A multi-substituted pentacyclic spiroindoline derivative and its preparation method

Abstract

The present invention discloses a preparation method of a multi-substituted pentacyclic spiroindoline derivative. It dissolves compound 1, trifluoroacetic anhydride and trifluoroacetic acid in a solvent at room temperature, and reacts for 5 minutes to 60 hours at 30°C to 100°C under a nitrogen atmosphere to obtain compound 2; or dissolves compound 1, trifluoroacetic anhydride and 1,4-diazabicyclo[2.2.2]octane in a solvent to obtain compound 2; or dissolves compound 1, trifluoroacetic anhydride and N,N-dimethyl-4-pyridinamine in a solvent to obtain compound 2. The present invention adopts a "tandem reaction" to synthesize the multi-substituted pentacyclic spiroindoline derivative in one step. The reaction conditions are mild, the cost is low, and there is no need to additionally add precious metal catalysts and reagents, which is suitable for industrial production and market promotion and application.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a polysubstituted pentacyclic spiroindoline derivative and a preparation method thereof. Background Art

[0002] The polycyclic spiroindoline structure is an important structural fragment of many natural monoterpene indole alkaloids. For example, the structures of kopsia alkaloids, strychnos alkaloids, and quebrachamine alkaloids all contain the polycyclic spiroindoline structure. These alkaloids generally have various good biological activities such as anti-cancer, anti-arrhythmic, and anti-malaria effects. Some of these alkaloids have been developed into first-line drugs for clinical chemotherapy. For example, vinblastine and vincristine. At present, the main sources of these two drugs still rely on limited plant extraction and semi-synthesis using plant-extracted raw materials. However, the content of the drug or the required component in the plant is affected by various factors such as natural climate like sunlight and field management. In addition, the cultivation of plants requires a large amount of land resources and consumes a large amount of human resources. So far, although the artificial total synthesis routes of these two drugs have been reported in the literature, there has not yet appeared a synthetic route with true industrial application value. The main difficulty in their synthesis is to construct a polycyclic spiroindoline structure with multiple chiral centers.

[0003] Since the polycyclic spiroindoline structure is an important structural unit of many bioactive indole alkaloids and at the same time is a synthetic bottleneck that must be overcome in the artificial synthesis of the clinical first-line anti-tumor drugs vinblastine and vincristine, its synthesis method has attracted much attention. From the perspective of reaction types, the currently developed construction methods for polysubstituted polycyclic spiroindoline structures mainly include nucleophilic addition reactions, Diels-Alder cycloaddition reactions, palladium-catalyzed coupling reactions, radical cyclization reactions, tandem reactions, or multi-step reactions in one-pot methods. However, the raw materials used in the existing construction methods of polycyclic spiroindoline structures are all difficult to obtain and most of the conditions are relatively harsh, often requiring high temperatures, using environmentally unfriendly reagents or expensive transition metal reagents. Some synthesis methods often require multi-step synthesis, and have disadvantages such as low chemical selectivity of the reaction, poor functional group compatibility, single substitution site, generation of a large amount of waste, and inconvenience in subsequent modification or derivatization synthesis. Therefore, developing a simple and efficient method for synthesizing complex polysubstituted polycyclic spiroindoline structures has important scientific significance and application value. Summary of the Invention

[0004] Aiming at the disadvantages of the existing preparation methods of polysubstituted polycyclic spiroindoline derivatives, the present invention provides a new method for synthesizing a polysubstituted pentacyclic spiroindoline derivative. This method is based on a novel tandem reaction and has the characteristics that the reaction substrates are easy to prepare from commercially available raw materials, the reaction conditions are mild, there is no need for expensive transition metal catalysis, the synthesized pentacyclic spiroindoline compounds contain multiple functional groups, and it is convenient for derivatization.

[0005] The preparation method of the multi-substituted pentacyclic spiroindoline derivative of the present invention is as follows:

[0006]

[0007] In the formula: R 1 is selected from C1-C 10 alkyl, C2-C 10 alkenyl, C3-C8 cycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl; R 1-1 is the substituent group on R 1 , R 1-1 is selected from halogen, nitro, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl;

[0008] R 2 is selected from C1-C 10 alkyl, C2-C 10 alkenyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C1-C 10 dioxolanyl; R 2-1 is the substituent group on R 2 , R 2-1 is selected from halogen, nitro, C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, C2-C8 heterocycloalkyl; silyl ether protecting group; R 2-1-1 is the substituent group on R 2-1 , R 2-1-1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, C2-C8 heterocycloalkyl;

[0009] R 3 is selected from H, C1-C 10 alkyl, C2-C 10 alkenyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, nitro; R 3-1 is the substituent group on R 3 , R 3-1 is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, C2-C8 heterocycloalkyl;

[0010] R 4 is selected from H, C1-C 10 alkyl, C3-C 10 alkenyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl; R 4-1 is the substituent group on R 4 ; R4-1 Selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, C3-C8 heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl; R 4-1-1 is a substituent group on R 4-1 and R 4-1-1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, C2-C8 heterocycloalkyl;

[0011] R 5 is selected from H, C1-C 10 alkyl, C2-C 10 alkenyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, halogen, nitro; R 5-1 is a substituent group on R 5 and R 5-1 is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, C3-C8 heterocycloalkyl, nitro; R 5-1-1 is a substituent group on R 5-1 and R 5-1-1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, C2-C8 heterocycloalkyl;

[0012] R 6 is selected from H, C1-C 10 alkyl, C2-C 10 alkenyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, halogen, nitro; R 6-1 is a substituent group on R 6 and R 6-1 is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, C3-C8 heterocycloalkyl, nitro; R 6-1-1 is a substituent group on R 6-1 and R 6-1-1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, C2-C8 heterocycloalkyl;

