Method for synthesizing amanitin and derivative thereof

Abstract

Disclosed in the present invention is a method for synthesizing amanitin and a derivative thereof. The present invention particularly relates to a method for preparing a compound of formula 7 in a liquid phase, which method comprises the following step: subjecting a compound of formula 6 to a ring-closing reaction with iodine in a solvent to obtain compound 7. The preparation method of the present invention is simple to operate, has easily controllable reactions, and has high selectivity and a high yield. The key step of S ether formation for the amanitin of the present invention has a high yield, and no byproduct disulfide is generated in this step. The preparation method reduces the production cost, ensures the subsequent drug quality, avoids the difficulty and defects of impurities in the prior art, and is suitable for industrial scaled-up production.

Description

Synthesis method of amanitin and its derivatives This application claims the priority of Chinese Patent Application No. 2023116467215 with the filing date of December 4, 2023. This application incorporates the entire text of the above-mentioned Chinese patent application by reference. Technical Field The present invention relates to a synthesis method of amanitin and its derivatives, belonging to the technical fields of medicine and chemistry. Background Art Amanitin, also known as amanitin in English, is a natural and highly efficient RNA pol II inhibitor derived from Amanita mushrooms. There has been relatively little research on its preparation method. In Patent CN115715294A, the specification

[0344] ~

[0358] discloses the total synthesis of α-amanitin, in which amino acids are successively coupled by 2-CTC resin, the S-ether is formed through ring closure, deprotection, condensation, and oxidation to obtain α-amanitin. The reaction conditions for forming the S-ether by ring closure are TFE / HOAc / DCM (1:1:8); meanwhile, the specification

