Method for preparing linker-toxin molecule compound and intermediate thereof

Abstract

Provided in the present disclosure are a method for preparing a linker-toxin molecule and an intermediate thereof. The preparation method can significantly reduce production costs, acheives a high product yield, and is suitable for the industrial production of the product.

Description

Preparation methods of linker-toxin molecules and their intermediates Technical Field

[0001] This disclosure relates to the field of biomedicine, and more specifically, to a method for preparing a linker-toxin molecule compound and related intermediates. Background Technology

[0002] Antibody-drug conjugates (ADCs) are a new type of anti-tumor drug that uses a linker to bridge antibodies and cytotoxic molecules. The antibody recognizes specific antigens on the surface of tumor cells and enters the tumor cells through endocytosis, thereby transporting the cytotoxic toxins to the target site. This allows the antibody to exert its targeting ability and the toxin molecules to kill tumor cells at the same time, which is beneficial to expanding the therapeutic window of tumors.

[0003] WO2023280092 discloses a compound, DBCO-PEG4-GGFG-Dxd, containing a linker and a toxin molecule. The DBCO group in the compound allows for site-specific conjugation with antibodies. The ADC drug obtained using this compound exhibits good homogeneity, excellent antitumor activity, and outstanding stability.

[0004] CN113264983A discloses a method for synthesizing DBCO-PEG4-GGFG-Dxd, but it introduces the toxic substance eczema in the first step of the synthesis route, which is costly. Furthermore, the reaction and subsequent steps need to be carried out in a highly active workshop, which further increases the cost and safety risks, making it unsuitable for large-scale production.

[0005] Therefore, it is necessary to develop an improved preparation method suitable for the industrial-scale production of the compound. Summary of the Invention

[0006] In a first aspect, this disclosure relates to a method for preparing a compound of formula (A-1) or its stereoisomers, which mainly includes the following steps:

[0007] ; where n is an integer selected from 0 to 20.

[0008] Compared to existing reported processes, the key advantage of this disclosed preparation method lies in the final step of adding the toxin molecule eczemab for the chemical reaction. While several improved eczemab synthetic routes have been reported, their processes remain complex and costly. Introducing it at the final step significantly reduces the production cost of the target molecule. Furthermore, in actual industrial production, reactions using molecules with highly active fragments require specific high-activity workshops, placing high demands on equipment. This disclosed method, however, introduces the highly active molecule only at the final step, allowing all preceding steps to be completed in non-high-activity workshops, further reducing costs and ensuring high safety, making it suitable for large-scale production. Moreover, the target product obtained through this method has high purity, meeting the requirements for drug registration.

[0009] Secondly, this disclosure also relates to an improved synthetic method for the key intermediate C-1. Specifically, the protecting group of the carboxyl group in intermediate F-1 is first removed to obtain E-1, and then the amino protecting group in E-1 is removed to obtain C-1. The overall yield of the two-step reaction is over 80%, which is significantly higher than the level reported in the prior art.

[0010] Thirdly, this disclosure also relates to a method for preparing a compound of formula (F-1) or its stereoisomers, which mainly includes the following steps:

[0011] ; where n is an integer selected from 0 to 20.

[0012] Compared with existing technologies, the preparation method disclosed herein uses a highly toxic strong oxidant (such as lead tetraacetate) only in the penultimate step, which is lower in cost, safer, and has a higher overall yield, making it suitable for industrial production.

[0013] Terminology Definition

[0014] Unless otherwise indicated or defined, all terms used herein have their ordinary meaning as will be understood by those skilled in the art. References include, for example, standard manuals such as Sambrook et al., “Molecular Cloning: A Laboratory Manual” (2nd edition), Volumes 1–3, Cold Spring Harbor Laboratory Press (1989); Lewin, “Genes IV”, Oxford University Press, New York (1990); and Roitt et al., “Immunology” (2nd edition), Gower Medical Publishing, London, New York (1989), and general prior art cited herein; furthermore, unless otherwise stated, all methods, steps, techniques, and operations not specifically detailed herein can and have been performed in a manner known per se as will be understood by those skilled in the art. Also refer to, for example, standard manuals, the aforementioned general prior art, and other references cited therein.

[0015] As used herein, the term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 10 carbon atoms, and most preferably an alkyl group containing 1 to 6 carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl.

[0016] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, 3 to 10 carbon atoms, or 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. In this text, C... 3-6 Cycloalkyl or 3-6 membered cycloalkyl means cycloalkyl containing 3 to 6 carbon atoms.