[0013] R 7 is selected from H, C1-C 10 alkyl, C2-C 10 alkenyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, halogen, nitro; R 7-1 is a substituent group on R 7The substituent group on R 7-1 is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, C3-C8 heterocycloalkyl, nitro; R 7-1-1 is the substituent group on R 7-1 and is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C 7-1-1 cycloalkyl, C2-C8 heterocycloalkyl; 12

[0014] R 8 is selected from H, C1-C 10 alkyl, C2-C 10 alkenyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, halogen, nitro; R 8-1 is the substituent group on R 8 and is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 8-1 cycloalkyl, C3-C8 heterocycloalkyl, nitro; R 12 is the substituent group on R 8-1-1 and is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C 8-1 cycloalkyl, C2-C8 heterocycloalkyl. 8-1-1 12

[0015] Method 1: At room temperature, dissolve Compound 1, trifluoroacetic anhydride and trifluoroacetic acid in a solvent, and react at 30°C to 100°C under a nitrogen atmosphere for 5 minutes to 60 hours to prepare Compound 2.

[0016] The solvent is an ether or halogenated alkane solvent such as tetrahydrofuran, for example, diethyl ether, 1,2-dichloroethane, dichloromethane, chloroform, etc. The molar ratio of Compound 1: trifluoroacetic anhydride: trifluoroacetic acid is 1: 0.5 to 10: 0.5 to 10.

[0017] Method 2: At room temperature, dissolve Compound 1, trifluoroacetic anhydride and 1,4-diazabicyclo[2.2.2]octane in a solvent, and react at 30°C to 100°C under a nitrogen atmosphere for 5 minutes to 60 hours to prepare Compound 2.

[0018] The solvent is an ether or halogenated alkane solvent such as tetrahydrofuran, for example, diethyl ether, 1,2-dichloroethane, dichloromethane, chloroform, etc. The molar ratio of Compound 1: trifluoroacetic anhydride: 1,4-diazabicyclo[2.2.2]octane is 1: 0.5 to 10: 0.5 to 10.

[0019] ​​​Method 3: At room temperature, dissolve Compound 1, trifluoroacetic anhydride, and N,N-dimethyl-4-pyridinamine in a solvent, and react at 30 °C to 100 °C under a nitrogen atmosphere for 5 minutes to 60 hours to prepare Compound 2.

[0020] The solvent is an ether or halogenated alkane solvent such as tetrahydrofuran, for example, diethyl ether, 1,2-dichloroethane, dichloromethane, chloroform, etc. The molar ratio of Compound 1:trifluoroacetic anhydride:N,N-dimethyl-4-pyridinamine is 1:0.5 to 10:0.5 to 10.

[0021] The concentration of Compound 1 in the solvent in the above 3 methods can be the conventional concentration for such reactions in the art, preferably 0.01 mol / L to 10 mol / L, more preferably 0.05 mol / L to 1.0 mol / L.

[0022] In the synthesis, R 1 is preferably methyl, ethyl, tert-butyl, and phenyl;

[0023] R 2 is preferably

[0024] R 3 is preferably H, methyl, ethyl, n-propyl, n-butyl, and nitro;

[0025] R 4 is preferably H, methyl, ethyl, n-propyl, allyl, benzyl, and p-methoxybenzyl;

[0026] R 5 is preferably H, F, Cl, Br, I, methyl, methoxy, nitro, trifluoromethyl, difluoromethyl, and fluoromethyl;

[0027] R 6 is preferably H, F, Cl, Br, I, methyl, methoxy, nitro, trifluoromethyl, difluoromethyl, and fluoromethyl;

[0028] R 7 is preferably H, F, Cl, Br, I, methyl, methoxy, nitro, trifluoromethyl, difluoromethyl, and fluoromethyl;

[0029] R 8 is preferably H, F, Cl, Br, I, methyl, methoxy, nitro, trifluoromethyl, difluoromethyl, and fluoromethyl;

[0030] The substitution patterns in the above preferred schemes include any permutation and combination schemes of single substitution, double substitution, triple substitution, quadruple substitution, quintuple substitution, sextuple substitution, septuple substitution, and octuple substitution of the above preferred schemes, but are not limited to this scheme.

[0031] Compound 1 was prepared according to the methods in the existing literature. For example: (1) The amine compound was prepared according to the method in Chen, W.; Yang, X.D.; Tan, W.Y.; Zhang, X.Y.; Liao, X.L.; Zhang, H.B. Angew. Chem. Int. Ed. 2017, 56, 12327-12331. (2) According to the method in Osorio-Lozada, A.; Prisinzano, T.; Olivo, H.F. Tetrahedron: Asymmetry 2004, 15, 3811-3815., the amine compound in (1) was subjected to a condensation reaction with a sulfinylacetic acid compound to obtain Compound 1.

[0032] Compound 1 includes, but is not limited to, the following structures:

[0033]

[0034] Another object of the present invention is to provide a polysubstituted pentacyclic spiroindoline derivative (Compound 2) prepared by the above method. Compound 2 includes, but is not limited to, the following structures:

[0035]

[0036] In the present invention, unless otherwise specified, the following terms used in the specification and claims of the present invention have the following meanings:

[0037] The term "alkyl" means a branched or straight-chain saturated aliphatic hydrocarbon group having the specified number of carbon atoms, which may optionally and independently be substituted by one or more substituents described in the present invention. Thus, "C1-C6 alkyl" means an alkyl group having 1 to 6 carbon atoms (e.g., C1-C3 alkyl, and for example, methyl); specific examples thereof include, but are not limited to: methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), 2-methylpropyl or isobutyl (i-Bu, -CH2CH(CH3)2), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 4-methylpentyl (-CH2CH2CH2CH(CH3)CH3), 3-methylpentyl (-CH2CH2CH(CH3)CH2CH3), 2-methylpentyl (-CH2CH(CH3)CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 3,3-dimethylbutyl (-CH2CH2CH2(CH3)2CH3), 2,2-dimethylbutyl (-CH2C(CH3)2CH2CH3), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2) or 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3).