[0513] ~

[0516] discloses that 2 I-mediated cyclization to obtain the S-ether, the reaction solvent is TFE / water 9:1 or DCM / TFA 95:1, the reagent is I 2 , and the reaction yield is 26% (based on the initial resin loading), and the by-product obtained is the deprotected disulfide. The literature Journal of the American Chemical Society 2021, 143, 35, 14322-14331 discloses the influence of the sequence dependence of the reaction on the iodine-mediated ring closure. The reaction yields for different sequences are 14%~52%. It can be seen that different sequences have a great influence on the ring closure yield. Therefore, the formation of the thioether ring is a very crucial step in the preparation of amanitin. In the prior art, the peptide chain of amanitin is synthesized by the method of successive coupling. Along with the extension of the peptide chain, the coupling degree becomes more and more difficult, and it is easy to produce missing peptides and racemic peptides, which reduce the purity of the product, and the production cycle is long and the efficiency is relatively low. For the formation of the key step S-ether of amanitin, the yield of the prior art is low. Therefore, based on the prior art and the application of amanitin, there is a need for a better method for synthesizing amanitin in this field. Summary of the Invention The first aspect of the present invention relates to a preparation method of a compound of formula 7, comprising the following steps: Step S4: In a solvent, subject the compound of formula 6 to a ring closure reaction with iodine to obtain compound 7, wherein the R 1Independently selected from hydrogen, a hydroxyl protecting group, especially a hydroxyl protecting group that can be removed under acidic conditions, selected from silyl groups, alkyl ethers, alkyl groups, preferably trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS), methyl, trityl (Tr), tert-butyl or methoxymethyl (MOM), preferably tert-butyl, TBDMS; R 3 Independently selected from hydrogen, a hydroxyl protecting group, especially a hydroxyl protecting group that can be removed under acidic or basic conditions, selected from one of silyl groups, alkyl groups, carboxylic acid esters, preferably trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS), methyl, trityl (Tr), tert-butyl, methoxymethyl (MOM), acetyl (Ac), dichloroacetyl (CAc), benzoyl (Bz) or pivaloyl (Piv), more preferably Ac; R 4 Selected from NH 2 、-Z-R 7 、OH、OR 8 、NHR 9 、any PEG substituted at the end with an amino group, a carboxyl group, a protected amino group or a protected carboxyl group 1- 8 chain or any C 1 -C 12 alkyl chain; PEG 1-8 chain is represented as For example PEG 1-7 、PEG 1-6 、PEG 1-5 、PEG 1-4 、PEG 1-3 、PEG 1-2 、PEG 8 、PEG 7 、PEG 6 、PEG 5 、PEG 4 、PEG 3 、PEG 2 、 (PEG) ； Z can be selected from -C 1 -C 5 alkylene-, -NH-, -C 1 -C8 Alkylene-PEG 1-8 -, -PEG 1-8 - or any combination thereof; R 7 is optionally selected from: R 8 is a carboxyl protecting group, especially a protecting group that is prone to amine-lipid exchange or a protecting group that is prone to hydrolysis reaction, especially a C1-C3 carbon chain, preferably methyl, ethyl, Allyl; R 9 is selected from amino protecting groups, especially amino protecting groups that can be removed under acidic, basic or reducing conditions, and can be selectively removed during the reaction according to different protecting groups; R 10 is selected from H, a hydroxyl group protected by a protecting group or n can be 1-7, for example, n = 1, 2, 3, 4, 5, 6 or 7; the hydroxyl group protected by a protecting group is preferably a hydroxyl group protected by benzyl (Bn) or any substituted benzyl, such as -OBn substituted at the 1st, 2nd, 3rd or 4th position of the indole ring or -O-any substituted benzyl substituted at the 1st, 2nd, 3rd or 4th position of the indole ring, and the any substituted benzyl can be selected from groups such as halogen (F, Cl, Br or I), methoxy, nitro, cyano and other groups of the benzene ring any substituted benzyl. In certain embodiments, R 1 is selected from hydrogen and hydroxyl protecting groups, and the hydroxyl protecting groups are selected from C 1-6 alkyl and C d alkyl substituted by one or more R 1-6 alkyl; R 3 is independently selected from hydrogen and hydroxyl protecting groups, and the hydroxyl protecting groups are selected from C 1-6 alkyl, C d alkyl substituted by one or more R 1-6 alkyl and -C(O)-R e ; R a 、R b and R c are each independently selected from C 1-6 alkyl or phenyl; R d is independently selected from C 1-6 alkoxy or phenyl; R e is selected from C 1-6 alkyl, C 1-6 haloalkyl or phenyl; R4 Selected from NH 2 , -Z-R 7 , OH, OR 8 , NHR 9 , PEG substituted by an amino group, a carboxyl group, an amino group protected by an amino protecting group or a carboxyl group protected by a carboxyl protecting group 1-8 group and C substituted by an amino group, a carboxyl group, an amino group protected by an amino protecting group or a carboxyl group protected by a carboxyl protecting group 1 -C 12 alkyl; the amino protecting group is selected from benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), tert-butoxycarbonyl (Boc), pivaloyl, acetyl and trityl (Trt); the carboxyl protecting group is selected from C 1-6 alkyl and C substituted by a vinyl group 1-6 alkyl; PEG 1-8 chain is represented as Z is selected from -C 1 -C 5 alkylene-, -NH-, -C 1 -C 8 alkylene-PEG 1-8 -, -PEG 1-8 - or any combination thereof; R 7 is selected from: R 8 is C 1-6 alkyl or C substituted by a vinyl group 1-6 alkyl; R 9 is selected from amino protecting groups, and the amino protecting groups are selected from benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), tert-butoxycarbonyl (Boc), pivaloyl, benzyloxycarbonyl (Cbz) or acetyl and trityl (Trt); R 10 is selected from H, -O-R f or n is 1-7; R f is benzyl or benzyl substituted by one or more R f-1 substituents; R f-1 is independently selected from halogen, C 1-6 alkoxy, nitro or cyano. In certain embodiments, in R 1 , the hydroxyl protecting group is selected from C 1-6An alkyl group and a C alkyl group substituted by one or more R d ; 1-6 alkyl group; R a 、R b and R c are each independently selected from C 1-6 alkyl group and phenyl group; R d is independently selected from C 1-6 alkoxy group and phenyl group. In certain embodiments, in R 3 , the hydroxyl protecting group is selected from C 1-6 alkyl group, a C alkyl group substituted by one or more R d or -C(O)-R 1-6 ; e ; R a 、R b and R c are each independently selected from C 1-6 alkyl group and phenyl group; R d is independently selected from C 1-6 alkoxy group and phenyl group; R e is selected from C 1-6 alkyl group, C 1-6 haloalkyl group and phenyl group. In certain embodiments, in R 8 , the carboxyl protecting group is C 1-6 alkyl group or a C alkyl group substituted by vinyl 1-6 alkyl group. In certain embodiments, R 1 is independently selected from H, and C 1-6 alkyl group; R a 、R b and R c are each independently preferably selected from C 1-6 alkyl group. In certain embodiments, R 3 is -C(O)-R e ; R e is selected from C 1-6 alkyl group. In certain embodiments, R 4 is selected from NH 2 , OH or OR 8 , R 8 is C 1-6 alkyl group or a C alkyl group substituted by vinyl 1-6Alkyl; preferably a C alkyl substituted with a vinyl group 1-6 alkyl group. In certain embodiments, R 10 is -O-R f ; R f is benzyl or benzyl substituted with one or more R f-1 substituents; R f-1 is independently selected from halogen, C 1-6 alkoxy, nitro or cyano. In certain embodiments, the C 1-6 alkyl group is selected from methyl, ethyl, n-propyl, isopropyl or tert-butyl, preferably methyl or tert-butyl. In certain embodiments, R 1 is tert-butyldimethylsilyl or tert-butyl, preferably tert-butyldimethylsilyl. In certain embodiments, R 3 is acetyl. In certain embodiments, R 4 is selected from NH 2 , OH or OR 8 , where R 8 is allyl; preferably OR 8 , where R 8 is allyl. In certain embodiments, R 10 is benzyloxy. In certain embodiments, the compound of formula 6 is any one of the following compounds: In certain embodiments, in step S4, the ring-closing reaction is shown in any one of the following schemes: In certain embodiments, in step S4, the molar ratio of the compound 6 to iodine is 1:1 to 5, preferably 1:1 to 3, more preferably 1:1 or 1:2. In certain embodiments, in step S4, the ring-closing reaction is carried out in an organic acidic reagent and an aprotic organic solvent or water or a mixed solvent of an organic solvent and water; the organic acidic reagent is selected from halogen-substituted C 1-10 alkyl alcohol; halogen-substituted C 1-10The alkyl alcohol is selected from, for example, 2,2,2-tribromoethanol, trifluoromethanol, 2,2,2-trifluoroethanol, perfluoroethanol, trifluoropropanol, 2,2,3,3-tetrafluoropropanol, hexafluoropropanol, perfluoropropanol, trifluorobutanol, hexafluorobutanol, perfluorobutanol, trifluoropentanol, hexafluoropentanol, perfluoropentanol, trifluorohexanol, hexafluorohexanol or perfluorohexanol, or any combination thereof; preferably 2,2,2-tribromoethanol or 2,2,2-trifluoroethanol; The aprotic organic solvent can be selected from chloroalkanes, ether solvents, aromatic alkanes, etc.; Ether solvents such as THF, dioxane, methyltetrahydrofuran; Chloroalkanes such as dichloromethane, dichloroethane, chloroform, etc.; Aromatic alkanes such as toluene, etc. In certain embodiments, in step S4, the ring-closing reaction is carried out in the presence of 2,2,2-trifluoroethanol, water and dichloromethane. In certain embodiments, in step S4, the ring-closing reaction is carried out in an organic acidic reagent and water; The volume ratio of the organic acidic reagent to water is 6-10:1, preferably 7-9:1. In certain embodiments, in step S4, the volume ratio of 2,2,2-trifluoroethanol to water is 9:1 or 8.9:1. In certain embodiments, in step S4, when the ring-closing reaction is carried out in an organic acidic solvent, an aprotic organic solvent and water, the volume ratio of the organic acidic solvent, the aprotic organic solvent and water is 9:3:1. In certain embodiments, in step S4, the mass g of compound 6 to the volume mL of the organic acidic reagent is 1:10-100, preferably 1:30-90, more preferably 1:30 or 1:90. In certain embodiments, in step S4, the temperature of the ring-closing reaction is 0-30 °C, preferably 10-25 °C, more preferably 15-20 °C. In certain embodiments, in step S4, the time of the ring-closing reaction is 1-24 h, preferably 3-16 h. In certain embodiments, in step S4, the method for preparing compound 7 includes the following steps: dissolving compound 6 in an organic acidic reagent and / or water, and then adding iodine dissolved in an aprotic organic solvent (such as dichloromethane) to the above solution. In certain embodiments, in step S4, the method for preparing compound 7 includes the following steps: dissolving compound 6 in an organic acidic reagent and / or water, dissolving iodine in an aprotic organic solvent (such as dichloromethane) and adding it to the above solution at room temperature, controlling the reaction time for 1-24 h, and after the reaction is completed, performing post-treatment to obtain compound 7. In certain embodiments, in step S4, after the reaction is completed, the following steps are further included: extraction (for example, adding a 10% aqueous sodium sulfite solution to the reaction system). In certain embodiments, in step S4, after the reaction is completed, the following post-treatment steps are further included: washing (e.g., washing with saturated brine), liquid separation, drying, filtration, concentration, and column chromatography (e.g., PE:EA = 5:1). In certain embodiments, in step S4, after the reaction is completed, the following post-treatment steps are further included, and the post-treatment steps are conventional post-treatment steps for such reactions in the art, such as one or more of quenching, crystallization, filtration, washing, rotary evaporation, drying, or column chromatography. In certain embodiments, in step S4, the compound of formula 6 is prepared by the following method. The second aspect of the present invention relates to a liquid-phase preparation method of the compound of formula 6, including the following steps: Step S1: In a solvent, the compound of formula 1 and the compound of formula 2 are subjected to a condensation reaction under the action of a peptide bond-forming reagent to obtain compound 3. Step S2: In a solvent, the compound of formula 3 reacts with a deaminoprotecting reagent to obtain the compound of formula 4. Step S3: In a solvent, the compound of formula 4 and the compound of formula 5 react under the action of a peptide bond-forming reagent, and a condensation reaction is carried out to obtain the compound of formula 6. Wherein R 1 、R 3 、R 4 are the same as described in the above first aspect; R 6 is an amino protecting group, especially an amino protecting group that can be removed under basic or reducing conditions, more especially Pht, Alloc, Fmoc, preferably Fmoc; R 10 The substituents are the same as the definitions of the substituents in the first aspect of the present invention. In certain embodiments, when R 4 in the compound of formula 6 is an amino group, the preparation method of the compound of formula 6 further includes the following steps: Step S3': In a solvent, the product of step S3 is subjected to a deprotection reaction. Step S4': In a solvent, the product of step S3' and an ammonia source are subjected to a condensation reaction through a condensing agent to obtain the compound of formula 6. Wherein R 1 、R 3 、R 10 are as defined for the substituents in claim 1; in the compounds of formula 2, 3, and 4, R 4 is selected from OR 8 , R 8 is a carboxyl protecting group, especially a protecting group that is prone to amine-lipid exchange or a protecting group that is prone to hydrolysis reaction, especially a carbon chain of C 1 ~C 3 , preferably methyl, ethyl, Allyl; R6 is an amino protecting group, especially an amino protecting group that can be removed under basic or reducing conditions, more especially Pht, Alloc, Fmoc, preferably Fmoc. In certain embodiments, in step S1, the peptide bond forming reagent in the condensation reaction is selected from N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), N-cyclohexyl-N'-(2-morpholinoethyl)carbodiimide methyl-p-toluenesulfonate (CMC or CME-CDI), 1,1'-carbonyldiimidazole (CDI), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)urea hexafluorophosphate (HBTU), benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), 1-hydroxybenzotriazole (HOBt), NNN'N'tetramethylchloroformamidinium hexafluorophosphate (TCFH), 2-(7-azabenzotriazol)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP), hexafluorophosphate chlorotripyrrolidinophosphonium (PyClOP), S-(1-oxido-2-pyridyl)-N,N,N',N'-tetramethylthiuronium tetrafluoroborate, O-[(ethoxycarbonyl)cyano-methyleneamino]-N,N,N',N'-tetramethyluronium hexafluorophosphate (HOTU), (1-cyano-2-ethoxy-2-oxoethyliminoaminooxy)dimethylamino-morpholino-carbon hexafluorophosphate (COMU), O-(benzotriazol-1-yl)-N,N,N',N'-bis(tetramethylene)urea