[0017] The term "heterocyclic alkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group containing 3 to 20, for example, 3 to 10, 3 to 6, or 5 to 6 ring atoms, wherein one or more (for example, 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, but excluding the ring portions of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.

[0018] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein the definitions of alkyl or cycloalkyl are as described above.

[0019] The term "halogen" refers to fluorine (-F), chlorine (-Cl), bromine (-Br), or iodine (-I). The term "stereoisomer" refers to any of the various stereoisomeric configurations that can exist for the compounds of the present invention. Stereoisomers of a compound include enantiomers, diastereomers, or racemates of the compound. An "enantiomer" is a pair of stereoisomers that are mirror images of each other and do not overlap. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. This term is used where appropriate to refer to racemic mixtures. A "diastereomer" is a stereoisomer having at least two asymmetric atoms, but which are not mirror images of each other. Absolute stereochemistry is determined according to the Cahn-Lngold-Prelog RS system. When the compound is a pure enantiomer, the stereochemistry of each chiral carbon can be designated as R or S.

[0020] The term "optional" or "optionally" means that the event or condition described below either occurs or does not occur, and the description includes instances where the event or condition occurs as well as instances where the event or condition does not occur. For example, when a group or structure is "optionally substituted," the group or structure may or may not be substituted.

[0021] The term "salt" refers to a salt formed by the compounds of the present invention with an acid or base. The compounds of the present invention can exist in the form of their salts, including acid addition salts and base addition salts. In the present invention, an acid addition salt refers to a salt formed by the compounds of the present invention with an organic or inorganic acid, including but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc. A base addition salt refers to a salt formed by the compounds of the present invention with an organic or inorganic base, including but not limited to alkali metal salts, such as lithium, sodium, or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and organic base salts, such as ammonium salts formed by reacting with an organic base containing an N-group.

[0022] As used herein, the term “and / or” refers to any one of the options or two or more of the options.

[0023] As used herein, the terms “comprising” or “including” mean to include the stated elements, integers, or steps, but do not exclude any other elements, integers, or steps. In this document, when the terms “comprising” or “including” are used, unless otherwise specified, they also cover combinations of the stated elements, integers, or steps.

[0024] Invention Details

[0025] Preparation method

[0026] In a first aspect, this disclosure provides a method for preparing a compound of formula (A) or a stereoisomer thereof, the method comprising the step of reacting a compound of formula (B) with eczema or a salt thereof to obtain a compound of formula (A):

[0027] Where n is selected from integers from 0 to 20;

[0028] R1 and R2 are each independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyl, amino, cyano and nitro; or, R1 and R2 together with the carbon atom they are attached to form a 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl or carbonyl;

[0029] The alkyl, alkoxy, cycloalkyl, and heterocycloalkyl groups are each optionally and independently further substituted with groups selected from deuterium, halogen, hydroxyl, amino, cyano, and nitro groups.

[0030] In some implementations, n = 0, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18 or 20; preferably, n = 2, 4 or 8, more preferably, n = 4.

[0031] In some implementation schemes, R1 and R2 are each independently selected from hydrogen, deuterium, halogen, and C. 1-6 Alkyl, C 3-6 Cycloalkyl and 3-6-membered heterocycloalkyl, or R1 and R2 together with the carbon atoms they are attached to form 3-6-membered cycloalkyl or 3-6-membered heterocycloalkyl; each of the alkyl, cycloalkyl and heterocycloalkyl is optionally further substituted independently by a group selected from deuterium, halogen, hydroxyl and amino.

[0032] In some implementation schemes, R1 and R2 are each independently selected from hydrogen, deuterium, halogen, and C. 1-6 Alkyl and C 3-6 The cycloalkyl group, or R1 and R2 together with the carbon atom attached to them, forms a 3-6 membered cycloalkyl group; each of the alkyl and cycloalkyl groups is optionally further substituted independently by a group selected from deuterium, halogen, hydroxyl and amino groups.

[0033] In some implementations, R1 and R2 are selected from the following group:

[0034] (1) R1 and R2 are both hydrogen; (2) R1 is deuterium and R2 is hydrogen; (3) R1 and R2 are both deuterium; (4) R1 is methyl and R2 is hydrogen; (5) R1 is cyclopropyl and R2 is hydrogen; and (6) R1 and R2 together with the carbon atoms attached to them form cyclopropyl or cyclobutyl.

[0035] In some implementations, both R1 and R2 are hydrogen.

[0036] In some embodiments, the ecientecan described in this disclosure is its free base.

[0037] In some embodiments, the salt of eczetidine is selected from its methanesulfonate, hydrochloride, trifluoroacetate, hydrobromide, sulfate, phosphate, citrate, tartrate, and acetate; preferably, the salt of eczetidine is its methanesulfonate.