[0038] In the present invention, the term "alkenyl" refers to a straight-chain, branched-chain or cyclic non-aromatic hydrocarbon group containing a specified number of carbon atoms and at least one carbon-carbon double bond. Preferably, there is one carbon-carbon double bond, and up to four non-aromatic carbon-carbon double bonds may be present. Thus, "C2-C6 alkenyl" refers to an alkenyl group having 2-6 carbon atoms (e.g., C2-C4 alkenyl or C2-C3 alkenyl), including vinyl, propenyl, butenyl, 2-methylbutenyl, and cyclohexenyl. The straight-chain, branched-chain or cyclic moiety of the alkenyl group may contain a double bond, and if it is indicated as a substituted alkenyl, it may be substituted.

[0039] The term "C1-C6 alkoxy" represents a C1-C6 alkyl group linked by an oxygen bridge; the C1-C6 alkyl group is defined as above.

[0040] The term "C3-C 12 cycloalkyl" represents a cyclic hydrocarbon group containing 3-12 ring-forming carbon atoms, which may be saturated or partially unsaturated (including 1 or 2 double bonds, but none of the rings has a completely conjugated π-electron system), and does not contain heteroatoms; including monocyclic groups of 3-12 carbon atoms or bicyclic or tricyclic groups of 7-12 carbon atoms (including spiro ring systems, bridged ring systems, and fused ring systems); wherein, one or more hydrogen atoms on the ring are independently optionally substituted by one or more substituents described in the present invention, and the carbon atoms may be oxidized. The bicyclic ring with 7-12 atoms may be a bicyclo[4,5], [5,5], [5,6] or [6,6] system, and the bicyclic ring with 9 or 10 atoms may be a bicyclo[5,6] or [6,6] system. Suitable cycloalkyl groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl, such as: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantyl, and the like.

[0041] The term "C2-C8 heterocycloalkyl" represents a 3-12 membered monocyclic or polycyclic group (including spiro, bridged, and fused rings, preferably 5-6 membered monocyclic rings) containing 1, 2, 3, or 4 heteroatoms (selected from one or more of N, S, and O), wherein each ring may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system; the heteroatoms may or may not be substituted, and the N atom may be quaternized. Suitable heterocycloalkyl groups include, but are not limited to, piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiazolyl, and the like.

[0042] The term "heteroaryl" refers to a 5- to 10-membered monocyclic or polycyclic aromatic system (preferably a 5- to 6-membered monocyclic aromatic system) containing 1, 2, 3, or 4 heteroatoms (selected from one or more of N, S, and O). The heteroaryl can be attached to the main structure at any heteroatom or carbon atom to form a stable compound. Heteroaryl includes, but is not limited to, a monocyclic ring composed of 3 to 7 atoms, or a bicyclic ring composed of 7 to 10 atoms. The bicyclic ring with 7 to 10 atoms can be a bicyclo[4,5], [5,5], [5,6], or [6,6] system. Heteroaryl includes, but is not limited to: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazol-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl, benzo[d]thiazol-2-yl, imidazo[1,5-a]pyridin-6-yl, benzimidazolyl, benzoxazolyl, quinoxalinyl, 1,8-naphthyridinyl, benzofuranyl, benzothiophenyl, benzothiazolyl, indolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinoline), isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), or tetrahydronaphthyl.

[0043] The term "aryl" refers to a monocyclic or bicyclic carbocyclic system, wherein at least one ring system is aromatic, each ring system contains 3 to 7 carbon atoms, and one or more hydrogen atoms on the ring are independently optionally substituted by one or more substituents described in the present invention. For example, but not limited to, phenyl, naphthyl, and anthracene.

[0044] The abbreviation "PMB" in the chemical structural formula represents p-methoxybenzyl; the abbreviation "TBS" in the chemical structural formula represents tert-butyldimethylsilyl; the abbreviation "TIPS" in the chemical structural formula represents triisopropylsilyl; the abbreviation "TBDPS" in the chemical structural formula represents tert-butyldiphenylsilyl.

[0045] The positive and progressive effects of the present invention are as follows:

[0046] (1) It is possible to obtain polysubstituted pentacyclic spiroindoline derivatives that are difficult to prepare by other methods, and such pentacyclic spiroindolines are more easily derivatized, providing a large number of candidate compounds for the research and development of related new drugs. In particular, it overcomes the bottleneck in the artificial synthesis of the first-line clinical anti-tumor drugs vinblastine and vincristine, and is expected to be applied to the industrial synthesis of these two drugs or their synthetic precursors;

[0047] (2) The preparation method in this application is a one-component "tandem reaction" for synthesizing pentacyclic spiroindoline, which has very good step economy; most of the traditional preparation methods of polysubstituted pentacyclic spiroindoline require expensive transition metal catalysis to obtain high-yield polysubstituted pentacyclic spiroindoline, while the present invention realizes the preparation of polysubstituted pentacyclic spiroindoline through only one-step reaction without the need to additionally add expensive transition metal catalysts, greatly reducing the synthesis cost; the structure of the polysubstituted pentacyclic spiroindoline synthesized by the traditional method is relatively single, and there are few methods for functionalizing pentacyclic spiroindoline, which is not conducive to further derivatization. This method can achieve one-step multi-functionalization;