hexafluorophosphate (HBPyU), dipyrrolidino(N-succinimidyloxy)hexafluorophosphate (HSPyU), chlorodipyrrolidinocarbon hexafluorophosphate (PyClU), (benzotriazol-1-yloxy)dipiperidinocarbonium hexafluorophosphate (HBPipU), O-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU), 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (HCTU), bromotris(dimethylamino)-hexafluorophosphonium (BrOP), propylphosphonic anhydride (T 3P), N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium hexafluorophosphate (HSTU), O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (MMTM, DMTMM), N,N,N',N'-tetramethyl-O-(N-succinimidyl)-neodymium tetrafluoroborate (TSTU), O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TDBTU), NMM, HOPO, HOAT, EDCI, or any combination thereof; preferably one or more selected from HOBt, PyBOP, and EDC, more preferably PyBOP and HOBt, or NMM, HOAT, and EDCI. In certain embodiments, in step S1, the condensation reaction is also carried out in the presence of a base selected from triethylamine, diethylamine, pyridine, diisopropylethylamine, preferably diisopropylethylamine. In certain embodiments, in step S1, the solvent in the condensation reaction is selected from tetrahydrofuran, dioxane, dichloromethane, chloroform, N,N'-dimethylformamide DMF, ethyl acetate, preferably DMF. In certain embodiments, in step S1, the molar ratio of the compound of formula 2 to the compound of formula 1 is 1:1. In certain embodiments, in step S1, the condensation reaction is carried out in the presence of DIEA, HOBt, and PyBOP. Preferably, the molar ratio of DIEA, HOBt, and PyBOP is 2:1:1. In certain embodiments, in step S1, the condensation reaction is carried out in the presence of NMM, HOAT, and EDCI. Preferably, the molar ratio of NMM, HOAT, and EDCI is 2:1:1. In certain embodiments, in step S1, when the peptide bond forming reagents are PyBOP and HOBt, the molar ratio of the peptide bond forming reagents to the compound of formula 1 is 2.4:1. In certain embodiments, in step S1, when the peptide bond forming reagents are NMM, HOAT, and EDCI, the molar ratio of the peptide bond forming reagents to the compound of formula 1 is 4.7:1. In certain embodiments, in step S1, the condensation reaction is carried out in the presence of argon. In certain embodiments, in step S1, the reaction temperature of the condensation reaction is 0 to 10 °C. In certain embodiments, in step S1, the condensation reaction includes the following post-treatment steps: precipitation (for example, pouring into ice water for precipitation), filtration, washing (for example, with water), dissolving the filter cake (for example, using methyl tert-butyl ether for dissolution), washing (for example, with saturated brine), liquid separation, drying, filtration, and concentration. In certain embodiments, in step S2, the deprotecting reagent is a conventional amino deprotecting reagent. For example, when R 6 is Fmoc, it is removed using one or more of the following bases: piperidine, pyridine, diethylamine (DEA), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably 20% piperidine. In certain embodiments, in step S2, the solvent is DMF. In certain embodiments, in step S2, the volume ratio of the deprotecting reagent to the solvent is 1:4. In certain embodiments, step S2 further includes the following steps: washing (for example, using ice water), extraction (for example, using methyl tert-butyl ether), washing (for example, with water and saturated brine), drying, filtration, concentration, and column chromatography (for example, DCM:MeOH = 1:25). In certain embodiments, in step S3, the peptide bond-forming reagent, base, and solvent in the condensation reaction are the same as in step S1. In certain embodiments, the reaction conditions of step S3 are the same as those of step S1. In certain embodiments, in step S3, in the condensation reaction, for example, the peptide bond-forming reagents are HOBt and PyBOP, and the molar ratio of HOBt to PyBOP is, for example, 1:1. In certain embodiments, in step S3, in the condensation reaction, the reaction temperature is, for example, 0 - 5 °C, and the reaction time is, for example, 2 - 3 hours. In certain embodiments, in step S3, in the condensation reaction, the molar ratio of the compound of formula 4 to the compound of formula 5 is, for example, 1:1 to 1:1.2. In certain embodiments, in step S4’, the solvent is DMF. In certain embodiments, in the condensation reaction of the [compound] with the ammonia source through a condensing agent, for example, the condensing agents are HOBt and EDCI, and the molar ratio of HOBt to EDCI is, for example, 1:1. In certain embodiments, in step S4’, the molar ratio of the condensing agent to the product of step S3’ is 2.5:1 or 2.6:1. In certain embodiments, in step S4’, the condensation reaction is also carried out in the presence of a base, and the base is selected from triethylamine, diethylamine, pyridine, diisopropylethylamine, preferably diisopropylethylamine. In certain embodiments, in step S4', the condensation reaction is carried out in the presence of DIEA, HOBt and EDCI. Preferably, the molar ratio of DIEA, HOBt and PyBOP is 2.5:1:1 or 2.3:1:1. In certain embodiments, in step S4', the ammonia source is selected from one or more of ammonium acetate, ammonium formate, ammonia gas, ammonia water, ammonia solution, ammonium chloride, ammonium sulfate, ammonium carbonate; the ammonia source is preferably ammonium chloride. In certain embodiments, in step S4', the molar ratio of the ammonia source to the product of step S3' is 6.25:1 or 8:1. In certain embodiments, in step S4', in the condensation reaction with the ammonia source through a condensing agent, the reaction temperature is, for example, 10 to 30 °C, preferably 20 °C; the reaction time is, for example, 2 to 24 hours, preferably 3 to 16 hours. In certain embodiments, step S4' further includes the following reaction steps: precipitation (for example, adding ice water for precipitation), filtration, washing the filter cake, drying, dissolving the filter cake (for example, using methyl tert-butyl ether for dissolution), washing (for example, using saturated brine for washing), drying (for example, using sodium sulfate for drying), rotary evaporation, column chromatography (for example, DCM:MeOH = 1:50 - 1:10) and rotary evaporation. In certain embodiments, in step S3', the solvent is DCM. In certain embodiments, in step S3', the catalyst in the deprotection reaction is selected from palladium catalysts, such as tetrakis(triphenylphosphine)palladium, palladium chloride, palladium acetate, bis(triphenylphosphine)dichloropalladium, [1,1''-bis(diphenylphosphino)ferrocene]dichloropalladium, bis(acetonitrile)chloropalladium or tris(dibenzylideneacetone)dipalladium, or a mixture of any two or more of them, preferably tetrakis(triphenylphosphine)palladium. In certain embodiments, in step S3', the deprotection reaction is carried out in the presence of a palladium catalyst and phenylsilane, for example, in the presence of tetrakis(triphenylphosphine)palladium and phenylsilane. In certain embodiments, in step S3', the deprotection reaction is carried out in the presence of argon. In certain embodiments, the product obtained in step S3' is directly subjected to the next step without purification. The third aspect of the present invention relates to a liquid-phase preparation method of a compound of formula 9 or a compound of formula 10, comprising the following steps: Step S5: In a solvent, the compound of formula 7 reacts with a deprotection reagent to obtain a compound of formula 8. Step S6: In a solvent, the compound of formula 8 reacts under the action of a peptide bond-forming reagent, and undergoes a condensation reaction to obtain a compound of formula 9. Optionally, step S7: In a solvent, when R 10When the hydroxyl group is protected by a protecting group, the compound of formula 9 reacts with a deprotecting reagent to obtain the compound of formula 10, wherein R 1 、R 3 、R 4 、R 10 are the same as described in the first aspect above. In certain embodiments, in step S5, the deprotecting reagent is a conventional deprotecting reagent, such as an acid, a combination of an acid and a silane; the acid is, for example, trifluoroacetic acid (TFA), hydrochloric acid, HCl / MeOH, HCl / EA, HCl / dioxane; the silane is, for example, trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS). In certain embodiments, in step S5, the deprotecting reagent is a combination of trifluoroacetic acid (TFA) and triisopropylsilyl (TIPS), and the molar ratio of TIPS to the compound of formula 7 can be 3:1. In certain embodiments, in step S5, the solvent is a mixed solvent formed by TFA and DCM, and the volume ratio of TFA to DCM can be 2:1. In certain embodiments, in step S5, the deprotecting reagent is TFA. In certain embodiments, step S5 includes the following operations: in a TFA / DCM mixed solvent, TIPS reacts with the compound of formula 7. In certain embodiments, step S5 further includes the following post-treatment steps: after the reaction is completed, the reaction solution is mixed with an aqueous sodium bicarbonate solution and a mixed solution formed by DCM / IPA, the organic phase is separated, the aqueous phase is extracted (for example, extracted with DCM / IPA), the organic phases are combined, concentrated under reduced pressure, prepared by reverse phase, and freeze-dried. In certain embodiments, step S5 includes the following operations: in a DCM solvent, the compound of formula 7 reacts with TFA. In certain embodiments, step S5 further includes the following post-treatment steps: after the reaction is completed, it is concentrated, freeze-dried using acetonitrile and water, prepared by reverse phase, and freeze-dried. In certain embodiments, in step S6, the peptide bond forming reagent is the same as in step S1, preferably HATU. In certain embodiments, in step S6, the molar ratio of the peptide bond forming reagent to the compound of formula 8 is 2:1. In certain embodiments, in step S6, the base and the solvent in the condensation reaction are the same as in step S1. In certain embodiments, in step S6, the solvent is DMF. In certain embodiments, in step S6, the base is DIEA. In certain embodiments, in step S6, the molar ratio of the base to the compound of formula 8 is 4:1. In certain embodiments, in step S7, the deprotecting reagent is a conventional debenzylating reagent, such as boron trichloride, boron tribromide, boron trifluoride, preferably BF 3 -Et 2 O. In certain embodiments, in step S7, the molar ratio of the deprotecting reagent to the compound of formula 9 is 20:1. In certain embodiments, in step S7, the solvent is 1,2-ethanedithiol. In certain embodiments, the compound of formula 7 is prepared by the method for preparing the compound of formula 7 according to the first aspect above. The fourth aspect of the present invention relates to a method for preparing a compound of formula 14, wherein, R 12 is selected from NH 2 or OH Scheme 1: When R 12 is NH 2 the structure of the compound of formula 14 is the compound shown in formula 14.1, which comprises the following steps S8 to S11, Step S8: In a solvent, the compound of formula 10-1 is selectively deprotected to obtain the compound of formula 11. Step S9: In a solvent, the compound of formula 11 reacts with an ammonia source through a condensation reaction to obtain the compound of formula 12-1. Step S10: In a solvent, the compound of formula 12-1 is deprotected to obtain the compound of formula 13.1. Step S11: In a solvent, the compound of formula 13.1 is oxidized to obtain the compound of formula 14.1. The reaction route is as follows: where R 3 is as described in the first aspect above; R 8 is a carboxyl protecting group, especially a protecting group that is prone to amine-lipid exchange or a protecting group that is prone to hydrolysis reaction, especially a C 1 -C 3 carbon chain, preferably methyl, ethyl, Allyl; R 11 is H or a hydroxyl group substituted at any of the 1st, 2nd, 3rd or 4th positions of the indole ring, preferably a hydroxyl group. In certain embodiments, in step S8 of Scheme 1, the decarboxyl protection is a conventional reagent, such as when R8 When it is Allyl, a palladium catalyst is selected for removal, such as one of tetrakis(triphenylphosphine)palladium, palladium chloride, palladium acetate, bis(triphenylphosphine)dichloropalladium, [1,1''-bis(diphenylphosphino)ferrocene]dichloropalladium, bis(acetonitrile)palladium dichloride or tris(dibenzylideneacetone)dipalladium, or a mixture of any two or more of them. In certain embodiments, in step S8 of the described process, the condensing agent in the condensation reaction is selected from N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), N-cyclohexyl-N'-(2-morpholinoethyl)carbodiimide methyl-p-toluenesulfonate (CMC or CME-CDI), 1,1'-carbonyldiimidazole (CDI), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)urea hexafluorophosphate (HBTU), benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), 1-hydroxybenzotriazole (HOBt), NNN'N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH), 2-(7-azabenzotriazol)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP), hexafluorophosphate chlorotripyrrolidinophosphonium (PyClOP), S-(1-oxido-2-pyridyl)-N,N,N',N'-tetramethylthiuronium tetrafluoroborate, O-[(ethoxycarbonyl)cyano-methyleneamino]-N,N,N',N'-tetramethyluronium hexafluorophosphate (HOTU), (1-cyano-2-ethoxy-2-oxoethyliminoaminooxy)dimethylamino-morpholino-carbon hexafluorophosphate (COMU), O-(benzotriazol-1-yl)-N,N,N',N'-bis(tetramethylene)urea hexafluorophosphate (HBPyU), dipyrrolidino(N-succinimidyloxy)hexafluorophosphate (HSPyU), chlorodipyrrolidinocarbon hexafluorophosphate (PyClU), (benzotriazol-1-yloxy)dipiperidinocarbonium hexafluorophosphate (HBPipU), O-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU), 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (HCTU), bromotris(dimethylamino)-hexafluorophosphonium (BrOP), propylphosphonic anhydride (T3P), N,N,N',N'-tetramethyl-O-(N-succinimido)urea hexafluorophosphate (HSTU), O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, N,N,N',N'-tetramethyl-O-(N-succinimido)-neodymium tetrafluoroborate, O-(3,4-dihydro-4-oxo-1,2,3-Benzotriazin-3-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, one or any combination thereof, preferably HOBt, EDC., In certain embodiments, in step S9 of the method, the ammonia source is selected from one or more of ammonium acetate (NH 4 OAc), ammonium formate, ammonia gas, aqueous ammonia, ammonia solution, ammonium chloride, ammonium sulfate, ammonium carbonate; the ammonia source is preferably ammonium acetate. For example, the molar ratio of compound 11 to the ammonia source (such as ammonium acetate) is 1:1 to 2. In certain embodiments, in step S10 of the method, the deprotecting reagent is selected from ammonia organic solvent solutions, and the organic solvent is an alcohol solvent, an ether solvent, etc., such as methanol, ethanol, isopropanol, dioxane, tetrahydrofuran. In certain embodiments, in step S10 of the method, for example, the molar concentration of the ammonia