[0038] In some embodiments, the method for preparing the compound of formula (A) or its stereoisomer may further include the step of reacting the compound of formula (C) and the compound of formula (D) to obtain the compound of formula (B):

[0039] R1, R2, and n are as defined above.

[0040] In some embodiments, the method for preparing the compound of formula (A) or its stereoisomer may further include the step of reacting the compound of formula (E) to obtain the compound of formula (C):

[0041] Where R1, R2, and n are as defined above;

[0042] R3 is an amino protecting group. For example, R3 can be selected from fluorenemethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), p-methoxybenzyl (PMB), benzyl (Bn), triphenylmethyl (Trt), p-toluenesulfonyl (Tos), phthaloyl (Pht), and allyloxycarbonyl (Alloc). Preferably, R3 is fluorenemethyloxycarbonyl (Fmoc).

[0043] In some embodiments, the method for preparing the compound of formula (A) or its stereoisomers may further include the step of reacting the compound of formula (F) to obtain the compound of formula (E):

[0044] R1, R2, R3 and n are as defined above.

[0045] In some embodiments, the method for preparing the compound of formula (A) or its stereoisomer may further include the steps of reacting the compound of formula (F) to obtain the compound of formula (E), and then reacting the compound of formula (E) to obtain the compound of formula (C).

[0046] In some embodiments, the method for preparing the compound of formula (A) or its stereoisomer may further include the step of reacting the compound of formula (G) preferably with benzyl glycolate to obtain the compound of formula (F):

[0047] R1, R2, R3 and n are as defined above.

[0048] In some embodiments, the method for preparing the compound of formula (A) or its stereoisomer may further include the step of reacting the compound of formula (H) to obtain the compound of formula (G):

[0049] ; where R1, R2, R3 and n are as defined above.

[0050] In some embodiments, the compound of formula (G) is obtained by reacting the compound of formula (H) with lead tetraacetate.

[0051] In some embodiments, the compound of formula (G) is obtained by reacting the compound of formula (H) with lead tetraacetate and copper acetate.

[0052] In some embodiments, the method for preparing the compound of formula (A) or its stereoisomer may further include the step of reacting the compound of formula (I) to obtain the compound of formula (H):

[0053] Where R1, R2, R3 and n are as defined above;

[0054] R4 is a carboxyl protecting group, for example, R4 can be selected from methyl, ethyl, allyl, benzyl and tert-butyl, preferably tert-butyl.

[0055] In some embodiments, the method for preparing the compound of formula (A) or its stereoisomer may further include the step of reacting the compound of formula (J) with the compound of formula (K) to obtain the compound of formula (I):

[0056] ; where R1, R2, R3, R4 and n are as defined above.

[0057] In some embodiments, the method for preparing the compound of formula (A) or its stereoisomer may further include the step of reacting the compound of formula (L) to obtain the compound of formula (J):

[0058] R1, R2, and R4 are as defined above;

[0059] R5 is an amino protecting group, for example, R5 can be selected from fluorenemethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), p-methoxybenzyl (PMB), benzyl (Bn), triphenylmethyl (Trt), p-toluenesulfonyl (Tos), phthaloyl (Pht), and allyloxycarbonyl (Alloc), preferably, R3 is fluorenemethyloxycarbonyl (Fmoc).

[0060] In some embodiments, this disclosure provides a method for preparing a compound of formula (A-1) or a stereoisomer thereof, the method comprising the step of reacting a compound of formula (B-1) with eczema or a salt thereof to obtain a compound of formula (A-1):

[0061] Where n is as defined above.

[0062] In some embodiments, the method for preparing the compound of formula (A-1) or its stereoisomers disclosed herein further includes the step of reacting the compound of formula (C-1) and the compound of formula (D) to obtain the compound of formula (B-1):

[0063] Where n is as defined above.

[0064] In some embodiments, the method for preparing the compound of formula (A-1) or its stereoisomers disclosed herein further includes the step of obtaining the compound of formula (C-1) by a reaction of formula (E-1):

[0065] ; where n is as defined above.

[0066] In some embodiments, the method for preparing the compound of formula (A-1) or its stereoisomers as disclosed herein further includes the step of obtaining the compound of formula (E-1) by reacting with formula (F-1):

[0067] Where n is as defined above.

[0068] In some embodiments, the method for preparing the compound of formula (A-1) or its stereoisomer may further include the steps of reacting the compound of formula (F-1) to obtain the compound of formula (E-1), and then reacting the compound of formula (E-1) to obtain the compound of formula (C-1).