[0048] (3) The reaction is carried out at 30 °C to 100 °C, with high reaction efficiency, simple operation, and avoiding the use of severe reaction conditions such as high temperature and high pressure or complex operations. Specific Embodiments

[0049] The present invention will be further illustrated by the following examples, but the present invention is not limited to the scope of the described examples. The experimental methods without specific conditions in the following examples are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0050] Example 1: Substrate 1 (19.0 mg, 0.05 mmol) was dissolved in tetrahydrofuran (2 mL). Trifluoroacetic anhydride (11 μL, 0.15 mmol) and trifluoroacetic acid (11 μL, 0.15 mmol) were added at room temperature. The mixture was transferred to an oil bath at 80 °C under a nitrogen atmosphere and reacted for 2 h. The organic solvent was removed by concentration under reduced pressure, and the product was separated by silica gel column chromatography. The eluent was a mixture of petroleum ether - ethyl acetate (volume ratio 1.5:1), and a pale yellow solid compound 2 (4.6 mg, diastereoselectivity > 20:1) was obtained;

[0051] Either substrate 1 (19.0 mg, 0.05 mmol) was dissolved in tetrahydrofuran (2 mL). Trifluoroacetic anhydride (11 μL, 0.15 mmol) and 1,4-diazabicyclo[2.2.2]octane (16.8 mg, 0.15 mmol) were added at room temperature. The reaction mixture was transferred to an oil bath at 80 °C under a nitrogen atmosphere and reacted for 2 h. The organic solvent was removed by concentration under reduced pressure. The product was separated by silica gel column chromatography, and the eluent was a petroleum ether - ethyl acetate mixture (volume ratio 1.5:1), obtaining a pale yellow solid compound 2 (7.0 mg, diastereoselectivity >20:1);

[0052] Or substrate 1 (19.0 mg, 0.05 mmol) was dissolved in tetrahydrofuran (2 mL). Trifluoroacetic anhydride (11 μL, 0.15 mmol) and N,N-dimethyl-4-pyridinamine (9.1 mg, 0.15 mmol) were added at room temperature. The reaction mixture was transferred to an oil bath at 80 °C under a nitrogen atmosphere and reacted for 2 h. The organic solvent was removed by concentration under reduced pressure. The product was separated by silica gel column chromatography, and the eluent was a petroleum ether - ethyl acetate mixture (volume ratio 1.5:1), obtaining a pale yellow solid compound 2 (7.5 mg, diastereoselectivity >20:1);

[0053] (4bS,5S,7aS,12bS)-13-(4-methoxybenzyl)-7-(3-((4-methoxybenzyl)oxy)propyl)-10,10-dimethyl-5-(phenylthio)-7a,8,12b,13-tetrahydro-[1,3]dioxino[5,4-a]pyrrolo[2,3-d]carbazole-6,12(5H,7H)-dione, with a yield of 25% (method 1); 38% (method 2); 41% (method 3);

[0054]

[0055] 11H NMR (600 MHz, Chloroform-d) δ 7.42–7.40 (m, 2H), 7.22–7.17 (m, 8H), 7.15 (t, J = 7.7 Hz, 1H), 6.86 (d, J = 8.2 Hz, 2H), 6.79 (d, J = 8.3 Hz, 2H), 6.73 (t, J = 7.5 Hz, 1H), 6.53 (d, J = 7.9 Hz, 1H), 4.84 (s, 1H), 4.48 (d, J = 16.1 Hz, 1H), 4.44–4.31 (m, 3H), 3.97 (t, J = 5.6 Hz, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 3.75–3.70 (m, 1H), 3.59 (s, 1H), 3.49–3.42 (m, 2H), 3.05 (dt, J = 14.0, 7.0 Hz, 1H), 2.71 (dd, J = 18.7, 6.4 Hz, 1H), 2.41 (dd, J = 18.7, 4.7 Hz, 1H), 1.89–1.75 (m, 2H), 1.61 (s, 3H), 1.30 (s, 3H). 13 13C NMR (151 MHz, CDCl3) δ 171.7, 165.1, 161.1, 159.4, 158.9, 134.8, 132.3, 131.0, 130.4, 130.0, 129.5, 129.1, 128.7, 127.6, 124.8, 118.6, 114.1, 114.0, 108.9, 106.5, 72.9, 67.3, 64.1, 59.8, 57.5, 55.4, 55.4, 53.2, 51.6, 38.9, 29.8, 27.8, 27.2, 22.9.

[0056] Example 2: Substrate 1 (73.1 mg, 0.10 mmol) was dissolved in tetrahydrofuran (5 mL). Trifluoroacetic anhydride (42 μL, 0.30 mmol) and N,N-dimethyl-4-pyridinamine (37.2 mg, 0.30 mmol) were added at room temperature. The reaction mixture was transferred to an 80 °C oil bath under a nitrogen atmosphere and reacted for 2 h. The organic solvent was removed by concentration under reduced pressure. The product was separated by silica gel column chromatography with a petroleum ether - ethyl acetate mixture (volume ratio 1.5:1) as the eluent, to obtain a pale yellow solid compound 2 (45.5 mg) and its diastereomer (13.0 mg);

[0057] (4bS,5S,7aS,12bS)-5-(tert-butylthio)-13-(4-methoxybenzyl)-7-(3-((4-methoxybenzyl)oxy)propyl)-10,10-dimethyl-7a,8,12b,13-tetrahydro-[1,3]dioxino[5,4-a]pyrrolo[2,3-d]carbazole-6,12(5H,7H)-dione, yield 64%;