organic solvent solution is 7 mol / L. In certain embodiments, in step S11 of the method, the oxidant is selected from one or more of polyphenylene ether, benzoyl peroxide, tert-butyl peroxybenzoate, lauroyl peroxide, Jones reagent, Collins reagent, pyridinium chlorochromate, pyridinium dichromate, manganese dioxide, Dess-Martin oxidant, potassium permanganate, periodic acid, osmium tetroxide, 30% hydrogen peroxide, meta-chloroperoxybenzoic acid, and tert-butyl hydroperoxide; for example, meta-chloroperoxybenzoic acid (m-CPBA). Or preferably, Scheme 2: It is prepared by including steps S8' and S11, Step S8': In a solvent, the compound of formula 10-1 undergoes an aminolysis reaction of the ester to obtain the compound of formula 13.1. Step S11, in a solvent, the compound of formula 13.1 can be selectively oxidized to obtain the compound of formula 14.1. The reaction route is as follows: Wherein R 3 Is the same as described in the first aspect of the present invention; R 8 Is a carboxyl protecting group, especially a protecting group that is prone to aminolysis of the ester or a protecting group that is prone to hydrolysis reaction, especially a C 1 To C 3 Carbon chain, preferably methyl, ethyl, Allyl; R 11 Is H or a hydroxyl group substituted at any of the 1st, 2nd, 3rd, or 4th positions of the indole ring. In certain embodiments, in step S8' of Scheme 2, the aminolysis reagent of the ester is selected from ammonia gas, aqueous ammonia, or ammonia organic solvent solutions; the organic solvent is an alcohol solvent, an ether solvent, etc., such as methanol, ethanol, isopropanol, dioxane, tetrahydrofuran. In certain embodiments, in step S8' of Scheme 2, ammonia methanol solution is selected for amine transesterification, such as 7 mol / L ammonia methanol solution. In certain embodiments, in step S8' of Scheme 2, ammonia methanol solution is selected for amine transesterification, and the reaction temperature is selected from 10 - 35 °C, such as 15 - 20 °C. In certain embodiments, in step S11 of Scheme 2, the oxidant is the same as that in step S11 of Scheme 1. In certain embodiments, the compound of Formula 10-1 is prepared by the preparation method described in the third aspect of the present invention. Scheme 3: When R 12 is OH, the structure of the compound of Formula 14 is the compound shown in Formula 14.2, which is prepared through the following S8” and S11’ steps, Step S8”: In a solvent, the compound of Formula 10-1 reacts with a deprotecting agent to obtain the compound of Formula 11.2. Step S11’: In a solvent, the compound of Formula 11.2 optionally reacts with an oxidant to obtain the compound of Formula 14.2. The reaction route is as follows: wherein R 3 is the same as described in the first aspect above. R 8 is a carboxyl protecting group, especially a protecting group that is prone to amine transesterification or hydrolysis reaction, especially a C 1 ~C 3 carbon chain, preferably methyl, ethyl, Allyl; R 11 is H or a hydroxyl group substituted at any position of the 1st, 2nd, 3rd or 4th position of the indole ring. In certain embodiments, in step S8” of Scheme 3, the deprotecting agent is a conventional reagent. When R 3 is Ac and R 8 is Allyl, a palladium catalyst and a base are selected for deprotection, and the deprotection sequence can first use a base to remove Ac or first use a palladium catalyst to remove Allyl as needed. In certain embodiments, in step S11’ of Scheme 3, the oxidant is the same as that in step S11 of Scheme 1. The fifth aspect of the present invention relates to the compound of Formula 9’, the compound of Formula 9”, the compound of Formula 10’ or the compound of Formula 10” and their preparation methods or the application of the compounds in preparing ADC conjugate toxin linkers. R 3' is selected from hydroxyl protecting groups, especially hydroxyl protecting groups that can be removed under acidic or alkaline conditions, and is selected from one of silyl groups, alkyl groups, and carboxylic acid esters, preferably one of trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS), methyl, trityl (Tr), tert-butyl, methoxymethyl (MOM), acetyl (Ac), dichloroacetyl (CAc), benzoyl (Bz), pivaloyl (Piv), and more preferably Ac; R 11 is H or a hydroxyl group that is arbitrarily substituted at the 1st, 2nd, 3rd, or 4th position of the indole ring. First, in the technical solutions of the compound of formula 9' and the compound of formula 9": In certain embodiments, R 11 is H or a hydroxyl group that is arbitrarily substituted at the 1st, 2nd, 3rd, or 4th position of the indole ring; R 4 ' is selected from X 1 is selected from dipeptides, tripeptides, or tetrapeptides, for example: or its isomers; X 2 is selected from spacer units, for example m can be 1 - 7, for example m = 1, 2, 3, 4, 5, 6, or 7; The preferred compounds of the compound of formula 9' and the compound of formula 9" are as follows: R 3 ' is selected from hydroxyl protecting groups, and the substituents are defined as above, for example Ac; In certain embodiments, the compound of formula 9' can be prepared by condensing the compound of formula 11 when R 11 is OH with or its salt form through a condensation reaction; for example, through a condensation reaction of a condensing agent in an organic solvent; salts such as trifluoroacetate, hydrochloride, and dichloroacetate. In certain embodiments, the compound of formula 9' is oxidized under the action of an oxidizing agent to obtain the compound of formula 9"; the oxidizing agent is, for example, m-chloroperoxybenzoic acid (m-CPBA). In certain embodiments, for the application of the compound of formula 9' and the compound of formula 9" in preparing an ADC conjugate toxin linker, R 3Application of the protected base post-toxin linker in the preparation of ADC conjugates, such as the application in the preparation of ADC conjugate HDP101. Second, in the technical solutions of the compound of formula 10' and the compound of formula 10": R 4 " is selected from OH hydroxyl group or NH 2 amino group; R 11 ' is selected from n can be 1-7, for example, n = 1, 2, 3, 4, 5, 6 or 7; The preferred compounds of the compound of formula 10' and the compound of formula 10" are as follows: In certain embodiments, the compound of formula 10' can be obtained by reacting the compound of formula 9-1 with After etherification reaction, and then through the reaction steps of step S8 or step S8, S9 of the fourth aspect of the present invention; in addition, the compound of formula 10' can also be further deprotected according to need through the reaction step of step S10 of the fourth aspect; the structural formula of the compound of formula 9-1 is as follows: R 3 ' is selected from hydroxyl protecting groups, and the substituents are defined as above, for example, Ac; R 8 is a carboxyl protecting group, especially a protecting group that is prone to amine-lipid exchange or a protecting group that is prone to hydrolysis reaction, especially a C 1 ~C 3 carbon chain, preferably methyl, ethyl, Allyl; Or in certain embodiments, the deprotected compound of the compound of formula 10' can be obtained by reacting the compound of formula 9-1 with After etherification reaction, and then through the reaction steps of step S8' or step S8" of the fourth aspect of the present invention; In certain embodiments, the compound of formula 10' is oxidized under the action of an oxidant to obtain the compound of formula 10"; the oxidant is, for example, m-chloroperbenzoic acid (m-CPBA). In certain embodiments, the application of the compound of formula 10' and the compound of formula 10" in the preparation of the ADC conjugate toxin linker can be further deprotected according to need to obtain the application of the post-toxin linker in the preparation of the ADC conjugate. 3 ' protecting group. The sixth aspect of the present invention relates to a method for preparing an ADC conjugate toxin linker compound, comprising the following steps: Obtaining the compound of formula 11.2 and the compound of formula 14.2 prepared by the fourth aspect of the present invention and or its salt form directly obtains the ADC conjugate toxin linker compound through a condensation reaction, and the salt is, for example, trifluoroacetate, hydrochloride, dichloroacetate; or when R 11 is OH, the compound of formula 13.1 and R 11 is OH, the compound of formula 14.1 and The ADC conjugate toxin linker compound is prepared through an etherification reaction. This ADC conjugate toxin linker compound undergoes a conjugation reaction with an antibody molecule, and this ADC conjugate toxin linker compound can be used in the preparation of ADC conjugates; wherein X 1 and X 2 For the definitions of the substituents, see the definitions of the substituents in the fifth aspect of the present invention. The seventh aspect of the present invention relates to the compound of formula 7 or the compound of formula 10, and their structures are shown as follows: Wherein, R 1 , R3, R 4 are the same as described in the first aspect above. In certain embodiments, the compound 7 or compound 10 is selected from the compounds shown below: In certain embodiments, the preparation method of the compound of formula 1 includes 4 steps of preparation, as described in the following figure: Wherein, R 1 The definition of the substituent is the same as that in the first aspect of the present invention, preferably a hydroxyl protecting group, especially a hydroxyl protecting group that can be removed under acidic conditions, and is selected from silyl groups, alkyl ethers, preferably trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS), methyl, trityl (Tr), tert-butyl, methoxymethyl (MOM), and preferably hydrogen, TBDMS; R 2 is an amino protecting group, especially an amino protecting group that can be removed by a palladium catalyst, preferably benzyloxycarbonyl (Cbz), benzyl or substituted benzyl; The above term "substituted benzyl" refers to a benzyl group substituted on the benzene ring by 1-4 groups selected from the following group: C1-4 alkyl, C1-4 alkoxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, and these substituents are at any possible position on the benzene ring of the benzyl group; R 3The substituents are defined as in the first aspect of the present invention, preferably as hydroxyl protecting groups, especially hydroxyl protecting groups that can be removed under acidic or basic conditions, and are selected from one of silyl groups, alkyl groups, and carboxylic acid esters, preferably one of trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS), methyl, trityl (Tr), tert-butyl, methoxymethyl (MOM), acetyl (Ac), dichloroacetyl (CAc), benzoyl (Bz), pivaloyl (Piv), and preferably Ac; comprising the following steps: Step 1: Using compound A and tert-butyl (2S,3S)-2-amino-3-methylpent-4-enoate as starting materials, condensing them with a conventional condensing reagent to obtain compound C; Step 2: Obtaining compound D from compound C in the presence of K 2 OsO 4 ·H 2 O and NMO; Step 3: Obtaining compound E from compound D under the action of an upper protecting reagent and a base; Step 4: Obtaining compound 1 from compound E under the action of a conventional deprotecting agent. The condensing reagent described in Step 1 is selected from 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (HOOBt), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 4,5-dicyanoimidazole (DCI), N,N'-carbonyldiimidazole (CDI), 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), benzotriazol-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), 6-chlorobenzotriazol-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), (benzotriazol-1-yl)-N,N,N',N'-dipyrrolidylurea hexafluorophosphate (HBPyU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), 1H-benzotriazol-1-yloxytripyrrolidinium hexafluorophosphate (PyBOP), hexafluorophosphate(7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium (PyAOP), (ethyl 2-oximino-cyanoacetate)-N,N-dimethyl-morpholinourea hexafluorophosphate (COMU), 1-propylphosphonic anhydride (T 3P), diphenylphosphinic chloride (DPP-Cl), diphenylphosphoryl azide (DPPA), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), or one or more of them; The upper protecting reagent described in step 3 is preferably an acyl chloride, an acid anhydride, or a methylation reagent. The methylation reagent is preferably MeI, Me 2 SO 4 , MeOTf, CH 2 N 2 ; The base described in step 3 is selected from one or more of organic bases or inorganic bases. The organic base is preferably triethylamine, diethylamine, N,N-diisopropylethylamine (diisopropylethylamine), or pyridine. The inorganic base is selected from sodium hydride, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, or cesium carbonate. In certain embodiments, the method for preparing compound 1 may include the following steps: Wherein, R 1 , R 2 or R 3 The definitions of the substituents are the same as those of the same substituents in the method for preparing the compound of formula 1 described above; when R 3 is H, compound D directly obtains compound 1 after removing the R 2 protecting group. The compound of formula 1 is synthesized in 4 steps, using compound A and (2S,3S)-tert-butyl 2-amino-3-methylpent-4-enoate as starting materials, and using a conventional condensation reagent for condensation to obtain compound C in a relatively high yield (refer to Angewandte Chemie, International Edition (2020), 59(14), 5500-5504). Using K 2 OsO 4 ·H 2 O and NMO for oxidation and column purification to obtain a diol compound D with a chiral purity of more than 99% in a medium yield (refer to CN114080395A). Compound D reacts with an acid anhydride or an acyl chloride and a base to obtain compound E in a relatively high yield. Finally, the amino protecting group is removed using a palladium catalyst and hydrogen to obtain compound 1. In certain embodiments, the synthesis of the pentapeptide structure compound 2 includes the following steps: Furthermore, the present invention provides a method for preparing a compound of formula J. The method for preparing the compound of formula J includes the following 3 steps, as described in the following figure: Wherein R 5 is an amino protecting group, especially an amino protecting group that can be removed under basic or reducing conditions, more especially Pht, Alloc, Fmoc, preferably Fmoc; R 4 The substituent is the same as R in the first aspect of the present invention 4 as defined comprising the following steps: Step 5: Compound F reacts with N-hydroxysuccinimide (Hosu) to form compound G; this step is a conventional reaction in the art. When R 5 is Fmoc, compound G is Fmoc-Cys(trt)-NHS, and the preparation method of compound Fmoc-Cys(trt)-NHS can be referred to in Macromolecular Chemistry and Physics (2010), 211(8), 956-961; when R 5 is other protecting groups, it can also be prepared with reference to this method; Step 6: Compound G reacts with compound H under the action of a peptide bond forming reagent to obtain compound I; this step is a conventional reaction in the art, and the preparation method can be referred to in the method described in

