, a nitrogen molecule is removed to form an iron nitride intermediate for an amination ring-closure reaction. In some specific embodiments, the preparation steps of the product compounds B-1a and B-1b include: adding azide 1 (0.20 mmol), di-tert-butyl dicarbonate (87 mg, 0.40 mmol) and [FeIII (TDCPP) (IMe) 2] I (0.004 mmol) to a round-bottom flask, and then the reaction flask is purged with argon three times. Then, toluene (3.0 mL) is injected into the flask, and the resulting mixture is stirred at 150 ° C (oil bath) for 0.5 h. TLC thin-layer chromatography analysis shows that the azide compounds A-1a and A-1b are completely consumed. After concentration under reduced pressure, the residue was purified by silica gel flash column chromatography to obtain the corresponding tetrahydroisoquinoline (B-1a, yield 79%; B-1b, yield 72%). 5-Benzyl-7,8-dihydro-[1,3]dioxacyclo[4,5-g]isoquinoline-6(5H)-carboxylic acid tert-butyl ester (B-2a) (1:2 dual stereoisomers). Figure 1 As shown, 1H NMR(500MHz, CDCl3)δmajorpeaks.7.28–7.20(m,3H),7.12(d,J=5.0Hz,2H),6.59(s,1H),6.51(s,1H),5.92(s,1H),5.90(s,1H),5.10(dd,J=8.7,5.4Hz,1 H),4.15(ddd,J=13.2,5.9,3.4Hz,1H),3.26–3.21(m,1H),3.05–3.02(m,1H), 3.00–2.97(m,1H),2.82(m,1H),2.58(dt,J=16.0,3.9Hz,1H),1.21(s,9H).As attached Figure 2 As shown, 13 C NMR (126MHz, CDCl3) δ154.38,146.32,145.88,138.51,130.04,129.64,128.36,127.88,12 6.43,108.66,107.18,100.88,79.62,56.76,42.97,36.94,28.10.HRMS(ESI)m / z:calcdfor C 22 H 25 NO4Na([M+Na] + )390.1676, found 390.1672. 5-propyl-7,8-dihydro-[1,3]dioxacyclo[4,5-g]isoquinoline-6(5H)-carboxylic acid tert-butyl ester (B-2b) (3:2 dual stereoisomers). Figure 3 As shown, 1 H NMR (500 MHz, CDCl3) δ 6.56 (s, 2H), 5.89 (s, 2H), 5.07–4.88 (m, 1H), 4.19–3.82 (m, 1H), 3.29–3.10 (m, 1H), 2.88–2.72 (m, 1H), 2.65–2.56 (m, 1H), 1.80–1.72 (m, 1H), 1.66–1.56 (m, 1H), 1.47 (s, 9H), 1.43–1.37 (m, 2H), 0.99–0.90 (m, 3H). Figure 4 As shown, 13 C NMR (126MHz, CDCl3) δ154.88,146.06,145.85,131.34,127.46,108.65,106.98, 100.79,79.76,54.54,39.39,36.66,28.49,19.64,14.06.HRMS(ESI)m / z:calcd for C 13 H18 NO2([M–Boc+H2] + )220.1332,found220.1328.

[0068] In some possible implementations, the steps of preparing the product compound B-2 include: using methyl 2-(2-iodo-4,5-dimethoxyphenyl)acetate as a raw material, sequentially performing a Sonogashira coupling reaction, a catalytic hydrogenation reduction reaction, an alcohol condensation reaction, a reduction reaction, an esterification reaction, and a nucleophilic substitution reaction to obtain an azide compound A-2; dissolving the azide compound A-2 and an amino protecting agent in an organic solvent, reacting in an inert atmosphere at a temperature of 100 to 200° C. for 0.5 to 1 hour, and isolating the product compound B-2.

[0069] In some specific embodiments, the process route for synthesizing the product compound B-2 is:

[0070]

[0071] Wherein, methyl 2-(2-iodo-4,5-dimethoxyphenyl)acetate was purchased commercially or synthesized according to the documented method.

[0072] Among them, the reaction type for synthesizing compound D is sonogashira coupling reaction (sonogashira coupling reaction), and the reaction mechanism is to use palladium catalyst and monovalent copper as co-catalysts for catalytic coupling under relatively mild reaction conditions. Ditriphenylphosphine palladium dichloride, cuprous iodide are catalysts, triethylamine acts as a base and solvent, ditriphenylphosphine palladium dichloride can be replaced by other types of zero-valent palladium, and cuprous iodide can also be replaced by other monovalent copper. In some specific embodiments, the preparation step of synthesizing compound D comprises: adding 2-(2-iodo-4,5-dimethoxyphenyl)acetic acid methyl ester (2.877g, 8.56mmol), ditriphenylphosphine palladium dichloride (300mg, 0.43mmol) and cuprous iodide (245mg, 1.28mmol) to a 25mL round-bottom flask. The flask is ventilated three times with argon. Triethylamine (10 mL) and but-3-yn-1-ol (720 mg, 10.27 mmol) were then added via syringe, and the resulting reaction mixture was stirred at room temperature for 24 hours. Triethylamine was then removed under reduced pressure, and the resulting residue was purified by flash silica gel chromatography to afford D as an orange oil in 81% yield. Methyl 2-(2-(4-hydroxybut-1-yn-1-yl)-4,5-dimethoxyphenyl)acetate (D) 1H NMR (500MHz, CDCl3) δ6.91(s,1H),6.76(s,1H),3.87(s,3H),3.84(s,3H),3.79(q,J =6.2Hz,2H),3.74(s,2H),3.69(s,3H),3.35(t,J=6.4Hz,1H),2.67(t,J=6.2Hz,2H). 13 C NMR (126MHz, CDCl3) δ172.22,148.90,147.71,129.03,115.62,114.33,112.78,90.28,80.12,61.06,55.86,52.16,39.76,23.95.HRMS(ESI)m / z:calcd for C 15 H 19 O5([M+H] + )279.1227,found279.1224.

[0073] Among them, the reaction for synthesizing compound E is a catalytic hydrogenation reduction reaction, and the reaction principle is to utilize hydrogen to combine with palladium carbon to activate hydrogen to form free hydrogen, and then carry out a reduction reaction. In some specific embodiments, the step of synthesizing compound E comprises: under a hydrogen atmosphere (1atm), adding ethanol (10mL) to a round-bottom flask containing D (1.90g, 6.83mmol) and Pd / C (0.68mmol, 10% w / t). The mixture is stirred at room temperature for 12 hours. Afterwards, the mixture is filtered and washed with dichloromethane. The filtrate is concentrated under reduced pressure. The residue obtained is purified by flash silica gel column chromatography to obtain E with a yield of 80%. 2-(2-(4-hydroxybutyl)-4,5-dimethoxyphenyl)acetic acid methyl ester (E). 1 H NMR (400MHz, CDCl3) δ6.71(dd,J=9.0,4.8Hz,2H),5.46(s,1H),3.83(d,J=6.7Hz,6H),3.72–3.53(m,8H),3.37(dd,J=14.9,7.7Hz,3H),2.56(s,2H). 13 C NMR (101MHz, CDCl3) δ172.65,147.97,146.89,133.38,123.79,113.72,112 .62,62.04,55.81,55.76,51.95,37.83,32.30,27.27.HRMS(ESI)m / z:[M+H] + calcd.for[C 15 H 23 O5] +:283.1540,found:283.1537.

[0074] Among them, the reaction type for synthesizing compound F is the condensation reaction of alcohol. The reaction principle is that tetrahydropyran is protonated under acidic conditions, and the protonated intermediate reacts with alcohol to condense to form compound F. In some specific embodiments, the steps for synthesizing compound F include: adding 3,4-dihydro-2H-pyran (918 mg, 10.91 mmol) and p-toluenesulfonic acid (94 mg, 0.55 mmol) to a solution of E (1.545 g, 5.45 mmol) in dichloromethane (15.0 mL) under argon atmosphere. After stirring for 30 minutes, the reaction mixture was quenched with aqueous sodium bicarbonate solution (saturated, 5.0 mL), extracted with ethyl acetate (3×20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography to obtain F with a yield of 60%. 2-(4,5-dimethoxy-2-(4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)phenyl)acetate (F) 1 H NMR (400MHz, CDCl3) δ6.71(s,1H),6.67(s,1H),4.57–4.54(m,1H),3.88–3.80(m,1H),3.84(s,3H),3.83(s,3H),3.79–3.72(m,1 H),3.66(s,3H),3.57(s,2H),3.50–3.44(m,1H),3.43–3.35(m,1H),2.57(t,J=7.5Hz,2H),1.84–1.76(m,1H),1.72–1.45(m,9H). 13 C NMR (101MHz, CDCl3) δ172.37,148.06,147.02,133.38,123.88,113.62,112.64,98.89,67.34,62 .33,55.94,55.87,51.97,37.93,32.49,30.75,29.61,27.92,25.47,19.66.HRMS(ESI)m / z:calcd forC 20 H 30 O6Na([M+Na] + )389.1935,found389.1929.

[0075] Among them, the reaction type for synthesizing compound G is a reduction reaction, and the reaction principle is to use lithium aluminum hydride as a reducing agent to reduce the ester group. In some specific embodiments, lithium aluminum hydride (187 mg, 4.91 mmol) is added to a tetrahydrofuran solution of F (1.20 g, 3.27 mmol) at 0 ° C (ice bath) under an argon atmosphere. The resulting mixture is stirred at 70 ° C until F is completely consumed (TLC monitoring). Then, after carefully adding a minimum amount of water to quench the excess lithium aluminum hydride, the reaction mixture is filtered and washed with ethyl acetate. The combined organic portion is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to obtain G as a colorless oil with a yield of 86%. 2-(4,5-dimethoxy-2-(4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)phenyl)ethan-1-ol (G). 1 H NMR(400MHz, CDCl3)δ6.68(s,1H),6.67(s,1H),4.57–4.53(m,1H),3.90–3.83(m,1H),3.84(s,3H),3.83(s,3H),3.81–3.75(m,3H),3 .51–3.45(m,1H),3.44–3.38(m,1H),2.83(t,J=7.0Hz,2H),2.63–2.56(m,2H),1.95(brs,1H),1.86–1.76(m,1H),1.74–1.44(m,9H). 13 C NMR (101MHz, CDCl3) δ147.45,147.03,133.23,127.84,113.21,112.87,99.18,67.38,63.57, 62.64,55.97,55.93,35.63,32.22,30.79,29.58,28.40,25.44,19.82.HRMS(ESI)m / z:calcd for C 19 H 30 O5Na([M+Na] + )361.1985,found361.1982.