[0058]

[0059] 1 H NMR(600MHz,Chloroform-d)δ7.21(d,J = 8.8Hz,2H),7.20(d,J = 8.8Hz,2H),7.10(t,J = 7.7Hz,1H),7.01(d,J = 7.5Hz,1H),6.85(d,J = 8.5Hz,2H),6.81(d,J = 8.5Hz,2H),6.66(t,J = 7.5Hz,1H),6.46(d,J = 7.9Hz,1H),4.88(s,1H),4.45(d,J = 16.3Hz,1H),4.37–4.30(m,3H),3.85(dd,J = 6.7,5.2Hz,1H),3.79(s,3H),3.76(s,3H),3.76–3.71(m,1H),3.42(t,J = 6.0Hz,2H),3.24(br s,1H),3.02(dt,J = 14.0,7.1Hz,1H),2.75(dd,J = 19.0,7.1Hz,1H),2.44(dd,J = 19.0,4.9Hz,1H),1.84–1.75(m,2H),1.64(s,3H),1.26(s,3H),1.21(s,9H). 13 C NMR(150MHz,CDCl3)δ172.8,165.6,161.1,159.3,158.8,151.6,131.6,130.4,129.6,129.5,128.5,124.3,118.1,114.1,114.0,108.4,106.4,100.7,72.8,67.4,63.4,59.6,55.4,53.0,51.5,50.1,44.2,39.1,31.3,30.5,27.8,27.2,22.7.

[0060] Example 3: Substrate 1 (1.19 g, 1.73 mmol) was dissolved in tetrahydrofuran (30 mL). Trifluoroacetic anhydride (731 μL, 5.19 mmol) and N,N-dimethyl-4-pyridinamine (634 mg, 5.19 mmol) were added at room temperature. The reaction mixture was transferred to an oil bath at 80 °C under a nitrogen atmosphere and reacted for 2 h. The organic solvent was removed by concentration under reduced pressure. The product was separated by silica gel column chromatography, and the eluent was a petroleum ether-ethyl acetate mixture (volume ratio 1.5:1), obtaining a pale yellow solid compound 2 (940.1 mg, diastereoselectivity > 8:1);

[0061] (4bS,5S,7aS,12bS)-13-(4-methoxybenzyl)-7-(3-((4-methoxybenzyl)oxy)propyl)-10,10-dimethyl-5-(methylthio)-7a,8,12b,13-tetrahydro-[1,3]dioxino[5,4-a]pyrrolo[2,3-d]carbazole-6,12(5H,7H)-dione, yield 81%;

[0062]

[0063] 1 H NMR (600 MHz, Chloroform-d) δ 7.24 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 7.4 Hz, 1H), 7.18 (d, J = 8.5 Hz, 2H), 7.17 (t, J = 8.1 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 6.72 (t, J = 7.4 Hz, 1H), 6.57 (d, J = 7.9 Hz, 1H), 4.60 (s, 1H), 4.49 (d, J = 15.8 Hz, 1H), 4.43–4.36 (m, 3H), 3.85 (t, J = 3.8 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 3.73–3.68 (m, 1H), 3.50–3.47 (m, 1H), 3.45–3.42 (m, 1H), 2.99 (dt, J = 13.6, 6.8 Hz, 1H), 2.91 (s, 1H), 2.56 (dd, J = 18.2, 4.7 Hz, 1H), 2.47 (dd, J = 18.2, 3.0 Hz, 1H), 2.06 (s, 3H), 1.88–1.79 (m, 1H), 1.79–1.72 (m, 1H), 1.63 (s, 3H), 1.38 (s, 3H). 1313C NMR (150 MHz, CDCl3) δ 172.2, 164.3, 161.0, 159.3, 159.0, 152.2, 130.9, 130.4, 130.1, 129.5, 128.9, 126.2, 125.7, 118.0, 114.1, 113.9, 109.0, 106.6, 102.4, 72.9, 67.3, 65.1, 59.6, 56.5, 55.39, 55.37, 53.6, 51.5, 37.9, 27.9, 27.7, 27.0, 23.2, 16.2.

[0064] Example 4: Substrate 1 (120.0 mg, 0.20 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (60 μL, 0.60 mmol) and trifluoroacetic anhydride (141 μL, 1.00 mmol) were added at room temperature. The reaction mixture was transferred to an oil bath at 50 °C under a nitrogen atmosphere and reacted for 10 min. The reaction was quenched by adding water (30 mL). The mixture was extracted with DCM (3 times, 20 mL each time). The combined organic phases were washed with saturated brine (50 mL), then dried over anhydrous Na2SO4, filtered, and the filtrate was collected. The organic solvent was removed by concentration under reduced pressure. The product was separated by silica gel column chromatography, and the eluent was a petroleum ether - ethyl acetate mixture (volume ratio 1:1), to obtain a pale yellow solid compound 2 (33.2 mg) and a diastereoisomer of compound 2 (33.8 mg);

[0065] (4bS,5S,7aS,12bS)-7-(but-3-en-1-yl)-5-(tert-butylthio)-13-(4-methoxybenzyl)-10,10-dimethyl-7a,8,12b,13-tetrahydro-[1,3]dioxino[5,4-a]pyrrolo[2,3-d]carbazole-6,12(5H,7H)-dione, yield 65%;

[0066]