[0069] In some embodiments, the method for preparing the compound of formula (A-1) or its stereoisomer may further include the step of reacting the compound of formula (G-1) preferably with benzyl glycolate to obtain the compound of formula (F-1):

[0070] Where n is as defined above.

[0071] In some embodiments, the method for preparing the compound of formula (A-1) or its stereoisomer may further include the step of reacting the compound of formula (H-1) to obtain the compound of formula (G-1):

[0072] ; where n is as defined above.

[0073] In some embodiments, the compound of formula (G-1) is obtained by reacting the compound of formula (H-1) with lead tetraacetate.

[0074] In some embodiments, the compound of formula (G-1) is obtained by reacting the compound of formula (H-1) with lead tetraacetate and copper acetate.

[0075] In some embodiments, the method for preparing the compound of formula (A-1) or its stereoisomer may further include the step of reacting the compound of formula (I-1) to obtain the compound of formula (H-1):

[0076] ; where n is as defined above.

[0077] In some embodiments, the method for preparing the compound of formula (A-1) or its stereoisomer may further include the step of reacting the compound of formula (J-1) with the compound of formula (K-1) to obtain the compound of formula (I-1):

[0078] ; where n is as defined above.

[0079] In some embodiments, the method for preparing the compound of formula (A-1) or its stereoisomer may further include the step of reacting the compound of formula (L-1) to obtain the compound of formula (J-1):

[0080] Secondly, this disclosure also provides a method for preparing the compound of formula (C) or its stereoisomers, including the step of reacting the compound of formula (E) to obtain the compound of formula (C).

[0081] In some embodiments, the method for preparing the compound of formula (C) or its stereoisomer may further include the step of reacting the compound of formula (F) to obtain the compound of formula (E).

[0082] In some embodiments, the method for preparing the compound of formula (C) or its stereoisomer may include the steps of reacting the compound of formula (F) to obtain the compound of formula (E), and then reacting the compound of formula (E) to obtain the compound of formula (C).

[0083] In some embodiments, this disclosure also provides a method for preparing a compound of formula (C-1) or a stereoisomer thereof, including the step of reacting a compound of formula (E-1) to obtain a compound of formula (C-1).

[0084] In some embodiments, the method for preparing the compound of formula (C-1) or its stereoisomer may further include the step of reacting the compound of formula (F-1) to obtain the compound of formula (E-1).

[0085] In some embodiments, the method for preparing the compound of formula (C-1) or its stereoisomer may include the steps of reacting the compound of formula (F-1) to obtain the compound of formula (E-1), and then reacting the compound of formula (E-1) to obtain the compound of formula (C-1).

[0086] In the preparation method of the second aspect mentioned above, the compounds of formulas (C), (E), (F), (C-1), (E-1), and (F-1) are as defined in the first aspect.

[0087] It should be particularly noted that compound C-2 is a key intermediate for the synthesis of compound A-2 (DBCO-PEG4-GGFG-Dxd). The synthesis of this compound is already described in prior art WO2023025256 (see pages 70-73 of the specification). However, the route in WO2023025256 suffers from problems such as complexity and low yield, especially the step of preparing compound C-2 (i.e., compound 28-9) from compound F-2 (i.e., compound 28-7), where the two-step reaction yield is only 30%, resulting in a very low overall yield. Through in-depth research, the inventors unexpectedly discovered that by adjusting the deprotection sequence of compound F-2, the yield of the two-step reaction was significantly increased to nearly 80%, greatly reducing production costs.

[0088] Thirdly, this disclosure also provides a method for preparing a compound of formula (F) or a stereoisomer thereof, comprising the step of reacting a compound of formula (G) to obtain a compound of formula (F). For example, it may include the step of reacting a compound of formula (G) with benzyl glycolate to obtain a compound of formula (F).

[0089] In some embodiments, the method for preparing the compound of formula (F) or its stereoisomer may further include the step of reacting the compound of formula (H) to obtain the compound of formula (G).

[0090] In some embodiments, the preparation method includes the step of reacting the compound of formula (H) with lead tetraacetate to obtain the compound of formula (G).

[0091] In some embodiments, the preparation method includes the step of reacting the compound of formula (H) with lead tetraacetate and copper acetate to obtain the compound of formula (G).

[0092] In some embodiments, the method for preparing the compound of formula (F) or its stereoisomer may further include the step of reacting the compound of formula (I) to obtain the compound of formula (H).

[0093] In some embodiments, the method for preparing the compound of formula (F) or its stereoisomer may further include the step of reacting the compound of formula (J) with the compound of formula (K) to obtain the compound of formula (I).