[0080] of the specification of Patent CN109824759A; the peptide bond forming reagent described in Step 6 is particularly selected from coupling reagents of carbodiimide, imidazolinium reagent, phosphonium salt, organophosphorus reagent, uronium salt, pyridinium reagent and phosphonic acid, and more particularly reacts with DIC, DCC, HBTU, PyBOP, BOP, HATU, HOBT, HOSu, TBTU, DIC / HOBT, DCC / DMAP, EDCI / DMAP, EDCI / HOBT, HATU / HOBT. Any single condensing agent or composite condensing agent is preferred, preferably EDCI / DMAP, EDCI / HOBT or HATU, and more preferably EDCI / HOBT; Step 7: Deprotect the protecting group R of compound I 5 to obtain compound J; different reagents can be selected for deprotection according to different protecting groups. For example, when R 5 is protected with benzyl (Bn) protecting group, the deprotecting reagent can be palladium on carbon (Pd / C), while when R 5 is protected with 9-fluorenylmethoxycarbonyl (Fmoc) as the protecting group, the deprotecting reagent can be piperidine; Furthermore, the present invention provides a preparation method of a compound of formula 2, and the preparation method of the compound of formula 2 comprises the following 2 steps, as described in the following figure: wherein, R 4 the substituent is the same as R in the first aspect of the present invention 4 as defined; R 6 is an amino protecting group, especially an amino protecting group that can be removed under basic or reducing conditions, more especially Pht, Alloc, Fmoc, preferably Fmoc; Step 8: Compound K is converted to compound L using the same method as in step 5. When R 6 is Fmoc, compound L is Fmoc-Gly-Ile-Gly-OtBu. The synthesis method of Fmoc-Gly-Ile-Gly-OtBu (6-1) can be referred to in Example 9 of Patent CN113423430A. When R 6 is other protecting groups, a similar method can also be used for synthesis. Those skilled in the art can easily think of splitting the tripeptide of compound K into different two fragments for synthesis and using different protecting groups for protection; Step 9: Compound L is converted to compound 2 using the same method as in step 6. Advantages of the present invention: 1. The present invention overcomes the deficiencies in the above-mentioned prior art and provides a new liquid-phase synthesis method of amanitin according to the structural characteristics of amanitin itself. 2. The present invention provides a liquid-phase synthesis method of amanitin. The intermediate compound 1.1 for liquid-phase synthesis of amanitin is used as the first fragment; the pentapeptide amino acid (compound 2.1) for liquid-phase synthesis of amanitin is used as the second fragment, that is, a completely new preparation method of amanitin is provided. 3. The present invention provides a completely new series of intermediate compounds 6, 7, 7.1', 8, 9, 10, 10-1, 10.1, 11, 11.2, 12 and 12.1 for the preparation of amanitin. This new series of intermediate compounds has made great contributions to the successful commercial preparation of amanitin. The present invention overcomes the defects of the prior art and provides a completely new preparation method for amanitin. Each step of this method has high selectivity and can obtain high-purity products, which is superior to the methods reported in the prior art of amanitin at present. 4. The present invention also provides compounds of formula 9', formula 9", formula 10' and formula 10" obtained by the preparation methods of the first aspect to the fifth aspect, and the compounds of formula 9', formula 9", formula 10' and formula 10" can be further deprotected by R 3 ' to obtain the application of the toxin linker in the preparation of ADC conjugates as needed. 5. The yield of the key step of forming S-ether in the present invention of amanitin is 80%, which is increased by about 30% compared with the prior art, and no by-product disulfide is produced in this step. 6. The reaction conditions for ring closure to form S-ether in Patent CN115715294A are TFE / HOAc / DCM. In Comparative Example 1 of the present invention, the same conditions were used for reaction for 24 h, and no product was detected by LCMS, indicating that the new substrate of the present invention is not suitable for the TFE / HOAc / DCM conditions. Detailed implementation manners The preparation method of the present invention will be further described in detail below in combination with specific embodiments. It should be understood that the following embodiments are only for exemplarily illustrating and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention. Unless otherwise specified, the experimental methods used in the following embodiments are all conventional methods; unless otherwise specified, the reagents, materials, etc. used in the following embodiments can all be obtained from commercial channels. Example 1 Compound 1.1 was obtained by referring to the preparation method of the compound of Formula 1 from compound A (R 1 =TBS, R 2 =Cbz). Compound 1.1 (2R,3R,4S)-5-(tert-butoxy)-4-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxamido)-3-methyl-5-oxopentane-1,2-diacetic acid diester: The NMR data of compound 1.1 are as follows: 1 H NMR (400 MHz, DMSO) δ 8.17 (d, J = 8.8 Hz, 1H), 4.86–4.78 (s, 1H), 4.51–4.25 (m, 4H), 4.02 (dd, J = 12.6, 5.4 Hz, 1H), 3.72 (t, J = 7.9 Hz, 1H), 2.89 (dd, J = 11.4, 4.0 Hz, 1H), 2.77–2.64 (m, 1H), 2.43–2.35 (m, 1H), 1.99 (d, J = 5.5 Hz, 6H), 1.94 (s, 1H), 1.78 (dd, J = 11.6, 6.1 Hz, 1H), 1.40 (s, 9H), 1.26–1.22 (m, 3H), 0.85 (d, J = 3.9 Hz, 9H), 0.06–0.02 (m, 6H). Example 2 Synthesis of compound 2.1: Compound 2.1 was prepared by referring to the synthetic route of the compound of Formula 2. The NMR data of compound 2.1 are as follows: 11H NMR (400 MHz, DMSO) δ 8.37 (d, J = 33.2 Hz, 2H), 7.99 (d, J = 8.6 Hz, 1H), 7.91 (d, J = 7.5 Hz, 2H), 7.75 (t, J = 9.4 Hz, 2H), 7.63 (d, J = 6.7 Hz, 1H), 7.43 (t, J = 7.4 Hz, 2H), 7.36–7.25 (m, 18H), 5.90–5.79 (m, 1H), 5.77 (s, 1H), 5.30–5.21 (m, 1H), 5.13 (dd, J = 10.5, 1.5 Hz, 1H), 4.50–4.39 (m, 2H), 4.29–4.22 (m, 5H), 3.84–3.66 (m, 4H), 2.74 (dd, J = 15.2, 5.9 Hz, 1H), 2.59 (dd, J = 15.4, 6.5 Hz, 1H), 2.45 (d, J = 5.4 Hz, 2H), 1.75 (d, J = 6.3 Hz, 1H), 1.44 (d, J = 4.4 Hz, 1H), 1.07 (q, J = 11.6 Hz, 2H), 0.84 (d, J = 6.8 Hz, 3H), 0.78 (t, J = 7.3 Hz, 3H). Example 3 Example 3.1 Compound 2.1 (67.5 g, 69.72 mmol, 1 eq) was added to DMF (1 L), and the temperature was cooled to 0 °C under argon protection. DIEA (22.5 g, 174.30 mmol, 2.5 eq), PyBOP (43.5 g, 83.66 mmol, 1.2 eq), and HOBt (11.3 g, 83.66 mmol, 1.2 eq) were added successively. The reaction was carried out at 0 °C for 40 min, and then a solution of compound 1.1 (37 g, 69.72 mmol, 1 eq) dissolved in DMF (500 mL) was added. After the addition, the reaction was carried out at 0 °C for 2 h. LCMS detected that the raw materials had completely reacted. The reaction solution was poured into ice water (3 L), stirred for 10 min, filtered, the filter cake was washed with water, the filter cake was dissolved in methyl tert-butyl ether, washed with saturated brine, separated, dried, filtered, and concentrated to obtain compound 3.1, which could be directly used for the next step. Example 3.2 Compound 2.1 (92 g, 94.96 mmol) was added to DMF (960 mL). The temperature was lowered to 0 - 10 °C. NMM (22.87 g, 226.11 mmol), HOAT (14.83 g, 108.95 mmol), and EDCI (20.81 g, 108.53 mmol) were added successively. The reaction was maintained at 0 - 10 °C for 40 min, and then compound 1.1 (48 g, 90.44 mmol, 1 eq) was added. After the addition, the reaction was maintained at 0 - 10 °C for 5 h. LCMS detection showed that the raw material compound 2.1 had basically completed the reaction, with a conversion rate of 98%. The reaction solution was slowly added to ice water (4000 mL), filtered, and the filter cake was dissolved in methyl tert-butyl ether (2000 mL), washed once with saturated brine (500 mL), dried over sodium sulfate, and concentrated by rotary evaporation to obtain a white solid compound 3.1 (134 g). 1 H NMR (400 MHz, DMSO) δ 8.35 (d, J = 8.5 Hz, 1H), 8.22 (t, J = 6.6 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 7.3 Hz, 2H), 7.80 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 7.7 Hz, 2H), 7.49 (t, J = 6.9 Hz, 1H), 7.41 (t, J = 7.3 Hz, 2H), 7.34 - 7.26 (m, 15H), 7.24 (d, J = 6.7 Hz, 2H), 5.87 (ddd, J = 22.4, 10.7, 5.6 Hz, 1H), 5.26 (dd, J = 17.3, 1.6 Hz, 1H), 5.16 (dd, J = 10.3, 1.3 Hz, 1H), 4.94 - 4.79 (m, 2H), 4.50 - 4.36 (m, 5H), 4.35 - 4.25 (m, 5H), 4.22 (dd, J = 8.9, 4.1 Hz, 2H), 4.04 (dd, J = 12.6, 5.1 Hz, 1H), 3.81–3.75 (m, 2H), 3.73 (s, 1H), 3.68 (s, 1H), 2.78 (dd, J = 16.6, 7.0 Hz, 1H), 2.36 - 2.23 (m, 3H), 1.99 (d, J = 1.8 Hz, 6H), 1.89 - 1.81 (m, 1H), 1.76 - 1.66 (m, 1H), 1.38 (s, 9H), 1.04 (s, 3H), 1.03 (s, 3H), 0.91 (d, J = 7.1 Hz, 3H), 0.82 (d, J = 5.7 Hz, 12H), 0.77 (d, J = 7.4 Hz, 2H), 0.03 (s, 3H), -0.00 (s, 3H). Example 4 Compound 2.1 (52 g, 53.77 mmol, 1 eq) was added to DMF (1 L). The temperature was lowered to 0 °C under argon protection. DIEA (17.3 g, 134.43 mmol, 2.5 eq), PyBOP (34.2 g, 64.52 mmol, 1.2 eq), and HOBt (8.7 g, 64.52 mmol, 1.2 eq) were added in sequence. The reaction was maintained at 0 °C for 40 min, and then a solution of compound 1.1A (25.4 g, 53.77 mmol, 1 eq) dissolved in DMF (400 mL) was added. After the addition, the reaction was maintained at 0 °C for 2 h. LCMS detected that the raw materials had completely reacted. The reaction solution was poured into ice water (2 L), stirred for 10 min, filtered, and the filter cake was washed with water. The filter cake was dissolved in methyl tert-butyl ether, washed with saturated brine, separated, dried, filtered, and concentrated to obtain 69.1 g of compound 3.1A, which could be directly used for the next step. Example 5 Compound 3.1 obtained in Example 3 was dissolved in 20% piperidine / DMF (2000 mL, volume ratio of piperidine:DMF = 1:4), and stirred at room temperature for 2 h; LCMS detected that the raw materials had completely reacted. The reaction solution was poured into ice water (4 L), stirred for 10 min, extracted with methyl tert-butyl ether (1 L × 4), the organic phases were combined, washed with water, washed with saturated brine, dried, filtered, concentrated, and column chromatography (DCM:MeOH = 1:25) was used to obtain 70.2 g of solid compound 4.1, and the two-step yield was 80%. Example 6 Compound 3.1 obtained in Example 4 was dissolved in 20% piperidine / DMF (2000 mL, volume ratio of piperidine:DMF = 1:4), and stirred at room temperature for 2 h; LCMS detected that the raw materials had completely reacted. The reaction solution was poured into ice water (3 L), stirred for 10 min, extracted with methyl tert-butyl ether (1 L × 4), the organic phases were combined, washed with water, washed with saturated brine, dried, filtered, concentrated, and column chromatography (DCM:MeOH = 1:22) was used to obtain 50.93 g of solid compound 4.1A, and the two-step yield was 79%. Example 7 Compound 5 (27 g, 65.78 mmol, 1 eq) was added to DMF (750 mL). The temperature was cooled to 0 °C under argon protection. DIEA (17 g, 131.56 mmol, 2 eq), PyBOP (41.08 g, 78.94 mmol, 1.2 eq), and HOBt (10.67 g, 78.94 mmol, 1.2 eq) were added successively. The reaction was maintained at 0 °C for 50 min, and then a solution of compound 4.1 (82.79 g, 65.78 mmol, 1 eq) in DMF (400 mL) was added. After the addition, the reaction was maintained at 0 °C for 2 h. LCMS detected that the raw material reaction was complete. The reaction solution was poured into ice water (2 L), filtered, the filter cake was washed with water, the filter cake was dissolved in EA, washed with saturated brine, separated, dried, filtered, concentrated, and column chromatographed (volume ratio MeOH:DCM = 0 - 5%:1) to obtain 100 g of solid compound 6.1', with a yield of 92%. The NMR data of compound 6.1' are as follows: 1 H NMR (400 MHz, CDCl 3)δ8.45(s,1H),7.61–7.42(m,4H),7.36(dd,J=14.8,7.3Hz,9H),7.31(s,2H),7.23(t,J=7.6Hz,6H),7.14(dd,J=30.7,23.6Hz,3H),6.89(dd,J=20.5,12.2Hz,4H),5.82(ddd,J=16.6,10.9,5.5Hz,1H),5.21(dd,J=29.5,13.8Hz,3H),5.08(d,J=12.8Hz,3H),4.87(s,1H),4.54(ddd,J=24.4,14.6,6.4Hz,4H),4.39(dd,J=15.6,9.3Hz,3H),4.31(s,1H),4.11(s,1H),3.99(dd,J=12.5,5.2Hz,2H),3.85(s,2H),3.67(s,2H),3.49(d,J=14.0Hz,1H),3.17(s,2H),2.87(dd,J=16.0,7.4Hz,1H),2.60(t,J=24.1Hz,4H),2.29(d,J=6.1Hz,1H),2.02(dd,J=8.9,7.0Hz,8H),1.88(s,3H),1.43(dd,J=23.8,8.9Hz,19H),1.13(s,1H),0.96(d,J=6.9Hz,2H),0.89(d,J=6.8Hz,3H),0.83(d,J=8.1Hz,12H),0.08–0.01(m,6H). Example 8 Compound 5 (17.1 g, 41.67 mmol, 1 eq) was added to DMF (300 mL). The temperature was lowered to 0 °C under argon protection. DIEA (10.71 g, 82.83 mmol, 2 eq), PyBOP (26.01 g, 50.00 mmol, 1.2 eq), and HOBt (6.75 g, 50.00 mmol, 1.2 eq) were added successively. The reaction was carried out at 0 °C for 50 min, and then a solution of compound 4.1A (50 g, 41.67 mmol, 1 eq) dissolved in DMF (300 mL) was added. After the addition, the reaction was carried out at 0 °C for 2 h. LCMS detected that the raw materials had completely reacted. The reaction solution was poured into ice water (2 L), filtered, the filter cake was washed