[0076] The reaction type for synthesizing Compound H is an esterification reaction. The reaction principle involves condensing p-toluenesulfonyl chloride and Compound G to form an ester to produce Compound H. Triethylamine, as a base, binds to the byproduct HCl, promoting the reaction toward the product. 4-(Dimethylamino)pyridine, as a nucleophile, enhances the activity of the reactant p-toluenesulfonyl chloride. In some embodiments, the steps for synthesizing Compound H include: adding p-toluenesulfonyl chloride (803 mg, 4.21 mmol), triethylamine (426 mg, 4.21 mmol), and 4-(dimethylamino)pyridine (35 mg, 0.28 mmol) to a solution of Compound G (951 mg, 2.81 mmol) in dichloroethane (10.0 mL), and stirring the resulting mixture at room temperature under an argon atmosphere for 12 hours. After adding 20 mL of water to quench the reaction, the mixture was extracted with ethyl acetate (2 x 30 mL). The combined organic fractions were washed with saturated sodium bicarbonate solution (10.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford H as a colorless oil in 72% yield: 4,5-dimethoxy-2-(4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)phenethyl 4-methylbenzenesulfonate (H). 1 H NMR (500MHz, CDCl3) δ7.68(d,J=8.3Hz,2H),7.28(d,J=8.1Hz,2H),6.63(s,1H),6.53(s,1 H),4.57(dd,J=8.6,6.1Hz,1H),4.15(d,7.2Hz,2H),3.90–3.84(m,1H),3.85(s,3H),3.79– 3.73(m,1H),3.78(s,3H),3.53–3.49(m,1H),3.44–3.35(m,1H),2.92(t,J=7.3Hz,2H),2. 49(t,J=7.6Hz,2H),2.43(s,3H),1.86–1.78(m,1H),1.75–1.68(m,1H),1.66–1.59(m,8H). 13 C NMR (126MHz, CDCl3) δ147.80,147.01,144.67,133.13,132.94,129.73,127.76,125.45,112.90,112.60,98.96,7 0.47,67.27,62.44,55.86,55.85,32.09,31.78,30.77,29.56,28.27,25.46,21.58,19.74.HRMS(ESI)m / z:calcd for C 26 H 36 O7SNa([M+Na]+ )515.2074,found 515.2070.

[0077] Among them, the reaction for synthesizing azide compound A-2 is a nucleophilic substitution reaction. The reaction principle is to use N 3- The nucleophile NaN3 replaces the leaving group OTs - . In some specific embodiments, the step of synthesizing the azide compound A-2 comprises: adding sodium azide (190 mg, 2.93 mmol) to a solution of compound H (1.00 g, 1.95 mmol) in dimethylformamide (10.0 mL) under an argon atmosphere. The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the crude product was extracted with diethyl ether (10.0 mL×3). The combined organic layer was washed with water (10.0 mL×4), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the azide compound A-2 with a yield of 81%. 2-(4-(2-(2-azidoethyl)-4,5-dimethoxyphenyl)butoxy)tetrahydro-2H-pyran (A-2) 1 H NMR(400MHz, CDCl3)δ6.66(s,1H),6.64(s,1H),4.56–4.53(m,1H),3.87–3.81(m,1H),3.82(s,6H),3.78–3.73(m,1H),3.43–3.38(m,1H),3.4 2–3.38(m,1H),3.41(t,J=7.5Hz,2H),2.82(t,J=7.5Hz,2H),2.57(t,J=7.7Hz,2H),1.84–1.75(m,1H),1.72–1.60(m,5H),1.57–1.46(m,4H). 13 C NMR (101MHz, CDCl3) δ147.76,147.15,132.95,127.40,112.83,112.79,98.90,67.26,62.34, 55.97,55.87,52.35,32.18,31.81,30.76,29.62,28.37,25.48,19.68.HRMS(ESI)m / z:calcd forC 19 H 29 N3O4Na([M+Na] + )386.2050,found386.2044.

[0078] Among them, the reaction type of the synthetic product compound B-2 is an iron nitride amination reaction. The reaction principle is that after the iron porphyrin and the azide substrate are combined, a nitrogen molecule is removed to form an iron nitride intermediate for an amination ring-closure reaction. In some specific embodiments, the steps of synthesizing the product compound B-2 include: adding the azide compound A-2 (218 mg, 0.60 mmol), di-tert-butyl dicarbonate (262 mg, 1.20 mmol) and [FeIII (TDCPP) (IMe) 2] I (15.4 mg, 0.012 mmol) to a round-bottom flask, and the reaction flask is purged with argon three times. Then, toluene (3.0 mL) is injected into the flask, and the resulting mixture is stirred at 150 ° C (oil bath) for 0.5 h. TLC analysis shows that the azide compound 3 is completely consumed. After concentration under reduced pressure, the residue is purified by silica gel flash column chromatography to obtain the corresponding product compound B-2, i.e., a tetrahydroisoquinoline compound, with a yield of 72%. 6,7-dimethoxy-1-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (B-2) (2:3 dual stereoisomers). Figure 5 As shown, 1 H NMR (400 MHz, CDCl3) δ 6.61–6.54 (m, 2H), 5.15–4.90 (m, 1H), 4.55 (m, 1H), 4.26–3.92 (m, 1H), 3.89–3.70 (m, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 3.50–3.37 (m, 2H), 3.30–3.04 (m, 1H), 2.90–2.72 (m, 1H), 2.65–2.52 (m, 1H), 1.88–1.40 (m, 10H), 1.46 (s, 9H). Figure 6 As shown, 13 C NMR (101MHz, CDCl3) δ154.86,147.33,129.96,126.33,111.53,109.97,98.95,79.82,67.30,62.36,56. 02,55.89,54.31,38.24,36.61,33.81,33.31,30.77,28.49,26.66,25.46,19.68.HRMS(ESI)m / z:calcd for C 24 H 37 NO6Na([M+Na] + )458.2513,found458.2509.

[0079] Furthermore, wherein, p-toluenesulfonic acid is used as a catalyst to hydrolyze the product compound B-2 under acidic conditions to generate compound B-2-1. In some specific embodiments, the synthesis step of compound B-2-1 comprises: under an argon atmosphere, a mixture of compound tetrahydroisoquinoline 4 (190 mg, 0.44 mmol) and a catalytic amount of recrystallized 4-toluenesulfonic acid (7.6 mg, 0.044 mmol) is stirred in methanol (8.80 mL) at 25°C for 10 hours. Subsequently, sodium bicarbonate is added and the solution is concentrated to one-third. After dilution with brine, the aqueous suspension is extracted 4 times with ether. The combined ether extracts are dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography to obtain compound B-2-1 (yield 73%). 3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-1-ol (5). As shown in the attached Figure 7 As shown, 1 H NMR(500MHz, CDCl3)δ6.59(s,1H),6.56(s,1H),5.00–4.77(br,2H),3.94( dd,J=8.1,3.1Hz,1H),3.86(s,3H0,3.85(s,3H),3.68–3.64(m,1H),3.59–3 .51(m,1H),3.23–3.16(m,1H),3.08–3.01(m,1H),2.77(dt,J=16.1,5.6Hz, 1H),2.67(dt,J=16.2,6.0Hz,1H),2.00–1.94(m,2H),1.84–1.66(m,2H).As attached Figure 8 As shown, 13 C NMR(126MHz, CDCl3)δ147.51,147.39,130.38,126.71,111.69,109.38,62.83,56.04,55.84,55.44,39.73,35.66,30.65,28.75.HRMS(ESI)m / z:[M+H] + calcd.for[C 14 H 22 NO3] + :252.1594,found:252.1592.

[0080] Furthermore, 8,9-dimethoxy-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline (crispine A) can be synthesized from compound B-2-1. 1H NMR (400MHz, CDCl3) δ6.59(s,1H),6.55(s,1H),3.83,(s,3H),3.82(s,3H),3.51–3.46(m,1H),3.15(ddd,J=11.1 ,6.0,3.0Hz,1H),3.08–2.94(m,2H),2.76–2.57(m,3H),2.37–2.27(m,1H),1.99–1.80(m,2H),1.77–1.67(m,1H). 13 C NMR (101MHz, CDCl3) δ147.41,147.30,130.54,126.06,111.33,108.89,62.76,56.00,55.89,53.09,48.20,30.61,27.82,22.25.HRMS(ESI)m / z:calcd for C 14 H 20 NO2([M+H] + )234.1489,found234.1486.

[0081] In some possible implementations, the steps of preparing the product compound B-3 include: using methyl 2-(2-iodo-4,5-dimethoxyphenyl)acetate as a raw material, sequentially performing a Wittig reaction, a hydroboration oxidation reaction, an esterification reaction, and a nucleophilic substitution reaction to obtain an azide compound A-3; dissolving the azide compound A-3 and an amino protecting agent in an organic solvent, reacting in an inert atmosphere at a temperature of 100 to 200° C. for 0.5 to 1 hour, and isolating to obtain the product compound B-3.

[0082] In some specific embodiments, the process route for synthesizing the product compound B-3 is:

[0083]

[0084] Wherein, 1-(3,4-dimethoxyphenyl)cyclohexane-1-carbaldehyde was purchased commercially or synthesized according to documented methods.

[0085] Among them, the reaction type for synthesizing compound I is the Wittig reaction, and reaction principle 1 is to use hydrocarbon bromide to react with triphenylphosphine to generate a ylide reagent, which is then reacted with an aldehyde to obtain an olefin. In some specific embodiments, the steps for synthesizing compound I include: injecting anhydrous tetrahydrofuran into a Witting reagent (4.144 g, 11.60 mmol) and tert-butyl potassium (1.301 g, 11.60 mmol), and stirring the mixture under an argon atmosphere for half an hour. Then, 1-(3,4-dimethoxyphenyl)cyclohexane-1-carboxaldehyde (2.399 g, 9.66 mmol) dissolved in tetrahydrofuran is added, and the reaction mixture is further stirred at room temperature for 18 hours. After dilution with water, the mixture is extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel chromatography to obtain I with a yield of 76%. 1,2-dimethoxy-4-(1-vinylcyclohexyl)benzene (I). 1 H NMR (500MHz, CDCl3) δ6.95–6.90(m,2H),6.84(d,J=8.3Hz,1H),5.84(dd,J=17.6,10.7Hz,1H),5.07(dd,J=10.7,0.8Hz,1H),4.91(dd,J=1 7.6,0.9Hz,1H),3.89(s,3H),3.88(s,3H),2.05–1.97(m,2H),1.89–1.82(m,2H),1.66–1.57(m,2H),1.56–1.40(m,3H),1.45–1.39(m,1H). 13 C NMR(126MHz, CDCl3)δ148.59,147.59,146.96,139.68,118.86,112.25,110.82,110.66,55.86,55.78,44.43,36.07,26.37,22.58.HRMS(ESI)m / z:calcd for C 16 H 23 O2([M+H] + )247.1693,found247.1689.