[0094] In some embodiments, the method for preparing the compound of formula (F) or its stereoisomer may further include the step of reacting the compound of formula (L) to obtain the compound of formula (J).

[0095] In other embodiments, this disclosure also provides a method for preparing a compound of formula (F-1) or a stereoisomer thereof, comprising the step of reacting a compound of formula (G-1) to obtain a compound of formula (F-1). For example, it may include the step of reacting a compound of formula (G-1) with benzyl glycolate to obtain a compound of formula (F-1).

[0096] In some embodiments, the method for preparing the compound of formula (F-1) or its stereoisomer may further include the step of reacting the compound of formula (H-1) to obtain the compound of formula (G-1).

[0097] In some embodiments, the preparation method includes the step of reacting the compound of formula (H-1) with lead tetraacetate to obtain the compound of formula (G-1).

[0098] In some embodiments, the preparation method includes the step of reacting the compound of formula (H-1) with lead tetraacetate and copper acetate to obtain the compound of formula (G-1).

[0099] In some embodiments, the method for preparing the compound of formula (F-1) or its stereoisomer may further include the step of reacting the compound of formula (I-1) to obtain the compound of formula (H-1).

[0100] In some embodiments, the method for preparing the compound of formula (F-1) or its stereoisomer may further include the step of reacting the compound of formula (J-1) with the compound of formula (K-1) to obtain the compound of formula (I-1).

[0101] In some embodiments, the method for preparing the compound of formula (F-1) or its stereoisomer may further include the step of reacting the compound of formula (L-1) to obtain the compound of formula (J-1).

[0102] In the preparation method of the aforementioned third aspect, the compounds of formula (F), (G), (H), (I), (J), (K), (L), (F-1), (G-1), (H-1), (I-1), (J-1), (K-1), (L-1) are as defined in the first aspect.

[0103] On the other hand, this disclosure also provides a method for preparing a compound of formula (A) or a stereoisomer thereof, the method comprising reacting a compound of formula (F) to obtain a compound of formula (E), and then reacting a compound of formula (E) to obtain a compound of formula (C).

[0104] In some embodiments, this disclosure also provides a method for preparing a compound of formula (A-1) or a stereoisomer thereof, the method comprising reacting a compound of formula (F-1) to obtain a compound of formula (E-1), and then reacting a compound of formula (E-1) to obtain a compound of formula (C-1).

[0105] It should also be understood that the reactions of the present invention can be carried out under conventional reaction conditions known in the art. For example, a certain reaction temperature and pressure can be controlled according to the characteristics of the reactants until the reaction is complete. For example, suitable reaction conditions as described below can be selected.

[0106] Typically, reactions can be carried out in solvents, including but not limited to organic solvents such as methanol, ethanol, isopropanol, acetonitrile, heptane, toluene, acetone, dichloromethane, tetrahydrofuran, methyltetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, DMAc, ethyl acetate, diethyl ether, isopropyl ether, methyl tert-butyl ether, methyl cyclopentyl ether, and any combination thereof. Where appropriate, mixtures of organic solvents and water may be used. In some reactions, no additional solvent may be used, and the reactants themselves may also serve as solvents.

[0107] The reaction can be carried out at suitable temperatures, such as between -78°C and 100°C, for example -78°C-0°C, -20°C-20°C, -20°C-50°C, -10°C-10°C, 0°C-20°C, 20°C-30°C, 20°C-50°C, or 30°C-70°C, for example -30°C, -20°C, -10°C, 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, or 90°C.

[0108] For the reaction of the present invention, the molar ratio between the two reactants can be 10:1 to 1:10, 5:1 to 1:5, 2:1 to 1:2, 1:1 to 1:5, 1:1 to 1:2, 1:1 to 1:3, 1:1 to 1:1.5 or 1:1 to 1:1.2.

[0109] The reaction can be carried out under normal pressure, pressure or pressure, depending on the circumstances.

[0110] The reactions of the present invention can be carried out in the presence of a base; optionally, the reactions of the present invention can also be carried out in the presence of a condensing agent, such as the reaction of compound (B) with eczema or a salt thereof, or the reaction of compound (C) with compound (D).

[0111] In the reaction of the present invention, preferably, the base is selected from triethylamine, pyridine, 4-dimethylaminopyridine, DIPEA, HOBT, DBU or a combination thereof; preferably, the condensing agent is selected from HBTU, DCC, EDCI, DIC, CDI, PPTS or a combination thereof; preferably, the condensing agent may also be selected from HATU or HOPO.