[0067] 11H NMR (400 MHz, Chloroform-d) δ 7.22 (d, J = 8.3 Hz, 2H), 7.10 (td, J = 7.7, 1.2 Hz, 1H), 7.05 (d, J = 7.4 Hz, 1H), 6.81 (d, J = 8.6 Hz, 2H), 6.67 (t, J = 7.4 Hz, 1H), 6.46 (d, J = 7.9 Hz, 1H), 5.73 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.12–5.02 (m, 2H), 4.87 (s, 1H), 4.44 (d, J = 16.2 Hz, 1H), 4.33 (d, J = 16.2 Hz, 1H), 3.90 (dd, J = 6.9, 4.7 Hz, 1H), 3.77 (s, 4H), 3.25 (s, 1H), 2.96 (dt, J = 13.8, 6.9 Hz, 1H), 2.79 (dd, J = 18.8, 7.0 Hz, 1H), 2.45 (dd, J = 18.8, 4.7 Hz, 1H), 2.25 (q, J = 7.1 Hz, 2H), 1.65 (s, 4H), 1.29 (s, 3H), 1.21 (s, 9H). 13 13C NMR (100 MHz, CDCl3) δ 172.7, 165.3, 161.0, 158.7, 151.6, 134.5, 131.5, 129.4, 129.2, 128.4, 124.5, 118.0, 117.5, 114.0, 108.2, 106.4, 100.7, 63.4, 59.4, 55.3, 52.9, 51.4, 50.4, 44.2, 41.0, 31.7, 31.1, 30.3, 27.1, 22.6. Isomers of Compound 2: 1HNMR (400 MHz, Chloroform-d) δ 7.20 (d, J = 8.4 Hz, 2H), 7.08 (t, J = 7.7 Hz, 1H), 7.06 (d, J = 7.4 Hz, 1H), 6.81 (d, J = 8.6 Hz, 2H), 6.73 (t, J = 7.4 Hz, 1H), 6.38 (d, J = 7.9 Hz, 1H), 5.78 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.21 (s, 1H), 5.12–5.08 (m, 2H), 4.46 (d, J = 16.2 Hz, 1H), 4.25 (d, J = 16.2 Hz, 1H), 3.97 (dd, J = 6.9, 4.7 Hz, 1H), 3.81 (s, 1H), 3.78–3.73 (m, 1H), 3.77 (s, 3H), 2.97 (dt, J = 13.8, 6.9 Hz, 1H), 2.77 (dd, J = 18.8, 7.0 Hz, 1H), 2.50 (dd, J = 18.8, 4.7 Hz, 1H), 2.36–2.16 (m, 2H), 1.69–1.64 (m, 1H), 1.60 (s, 3H), 1.35 (s, 3H), 1.21 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ 172.7, 165.6, 160.2, 158.6, 152.3, 134.9, 131.4, 129.9, 129.4, 128.3, 122.4, 118.2, 117.4, 113.9, 107.8, 106.7, 101.9, 62.4, 62.1, 55.3, 53.1, 53.0, 51.5, 44.2, 40.1, 31.8, 31.4, 29.5, 26.3, 23.9.

[0068] Example 5: Substrate 1 (154.0 mg, 0.2 mmol) was dissolved in tetrahydrofuran (10 mL). Trifluoroacetic anhydride (84 μL, 0.6 mmol) and N,N-dimethyl-4-pyridinamine (74.1 mg, 0.6 mmol) were added at room temperature. The reaction mixture was transferred to an oil bath at 80 °C under a nitrogen atmosphere and reacted for 2 h. The organic solvent was removed by concentration under reduced pressure. The product was separated by silica gel column chromatography, and the eluent was a petroleum ether - ethyl acetate mixture (volume ratio 1.5:1), obtaining a pale yellow solid compound 2 (125.1 mg, diastereoselectivity > 25:1);

[0069] (4bS,5S,7aS,12bS)-3-bromo-13-(4-methoxybenzyl)-7-(3-((4-methoxybenzyl)oxy)propyl)-10,10-dimethyl-5-(methylthio)-7a,8,12b,13-tetrahydro-[1,3]dioxino[5,4-a]pyrrolo[2,3-d]carbazole-6,12(5H,7H)-dione, yield: 83%;

[0070]

[0071] 1 H NMR(400MHz,Chloroform-d)δ7.35(d,J = 1.8Hz,1H),7.27–7.23(m,3H),7.16(d,J = 8.5Hz,2H),6.87(d,J = 8.6Hz,2H),6.81(d,J = 8.4Hz,2H),6.43(d,J = 8.5Hz,1H),4.60(s,1H),4.48–4.34(m,4H),4.05(t,J = 3.6Hz,1H),3.79(s,3H),3.76(s,3H),3.75–3.67(m,1H),3.52–3.41(m,2H),3.02–2.95(m,1H),2.89(s,1H),2.56(dd,J = 18.2,4.7Hz,1H),2.47(dd,J = 18.2,3.0Hz,1H),2.06(s,3H),1.86–1.68(m,2H),1.63(s,3H),1.40(s,3H). 13 C NMR(150MHz,CDCl3)δ171.7,164.1,160.8,159.2,159.0,151.1,132.7,130.3,130.2,129.4,128.8,128.4,128.1,114.0,113.8,110.1,109.2,106.5,102.2,72.8,67.1,65.0,59.2,56.1,55.3,55.2,53.4,51.1,37.8,27.6,27.5,26.9,23.1,16.0.