[0086] Among them, the reaction type for synthesizing compound J is a hydroboration oxidation reaction, and the reaction principle is the process of olefin addition with borane and then oxidation to form alcohol. In some specific embodiments, the synthesis of compound J is carried out at 0°C and under a nitrogen atmosphere. To a solution of compound I (700 mg, 2.84 mmol) in tetrahydrofuran (30 mL) is added a tetrahydrofuran solution of borane (3.41 mL, 3.41 mmol, 1.0 mol / L), and the resulting mixture is stirred at room temperature for 3 hours. Then, the mixture is cooled to 0°C, water (2.0 mL) is added dropwise, followed by 10% aqueous sodium hydroxide solution (5.0 mL) and 35% hydrogen peroxide solution (1.5 mL). After stirring for another 30 minutes, the reaction mixture is extracted with diethyl ether (3×20 mL). The combined organic phases are washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel flash column chromatography to obtain J with a yield of 77%. 2-(1-(3,4-dimethoxyphenyl)cyclohexyl)ethan-1-ol (J). 1 H NMR (400MHz, CDCl3) δ6.88–6.82(m,2H),6.83–6.79(m,1H),3.86(s,3H),3.84(s,3H),3.37(t,J=7. 3Hz, 2H), 2.03 (dd, J=12.4, 6.4Hz, 2H), 1.80 (t, J=7.3Hz, 2H), 1.62–1.51 (m, 4H), 1.44–1.35 (m, 4H). 13 C NMR(101MHz, CDCl3)δ148.78,146.87,139.03,118.88,110.98,110.18,59.37,55.94,55.79,39.80,36.71,26.45,22.23.HRMS(ESI)m / z:calcd for C 16 H 23 O2([M–OH] + )247.1693,found247.1688.

[0087] The reaction type for synthesizing compound K is an esterification reaction, and the reaction principle is to use p-toluenesulfonyl chloride and compound G to condense into an ester to produce compound K. In some specific embodiments, the steps of synthesizing compound K include: adding p-toluenesulfonyl chloride (541 mg, 2.83 mmol), triethylamine (286 mg, 2.83 mmol) and 4-(dimethylamino)pyridine (23 mg, 0.189 mmol) to a solution of compound J (500 mg, 1.89 mmol) in dichloroethane (10.0 mL), and stirring the resulting mixture at room temperature under an argon atmosphere for 12 hours. The mixture is extracted with ethyl acetate (2 x 30 mL). The combined organic fractions are washed with saturated sodium bicarbonate solution (10.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to obtain K as a colorless oil with a yield of 89%. 2-(1-(3,4-dimethoxyphenyl)cyclohexyl)ethyl 4-methylbenzenesulfonate (K). 1 H NMR (500MHz, CDCl3) δ7.64(d,J=8.3Hz,2H),7.28(d,J=8.0Hz,2H),6.77–6.71(m,3H),3.86(s,3H),3.83(s,3H),3.73(t ,J=7.4Hz,2H),2.43(s,3H),1.98(dd,J=12.4,5.5Hz,2H),1.87(t,J=7.4Hz,2H),1.58–1.47(m,4H),1.43–1.33(m,4H). 13 C NMR (126MHz, CDCl3) δ148.80,147.01,144.59,137.64,133.02,129.71,127.74,118.84,110 .89,109.86,67.98,55.84,55.76,39.88,36.47,26.21,22.12,21.60.HRMS(ESI)m / z:calcd forC 23 H 30 O5SNa([M+Na] + )441.1706,found441.1698.

[0088] Among them, the reaction type for synthesizing azide compound A-3 is a nucleophilic substitution reaction, and the reaction principle is to use N 3- The nucleophile NaN3 replaces the leaving group OTs -. In some specific embodiments, the step of synthesizing the azide compound B-3 comprises: adding sodium azide (163 mg, 2.51 mmol) to a solution of compound K (700 mg, 1.67 mmol) in DMF (10.0 mL). The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the crude product was extracted with diethyl ether (10.0 mL×3). The combined organic layer was washed with water (10.0 mL×4), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain azide compound A-3 with a yield of 83%. 4-(1-(2-azidoethyl)cyclohexyl)-1,2-dimethoxybenzene (A-3). 1 H NMR(500MHz, CDCl3)δ6.84(s,3H),3.88(s,3H),3.87(s,3H),2.94–2.88(m,2H),2.0 6(dd,J=13.0,6.1Hz,2H),1.84–1.79(m,2H),1.63–1.52(m,4H),1.48–1.36(m,4H). 13 CNMR(126MHz, CDCl3)δ148.85,147.02,137.96,118.96,110.96,110.02,55.94,55.77,47.41,41.99,39.99,36.47,26.37,22.22.HRMS(ESI)m / z:calcd for C 16 H 24 NO2([M–N2+H] + )262.1802,found262.1796.

[0089] Among them, the reaction type of the synthetic product compound B-3 is an iron nitride amination reaction. The reaction principle is that after the iron porphyrin and the azide substrate are combined, a nitrogen molecule is removed to form an iron nitride intermediate for an amination ring-closure reaction. In some specific embodiments, the steps of synthesizing the product compound B-3 include: adding the azide compound A-3 (58 mg, 0.20 mmol), di-tert-butyl dicarbonate (87 mg, 0.40 mmol) and [FeIII (TDCPP) (IMe) 2] I (5.1 mg, 0.004 mmol) to a round-bottom flask, and then the reaction flask is purged with argon three times. Then, toluene (3.0 mL) is injected into the flask, and the resulting mixture is stirred at 150 ° C (oil bath) for 0.5 h. TLC analysis shows that the azide compound A-3 is completely consumed. After evaporation under reduced pressure, the residue is purified by flash column chromatography on silica gel to obtain the product compound B-3 with a yield of 95%. tert-Butyl 3a-(3,4-dimethoxyphenyl)octahydro-1H-indole-1-carboxylate (B-3) (1:1 dual stereoisomers). Figure 9 As shown, 1 H NMR (400 MHz, CDCl3) δ 6.83 (m, 3H), 4.29–4.06 (m, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.41–3.23 (m, 1H), 3.14–2.95 (m, 1H), 2.40–2.27 (m, 1H), 2.20–2.02 (m, 2H), 1.92–1.81 (m, 1H), 1.72–1.20 (m, 6H), 1.47 (s, 4.5H), 1.41 (s, 4.5H). Figure 10 As shown, 13 C NMR (101MHz, CDCl3) δ154.33,148.60,147.01,140.54,117.81,110.92,109.26,78.99,59 .56,55.83,46.97,43.56,35.48,32.22,29.16,28.67,23.39,22.43.HRMS(ESI)m / z:calcd for C 21 H 31 NO4Na([M+Na] + )384.2145,found 384.2152.

[0090] Furthermore, the alkaloid (3aS, 7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indole (mesembrane) can be synthesized from the product compound B-3 according to the literature method.

[0091] In some possible implementations, the steps of preparing the product compound B-4 include: using (3-ethyl-2,3,4,9-tetrahydro-1H-carbazole-3-yl)methanol as a raw material, sequentially performing oxidation reaction, Horner-Wadsworth-Emmons reaction, catalytic hydrogenation reduction reaction, cyanide reduction reaction, aldehyde reduction reaction, esterification reaction and nucleophilic substitution reaction to obtain the azide compound A-4; dissolving the azide compound A-4 and an amino protecting agent in an organic solvent, reacting in an inert atmosphere at a temperature of 100-200°C for 0.5-1 hour, and isolating the product compound B-4.

[0092] In some specific embodiments, the process route for synthesizing the product compound B-4 is:

[0093]

[0094] Wherein, (3-ethyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl)methanol was purchased commercially or synthesized according to the documented method.

[0095] The reaction type for synthesizing compound L is an oxidation reaction. The reaction principle is to use sulfur trioxide pyridine as an oxidant to oxidize alcohol to aldehyde. In some specific embodiments, the step of synthesizing compound L comprises: under an argon atmosphere, adding dry dimethyl sulfoxide (5.0 mL) and dry triethylamine (5.0 mL) to a solution of (3-ethyl-2,3,4,9-tetrahydro-1H-carbazole-3-yl)methanol (1.147 g, 5.00 mmol) in dichloromethane (10.0 mL) in an ice-water bath. After adding solid pyridine sulfur trioxide (955 mg, 6.00 mmol) in batches at the same temperature, the reaction mixture is slowly warmed to room temperature and stirred for 2 h. Saturated aqueous ammonium chloride is added to the reaction mixture and extracted with dichloromethane (3×20 mL). The combined organic phases are washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to obtain compound L with a yield of 87%. 3-Ethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carbaldehyde (L). 1 H NMR(500MHz, CDCl3)δ9.56(s,1H),7.77(s,1H),7.55(d,J=7.4Hz,1H),7.28(d,J=7.5Hz,1H),7.20–7.13(m,2H),3.16(d,J=15.1Hz,1H),2.84–2.76 (m,1H),2.75–2.65(m,1H),2.66(d,J=15.1Hz,1H),2.28–2.21(m,1H),1.8 7(ddd,J=13.6,9.0,6.4Hz,1H),1.80–1.67(m,2H),0.99(t,J=7.6Hz,3H). 13 C NMR (126MHz, CDCl3) δ206.84,136.22,133.47,127.51,121.43,119.29,117.74, 110.59,107.77,49.63,28.61,27.48,26.59,19.98,8.47.HRMS(ESI)m / z:calcd for C 15 H 18 NO([M+H] + )228.1383,found 228.1384.