[0112] The reactions of the present invention, such as the reaction of a compound of formula (F) to obtain a compound of formula (E), can be carried out under catalytic hydrogenation conditions, for example in the presence of a palladium catalyst (e.g., palladium on carbon) and hydrogen.

[0113] The reaction of compound (I) to obtain compound (H) of the present invention, or a similar reaction, is carried out in the presence of an alkali metal alkoxide such as lithium tert-butoxide, sodium tert-butoxide, or potassium tert-butoxide; the reaction of compound (I) to obtain compound (H), or a similar reaction, can also be carried out in the presence of an acidic substance such as p-toluenesulfonic acid (TsOH).

[0114] It should be understood that those skilled in the art can easily detect the reaction process and thus determine the reaction time or reaction endpoint based on the actual situation.

[0115] intermediate

[0116] Fourthly, this disclosure also provides compounds, their salts, or stereoisomers as shown in formula (J-1):

[0117] In some embodiments, the compound represented by formula (J-1), its salt, or its stereoisomer can be obtained by reacting the compound represented by formula (L-1).

[0118] Fifthly, this disclosure also provides compounds, their salts, or stereoisomers as shown in formula (I-1):

[0119] Where n is as defined above. In some implementations, n = 4.

[0120] In some embodiments, the compound represented by formula (I-1), its salt, or its stereoisomer can be obtained by reacting the compound represented by formula (J-1) with the compound represented by formula (K-1). The compound represented by formula (J-1) can be obtained by reacting the compound represented by formula (L-1).

[0121] Sixthly, this disclosure also provides compounds, their salts, or stereoisomers as shown in formula (H-1):

[0122] Where n is as defined above. In some implementations, n = 4.

[0123] In some embodiments, the compound represented by formula (H-1), its salt, or its stereoisomer can be obtained by reacting the compound represented by formula (I-1). The compound represented by formula (I-1) can be obtained by reacting the compound represented by formula (J-1) with the compound represented by formula (K-1). The compound represented by formula (J-1) can be obtained by reacting the compound represented by formula (L-1).

[0124] In a seventh aspect, this disclosure also provides compounds of formula (G-1), their salts, or stereoisomers:

[0125] Where n is as defined above. In some implementations, n = 4.

[0126] In some embodiments, the compound represented by formula (G-1), its salt, or its stereoisomer can be obtained by reacting the compound represented by formula (H-1). The compound represented by formula (H-1) can be obtained by reacting the compound represented by formula (I-1). The compound represented by formula (I-1) can be obtained by reacting the compound represented by formula (J-1) with the compound represented by formula (K-1). The compound represented by formula (J-1) can be obtained by reacting the compound represented by formula (L-1).

[0127] Eighthly, this disclosure also provides compounds, their salts, or stereoisomers as shown in formula (E-1):

[0128] Where n is as defined above. In some implementations, n = 4.

[0129] In some embodiments, the compound represented by formula (E-1), its salt, or its stereoisomer can be obtained by reacting the compound represented by formula (F-1). The compound represented by formula (F-1) can be obtained by reacting the compound represented by formula (G-1). The compound represented by formula (G-1) can be obtained by reacting the compound represented by formula (H-1). The compound represented by formula (H-1) can be obtained by reacting the compound represented by formula (I-1). The compound represented by formula (I-1) can be obtained by reacting the compound represented by formula (J-1) with the compound represented by formula (K-1). The compound represented by formula (J-1) can be obtained by reacting the compound represented by formula (L-1). Detailed Implementation

[0130] The abbreviations used in this application have the following meanings. Abbreviations without explanation have the meanings commonly understood in the art.

[0131] Example 1: Preparation of Intermediate F-2

[0132] The starting compound L-2 can be prepared by referring to the methods in patent documents WO2024091437 (synthesis of compound I-1i) or CN117024438A (Example 26).

[0133] Steps 1 & 2

[0134] Compound L-2 (2.69 kg, 4.00 mol) and acetonitrile (53.8 L) were added to a reaction vessel. DBU (608.96 g, 4.00 mol) was added dropwise while maintaining the temperature at 0-5 °C. The reaction mixture was stirred until it became clear. Then, PPTS (1.01 kg, 4.00 mol), Fmoc-PEG4-carboxylic acid (2.15 kg, 4.40 mol), HOBT (648.58 g, 4.80 mol), and EDCI (920.16 g, 4.80 mol) were added, and the mixture was stirred. After the reaction was complete, ethyl acetate (107.6 L) was added. The organic phase was washed successively with hydrochloric acid, sodium bicarbonate aqueous solution, and water. The organic phase was concentrated to obtain a viscous liquid. Acetonitrile (13.5 L) and methyl tert-butyl ether (53.8 L) were added to the residue, and the mixture was stirred at 20-25 °C for 2 h. After filtration, the product compound I-2 (3.60 kg, 3.92 mol) was obtained by solid oil pumping. The two-step yield was 97.7%. [M+Na]+=941.8.