[0072] Example 6: Substrate 1 (145.0 mg, 0.2 mmol) was dissolved in tetrahydrofuran (10 mL). Trifluoroacetic anhydride (84 μL, 0.6 mmol) and N,N-dimethyl-4-pyridinamine (74.1 mg, 0.6 mmol) were added at room temperature. The reaction mixture was transferred to an oil bath at 80 °C under a nitrogen atmosphere and reacted for 2 h. The organic solvent was removed by concentration under reduced pressure. The product was separated by silica gel column chromatography, and the eluent was a petroleum ether-ethyl acetate mixture (volume ratio 1.5:1), to obtain a pale yellow solid compound 2 (109.2 mg, diastereoselectivity > 80:1);

[0073] (4bS,5S,7aS,12bS)-2-chloro-13-(4-methoxybenzyl)-7-(3-((4-methoxybenzyl)oxy)propyl)-10,10-dimethyl-5-(methylthio)-7a,8,12b,13-tetrahydro-[1,3]dioxino[5,4-a]pyrrolo[2,3-d]carbazole-6,12(5H,7H)-dione, yield: 77%;

[0074]

[0075] 1 H NMR (400 MHz, Chloroform-d) δ 7.24 (d, J = 7.7 Hz, 2H), 7.16 (d, J = 7.8 Hz, 2H), 7.09 (d, J = 7.9 Hz, 1H), 6.86 (d, J = 7.8 Hz, 2H), 6.81 (d, J = 7.8 Hz, 2H), 6.67 (d, J = 7.9 Hz, 1H), 6.52 (s, 1H), 4.63 (s, 1H), 4.48–4.35 (m, 4H), 4.01 (br s, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 3.72–3.67 (m, 1H), 3.52–3.42 (m, 2H), 3.00–2.96 (m, 1H), 2.92 (s, 1H), 2.53 (d, J = 18.2 Hz, 1H), 2.47 (dd, J = 18.2 Hz, 1H), 2.07 (s, 3H), 1.84–1.80 (m, 1H), 1.77–1.73 (m, 1H), 1.63 (s, 3H), 1.38 (s, 3H). 13CNMR (150 MHz, CDCl3) δ 171.8, 164.2, 160.8, 159.3, 159.0, 153.1, 136.0, 130.3, 130.1, 129.4, 128.7, 126.4, 124.4, 117.7, 114.1, 113.8, 108.7, 106.6, 102.4, 72.8, 67.1, 65.3, 59.3, 56.3, 55.3, 55.2, 53.1, 50.9, 37.9, 27.7, 27.6, 26.9, 23.1, 16.0.

[0076] Example 7: Substrate 1 (140.0 mg, 0.2 mmol) was dissolved in tetrahydrofuran (10 mL). Trifluoroacetic anhydride (84 μL, 0.6 mmol) and N,N-dimethyl-4-pyridinamine (74.1 mg, 0.6 mmol) were added at room temperature. The reaction mixture was transferred to an oil bath at 80 °C under a nitrogen atmosphere and reacted for 2 h. The organic solvent was removed by concentration under reduced pressure. The product was separated by silica gel column chromatography. The eluent was a petroleum ether-ethyl acetate mixture (volume ratio 1.5:1), and a pale yellow solid compound 2 (57.6 mg, diastereoselectivity > 25:1) was obtained;

[0077] (4bS,5S,7aS,12bS)-3-methoxy-13-(4-methoxybenzyl)-7-(3-((4-methoxybenzyl)oxy)propyl)-10,10-dimethyl-5-(methylthio)-7a,8,12b,13-tetrahydro-[1,3]dioxino[5,4-a]pyrrolo[2,3-d]carbazole-6,12(5H,7H)-dione, yield: 42%;

[0078]

[0079] 11H NMR (400 MHz, Chloroform-d) δ 7.23 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.87–6.85 (m, 3H), 6.81 (d, J = 8.0 Hz, 2H), 6.73 (d, J = 9.1 Hz, 1H), 6.57 (br s, 1H), 4.56 (s, 1H), 4.46–4.33 (m, 4H), 4.05 (br s, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 3.76 (s, 3H), 3.71–3.63 (m, 1H), 3.50–3.42 (m, 2H), 3.02–2.98 (m, 1H), 2.73 (s, 1H), 2.58 (dd, J = 18.2, 4.7 Hz, 1H), 2.47 (d, J = 18.2 Hz, 1H), 2.10 (s, 3H), 1.84–1.73 (m, 2H), 1.64 (s, 3H), 1.48 (s, 3H). 13 13C NMR (150 MHz, CDCl3) δ 172.0, 164.1, 160.9, 159.2, 130.3, 129.4, 115.2, 114.3, 114.0, 113.8, 112.2, 106.6, 72.8, 67.2, 65.4, 59.6, 56.0, 55.8, 55.3, 53.5, 53.3, 37.9, 27.8, 27.6, 26.9, 23.3, 16.0.

[0080] Example 8: Substrate 1 (130.0 mg, 0.18 mmol) was dissolved in tetrahydrofuran (10 mL). Trifluoroacetic anhydride (76 μL, 0.54 mmol) and N,N-dimethyl-4-pyridinamine (66.1 mg, 0.54 mmol) were added at room temperature. The reaction mixture was transferred to an oil bath at 80 °C under a nitrogen atmosphere and reacted for 2 h. The organic solvent was removed by concentration under reduced pressure. The product was separated by silica gel column chromatography. The eluent was a petroleum ether-ethyl acetate mixture (volume ratio 1.5:1), and a pale yellow solid compound 2 (65.6 mg, diastereoselectivity >20:1) was obtained;

[0081] (4bS,5S,7aS,12bS)-2-methoxy-13-(4-methoxybenzyl)-7-(3-((4-methoxybenzyl)oxy)propyl)-10,10-dimethyl-5-(methylthio)-7a,8,12b,13-tetrahydro-[1,3]dioxino[5,4-a]pyrrolo[2,3-d]carbazole-6,12(5H,7H)-dione, Yield: 48%;