[0096] The reaction type for synthesizing Compound M is the Wittig-Horner reaction (Horner-Wadsworth-Emmons reaction), which involves the addition of a phosphonate-stabilized carbanion to an aldehyde to form a β-hydroxyphosphine oxide, which then reacts with a base to eliminate the olefin. The stable phosphonate carbanion, instead of a phosphonium ylide, reacts with the aldehyde to form an olefin, primarily producing an E-type olefin. In some specific embodiments, the steps for synthesizing Compound M include: under an argon atmosphere, injecting anhydrous tetrahydrofuran (5.0 mL) into Compound L (950 mg, 4.18 mmol) and diethyl cyanomethylphosphonate (1.051 g, 5.93 mmol), followed by the addition of lithium hydroxide (150 mg, 6.27 mmol). The reaction mixture is heated under reflux under an argon atmosphere for 20 hours and then concentrated under reduced pressure. Ether (20 mL) is added to the resulting residue, which is then washed with water (2 x 10 mL) and brine (10 mL). The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give Compound M in 83% yield. (E)-3-(3-Ethyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl)acrylonitrile (M). 1 HNMR (400MHz, CDCl3) δ7.81 (s, 1H), 7.49 (d, J = 7.5Hz, 1H), 7.31 (dd, J = 7.2, 0.9Hz, 1H), 7.17(td,J=7.1,1.2Hz,1H),7.13(td,J=7.1,1.2Hz,1H),6.66(d,J=16.8Hz,1H),5.17( d,J=16.8Hz,1H),2.84(d,J=15.8Hz,1H),2.73(dt,J=11.1,5.0Hz,1H),2.67–2.57(m,1 H),2.63(d,J=15.8Hz,1H),1.95–1.85(m,2H),1.68–1.56(m,2H),0.94(t,J=7.5Hz,3H). 13 C NMR (101MHz, CDCl3) δ161.34,136.21,132.85,127.29,121.49,119.35,117.88,117.58,1 10.66,107.57,99.33,41.62,33.11,32.55,28.72,20.41,8.38.HRMS(ESI)m / z:calcdfor C 17 H 19 N2([M+H] + )251.1543,found251.1543.

[0097] Among them, the reaction type for synthesizing compound N is a catalytic hydrogenation reduction reaction, the principle of which is to use hydrogen to combine with palladium carbon to activate hydrogen to form free hydrogen, and then carry out a reduction reaction. In some specific embodiments, the step of synthesizing compound N includes: injecting ethanol (10.0 mL) into a round-bottom flask containing M (850 mg, 3.40 mmol) and Pd / C (0.40 mmol, 10 wt% Pd) under a hydrogen atmosphere (1 atm). The resulting mixture is stirred at room temperature for 18 hours. Thereafter, the mixture is filtered and washed with ethanol. The filtrate is concentrated under reduced pressure and purified by flash column chromatography on silica gel to obtain compound N with a yield of 80%. 3-(3-ethyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl)propionitrile (N). 1 HNMR(400MHz, CDCl3)δ7.72(s,1H),7.41(d,J=7.5Hz,1H),7.27–7.20(m,1H),7.09(dtd,J=17.5,7.1,1.2Hz,2H),2.6 8–2.58(m,2H),2.51–2.42(m,2H),2.26(t,J=8.2Hz,2H),1.81–1.61(m,4H),1.47–1.27(m,2H),0.87(t,J=7.5Hz,3H). 13 C NMR (101MHz, CDCl3) δ136.25,132.60,127.90,121.25,120.63,119.19,117.61,110.65,10 8.02,35.23,31.51(d,J=15.3Hz),31.06,28.32,19.87,11.89,7.80.HRMS(ESI)m / z:[M+H] + calcd.for[C 17 H 21 N2] + :253,1699,found:253.1700.

[0098] The reaction type for synthesizing Compound O is a reduction reaction, and the principle is to use diisobutylaluminum hydride DIBAL-H as a reducing agent to reduce the cyano group to an aldehyde group at low temperature. In some specific embodiments, the steps for synthesizing Compound O include: adding diisobutylaluminum hydride (677 mg, 4.76 mmol) dropwise to a solution of Compound N (601 mg, 2.38 mmol) in dichloromethane (5.0 mL) at -78°C, further stirring at this temperature for 2 hours, and then gradually warming to room temperature. The reaction mixture is quenched with saturated sodium bicarbonate, extracted with dichloromethane (3×15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography to obtain Compound O with a yield of 77%. 3-(3-ethyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl)propanal (O). 1 H NMR(400MHz, CDCl3)δ9.79(t,J=1.8Hz,1H),7.73(s,1H),7.46(d,J=7.4Hz,1H),7.30–7.26(m,1H),7.16–7.08(m,2H),2 .70(td,J=6.4,1.0Hz,2H),2.54(s,2H),2.50–2.43(m,2H),1.81–1.66(m,4H),1.53–1.35(m,2H),0.91(t,J=7.5Hz,3H). 13 C NMR (101MHz, CDCl3) δ202.99,136.18,132.78,128.05,121.11,119.11,117.60,110.47 ,108.63,38.72,34.81,31.81,31.32,28.65,27.75,20.01,7.80.HRMS(ESI)m / z:calcd for C 17 H 22 NO([M+H] + )256.1696,found256.1696.

[0099] Among them, the reaction type for synthesizing compound P is a reduction reaction, and the principle is to use sodium borohydride as a reducing agent to reduce the aldehyde group to an alcohol. In some specific embodiments, the step of synthesizing compound P comprises: adding sodium borohydride (100 mg, 2.64 mmol) to a solution of compound O (450 mg, 1.76 mmol) in methanol (5.0 mL) at 0°C, and then stirring the reaction mixture at room temperature overnight. Thereafter, the reaction mixture is diluted with water, extracted with dichloromethane (3×10.0 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography to obtain compound P with a yield of 86%. 3-(3-ethyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl)propan-1-ol (P). 1 H NMR(500MHz, CDCl3)δ7.75(s,1H),7.48(d,J=7.6Hz,1H),7.29(d,J=8.7Hz,1H),7.13(td,J=7.2,1.0Hz,1H),7.10(td,J=7.2,1.0Hz,1H),3.73–3.5 4(m,2H),2.70(t,J=6.4Hz,2H),2.55(s,2H),1.76(t,J=6.4Hz,2H),1.66– 1.59(m,2H),1.55–1.46(m,2H),1.45–1.36(m,2H),0.93(t,J=7.5Hz,3H). 13 C NMR (126MHz, CDCl3) δ136.14,133.07,128.20,120.96,119.02,117.62,110.42,109.0 4,63.87,34.94,31.99,31.67,36.63,28.95,26.83,20.09,7.87.HRMS(ESI)m / z:calcd for C 17 H 24 NO([M+H] + )258.1852,found258.1854.

[0100] The reaction type for synthesizing Compound Q is an esterification reaction, which involves condensing p-toluenesulfonyl chloride and Compound P to form an ester to produce Compound Q. In some specific embodiments, the steps for synthesizing Compound Q include adding 4-dimethylaminopyridine (17 mg, 0.13 mmol), p-toluenesulfonyl chloride (389 mg, 2.04 mmol), and triethylamine (206 mg, 2.04 mmol) to a solution of Compound P (350 mg, 1.36 mmol) in dichloromethane (5.0 mL) at 0°C, and stirring the resulting mixture overnight at room temperature under an argon atmosphere. After adding water (20 mL) to quench the reaction, the mixture was extracted with dichloromethane (3 × 10.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography to obtain Compound Q in an 81% yield. 3-(3-ethyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl)propyl-4-methylbenzenesulfonate (Q). 1 HNMR (500MHz, CDCl3) δ7.78(d,J=8.3Hz,2H),7.77(s,1H),7.44(d,J=7.6Hz,1H),7. 30(d,J=7.6Hz,1H),7.28(d,J=8.3Hz,2H),7.13(td,J=7.2,1.1Hz,1H),7.10(td,J= 7.2,1.1Hz,1H),4.09–3.98(m,2H),2.71–2.60(m,2H),2.51–2.42(m,2H),2.43(s,3 H),1.74–1.65(m,4H),1.48–1.32(m,3H),1.30–1.21(m,1H),0.87(t,J=7.5Hz,3H). 13 C NMR (126MHz, CDCl3) δ144.74,136.16,133.05,132.91,129.85,128.11,127.88,121.01,119.03,117.57,1 10.49,108.72,71.51,34.89,31.79,31.48,31.25,28.89,23.28,21.64,19.97,7.79.HRMS(ESI)m / z:calcd for C 24 H 30 NO3S([M+H] + )412.1941,found412.1942.

[0101] Among them, the reaction type of synthesizing azide compound A-4 is a nucleophilic substitution reaction. The reaction principle is to use N 3- The nucleophile NaN3 replaces the leaving group OTs -. In some specific embodiments, the step of synthesizing azide compound A-4 comprises: adding sodium azide (95 mg, 1.46 mmol) in batches to a solution of compound Q (400 mg, 0.97 mmol) in anhydrous dimethylformamide (6.0 mL). The mixture is stirred at room temperature overnight. Water is added to the reaction mixture, and the crude product is extracted with ethyl acetate (3×10.0 mL). The combined organic layers are washed with water to remove dimethylformamide, filtered and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to obtain azide compound A-4 with a yield of 89%. 3-(3-azidopropyl)-3-ethyl-2,3,4,9-tetrahydro-1H-carbazole (A-4). 1 H NMR(400MHz, CDCl3)δ7.56(s,1H),7.42(d,J=7.2Hz,1H),7.21(dd,J=7.0,1.2Hz,1H),7.12–7.04(m,2H),3.28–3.14(m,2H),2.62 (t,J=6.3Hz,2H),2.49(s,2H),1.74–1.66(m,2H),1.63–1.55(m,2H),1.50–1.40(m,2H),1.38–1.28(m,2H),0.87(t,J=7.5Hz,3H). 3 C NMR (101MHz, CDCl3) δ136.19,132.99,128.20,121.06,119.11,117.68,110.51,108.9 0,52.35,35.13,32.90,31.99,31.64,28.90,23.19,20.07,7.90.HRMS(ESI)m / z:calcd forC 17 H 23 N4([M+H] + )283.1917,found283.1918.

[0102] Among them, the reaction type of the synthetic product compound B-4 is an iron nitride amination reaction. The reaction principle is that after the iron porphyrin and the azide substrate are combined, a nitrogen molecule is removed to form an iron nitride intermediate for an amination ring-closure reaction. In some specific embodiments, the steps of synthesizing the product compound B-4 include: adding the azide compound A-4 (87 mg, 0.40 mmol), di-tert-butyl dicarbonate (0.80 mmol) and [FeIII (TDCPP) (IMe) 2] I (5.1 mg, 0.0040 mmol) to a round-bottom flask, and then the reaction flask is purged with argon three times. Then, toluene (2.0 mL) is injected into the flask, and the resulting mixture is stirred at 150 ° C (oil bath) for 0.5 h. TLC analysis shows that the azide compound A-4 is completely consumed. After concentration under reduced pressure, the residue is purified by silica gel flash column chromatography to obtain the product compound B-4 with a yield of 46%. Di-tert-butyl-4a-ethyl-3,4,4a,5,6,11c-hexahydro-1H-pyrido[3,2-c]carbazole-1,7(2H)-dicarboxylate (B-4). Figure 11 As shown, 1 H NMR (400MHz, CDCl3) δ8.19–8.10(m,1H),7.38–7.31(m,1H),7.26–7.22(m,1 H),7.20–7.14(m,1H),5.28–5.17(m,1H),4.10–3.85(m,1H),3.17–3.05(m, 1H),2.99–2.85(m,1H),2.45–2.27(m,1H),1.88–1.42(m,6H),1.68(s,9H), 1.54(s,9H),1.49–1.42(m,2H),1.33–1.24(m,2H),0.91(t,J=6.4Hz,3H).As attached Figure 12 As shown, 13 C NMR (101MHz, CDCl3) δ155.49,150.52,146.75,136.30,136.11,128.38,123.45,122.92,118.72,115.31,115.17,85. 21,83.67,79.82,54.40,38.66,34.92,31.59,28.64,28.33,25.93,27.43,22.47,20.57,7.76.HRMS(ESI)m / z:calcd forC 27 H 39 N2O4([M+H] + )455.2904,found455.2914.