with water, the filter cake was dissolved with EA, washed with saturated brine, separated, dried, filtered, concentrated, and column chromatography (volume ratio MeOH:DCM = 0 - 5%:1) was carried out to obtain 57.7 g of solid compound 6.1A with a yield of 87%. Example 9 Compound 6.1’ (99.4 g, 60.2 mmol, 1.0 eq.) was added to DCM (1100 mL), phenylsilane (13.03 g, 120.41 mmol, 2.0 eq.) was added, the mixture was purged with argon twice, then tetrakis(triphenylphosphine)palladium (5 g) was added, the mixture was purged with argon twice, and the mixture was stirred at 20 °C for 16 h. LCMS detected that the raw material reaction was complete, (TLC: DCM:MeOH = 10:1, iodine, R f = 0.3), the reaction solution was directly evaporated to dryness to obtain 85.4 g of crude brown solid 6.1” (yield 88.1%), and the next step was carried out directly. Example 10 Compound 6.1A (50 g, 30.30 mmol, 1.0 eq.) was added to DCM (1100 mL), phenylsilane (6.54 g, 60.60 mmol, 2.0 eq.) was added, the mixture was purged with argon twice, then tetrakis(triphenylphosphine)palladium (2.5 g) was added, the mixture was purged with argon twice, and the mixture was stirred at 20 °C for 16 h. LCMS detected that the raw material reaction was complete, (TLC: DCM:MeOH = 15:1, iodine, R f = 0.3), the reaction solution was directly evaporated to dryness to obtain 41.02 g of crude brown solid 6.1B (yield 84.16%), and the next step was carried out directly. Example 11 Compound 6.1” (97 g, 60.2 mmol, 1.0 eq.) was added to DMF (1000 mL), DIEA (24.3 g, 187.86 mmol, 3.12 eq.), HOBt (10.2 g, 75.26 mmol, 1.25 eq.), EDCI (14.43 g, 75.26 mmol, 1.25 eq.) and ammonium chloride (20.1 g, 376.32 mmol, 6.25 eq.) were added in sequence, and then the mixture was stirred at 20 °C overnight. LCMS detected that the raw material reaction was complete, the reaction solution was poured into 2000 mL of ice water, filtered, the filter cake was washed with 1000 mL of water, dried, the filter cake was dissolved in 2000 mL of methyl tert-butyl ether, washed with 500 mL of saturated brine once, dried over sodium sulfate, evaporated to dryness, the crude product was dissolved in 300 mL of DCM, directly loaded onto a normal-phase column, and the product was eluted with DCM:MeOH = 1:50 - 1:10, evaporated to dryness, to obtain 70 g of light brown solid, and the two-step yield was 78.3%. The NMR data of compound 6.1”’ are as follows: 11H NMR (400 MHz, DMSO) δ 10.59 (s, 1H), 8.32–8.16 (m, 2H), 8.16–7.96 (m, 3H), 7.77 (d, J = 8.3 Hz, 1H), 7.46 (d, J = 7.2 Hz, 3H), 7.42–7.19 (m, 21H), 7.01 (s, 1H), 6.90 (d, J = 2.0 Hz, 1H), 6.86 (s, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.72 (dd, J = 8.7, 2.0 Hz, 1H), 5.10 (s, 2H), 4.92 (s, 1H), 4.79 (q, J = 6.8 Hz, 1H), 4.49–4.30 (m, 4H), 4.30–4.09 (m, 3H), 4.03 (dd, J = 12.3, 5.3 Hz, 1H), 3.92–3.63 (m, 5H), 3.43 (dd, J = 9.9, 5.3 Hz, 1H), 3.13–2.99 (m, 1H), 2.93–2.82 (m, 1H), 2.56 (dd, J = 15.4, 6.7 Hz, 1H), 2.40–2.16 (m, 4H), 2.00 (d, J = 5.0 Hz, 7H), 1.90–1.79 (m, 1H), 1.73 (s, 1H), 1.40 (d, J = 22.4 Hz, 11H), 1.30 (s, 8H), 0.92 (d, J = 7.0 Hz, 3H), 0.87–0.73 (m, 16H), 0.03 (d, J = 8.4 Hz, 6H). Example 12 Compound 6.1B (40 g, 25.77 mmol, 1.0 eq.) was added to DMF (500 mL), and DIEA (9.97 g, 77.31 mmol, 3 eq.), HOBt (4.52 g, 33.50 mmol, 1.3 eq), EDCI (4.32 g, 33.50 mmol, 1.3 eq.), and ammonium chloride (10.93 g, 206.16 mmol, 8 eq.) were added successively, and then stirred at 20 °C overnight. LCMS detected that the raw material reaction was complete. The reaction solution was poured into 2000 mL of ice water, filtered, and the filter cake was washed with 1000 mL of water, dried. The filter cake was dissolved in 1000 mL of methyl tert-butyl ether, washed once with 500 mL of saturated brine, dried over sodium sulfate, and concentrated. The crude product was dissolved in 300 mL of DCM and directly loaded onto a normal-phase column, and the product was eluted with DCM:MeOH = 1:50 - 1:10, concentrated to obtain 38 g of a light brown solid, with a yield of 95.1%. Example 13 Compound 6.1’ (20 g, 12.11 mmol, 1.0 eq) was dissolved in a mixed solvent of 2,2,2-trifluoroethanol (600 mL) and pure water (67 mL), and a solution of I 2 (6.15 g, 24.22 mmol, 2.0 eq) in DCM (200 mL) was added dropwise at room temperature with the flask open. After the addition, the reaction mixture was stirred at room temperature overnight. LCMS detected that the raw material had completely reacted. 10% aqueous sodium sulfite solution (150 mL) was added to the reaction mixture. The organic phase was separated, washed with saturated brine, separated by liquid separation, dried, filtered, concentrated, and purified by column chromatography (PE:EA = 5:1) to obtain 13.3 g of solid compound 7.1', with a yield of 85% and a purity of 95%. The NMR data of compound 7.1' are as follows: 1 H NMR (400 MHz, DMSO) δ 10.98 (d, J = 12.4 Hz, 1H), 8.34 (d, J = 8.9 Hz, 1H), 8.11 (d, J = 7.8 Hz, 2H), 7.98 (d, J = 30.0 Hz, 2H), 7.53 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 7.2 Hz, 2H), 7.39 (t, J = 7.4 Hz, 2H), 7.32 (t, J = 7.2 Hz, 1H), 6.83 (s, 1H), 6.74 (d, J = 8.5 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 5.84 (ddd, J = 22.6, 10.7, 5.4 Hz, 1H), 5.34–5.20 (m, 1H), 5.19–5.04 (m, 4H), 4.93–4.83 (m, 2H), 4.46 (d, J = 5.5 Hz, 2H), 4.44–4.35 (m, 2H), 4.31 (dd, J = 7.7, 3.6 Hz, 1H), 4.27 (s, 1H), 4.19 (d, J = 5.1 Hz, 2H), 4.02 (dd, J = 12.5, 4.6 Hz, 2H), 3.97–3.82 (m, 2H), 3.63 (dd, J = 20.8, 8.7 Hz, 2H), 3.54 (d, J = 7.1 Hz, 1H), 3.30 (s, 3H), 3.20 (t, J = 12.5 Hz, 2H), 2.97–2.86 (m, 1H), 2.84–2.70 (m, 2H), 2.29–2.14 (m, 2H), 1.99 (d, J = 5.6 Hz, 6H), 1.94–1.76 (m, 2H), 1.49 (s, 1H), 1.37 (d, J = 3.8 Hz, 9H), 1.26 (s, 8H), 1.17–1.09 (m, 1H), 1.03 (s, 1H), 0.91 (t, J = 7.4 Hz, 3H), 0.88–0.81 (m, 6H). Example 14 Compound 6.1A (9.5 g, 5.96 mmol, 1.0 eq.) was dissolved in 2,2,2-trifluoroethanol (855 mL) and pure water (95 mL). I 2 (1.51 g, 5.96 mmol, 1.0 eq.) was dissolved in DCM (285 mL) and added dropwise to the above solution at room temperature with the flask open. After the addition, the reaction mixture was stirred at room temperature for 3 h. LCMS detected that the raw materials had completely reacted. 10% aqueous sodium sulfite solution (150 mL) was added to the reaction mixture. The organic phase was separated, washed with saturated brine, separated by liquid separation, dried, filtered, concentrated, and purified by column chromatography (PE:EA = 5:1) to obtain 6.6 g of solid compound 7.1, with a yield of 82% and a purity of 95%. The NMR data of compound 7.1 are as follows: 1 H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 8.18 (m, 2H), 8.09–7.88 (m, 2H), 7.55 (d, J = 8.7 Hz, 1H), 7.48 (d, J = 7.3 Hz, 2H), 7.41 (t, J = 7.4 Hz, 2H), 7.33 (t, J = 7.1 Hz, 1H), 6.85 (s, 1H), 6.77 (d, J = 8.4 Hz, 1H), 5.86 (m, 1H), 5.77 (s, 1H), 5.19 (m, 3H), 4.89 (d, J = 8.0 Hz, 1H), 4.46 (m, 3H), 4.34–4.29 (m, 1H), 4.22 (s, 2H), 4.04 (d, J = 11.9 Hz, 2H), 3.90 (dd, J = 15.8, 9.0 Hz, 1H), 3.69 (m, 3H), 3.23 (d, J = 9.7 Hz, 2H), 3.03 (td, J = 6.6, 4.0 Hz, 5H), 2.94–2.72 (m, 4H), 2.40–2.13 (m, 2H), 2.07–1.85 (m, 8H), 1.77–1.73 (m, 4H), 1.50 (s, 1H), 1.39 (m, 8H), 1.33–1.25 (m, 6H), 1.19–1.05 (m, 13H), 0.97–0.78 (m, 9H). Example 15 N 2Under protection, add triisopropylsilane TIPS (21 mg, 0.13 mmol, 3.0 eq.) to a mixed solvent of TFA (4 mL) / DCM (2 mL). After cooling to 0 °C, add compound 7.1 (60 mg, 0.044 mmol, 1.0 eq.). Stir the reaction solution at 0 °C for 22 h. When the raw materials are completely reacted as detected by LCMS, disperse NaHCO 3 (4.45 mg, 0.053 mmol, 1.2 eq.) in water (40 mL). Add DCM / IPA (3:1, 80 mL) thereto. Drop the above reaction solution into the solution prepared with sodium bicarbonate at 0 °C and stir for 0.5 h. Separate the organic phase. Extract the aqueous phase with DCM / IPA (3:1, 2 × 80 mL). Combine the organic phases, concentrate under reduced pressure, and then perform reverse-phase preparation (ACN and 0.1% TFA). After lyophilization, 30 mg of solid compound 8.1 is obtained with a purity of 95% and a yield of 60%. Example 16 Dissolve compound 7.1' (15.67 g, 12.12 mmol, 1 eq) in DCM (200 mL), displace with argon, cool to 0 °C, add TFA (100 mL), then warm to room temperature and stir for 6 h. When the raw materials are completely reacted as detected by LCMS, concentrate the reaction solution, add acetonitrile (150 mL) and water (70 mL), and perform reverse-phase preparation (ACN and 0.1% TFA) after lyophilization. After lyophilization, 10.3 g of solid compound 8.1 is obtained with a yield of 75% and a purity of 95%. Example 17 Dissolve compound 8.1 (5 g, 4.40 mmol, 1 eq) in DMF (1000 mL), displace with argon, cool to 0 °C, add DIEA (2.27 g, 17.60 mmol, 4 eq) and HATU (3.35 g, 8.80 mmol, 2 eq), and keep the reaction at room temperature for 3 h after addition. When the raw materials are completely reacted as detected by LCMS, pour the reaction solution into water (3 L), extract with EA (1.5 L × 3), combine the organic phases, wash with saturated brine, separate the liquid, dry, concentrate, and perform reverse-phase preparation (ACN / H 2 O). After lyophilization, 2.2 g of powder of compound 9.1 is obtained with a yield of 45%. Example 18 Dissolve compound 9.1 (100 mg, 0.089 mmol, 1 eq) in 1,2-ethanedithiol (50 mL), add BF 3 -Et 2O (253 mg, 1.78 mmol, 20 eq) was stirred at room temperature for 5 h. LC-MS detected that the raw material reaction was complete. Ether (20 ml) was added, and a solid precipitated. Reverse-phase preparation (ACN and 0.1% TFA) was carried out. After lyophilization, 67 mg of solid compound 10.1 was obtained, with a yield of 73%. The NMR data of compound 10.1 are as follows: 1 H NMR (400 MHz, DMSO) δ 10.83 (s, 1H), 9.06 (d, J = 7.9 Hz, 1H), 8.72 (t, J = 6.2 Hz, 1H), 8.63 (d, J = 3.5 Hz, 1H), 8.29 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 10.3 Hz, 1H), 7.83 (d, J = 7.0 Hz, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 6.60 (d, J = 2.1 Hz, 1H), 6.53 (dd, J = 8.5, 2.1 Hz, 1H), 5.98–5.82 (m, 1H), 5.32 (dd, J = 17.3, 1.7 Hz, 1H), 5.21 (dd, J = 10.5, 1.4 Hz, 2H), 5.05 (d, J = 4.0 Hz, 1H), 4.83–4.72 (m, 1H), 4.56 (d, J = 4.9 Hz, 2H), 4.45 (d, J = 9.7 Hz, 2H), 4.24 (t, J = 8.0 Hz, 1H), 4.05 (dd, J = 12.3, 7.2 Hz, 2H), 3.84 (dd, J = 11.1, 4.3 Hz, 2H), 3.72–3.63 (m, 2H), 3.47 (d, J = 5.0 Hz, 1H), 3.20–3.07 (m, 2H), 2.90 (ddd, J = 18.9, 10.8, 6.4 Hz, 3H), 2.67 (d, J = 6.3 Hz, 2H), 2.34–2.27 (m, 1H), 2.21–2.12 (m, 1H), 2.04 (s, 3H), 2.02 (d, J = 1.8 Hz, 1H), 2.00 (s, 3H), 1.66–1.56 (m, 2H), 1.21–1.03 (m, 2H), 0.93 (d, J = 6.8 Hz, 3H), 0.84 (m, 9H). Example 19 Compound 10.1 (100 mg, 0.097 mmol, 1 eq) was added to 7N ammonia in methanol (20 mL). After addition, the mixture was stirred at 17 °C overnight. The reaction was monitored by LCMS and was found to be complete. The reaction mixture was concentrated and co-evaporated with methanol (20 mL × 2) to remove ammonia from the product. Reverse-phase preparation (ACN and 0.1% TFA) was carried out, and after lyophilization, 61 mg of solid compound 13.1 was obtained with a yield of 70%. Example 20 Using compound 13.1 as the starting material and m-CPBA as the oxidant (reference: Angewandte Chemie, International Edition (2020), 59(14), 5500 - 5504, Supporting Information, page 87), compound 14.1 was obtained. The NMR data was consistent with the literature. Comparative Example 1 2,2,2-Trifluoroethanol (2 mL), HOAc (2 mL), and DCM (16 mL) were used to prepare a mixed solution (2,2,2-trifluoroethanol:HOAC:DCM = 1:1:8). Compound 6.1' (2 mg) was placed in a single-necked flask and dissolved in the mixed solution (1 mL). The reaction was stirred at room temperature for 4 h, and the target product 7.1' was not detected. The reaction was monitored continuously until 24 h, and the target product compound 7.1' was still not detected. Comparative Example 2 2,2,2-Trifluoroethanol (2 mL), HOAc (2 mL), and DCM (16 mL) were used to prepare a mixed solution (2,2,2-trifluoroethanol:HOAC:DCM = 1:1:8). Compound 6.1' (2 mg) was placed in a single-necked flask and dissolved in the mixed solution (1 mL). Then, 60 mg of iodine was completely dissolved in 10 mL of the mixed solution. 0.05 mL of the iodine-containing solution (0.3 mg, 1 eq) was added to the reaction solution, and the reaction was stirred at room temperature overnight. A large amount of starting material was detected remaining. After adding an additional 0.05 mL of the iodine-containing solution (0.3 mg, 1 eq), the reaction was continued at room temperature for 5 h. LCMS analysis showed that the product was approximately 5%, the starting material remained at 1%, and the rest were unknown impurities. The reaction was monitored continuously until 24 h, and the target product compound 7.1' was still approximately 5%. Although the specific embodiments of the present invention have been described above, those skilled in the art should understand that these are only examples. Without departing from the principles and essence of the present invention, various changes or modifications can be made to these embodiments. Therefore, the protection scope of the present invention is defined by the appended claims.