[0082]

[0083] 1 1H NMR (400 MHz, Chloroform-d) δ 7.24 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 8.3 Hz, 1H), 6.87 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 8.5 Hz, 1H), 6.27 (d, J = 7.9 Hz, 1H), 6.14 (br s, 1H), 4.60 (s, 1H), 4.49–4.36 (m, 4H), 4.04 (t, J = 3.6 Hz, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H), 3.72–3.67 (m, 1H), 3.51–3.42 (m, 2H), 3.00–2.96 (m, 1H), 2.89 (s, 1H), 2.56 (dd, J = 18.2, 4.7 Hz, 1H), 2.46 (dd, J = 18.2, 3.0 Hz, 1H), 2.08 (s, 3H), 1.86–1.72 (m, 2H), 1.62 (s, 3H), 1.39 (s, 3H). 13 13C NMR (150 MHz, CDCl3) δ 172.2, 164.2, 161.9, 160.9, 159.2, 158.9, 130.3, 129.4, 128.9, 126.1, 118.2, 114.0, 113.8, 106.5, 102.7, 102.4, 95.5, 72.8, 67.2, 65.7, 59.6, 56.6, 55.3, 55.2, 53.1, 51.2, 37.7, 29.7, 27.6, 26.9, 23.1, 15.9。

Claims

1. A preparation method of a multi-substituted pentacyclic spiroindoline derivative, characterized in that: Under room temperature conditions, dissolve Compound 1, trifluoroacetic anhydride, and trifluoroacetic acid in a solvent, and react at 30 °C to 100 °C under a nitrogen atmosphere for 5 minutes to 60 hours to obtain Compound 2; Alternatively, dissolve Compound 1, trifluoroacetic anhydride, and 1,4-diazabicyclo[2.2.2]octane in a solvent and react to obtain Compound 2; Alternatively, compound 2 is prepared by reacting compound 1, trifluoroacetic anhydride, and N , N N,N-dimethyl-4-pyridinamine dissolved in a solvent. ； Wherein: R 1 is selected from C1-C 10 alkyl, C2-C 10 alkenyl, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; R 1-1 is a substituent group on R 1 , and R 1-1 is selected from halogen, nitro, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl; R 2 selected from C1-C 10 alkyl, C2-C 10 alkenyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C1-C 10 dioxolanyl; R 2-1 is a substituent on R 2 , and R 2-1 is selected from halogen, nitro, C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, C2-C8 heterocycloalkyl; a silyl ether protecting group; R 2-1-1 is a substituent on R 2-1 , and R 2-1-1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, C2-C8 heterocycloalkyl; R 3 selected from H, C1-C 10 alkyl, C2-C 10 alkenyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, nitro; R 3-1 is a substituent group on R 3 and R 3-1 is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, C2-C8 heterocycloalkyl; R 4 selected from H, C1-C 10 alkyl, C3-C 10 alkenyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl; R 4-1 is a substituent on R 4 , and R 4-1 is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, C3-C8 heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl; R 4-1-1 is a substituent on R 4-1 , and R 4-1-1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, C2-C8 heterocycloalkyl; R 5 selected from H, C1-C 10 alkyl, C2-C 10 alkenyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, halogen, nitro; R 5-1 is a substituent on R 5 and R 5-1 is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, C3-C8 heterocycloalkyl, nitro; R 5-1-1 is a substituent on R 5-1 and R 5-1-1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, C2-C8 heterocycloalkyl; R 6 selected from H, C1-C 10 alkyl, C2-C 10 alkenyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, halogen, nitro; R 6-1 is a substitution group on R 6 ; R 6-1 is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, C3-C8 heterocycloalkyl, nitro; R 6-1-1 is a substitution group on R 6-1 ; R 6-1-1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, C2-C8 heterocycloalkyl; R 7 selected from H, C1-C 10 alkyl, C2-C 10 alkenyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, halogen, nitro; R 7-1 is a substituent group on R 7 ; R 7-1 is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, C3-C8 heterocycloalkyl, nitro; R 7-1-1 is a substituent group on R 7-1 ; R 7-1-1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, C2-C8 heterocycloalkyl; R 8 selected from H, C1-C 10 alkyl, C2-C 10 alkenyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl, halogen, nitro; R 8-1 is a substitution group on R 8 ; R 8-1 is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, C3-C8 heterocycloalkyl, nitro; R 8-1-1 is a substitution group on R 8-1 ; R 8-1-1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C 12 cycloalkyl, C2-C8 heterocycloalkyl.

2. The preparation method of the multi-substituted pentacyclic spiroindoline derivative according to claim 1, characterized in that: The solvent is an ether or halogenated alkane solvent, and the molar ratio of Compound 1:trifluoroacetic anhydride:trifluoroacetic acid is 1:0.5 to 10:0.5 to 10.

3. The preparation method of the polysubstituted pentacyclic spiroindoline derivative according to claim 1, characterized in that: The solvent is an ether or halogenated alkane solvent, and the molar ratio of Compound 1:trifluoroacetic anhydride:1,4-diazabicyclo[2.2.2]octane is 1:0.5 to 10:0.5 to 10.

4. The preparation method of the multi-substituted pentacyclic spiroindoline derivative according to claim 1, characterized in that: The solvent is an ether solvent or a halogenated alkane solvent, and the molar ratio of compound 1: trifluoroacetic anhydride: N , N -dimethyl-4-pyridinamine is 1: 0.5 to 10: 0.5 to 10.

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