[0103] Furthermore, the reaction type for synthesizing compound B-4-1 from product compound B-4 is a hydrolysis reaction, and the reaction principle is to use microwaves to hydrolyze product compound B-4 at high temperature to generate compound B-4-1. In some specific embodiments, the steps for synthesizing compound B-4-1 include: adding a solution of product compound B-4 (40 mg, 0.088 mmol) in 1,1,3,3,3-hexafluoropropane-2-ol (HFIP, 2.0 mL) to a silicon carbide tube. Then, the tube is irradiated under microwaves at 150°C for 2 hours. Thereafter, the reaction mixture is concentrated under reduced pressure, and the residue is purified by flash column chromatography on silica gel to obtain compound B-4-1 (yield 65%). 4a-Ethyl-2,3,4,4a,5,6,7,11c-octahydro-1H-pyrido[3,2-c]carbazole (10). As shown in the attached Figure 13 As shown, 1 H NMR(500MHz,MeOD)δ7.67(d,J=7.6Hz,1H),7.35(d,J=7.9Hz,1H),7.11(dtd,J=21.7,7 .2,1.1Hz,2H),4.31(s,1H),3.17(td,J=12.7,3.7Hz,1H),2.98–2.82(m,2H),2.40(ddd , J=14.2,11.7,6.9Hz,1H),1.98–1.85(m,3H),1.73(ddd,J=19.8,14.6,5.7Hz,2H),1.55(dq,J=15.1,7.6Hz,1H),1.30(td,J=15.0,14.2,8.0Hz,2H),0.93(t,J=7.6Hz,3H). Figure 14 As shown, 13 C NMR(126MHz,MeOD)δ136.71,136.62,125.82,121.32,119.18,116.83,110.65,103.53 ,55.56,43.82,34.61,32.11,28.60,22.95,19.02,17.98,6.32.HRMS(ESI)m / z:calcd for C 17 H 23 N2([M+H] + )255.1856,found255.1854.

[0104] Furthermore, (3aS, 3a1S, 5aR, 10bS)-3a-ethyl-2,3,3a, 3a1,4,5,5a,6,11,12-dodecahydro-1H-indolo[8,1-cd]carbazole (aspidospermidine natural product) can be synthesized from compound B-4-1.

[0105] In some possible implementations, the steps of preparing the product compound B-5 include: using N-(2-benzylphenyl)-2-bromoacetamide (304 mg, 1.00 mmol) in dimethylformamide as a raw material, obtaining the azide compound A-5 through a nucleophilic substitution reaction; dissolving the azide compound A-5 and an amino protecting agent in an organic solvent, reacting in an inert atmosphere at a temperature of 100 to 200° C. for 0.5 to 1 hour, and isolating the product compound B-5.

[0106] In some specific embodiments, the process route for synthesizing the product compound B-5 is:

[0107]

[0108] Wherein, N-(2-benzylphenyl)-2-bromoacetamide was purchased commercially or synthesized according to the documented method.

[0109] Among them, the reaction type for synthesizing azide compound A-5 is a nucleophilic substitution reaction. The reaction principle is to use N 3- The nucleophile NaN3 replaces the leaving group OTs - . In some specific embodiments, the step of synthesizing azide compound A-5 comprises: adding sodium azide (98 mg, 1.50 mmol) to a solution of N-(2-benzylphenyl)-2-bromoacetamide (304 mg, 1.00 mmol) in dimethylformamide (5.0 mL), and stirring the reaction mixture at room temperature for 18 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with water (10 mL×4), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain azide compound A-5 with a yield of 79%. 2-Azido-N-(2-benzylphenyl)acetamide (A-5). 1 H NMR (500MHz, CDCl3) δ7.94(d,J=8.0Hz,1H),7.85(s,1H),7.38–7.30(m,4H),7.20–7.26(m,1H),7.24–7.19(m,3H),4.04(s,2H),4.01(s,2H). 13C NMR(126MHz, CDCl3)δ164.62,138.57,134.93,131.42,131.14,128.88,128.45,127.75,126.93,125.70,123.40,53.06,38.57.HRMS(ESI)m / z:calcd for C 15 H 15 N4O([M+H] + )267.1240,found267.1235.

[0110] Among them, the reaction type of the synthetic product compound B-5 is an iron nitrene amination reaction. The reaction principle is that after the iron porphyrin and the azide substrate are combined, a nitrogen molecule is removed to form an iron nitrene intermediate for an amination ring-closure reaction. In some specific embodiments, the step of synthesizing the product compound B-5 comprises: adding azide compound A-5 (54 mg, 0.20 mmol), di-tert-butyl dicarbonate (87 mg, 0.40 mmol) and [FeIII (TDCPP) (IMe) 2] I (5.1 mg, 0.004 mmol) to a round-bottom flask, and then the reaction flask is purged with argon three times. Then, toluene (3.0 mL) is injected into the flask, and the resulting mixture is stirred at 150 ° C. (oil bath) for 0.5 h. TLC analysis shows that the azide is completely consumed. After concentration under reduced pressure, the residue is purified by silica gel flash column chromatography to obtain the product compound B-5 with a yield of 85%. 2-oxo-5-phenyl-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (B-5). As shown in the attached Figure 15 As shown, 1 H NMR (500 MHz, CDCl3) δ7.76 (d, J = 7.1 Hz, 1H), 7.33 (t, J = 7.5 Hz, 3H), 7.28–7.23 (m, 2H), 7.17 (d, J = 7.4 Hz, 3H), 7.09 (t, J = 7.6 Hz, 1H), 6.21 (s, 1H), 3.99 (s, 2H), 1.48 (s, 9H). Figure 16 As shown, 3 C NMR (126MHz, CDCl3) δ153.22,139.09,136.27,130.92,130.58,128.83,128.70,128.56,1 28.54,127.47,126.58,126.41,124.17,80.34,38.07,38.02,28.29.HRMS(ESI)m / z:calcd for C 20 H 23 N2O3([M+H] +)339.1703,found 339.1705.

[0111] In some possible implementations, the steps of preparing the product compound B-6 include: using (S)-2-azido-3-(4-(3-methylbut-2-en-1-yl)-1H-indol-3-yl)propionic acid as a raw material, sequentially performing an esterification reaction and an amidation reaction to obtain an azide compound A-6; dissolving the azide compound A-6 and an amino protecting agent in an organic solvent, reacting in an inert atmosphere at a temperature of 100 to 200° C. for 0.5 to 1 hour, and isolating to obtain the product compound B-6.

[0112] In some specific embodiments, the process route for synthesizing the product compound B-6 is:

[0113]

[0114] Among them, (S)-2-azido-3-(4-(3-methylbut-2-en-1-yl)-1H-indol-3-yl)propionic acid was purchased commercially or synthesized according to the documented method.

[0115] Wherein, the reaction type of synthetic compound R is esterification, and the reaction principle is to utilize the carboxyl group of substrate and the hydroxyl group of methanol to condense and generate ester.In some specific embodiments, the step of synthetic compound R comprises: to (S)-2-azido-3-(4-(3-methylbut-2-ene-1-yl)-1H-indol-3-yl) propionic acid (119mg, 0.40mmol) in anhydrous methanol (4.0mL) solution, dimethylaminopyridine (9.8mg, 0.08mmol) and dicyclohexylcarbodiimide (165mg, 0.80mmol), and the reaction mixture is stirred at room temperature overnight.After the reaction is completed by TLC inspection, the reaction mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain compound R, with a yield of 82%.(S)-2-azido-3-(4-(3-methylbut-2-ene-1-yl)-1H-indol-3-yl) methyl propionate (R). 1 H NMR (400MHz, CDCl3) δ8.12(s,1H),7.24(d,J=8.1Hz,1H),7.15–7.09(m,2H),6.92(d,J=7.2Hz,1H),5.37–5.32(m,1H),4.15(dd, J=8.6,5.6Hz,1H),3.78(s,3H),3.75(d,J=6.5Hz,2H),3.54(dd,J=15.1,5.5Hz,1H),3.29(dd,J=15.1,8.6Hz,1H),1.77(s,6H). 13C NMR (126MHz, CDCl3) δ170.81,136.89,134.35,132.56,124.81,123.60,123.53,122.40, 120.33,110.62,109.47,63.18,52.58,32.27,29.28,25.65,18.03.HRMS(ESI)m / z:calcd for C 17 H 21 N2O2([M–N2+H] + )285.1598,found285.1599.

[0116] Wherein, the reaction type of synthetic azide compound A-6 is amidation reaction, and the reaction principle is that the amino group of compound R is condensed with di-tert-butyl dicarbonate to form an amide compound.In some specific embodiments, dimethylaminopyridine (6.4mg, 0.052mmol) and di-tert-butyl dicarbonate (63mg, 0.29mmol) are added to a solution of anhydrous tetrahydrofuran (2.60mL) of compound R (81mg, 0.26mmol), and the reaction mixture is stirred at room temperature overnight. After the reaction is completed by TLC inspection, the reaction mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain azide compound A-6 with a yield of 91%.(S)-3-(2-azido-3-methoxy-3-oxopropyl)-4-(3-methylbut-2-ene-1-yl)-1H-indole-1-carboxylic acid tert-butyl ester (A-6). 1 H NMR (500MHz, CDCl3) δ8.07(d,J=7.8Hz,1H),7.47(s,1H),7.25–7.20(m,1H),7.03(d,J=7.3Hz,1H),5.26(t,J=6.3Hz,1H),4.17(dd,J= 8.8,5.3Hz,1H),3.80(s,3H),3.72–3.66(m,2H),3.46(dd,J=15.4,5.2Hz,1H),3.22(dd,J=15.4,8.8Hz,1H),1.74(s,6H),1.66(s,9H). 13 C NMR (126MHz, CDCl3) δ170.55,149.45,136.28,134.60,132.92,127.67,124.75,124.65,123.69,123 .39,115.37,113.45,83.75,62.34,52.74,32.12,29.14,28.22,25.67,18.10.HRMS(ESI)m / z:calcd for C 22 H 29N2O4([M–N2+H] + )385.2122,found 385.2124.