Claims

1. A liquid phase preparation method of a compound of formula 7, comprising the following steps: Step S4: In a solvent, the compound of formula 6 is subjected to a ring-closing reaction with iodine to obtain compound 7. R1 is independently selected from hydrogen and a hydroxy protecting group; R3 is independently selected from hydrogen and a hydroxy protecting group; R4 is independently selected from NH2, -Z-R7, OH, OR8, NHR9, PEG substituted with amino, carboxyl, "amino protected by an amino protecting group" or "carboxyl protected by a carboxyl protecting group" 1-8 groups and C1-C1-C1-substituted groups substituted with amino, carboxyl, "amino protected by an amino protecting group" or "carboxyl protected by a carboxyl protecting group" 12 alkyl; Z is selected from -C1-C5 alkylene-, -NH-, -C1-C8 alkylene-PEG 1-8 -, -PEG 1-8 - or any combination thereof; R7 is selected from R8 is a carboxyl protecting group; R9 is an amino protecting group; R 10 independently selected from hydrogen, a hydroxyl group protected by a hydroxyl protecting group or n is 1-7.

2. The liquid phase preparation method according to claim 1, comprising the following steps: R1 is independently selected from hydrogen and a hydroxyl protecting group selected from C 1-6 Alkyl and one or more R d Substituted C 1-6 alkyl; R3 is independently selected from hydrogen and a hydroxy protecting group selected from C 1-6 Alkyl, with one or more R d Substituted C 1-6 Alkyl and -C(O)-R e ; R a , R b and R c Each independently selected from C 1-6 Alkyl and phenyl; R d Independently selected from C 1-6 Alkoxy and phenyl; R e Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl and phenyl; R4 is independently selected from NH2, -Z-R7, OH, OR8, NHR9, PEG substituted with amino, carboxyl, "amino protected by an amino protecting group" or "carboxyl protected by a carboxyl protecting group" 1-8 groups and C1-C1-C1-substituted groups substituted with amino, carboxyl, "amino protected by an amino protecting group" or "carboxyl protected by a carboxyl protecting group" 12 The amino protecting group is selected from benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, tert-butyloxycarbonyl, pivaloyl, acetyl and trityl; the carboxyl protecting group is selected from C 1-6 Alkyl and vinyl substituted C 1-6 alkyl; Z is selected from -C1-C5 alkylene-, -NH-, -C1-C8 alkylene-PEG 1-8 -, -PEG 1-8 - or any combination thereof; R7 is selected from: R8 is C 1-6 Alkyl or vinyl substituted C 1-6 alkyl; R9 is selected from an amino protecting group, wherein the amino protecting group is selected from benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, tert-butyloxycarbonyl, pivaloyl, acetyl and trityl; R 10 Selected from H, -OR f or n is 1-7; R f is benzyl or is replaced by one or more R f-1 substituted benzyl; R f-1 independently selected from halogen, C 1-6 Alkoxy, nitro or cyano.

3. The liquid phase preparation method according to claim 2, characterized in that: It meets one or more of the following conditions: (1) R1 is independently selected from hydrogen, and C 1-6 Alkyl; R a , R b and R c Each independently selected from C 1-6 alkyl; Preferably, R1 is independently selected from and C 1-6 Alkyl; R a , R b and R c Each independently selected from C 1-6 alkyl; More preferably, R1 is tert-butyldimethylsilyl or tert-butyl; (2) R3 is independently selected from hydrogen and -C(O)-R e ; R e C 1-6 alkyl; Preferably, R3 is independently selected from hydrogen and -C(O)-R e ; R e C 1-6 alkyl; More preferably, R3 is acetyl; (3) R4 is independently selected from NH2, OH and OR8, R8 is C 1-6 Alkyl or vinyl substituted C 1-6 alkyl; Preferably, R4 is independently selected from OR8; R8 is C substituted by vinyl 1-6 alkyl; More preferably, R4 is OR8; R8 is C substituted by vinyl 1-6 alkyl; (4)R 10 For-OR f ; R f is benzyl or is replaced by one or more R f-1 Substituted benzyl; R f-1 independently selected from halogen, C 1-6 alkoxy, nitro or cyano; Preferably, R 10 For-OR f ; R f It is benzyl.

4. The liquid phase preparation method according to claim 1, characterized in that: The compound of formula 6 is any of the following compounds: Preferably, in step S4, the ring-closing reaction is as shown in any of the following schemes:

5. The liquid phase preparation method according to claim 1, characterized in that: The ring-closure reaction satisfies one or more of the following conditions: (1) In step S4, the molar ratio of compound 6 to iodine is 1:(1-5), preferably 1:(1-3), more preferably 1:1 or 1:2; (2) In step S4, the ring-closing reaction is carried out in an organic acidic reagent, an aprotic organic solvent and water; the organic acidic reagent is preferably selected from halogen-substituted C 1-10 Alkyl alcohol; halogen substituted C 1-10 The alkyl alcohol is selected from one or more of 2,2,2-tribromoethanol, trifluoromethanol, 2,2,2-trifluoroethanol, perfluoroethanol, trifluoropropanol, 2,2,3,3-tetrafluoropropanol, hexafluoropropanol, perfluoropropanol, trifluorobutanol, hexafluorobutanol, perfluorobutanol, trifluoropentanol, hexafluoropentanol, perfluoropentanol, trifluorohexanol, hexafluorohexanol and perfluorohexanol; preferably 2,2,2-tribromoethanol or 2,2,2-trifluoroethanol; the aprotic organic solvent is preferably selected from one or more of chlorinated alkanes, ether solvents and aromatic alkanes; ether solvents such as THF, dioxane or methyltetrahydrofuran; chlorinated alkanes such as dichloromethane, dichloroethane or chloroform; aromatic alkanes such as toluene; Preferably, the ring-closure reaction is carried out in the presence of 2,2,2-trifluoroethanol, water and dichloromethane; (3) In step S4, the volume ratio of the organic acid reagent to water is (6-10):1, preferably (7-9):1; Preferably, the volume ratio of the organic acidic solvent, the aprotic organic solvent and water is 9:3:1; (4) In step S4, the ratio of the mass g of the compound 6 to the volume mL of the organic acidic reagent is 1:(10-100), preferably 1:(30-90), more preferably 1:30 or 1:90; (5) In step S4, the method for preparing compound 7 comprises the following steps: dissolving compound 6 in an organic acidic reagent and / or water, and then dissolving iodine in an aprotic organic solvent and adding the solution to the solution; (6) In step S4, after the reaction is completed, the following steps are also included: extraction (for example, adding 10% sodium sulfite aqueous solution to the reaction system); Preferably, in step S4, after the reaction is completed, the following post-treatment steps are further included: washing (for example, washing with saturated brine), liquid separation, drying, filtration, concentration and column chromatography (for example, PE:EA=5:1).

6. The liquid phase preparation method according to claim 1, characterized in that: The preparation method further comprises the following steps: Step S1: In a solvent, the compound of formula 1 and the compound of formula 2 undergo condensation reaction under the action of a peptide bond forming reagent to obtain compound 3. Step S2: In a solvent, the compound of formula 3 reacts with a deamination protecting agent to obtain a compound of formula 4. Step S3: In a solvent, the compound of formula 4 reacts with the compound of formula 5 under the action of a peptide bond forming reagent to obtain a compound of formula 6 through a condensation reaction. Among them, R1, R3 and R 10 Independently as defined in claim 1; R6 is an amino protecting group, preferably Pht, Alloc or Fmoc, more preferably Fmoc; In the compounds of formula 2, 3 and 4, R4 is selected from OR8, and in the compound of formula 6, R4 is selected from OR8 and amino; Furthermore, when R4 in the compound of formula 6 is an amino group, the preparation method of the compound of formula 6 may further comprise the following steps: Step S3': in a solvent, the product of step S3 is subjected to a deprotection reaction; Step S4': In a solvent, the product of step S3' is subjected to condensation reaction with an ammonia source by a condensation agent to obtain a compound of formula 6.