[0135] Step 3

[0136] Compound I-2 (3.60 kg, 3.92 mol) and DCM (18.0 L) were added to a reaction vessel, and TFA (7.2 L) was added dropwise while maintaining the temperature at 0-5 °C. After the addition was complete, the temperature was raised to 20-25 °C and the reaction was carried out for 2 hours under controlled temperature. The reaction solution was evaporated to dryness, and methyl tert-butyl ether (108 L) was added to the residue to form a slurry. The mixture was filtered, and the solid was dried to obtain a white solid compound H-2 (3.24 kg, 3.75 mol), with a yield of 95.9%. [M+H]+ = 863.3.

[0137] Step 4

[0138] Under a nitrogen atmosphere, compound H-2 (3.24 kg, 3.75 mol), DMF (32.4 L), lead tetraacetate (1.66 kg, 11.25 mol), and copper acetate (0.34 kg, 1.88 mol) were added to a reactor. The mixture was heated to 38-42 °C and stirred under controlled temperature. Water (64.8 L) and DCM (97.2 L) were added for extraction. The mixture was filtered, and the filtrate was separated into layers. The organic phase was collected, washed with water, and concentrated to obtain a crude product. The crude product was then mixed with DCM (3.2 L) and MTBE (32.4 L), filtered, and dried under vacuum to obtain a white product compound G-2 (2.09 kg, 2.39 mol), with a yield of 63.6%. [M+Na]+ = 899.3.

[0139] Step 5

[0140] Compound G-2 (1.90 kg, 2.17 mol), tetrahydrofuran (38.0 L), and benzyl glycolate (0.54 kg, 3.26 mol) were added to a reaction flask. Lithium tert-butoxide (0.26 kg, 3.26 mol) was added at a controlled temperature of -10℃ to -5℃. The reaction was controlled at mid-temperature and quenched with acetic acid (0.26 kg). Extraction was performed with EA (38 L) and water (19 L), and the crude product was obtained after solvent removal. The crude product was purified by DCM:MeOH = 10:1 column chromatography. The purified product was then prepared by reverse-phase chromatography to obtain a white solid product, compound F-2 (0.80 kg, 0.81 mol), with a yield of 37% and an HPLC purity of 97.6%. [M+Na]+ = 1005.3

[0141] 1H NMR (400MHz, DMSO-d6) δ8.59(t,J=6.8Hz,1H),8.31(t,J=6.0Hz,1H),8.17(t,J=5.6Hz,1H),8.12(d,J=8.0Hz,1H),8.00(t,J=5.6Hz,1H),7 .89(d,J=7.6Hz,2H),7.68(ov,2H),7.47~7.28(ov,9H),7.28~7.21(ov,4H),7.21~7.12(m,1H),5.15(s,2H),4.64(d,J=6.8Hz,2H),4.55~4. 45(m,1H),4.29(d,J=7.2Hz,2H),4.21(t,J=6.4Hz,1H),4.16(s,2H),4.13~4.05(m,1H),3.80~3.65(ov,5H),3.64~3.55(ov,3H),3.48(t,J =6.0Hz,11H),3.40(t,J=6.0Hz,2H),3.20~3.10(ov,3H),3.06(dd,J=14.0,4.8Hz,1H),2.81(dd,J=13.6,9.6Hz,1H),2.39(t,J=6.4Hz,2H).

[0142] The preparation method disclosed herein involves five reaction steps to obtain the key intermediate F-2 with an overall yield of 22.05%. Compared to the method in the prior art WO2023025256 (Preparation of intermediate 28-7 in Example 28: a total of seven reaction steps, with a total yield of 17.69%), the synthetic route is shorter and the overall yield is higher. Furthermore, this disclosure uses highly toxic lead tetraacetate only in the penultimate step, while the prior art WO2023025256 requires its large-scale use in the first step. The method disclosed herein is safer and more suitable for industrial production. Moreover, the post-processing and purification steps of this disclosure can remove a large amount of lead, and as F-2 is an intermediate, its lead content can be further reduced in subsequent reactions and purification processes. Testing has shown that lead levels in multiple batches of the final product A-2 are below 1 ppm.