[0117] Among them, the reaction type of the synthetic product compound B-6 is an iron nitride amination reaction. The reaction principle is that after the iron porphyrin and the azide substrate are combined, a nitrogen molecule is removed to form an iron nitride intermediate for an amination ring-closure reaction. In some specific embodiments, the steps of synthesizing the product compound B-6 include: adding azide compound A-6 (83 mg, 0.20 mmol), di-tert-butyl dicarbonate (0.40 mmol) and [FeIII (TDCPP) (IMe) 2] I (5.1 mg, 0.004 mmol) to a round-bottom flask, and then the reaction flask is purged with argon three times. Then, toluene (3.0 mL) is injected into the flask, and the resulting mixture is stirred at 150 ° C (oil bath) for 0.5 h. TLC analysis shows that the azide is completely consumed. After concentration under reduced pressure, the residue is purified by silica gel column chromatography to obtain the product compound B-6 with a yield of 45%. 2,6-di-tert-butyl 3-methyl 1-(2-methylprop-1-en-1-yl)-3,4-dihydro-1H-aza[5,4,3-cd]indole-2,3,6-tricarboxylate (B-6) (1:1 dual stereoisomers). Figure 17 As shown, 1 H NMR (500MHz, CDCl3) δ7.97 (s, 1H), 7.44 (d, J = 12.0Hz, 1H), 7.25–7.21 (m, 1H), 7.10 (d, J = 7.2Hz, 0.5H), 6.96 (d, J = 7. 2Hz,0.5H),6.44(d,J=7.5Hz,0.5H),6.05(d,J=7.9Hz,0.5H),5.40(dd,J=17.1,7.8Hz,1H),5.19(dd,J=12.3,6.7Hz ,0.5H),4.77(dd,J=13.0,5.1Hz,0.5H),3.76(s,1.H),3.74(s,1.5H),3.61–3.52(m,1H),3.38(dd,J=15.6,5.1Hz,1 H),3.28(dd,J=15.6,5.1Hz,1H),1.88(d,J=4.6Hz,3H),1.74(s,3H),1.68(s,9H),1.37(s,4.5H),1.34(s,4.5H).As attached Figure 18 As shown, 13C NMR (126MHz, CDCl3) δ173.13,154.81,139.69,139.18,137.62,124.50,124.14,123.27,120.99,120 .36,117.03,114.11,80.53,60.24,57.59,51.98,28.22,27.21,25.65,18.97.HRMS(ESI)m / z:calcd for C 22 H 29 N2O4([M–Boc+H2] + )385.2122,found 385.2120.

[0118] In some possible implementations, the steps of preparing the product compound B-7 include: using 1-bromo-2-ethyl-4,5-dimethoxybenzene as a raw material, sequentially performing Miyaura borylation reaction, Suzuki reaction, reduction reaction, substitution reaction and nucleophilic substitution reaction to obtain the azide compound A-7; dissolving the azide compound A-7 and an amino protecting agent in an organic solvent, reacting in an inert atmosphere at a temperature of 100 to 200° C. for 0.5 to 1 hour, and isolating to obtain the product compound B-7.

[0119] In some specific embodiments, the process route for synthesizing the product compound B-7 is:

[0120]

[0121] Among them, 1-bromo-2-ethyl-4,5-dimethoxybenzene and 2-iodo-3,4,5-trimethoxybenzoic acid methyl ester compound 2-(benzyloxy)-4-ethyl-1-methoxybenzene were purchased commercially or synthesized according to the document method.

[0122] In some specific embodiments, the compound 2-(benzyloxy)-4-ethyl-1-methoxybenzene is prepared by stirring a mixture of (bromomethyl)benzene (3.70 g, 21.68 mmol), 5-ethyl-2-methoxyphenol (3.00 g, 19.71 mmol), and potassium carbonate (8.16 g, 59.14 mmol) in acetonitrile (20.0 mL) at 80°C overnight. The reaction mixture is then concentrated under reduced pressure, diluted with water, extracted with ethyl acetate (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by flash column chromatography to afford 2-(benzyloxy)-4-ethyl-1-methoxybenzene in an 81% yield. 2-(phenoxy)-4-ethyl-1-methoxybenzene. 1H NMR (400MHz, CDCl3) δ7.57(d,J=7.4Hz,2H),7.44(t,J=7.4Hz,2H),7.37(t,J=7.3Hz,1H),6.96(d,J=8.2Hz,1H),6.88 (d,J=1.8Hz,1H),6.81(dd,J=8.1,1.9Hz,1H),5.18(s,2H),3.91(s,3H),2.72(q,J=7.6Hz,2H),1.38(t,J=7.6Hz,3H). 13 C NMR (101MHz, CDCl3) δ149.93,146.59,137.79,137.66,128.60,127.85,127.5 1,119.78,114.63,112.20,71.28,55.89,28.71,16.05.HRMS(ESI)m / z:calcd for C 16 H 19 O2([M+H] + )243.1380,found243.1381.

[0123] In some specific embodiments, the compound 1-(benzyloxy)-4-bromo-5-ethyl-2-methoxybenzene was prepared. To a solution of 2-(benzyloxy)-4-ethyl-1-methoxybenzene (2.00 g, 8.25 mmol) in ethyl acetate (10.0 mL) were added hydrogen bromide (735 mg, 48 wt% in water, 19.71 mmol) and dimethyl sulfoxide (709 mg, 9.07 mmol), and the reaction mixture was stirred at 60°C overnight. The reaction mixture was then extracted with ethyl acetate (3×20 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash column chromatography to give 1-(benzyloxy)-4-bromo-5-ethyl-2-methoxybenzene in 80% yield. 1-(phenoxy)-4-bromo-5-ethyl-2-methoxybenzene. 1 H NMR (400MHz, CDCl3) δ7.45(d,J=7.3Hz,2H),7.39(t,J=7.3Hz,2H),7.33(t,J=7.2Hz,1H),7.0 7(s,1H),6.77(s,1H),5.10(s,2H),3.88(s,3H),2.69(q,J=7.5Hz,2H),1.22(t,J=7.5Hz,3H). 13C NMR (101MHz, CDCl3) δ149.16,146.88,136.69,136.03,128.60,128.02,127.4 5,118.19,113.64,112.88,71.40,56.20,29.13,14.59.HRMS(ESI)m / z:calcd for C 16 H 17 BrO2Na([M+Na] + )343.0304,found343.0308.

[0124] Among them, the reaction type for synthesizing compounds S1 and S2 is the Miyaura borylation reaction, and the reaction principle is the coupling reaction of aryl bromide and bispinacol borate under palladium catalysis and alkaline conditions. In some specific embodiments, taking S2 as an example, the synthesis steps include: under argon, potassium acetate (3.003g, 30.6mmol), bispinacol borate (3.108g, 12.24mmol) and ferrocenedichloride palladium (746mg, 1.02mmol) are added to a solution of 1-bromo-2-ethyl-4,5-dimethoxybenzene (2.50g, 10.20mmol) in anhydrous dioxane (20mL). The resulting reaction mixture is stirred under reflux overnight. After adding water, the mixture is extracted with dichloromethane, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography to obtain compound S2 with a yield of 76%. 2-(4-(Benzyloxy)-2-ethyl-5-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (S1). 1 H NMR (500MHz, CDCl3) δ7.50(d,J=7.4Hz,2H),7.40(s,1H),7.39(t,J=7.3Hz,2H),7.33(t,J=7.2Hz,1H ),6.76(s,1H),5.14(s,2H),3.91(s,3H),2.89(q,J=7.5Hz,2H),1.34(s,12H),1.21(t,J=7.5Hz,3H). 13 C NMR(126MHz, CDCl3)δ151.87,146.50,145.51,137.50,127.77,127.72,121.31,112.33,83.17,71.28,55.76,28.51,24.84,17.46.HRMS(ESI)m / z:calcd for C 22 H 30 BO4([M+H] +)369.2233,found 369.2234.2-(2-ethyl-4,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (S2). 1 HNMR (400MHz, CDCl3) δ7.26 (s, 1H), 6.71 (s, 1H), 3.90 (s, 6H), 2.88 (q, J = 7.1Hz, 2H), 1.33 (s, 12H), 1.18 (t, J = 7.3Hz, 3H). 13 CNMR(101MHz, CDCl3)δ151.07,145.94,118.23,111.83,83.19,55.97,55.66,28.49,24.86,17.52.HRMS(ESI)m / z:calcd for C 16 H 25 BO4Na([M+Na] + )315.1738,found 315.1745.

[0125] The reaction type for synthesizing compounds T1 and T2 is a Suziki reaction, which is a coupling reaction between an aryl borate and an aryl halide under zero-valent palladium, base, and oxygen-free conditions. In some specific embodiments, taking T2 as an example, the synthesis steps include: a flask containing S2 (2.00 g, 6.84 mmol), methyl 2-iodo-3,4,5-trimethoxybenzoate (2.408 g, 6.84 mmol), tris(dibenzylideneacetone)dipalladium (314 mg, 0.342 mmol), 2-dicyclohexylphosphine-2'6'-dimethoxy-1,1'-biphenyl (280 mg, 0.684 mmol), and potassium carbonate (4726 mg, 34.1 mmol) is purged with argon three times. Then, toluene (30 mL), ethanol (10 mL), and water (10 mL) are added to the reaction mixture, and the resulting mixture is refluxed and stirred for 36 hours. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to afford compound T2 in a 30% yield. Methyl 4'-(benzyloxy)-2'-ethyl-4,5,5',6-tetramethoxy-[1,1'-biphenyl]-2-carboxylate (T1). 1H NMR (500MHz, CDCl3) δ7.39(d,J=7.1Hz,2H),7.30(t,J=7.5Hz,2H),7.24(d,J=5.8Hz,2H),6.82(s,1H),6.56(s,1H),5.13(d,J=12 .6Hz,1H),5.08(d,J=12.6Hz,1H),3.94(s,3H),3.93(s,6H),3.48(s,3H),3.36(s,3H),2.34–2.25(m,2H),1.03(t,J=7.6Hz,3H). 13 C NMR (126MHz, CDCl3) δ167.58,152.12,151.69,148.77,145.38,144.88,137.48,135.42,129.94,128.41,127.66,127.57 ,127.27,126.30,115.79,111.20,108.78,70.87,60.96,60.78,56.09,55.85,51.89,26.07,14.73.HRMS(ESI)m / z:calcd forC 27 H 31 O7([M+H] + )467.2064,found467.2070.2'-Ethyl-4,4',5,5',6-pentamethoxy-[1,1'-biphenyl]-2-carboxylic acid methyl ester (T2). 1 H NMR (400MHz, CDCl3) δ7.25(s,1H),6.79(s,1H),6.56(s,1H),3.95(s,3H),3.94(s,3H),3.9 3(s,3H),3.81(s,3H),3.57(s,3H),3.56(s,3H),2.37–2.27(m,2H),1.05(t,J=7.6Hz,3H). 13 C NMR (101MHz, CDCl3) δ167.74,152.21,151.73,148.01,146.10,145.36,134.72,129.92,127.59,126.50 ,112.85,110.61,108.72,61.00,60.94,56.12,56.00,55.68,51.97,26.03,14.82.HRMS(ESI)m / z:calcd for C 21 H 27 O7([M+H] + )391.1751,found 391.1759.