7. The liquid phase preparation method according to claim 6, characterized in that: It meets one or more of the following conditions: (1) Step S1 is any of the following schemes: (2) Step S2 is any of the following solutions: (3) Step S3 is any of the following solutions: (4) Step S3' is any of the following schemes: (5) Step S4' is any of the following schemes:

8. The liquid phase preparation method according to claim 6, characterized in that: It meets one or more of the following conditions: (1) In step S1, the peptide bond forming reagent in the condensation reaction is selected from N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, N-cyclohexyl-N'-(2-morpholinoethyl)carbodiimide methyl-p-toluenesulfonate, 1,1'-carbonyldiimidazole, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate, benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, Fluorophosphate, 1-hydroxybenzotriazole, NNN'N'-tetramethylchloroformamidine hexafluorophosphate, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 2-chloro-1,3-dimethylimidazolidine hexafluorophosphate, chlorotripyrrolidinium phosphonium hexafluorophosphate, S-(1-oxido-2-pyridyl)-N,N,N',N'-tetramethylthiouronium tetrafluoroborate, O-[(ethoxycarbonyl)cyano-methyleneamino]-N,N,N',N'-tetramethyluronium hexafluorophosphate, (1-cyano-2-ethoxy-2-oxoethyliminoaminooxy)dimethylamino-morpholino-carbon hexafluorophosphate, O-(benzotriazol-1-yl)- N,N,N',N'-bis(tetramethylene)uronium hexafluorophosphate, dipyrrolidinyl(N-succinimidyloxy)hexafluorophosphate, chlorodipyrrolidinylcarbonium hexafluorophosphate, (benzotriazol-1-yloxy)dipiperidinylcarbonium hexafluorophosphate, O-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, 6-chlorobenzotriazol-1,1,3,3-tetramethyluronium hexafluorophosphate, bromotris(dimethylamino)phosphonium hexafluorophosphate, propylphosphonic anhydride, N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium hexafluorophosphate, O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N', One or more of N'-tetramethyluronium tetrafluoroborate, 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride, N,N,N',N'-tetramethyl-O-(N-succinimidyl)-neodymium tetrafluoroborate, O-(3,4-dihydro-4-oxo-1,2,3-benzotriazine-3-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, N-methylmorpholine, 2-hydroxypyridine-N-oxide, N-hydroxy-7-azobenzotriazole and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; preferably PyBOP and HOBt, or NMM, HOAT and EDCI; (2) In step S1, the condensation reaction is also carried out in the presence of a base, and the base is selected from triethylamine, diethylamine, pyridine, diisopropylethylamine, preferably diisopropylethylamine; (3) In step S1, the solvent in the condensation reaction is selected from one or more of tetrahydrofuran, dioxane, dichloromethane, chloroform, N,N'-dimethylformamide and ethyl acetate, preferably DMF; (4) In step S1, the molar ratio of the compound of formula 2 to the compound of formula 1 is 1:1; (5) In step S1, when the condensation reaction is carried out in the presence of DIEA, HOBt and PyBOP, the molar ratio of DIEA, HOBt and PyBOP is 2:1:1; (6) In step S1, when the condensation reaction is carried out in the presence of NMM, HOAT and EDCI, the molar ratio of NMM, HOAT and EDCI is 2:1:1; (7) In step S1, when the peptide bond forming reagent is PyBOP and HOBt, the molar ratio of the peptide bond forming reagent to the compound of formula 1 is 2.4:1; (8) In step S1, when the peptide bond forming reagent is NMM, HOAT and EDCI, the molar ratio of the peptide bond forming reagent to the compound of formula 1 is 4.7:1; (9) In step S2, when R6 is Fmoc, the deamination protecting agent is piperidine, pyridine, diethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene, preferably 20% piperidine; (10) In step S2, the solvent is DMF; (11) In step S2, the volume ratio of the deamination protecting agent to the solvent is 1:4; (12) In step S3, the types of the solvent, peptide bond forming reagent and base are the same as those in step S1; (13) In step S3, when the peptide bond forming reagent is PyBOP and HOBt, the molar ratio of the peptide bond forming reagent to the compound of formula 4 is 2.4:1; (14) In step S3, when the condensation reaction is carried out in the presence of DIEA, HOBt and PyBOP, the molar ratio of DIEA, HOBt and PyBOP is 1.7:1:1; (15) In step S3, the molar ratio of the compound of formula 4 to the compound of formula 5 is 1:(1-1.2); (16) In step S3′, the solvent is DCM; (17) In step S3', the catalyst in the deprotection reaction is selected from a palladium catalyst, such as one or more of tetrakistriphenylphosphine palladium, palladium chloride, palladium acetate, bistriphenylphosphine palladium dichloride, [1,1"-bis(diphenylphosphino)ferrocene]palladium dichloride, bisacetonitrile palladium chloride and tris(dibenzylideneacetone)dipalladium, preferably tetrakistriphenylphosphine palladium; (18) In step S3′, the deprotection reaction is carried out in the presence of a palladium catalyst and phenylsilane, for example, in the presence of tetrakistriphenylphosphine palladium and phenylsilane; (19) In step S4′, the solvent is DMF; (20) In step S4', the condensing agent is HOBt and EDCI, and the molar ratio of HOBt to EDCI is, for example, 1:1; (21) In step S4', the molar ratio of the condensing agent to the product of step S3' is 2.5:1 or 2.6:1; (22) In step S4', the condensation reaction is also carried out in the presence of a base, and the base is selected from triethylamine, diethylamine, pyridine, diisopropylethylamine, preferably diisopropylethylamine; (23) In step S4′, when the condensation reaction is carried out in the presence of DIEA, HOBt and EDCI, the molar ratio of DIEA, HOBt and PyBOP is 2.5:1:1 or 2.3:1:1; (24) In step S4', the ammonia source is selected from one or more of ammonium acetate, ammonium formate, ammonia gas, ammonia water, ammonia gas solution, ammonium chloride, ammonium sulfate and ammonium carbonate; preferably ammonium chloride; (25) In step S4', the molar ratio of the ammonia source to the product of step S3' is 6.25:1 or 8:

1.

9. A liquid phase preparation method of a compound of formula 9 or a compound of formula 10, comprising the following steps: Step S5: In a solvent, the compound of formula 7 reacts with a deprotection agent to obtain a compound of formula 8, Step S6: In a solvent, the compound of formula 8 reacts with a peptide bond forming reagent to obtain a compound of formula 9 through a condensation reaction. Optionally, step S7: in a solvent, when R 10 When the hydroxyl group is protected by a protecting group, the compound of formula 9 reacts with a deprotecting agent to obtain a compound of formula 10, Among them, R1, R3, R4, R 10 The definition is the same as that described in claim 1.

10. The liquid phase preparation method according to claim 9, characterized in that: It meets one or more of the following conditions: (1) Step S5 is any of the following schemes: (2) Step S6 is a scheme as shown below: (3) Step S7 is a scheme as shown below:

11. The liquid phase preparation method according to claim 9, characterized in that: It meets one or more of the following conditions: (1) In step S5, the deprotection reagent is an acid, or a combination of an acid and a silane; the acid is selected from trifluoroacetic acid, hydrochloric acid, HCl / MeOH, HCl / EA or HCl / dioxane; the silane is selected from trimethylsilane, triethylsilane, tert-butyldimethylsilane or triisopropylsilane; Preferably, the deprotection agent is a combination of trifluoroacetic acid and triisopropylsilane, wherein the molar ratio of triisopropylsilane to the compound of formula 7 may be 3:1; Alternatively, the deprotection agent is trifluoroacetic acid; (2) In step S5, the solvent is a mixed solvent formed by TFA and DCM, and the volume ratio of TFA to DCM can be 2:1; (3) Step S5 comprises the following operations: TIPS reacts with the compound of formula 7 in a TFA / DCM mixed solvent; Alternatively, step S5 comprises the following operations: reacting the compound of formula 7 with TFA in a DCM solvent; (4) Step S5 further includes the following post-treatment steps: after the reaction is completed, the reaction solution is mixed with a mixed solution formed by an aqueous sodium bicarbonate solution and DCM / IPA, the organic phase is separated, the aqueous phase is extracted (for example, with DCM / IPA), the organic phases are combined, concentrated under reduced pressure, reversed phase prepared and freeze-dried; (5) In step S6, the peptide bond forming reagent, base and solvent are the same as those in step S1 of claim 8, the peptide bond forming reagent may be HATU; the solvent may be DMF; and the base may be DIEA; (6) In step S6, the molar ratio of the peptide bond forming reagent to the compound of formula 8 is 2:1; (7) In step S6, the molar ratio of the base to the compound of formula 8 is 4:1; (8) In step S7, the deprotection reagent is boron trichloride, boron tribromide, or boron trifluoride, preferably BF3-Et2O; (9) In step S7, the molar ratio of the deprotection reagent to the compound of formula 9 is 20:1; (10) In step S7, the solvent is 1,2-ethanedithiol; (11) In step S5, the compound of formula 7 is prepared by the method for preparing the compound of formula 7 as claimed in claim 1.

12. A liquid phase preparation method of a compound of formula 14, Where R 12 Selected from NH2 or OH; When R 12 When is NH2, the structure of the compound of formula 14 is the compound shown in formula 14.1, It is prepared by the following scheme: Solution 1: including the following steps S8 to S11, Step S8: In a solvent, the compound of formula 10-1 can be selectively deprotected to obtain a compound of formula 11, Step S9: In a solvent, the compound of formula 11 reacts with an ammonia source through a condensation reaction to obtain a compound of formula 12-1. Step S10: In a solvent, the compound of formula 12-1 is deprotected to obtain a compound of formula 13.1, Step S11: In a solvent, the compound of formula 13.1 is oxidized to obtain the compound of formula 14.1, in, R3 and R8 are as defined in claim 1; R 11 is H or hydroxyl, preferably hydroxyl; Solution 2: including steps S8' and S11, Step S8': In a solvent, the compound of formula 10-1 undergoes an amine ester exchange reaction to obtain a compound of formula 13.1, Step S11, in a solvent, the compound of formula 13.1 can be selectively oxidized to obtain a compound of formula 14.1, wherein R3 and R8 are as defined in claim 1; R 11 is H or hydroxyl, preferably hydroxyl; When R 12 When is OH, the structure of the compound of formula 14 is the compound shown in formula 14.2, It is prepared by steps S8" and S11'. Step S8": In a solvent, the compound of formula 10-1 reacts with a deprotecting agent to obtain a compound of formula 11.2, Step S11': In a solvent, the compound of formula 11.2 is reacted with an optionally oxidizing agent to obtain a compound of formula 14.2, wherein R3 and R8 are as defined in claim 1; R 11 It is H or hydroxyl, preferably hydroxyl.

13. The liquid phase preparation method according to claim 12, characterized in that: The structure of the compound of formula 14 is the compound shown in formula 14.1, It is prepared by scheme 2; The scheme of step S8' is preferably as follows: The scheme of step S11 is preferably as follows:

14. The liquid phase preparation method according to claim 13, characterized in that: It meets one or more of the following conditions: (1) In step S8' of the second scheme, the amine transesterification reagent is selected from ammonia gas, ammonia water or an ammonia organic solvent solution; the organic solvent is selected from alcohol solvents and ether solvents, such as methanol, ethanol, isopropanol, dioxane, tetrahydrofuran; (2) In step S8' of the second scheme, the amine transesterification reaction is carried out in an ammonia-methanol solution, for example, a 7 mol / L ammonia-methanol solution; (3) In step S11 of the second scheme, the oxidant in the oxidation reaction is selected from one or more of polyphenylene ether, dibenzoyl peroxide, tert-butyl perbenzoate, lauroyl peroxide, Jones reagent, Collins reagent, pyridinium chlorochromate, pyridinium dichromate, manganese dioxide, Dess-Martin periodinane, potassium permanganate, periodic acid, osmium tetroxide, 30% hydrogen peroxide, meta-chloroperbenzoic acid and tert-butyl hydroperoxide; for example, meta-chloroperbenzoic acid; (4) The compound of formula 10-1 is prepared by the preparation method described in claim 9.

15. Any of the following compounds:

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