[0126] Among them, the reaction type for synthesizing compounds U1 and U2 is a reduction reaction, and the principle is to use lithium aluminum hydride as a reducing agent to reduce the ester group. In some specific embodiments, taking U2 as an example, the synthesis steps include: under argon, lithium aluminum hydride (156 mg, 4.10 mmol) dissolved in tetrahydrofuran (4.0 mL) is added to a solution of compound T2 (800 mg, 2.05 mmol) at 0°C (ice bath). The resulting mixture is stirred at 70°C until T2 is completely consumed (TLC monitoring). Then, the reaction mixture is quenched with isopropanol, filtered and washed with ethyl acetate. Compound U2 is purified by flash column chromatography on silica gel with a yield of 75%. (4'-(phenoxy)-2'-ethyl-4,5,5',6-tetramethoxy-[1,1'-biphenyl]-2-yl)methanol (U1). 1 H NMR (400MHz, CDCl3) δ7.40–7.35(m,2H),7.33–7.28(m,2H),7.26–7.21(m,1H),6.85(s,2H),6.57(s,1H),5. 14(s,2H),4.14(s,2H),3.94(s,3H),3.89(s,3H),3.87(s,3H),3.44(s,3H),2.26(q,J=7.4Hz,2H),1.49(br s,1H),1.02(t,J=7.6Hz,3H). 13 C NMR (101MHz, CDCl3) δ152.75,151.37,149.10,145.09,141.28,137.25,135.95,134.82,128.48,127.67,127.17, 126.55,126.37,116.42,111.79,106.52,70.77,62.95,60.91,60.85,55.94,25.94,14.88.HRMS(ESI)m / z:calcd for C 26 H 30 O6Na([M+Na] + )461.1935, found461.1935. (2'-Ethyl-4,4',5,5',6-pentamethoxy-[1,1'-biphenyl]-2-yl)methanol (U2). 1HNMR (400MHz, CDCl3) δ6.90(s,1H),6.82(s,1H),6.60(s,1H),4.32(d,J=12.9Hz,1H),4.27(d,J=12.9H z,1H),3.92(s,3H),3.91(s,3H),3.89(s,3H),3.80(s,3H),3.62(s,3H),2.29(q,J=7.6Hz,2H),1.74(br s,1H),1.04(t,J=7.6Hz,3H). 13 C NMR (101MHz, CDCl3) δ152.84,151.43,148.32,146.54,141.28,135.17,134.87,126.57,126.42, 113.18,111.16,106.38,63.06,60.97,60.93,56..00,55.99,25.88,14.99.HRMS(ESI)m / z:calcd for C 20 H 26 O6Na([M+Na] + )385.1622,found 385.1630.

[0127] Among them, the reaction type for synthesizing compounds V1 and V2 is a substitution reaction, and the principle is that bromine in phosphorus tribromide replaces the hydroxyl group of compound U to generate compound V. In some specific embodiments, taking V2 as an example, the synthesis steps include: adding phosphine tribromide (420 mg, 1.55 mmol) to a dichloromethane (13.0 mL) solution of compound U2 (550 mg, 1.293 mmol) at 0°C and argon. Stir the mixture from an ice-water bath to room temperature for 3 hours. Afterwards, the reaction mixture was diluted with saturated sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to obtain V2 with a yield of 77%. 6'-(Bromomethyl)-2-ethyl-2',3',4',5-tetramethoxy-[1,1'-biphenyl]-4-ol (V1), 1 HNMR (400MHz, CDCl3) δ6.84(s,1H),6.82(s,1H),6.74(s,1H),5.58(s,1H),4.27(d,J=9.9Hz,1H),4.14(d,J= 9.9Hz,1H),3.94(s,3H),3.91(s,3H),3.90(s,3H),3.60(s,3H),2.29(q,J=7.5Hz,2H),1.06(t,J=7.6Hz,3H). 13C NMR (101MHz, CDCl3) δ152.83,151.44,146.18,142.92,142.30,134.95,131.46,128.26,126.86, 116.17,110.36,108.92,60.99,60.94,56.01,55.83,32.39,25.97,14.90.HRMS(ESI)m / z:calcd for C 19 H 23 BrO5Na([M+Na] + )433.0621,found433.0626.6-(Bromomethyl)-2'-ethyl-2,3,4,4',5'-pentamethoxy-1,1'-biphenyl (V2), 1 H NMR (400MHz, CDCl3) δ6.83(s,1H),6.82(s,1H),6.73(s,1H),4.29(d,J=9.8Hz,1H),4.08(d,J=9.8Hz,1H),3. 93(s,3H),3.91(s,3H),3.90(s,3H),3.85(s,3H),3.60(s,3H),2.30(q,J=7.6Hz,2H),1.04(t,J=7.6Hz,3H). 13 C NMR (101MHz, CDCl3) δ152.94,151.46,148.41,146.29,142.38,135.37,131.56,128.40,126.06, 113.37,111.03,108.89,60.96,56.03,55.97,55.79,32.67,25.99,14.96.HRMS(ESI)m / z:calcd for C 20 H 25 BrO5Na([M+Na] + )447.0778,found447.0787.

[0128] Among them, the nucleophilic substitution reaction for synthesizing azide compounds A-7a and A-7b is based on the reaction principle of using N3 -The nucleophilic reagent NaN3 replaces the removable group bromine. In some specific embodiments, taking A-7b as an example, the synthesis steps include: adding sodium azide (98 mg, 1.50 mmol) to a solution of compound V2 (425 mg, 1.00 mmol) in dimethylformamide (10.0 mL). The reaction mixture was stirred at 110 ° C overnight for 36 hours (monitored by GC-MS). After the reaction was checked by TLC, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give an azide compound A-7b with a yield of 83%. 6'-(azidomethyl)-2-ethyl-2',3',4',5-tetramethoxy-[1,1'-biphenyl]-4-ol (A-7a), 1 HNMR(500MHz,Chloroform-d)δ6.86(s,1H),6.81(s,1H),6.70(s,1H),5.60(s,1H),4.09(d,J=13.8Hz,1H),4.05(d ,J=13.8Hz,1H),3.99(s,3H),3.98(s,3H),3.95(s,3H),3.67(s,3H),2.32(q,J=7.6Hz,2H),1.09(t,J=7.6Hz,3H). 13 C NMR (126MHz, CDCl3) δ152.84,151.67,146.17,143.14,141.90,134.80,129.72,127.61,127.08, 116.23,110.50,107.35,61.05,60.95,56.08,55.87,52.58,25.95,14.96.HRMS(ESI)m / z:calcd for C 19 H 23 N3O5Na([M+Na] + )396.1530, found396.1533. 6-(Azidomethyl)-2'-ethyl-2,3,4,4',5'-pentamethoxy-1,1'-biphenyl (A-7b), 1 H NMR(400MHz, CDCl3)δ6.80(s,1H),6.74(s,1H),6.57(s,1H),3.97(s,2H),3.89(s,3H),3.88 (s,3H),3.87(s,3H),3.79(s,3H),3.59(s,3H),2.25(q,J=7.6Hz,2H),1.01(t,J=7.6Hz,3H). 13C NMR (101MHz, CDCl3) δ152.90,151.63,148.44,146.55,141.95,135.21,129.71,127.86,126.26,113 .43,111.13,107.55,60.92,60.86,56.00,55.92,55.75,52.50,25.90,14.92.HRMS(ESI)m / z:calcd for C 20 H 25 N3O5Na([M+Na] + )410.1686,found410.1685.

[0129] Among them, the reaction type of the synthetic product compounds B-7a and B-7b is an iron nitride amination reaction. The reaction principle is that after the iron porphyrin and the azide substrate are combined, a nitrogen molecule is removed to form an iron nitride intermediate for an amination ring-closure reaction. In some specific embodiments, taking B-7b as an example, the synthesis steps include: adding the azide compound A-7b (300 mg, 0.774 mmol), di-tert-butyl dicarbonate (338 mg, 1.549 mmol) and [FeIII(TDCPP)(IMe)2]I (19.9 mg, 1.54% mmol) to a round-bottom flask, and then purging the flask with argon three times. Then, toluene (7.0 mL) was injected into the flask, and the resulting mixture was stirred at 150°C (oil bath) for 0.5 h. TLC analysis showed that the azide compound was completely consumed. After concentration under reduced pressure, the residue was purified by silica gel flash column chromatography to obtain the product compound B-7b with a yield of 87%. 9-(Benzyloxy)-1,2,3,10-tetramethoxy-7-methyl-5,7-dihydro-6H-dibenzo[c,e]azepine-6-carboxylic acid tert-butyl ester (B-7a) (1:1 dual stereoisomers), as shown in the attached Figure 19 As shown, 1 H NMR (500MHz, CDCl3) δ7.48(s,1H),6.97(s,0.5H),6.87(s,0.5H),6.77(s,0.5H),6.64(s,0.5H),5.21–5.13(m,0.5H),4.99–4. 89(m,1H),4.70(d,J=13.6Hz,0.5H),3.95–3.98(m,9H),3.96–3.53(m,4H),1.56(s,9H),1.53(s,9H),0.95(d,J=6.1Hz,3H).As attached Figure 20 As shown, 13 C NMR (126 MHz, CDCl 3)δ153.71,152.99,151.50,150.48,150.21,142.33,139.07,137.54,131.54,127.33,125.74,125.42,113.90 ,108.37,83.42,79.91,61.25,60.49,57.79,56.96,56.13,56.04,46.57,27.64,20.99.HRMS(ESI)m / z:calcd for C 29 H 39 NO9Na([M+Na] + )568.2517, found 568.2521. 1,2,3,9,10-pentamethoxy-7-methyl-5,7-dihydro-6H-dibenzo[c,e]azepine-6-carboxylic acid tert-butyl ester (B-7b) (1:1 dual stereoisomers). 1 H NMR(400MHz, CDCl3)δ7.21(s,1H),6.86(s,0.5H),6.78(s,1H),6.64(s,0.5H),5.13–5.05(m,0.5H),4.95–4 .83(m,1H),4.73–4.67(m,0.5H),4.00–3.87(m,12H),3.66–3.46(m,4H),1.52(s,9H),0.93(d,J=6.8Hz,3H). 13 C NMR (101MHz, CDCl3) δ153.78,152.84,150.37,148.01,147.87,147.69,142.30,131.75,127.29,126.25,114.4 5,112.91,108.48,79.79,61.30,60.52,57.56,56.14,56.03,55.95,46.63,28.65,21.27.HRMS(ESI)m / z:calcd for C 25 H 33 NO7Na([M+Na] + )482.2149,found482.2148.

[0130] In some possible implementations, the product compound B-7 is hydrolyzed and reacted with Carry out amidation reaction to obtain compound B-7-1,

[0131] In some specific embodiments, the process route for synthesizing compound B-7-1 is:

[0132]

[0133] Among them, the preparation of the compound ethyl 2-(4-(3,4-dichlorophenyl)piperazine-1-yl)acetate includes the steps of: adding ethyl 2-bromoacetate (400 mg, 2.40 mmol) to a dry acetone solution of 1-(3,4-dichlorophenyl)piperazine (462 mg, 2.0 mmol) and potassium carbonate (414 mg, 3.0 mmol) under argon. The reaction mixture was refluxed and stirred for 8 hours. After the reaction was completed by TLC, the reaction mixture was diluted with water, extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column to obtain ethyl 2-(4-(3,4-dichlorophenyl)piperazine-1-yl)acetate with a yield of 87%. 1,2,3,9,10-pentamethoxy-7-methyl-6,7-dihydro-5H-dibenzo[c,e]azepine (17). 1 H NMR (400MHz, CDCl3) δ7.03(s,1H),6.84(s,1H),6.57(s,1H),3.82(s,3H),3.81(s,3H),3.78(s,3H),3.77(s,3 H), 3.54 (s, 3H), 3.53 (q, J = 6.6Hz, 3H), 3.46 (d, J = 12.6Hz, 1H), 3.19 (d, J = 12.5Hz, 1H), 1.37 (d, J = 6.6Hz, 3H). 13 C NMR (101MHz, CDCl3) δ152.64,150.39,148.17,147.31,141.67,132.98,131.57,128.99,125.81, 112.69,107.54,107.46,61.00,60.65,55.86,55.73,49.44,49.42,18.56.HRMS(ESI)m / z:calcd for C 20 H 26 NO5([M+H] + )360.1805,found 360.1802.

[0134] Among them, the preparation of the compound 2-(4-(3,4-dichlorophenyl)piperazine-1-yl)acetic acid hydrochloride includes the steps of adding 2-(4-(3,4-dichlorophenyl)piperazine-1-yl)ethyl acetate (500mg, 1.58mmol) to a 4mol / L sodium hydroxide aqueous solution (5.0mL) and methanol (5.0mL) solution and stirring at 50°C overnight. After the reaction is completed by TLC, the reaction mixture is acidified to pH 2 with a 2mol / L hydrochloric acid aqueous solution at 0°C and stirred for another 0.5 hours. The reaction mixture is then washed with petroleum ether, and the aqueous phase is concentrated under reduced pressure. The residue is dissolved in methanol and purified by Celite545 Filtration and concentration gave 2-(4-(3,4-dichlorophenyl)piperazin-1-yl)acetic acid hydrochloride as a white amorphous powder, which was used directly in the next step.

[0135] The preparation of compound 17 comprises the following steps: adding trifluoroacetic acid (2.0 mL) to a solution of compound B-7b (300 mg, 0.652 mmol) in dichloromethane (6.0 mL) at room temperature and stirring the reaction mixture for 2 h. After adjusting the pH to approximately 8-9 by dropwise addition of saturated sodium bicarbonate, the reaction mixture is extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel flash column to obtain compound 17 (yield 80%).

[0136] Among them, the reaction type of synthetic compound B-7-1 is amidation reaction, and the reaction principle is that carboxylic acid hydrochloride and amino compound condense under the conditions of nucleophilic reagent HOBt and dehydrating agent EDCl to form amide compound B-7-1. In some specific embodiments, the step of synthesizing compound B-7-1 comprises: injecting anhydrous dichloromethane into a mixture of 2-(4-(3,4-dichlorophenyl)piperazine-1-yl)acetic acid (72mg, 0.22mmol), 1-hydroxybenzotriazole (30mg, 0.22mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (42mg, 0.22mmol), and the reaction mixture is stirred for 2 hours under argon at room temperature. Then, a solution of compound B-7 (36mg, 0.10mmol) in dimethylformamide (2.0mL) is added and further stirred at room temperature overnight. The reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column to obtain compound B-7-1 (80% yield). 2-(4-(3,4-dichlorophenyl)piperazin-1-yl)-1-(1,2,3,9,10-pentamethoxy-7-methyl-5,7-dihydro-6H-dibenzo[c,e]azepin-6-yl)ethan-1-one (18) (1:4 dual stereoisomers). Figure 21 As shown,1 H NMR(500MHz, CDCl3)δmajorpeaks.7.31–7.26(m,2H),6.97(d,J=2.8Hz,1H),6.87(d,J=3.8Hz ,1H),6.76(dd,J=8.9,2.7Hz,1H),5.45(q,J=6.8Hz,1H),4.88(d,J=12.9Hz,1H),3.96(s,3H), 3.93(s,3H),3.92(s,3H),3.90(d,J=12.9Hz,1H),3.82(s,3H),3.61(s,3H),3.58(d,J=12.9H z,1H),3.29–3.27(m,4H),3.17(d,J=12.8Hz,1H),2.77–2.75(m,4H),0.94(d,J=6.9Hz,3H).As attached Figure 22 As shown, 13 C NMR (126MHz, CDCl3) δ166.22,152.82,150.65,150.49,148.15,147.89,142.90,132.90,131.11,130.55,130.28,127.06,126.97,122.55,1 17.23,115.33,114.18,113.17,108.54,62.42,61.36,60.55,56.30,56.09,55.99,55.90,52.97,48.81,48.41,20.06.HRMS(ESI)m / z:calcd for C 32 H 38 Cl2N3O6([M+H] + )630.2132,found 630.2130.

[0137] The second aspect of the embodiment of the present application provides an alkaloid, which is prepared by the above method, and the chemical formula of the alkaloid is wherein X is selected from C-R5, CO, O, S, SO, SO2, Se or P-R6; n1 and n2 are each independently a positive integer of 1 to 4, and when n1 and n2 are greater than 1, multiple R2s are the same or different, and multiple R4s are the same or different; R1, R2, R3, R4, and R5 exist independently or form at least one polycyclic ring, and R1, R2, R3, R4, R5, and R6 are each independently selected from one of hydrogen, alkyl, substituted alkyl, hydroxyl, methoxy, methyl ester, vinyl, carbonyl, phenyl, substituted phenyl, heterocyclic group, heteroaromatic ring group, carbocyclic group, condensed ring group, and spirocyclic group.

[0138] The alkaloids provided in the second aspect of the present invention are prepared by the above-mentioned method, have a simple synthesis process, and employ a trivalent iron porphyrin catalyst, which is an inexpensive metal catalyst, thereby reducing the synthesis cost. These alkaloids have a diverse production process and can form alkaloids of different structures. These alkaloids are biologically active and can be used directly or as intermediates to synthesize other active substances, thus having a wide range of applications.

[0139] In some possible implementations, the chemical formula of the alkaloid includes:

[0140] In some possible implementations, the chemical formula of the alkaloid further comprises:

[0141] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent replacements and improvements made within the spirit and principles of the present application should be included in the scope of protection of the present application.

Claims

1. A method for synthesizing alkaloids by catalysis of ferric porphyrin, characterized in that: The following steps are involved: Using trivalent iron porphyrin as a catalyst, an azide compound A is converted into a product compound B through an iron nitre amination reaction; wherein the azide compound A is selected from A-2, A-5, or A-7; the corresponding synthesized product compound B is B-2, B-5 and B-7; The step of the ferric nitride amination reaction comprises: dissolving the trivalent ferrous porphyrin, the azide compound A and the amino protective agent in an organic solvent, reacting in an inert atmosphere at a temperature of 100-200° C. for 0.5-1 hour, and separating to obtain the product compound B; The ferric porphyrin is [Fe III (TDCPP)(IMe)2]I, wherein the ligand TDCPP is tetrakis(2,6-dichlorophenyl)porphyrin, the ligand IMe is 1,3-dimethylimidazole-2-ylidene; and the amino protecting agent is selected from di-tert-butyl dicarbonate.

2. The method for synthesizing alkaloids by ferric porphyrin catalysis as claimed in claim 1, characterized in that: The organic solvent is selected from at least one of toluene, chlorobenzene, fluorobenzene, trifluoromethylbenzene, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and methyl tert-butyl ether; Alternatively, the molar ratio of the ferric porphyrin, the azide compound A and the amino protecting agent is (0.02-0.06):1:(1-3).

3. The method for synthesizing alkaloids by ferric porphyrin catalysis as claimed in claim 2, characterized in that: The steps of preparing the product compound B-2 include: dissolving the azide compound A-2 and the amino protecting agent in the organic solvent, reacting in an inert atmosphere at a temperature of 100-200° C. for 0.5-1 hour, and separating to obtain the product compound B-2.

4. The method for synthesizing alkaloids by ferric porphyrin catalysis as claimed in claim 2, characterized in that: The steps of preparing the product compound B-5 include: dissolving the azide compound A-5 and the amino protecting agent in the organic solvent, reacting in an inert atmosphere at a temperature of 100-200° C. for 0.5-1 hour, and separating to obtain the product compound B-5.

5. The method for synthesizing alkaloids by catalysis of ferric porphyrin as claimed in claim 2, characterized in that: The steps of preparing the product compound B-7 include: dissolving the azide compound A-7 and the amino protecting agent in the organic solvent, reacting in an inert atmosphere at a temperature of 100-200° C. for 0.5-1 hour, and separating to obtain the product compound B-7.

6. The method for synthesizing alkaloids by catalysis of ferric porphyrin as claimed in claim 3, characterized in that: The product compound B-2 is subjected to a hydrolysis reaction to obtain a compound B-2-1.

7. The method for synthesizing alkaloids by catalysis of ferric porphyrin as claimed in claim 5, characterized in that: The product compound B-7 is hydrolyzed and Amidation reaction was performed to obtain compound B-7-1.

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