[0143] Example 2: Preparation of compound A-2 (DBCO-PEG4-GGFG-Dxd)

[0144] Step 1

[0145] Compound F-2 (668.6 g, 0.68 mol) and THF (5.98 kg) were added to the reaction vessel and stirred. 10% palladium on carbon (67.1 g) was added. After the addition was complete, the mixture was purged with nitrogen three times and hydrogen three times and pressurized to 0.2-0.3 MPa. The internal temperature was controlled at 20-25℃ and the reaction was carried out for 12±1 h. The reaction was monitored by HPLC.

[0146] After the reaction was completed, the pressure was released, and the mixture was filtered through diatomaceous earth. The filter cake was washed twice with THF (738.1 g * 2). The filtrate was concentrated to 1-2V at 15-25℃, and 1V of THF was added. MTBE (9.98 kg) and F-2 seed crystals (6.0 g) were placed in a crystallization vessel and stirred for 15-25 min at an external temperature of 10-20℃. A THF solution containing the product was added dropwise to the system (completed over 3-4 h), and the mixture was stirred for 3-4 h at an external temperature of 10-20℃. The mixture was then filtered, washed once with MTBE (1.21 kg), and the solid was transferred to a vacuum drying oven and dried at 15-25℃ for 16 ± 1 h. After drying, intermediate E-2 (503.3 g, 0.56 mol) was obtained with a yield of 82.4% and an HPLC purity of 98.0%. [M + Na] + (Measured value m / z = 915.3)

[0147] 1 H NMR (400MHz, DMSO-d6) δ8.58(t,J=6.8Hz,1H),8.31(t,J=6.0Hz,1H),8.19(t,J=5.6Hz,1H),8.15(d,J=8.0Hz,1H),8.04(t,J=5.6Hz,1 H),7.89(d,J=7.6Hz,2H),7.68(ov,2H),7.41(t,J=7.6Hz,2H),7.33(ov,3H),7.24(ov,4H),7.21~7.15(m,1H),4.62(d,J=6.4Hz,2H), 4.55~4.45(m,1H),4.29(d,J=6.8Hz,2H),4.21(t,J=6.8Hz,1H),3.98(s,2H),3.83~3.67(ov,5H),3.64~3.56(ov,3H),3.48(t,J=6.0H z,12H),3.40(t,J=5.6Hz,2H),3.13(dd,J=11.6,6.0Hz,2H),3.10~3.02(ov,2H),2.81(dd,J=14.0,9.6Hz,1H),2.39(t,J=6.4Hz,2H).

[0148] Step Two

[0149] Add E-2 (493.1g, 0.55mol) and DMAc (3.20kg) to the reaction vessel, stir, adjust the external temperature to -10~0℃, and control the internal temperature to -10~0℃. Add DBU (124.7g) dropwise. After the addition is complete, maintain the internal temperature at -10~0℃ for 4.5±0.5h. Take a sample (take 1-2ml of the reaction solution, adjust the pH to 6-7 with acetic acid, and send it for analysis) to HPLC control.

[0150] After the reaction was complete, HOBT (183.8 g) was added in batches at an internal temperature of -10 to 0℃. After the addition was complete, the internal temperature was adjusted to 15-25℃ and the mixture was stirred for 1-2 hours. THF (11.02 kg) and MTBE (9.08 kg) were added to the crystallization vessel, and the internal temperature was adjusted to 0-10℃ and stirred for 20±5 min. The solution in the reaction vessel was then added dropwise at an internal temperature of 0-10℃. After the addition was complete, the mixture was stirred at 0-10℃ for 2-3 hours. The mixture was filtered, and the filter cake was washed once with THF (2.20 kg). The solid was transferred to a vacuum drying oven and dried at 15-25℃ for 11±1 h to obtain intermediate C-2 (347.2 g, 0.52 mol), with a yield of 94.5% and an HPLC purity of 94.7%. [M+H] + (Measured value m / z = 671.3).

[0151] 1 H NMR (400MHz, DMSO-d6) δ8.70(t,J=6.0Hz,2H),8.63(t,J=5.6Hz,2H),8.53(ov,3H),8.41(t ,J=5.6Hz,2H),7.30~7.14(ov,8H),4.70~4.52(ov,4H),4.45~4.34(m,2H),3.85(d,J=6.8Hz ,1H),3.81(d,J=6.4Hz,1H),3.76(ov,2H),3.67(ov,2H),3.64~3.56(ov,7H),3.08(dd,J=1 3.6, 4.8Hz, 2H), 2.93 (t, J = 5.2Hz, 3H), 2.85 (dd, J = 14.0, 9.6Hz, 2H), 2.42 (t, J = 6.4Hz, 3H).

[0152] Step 3

[0153] Compound C-2 (340.8 g, 0.51 mol) and DCM (4.50 kg) were added to the reaction vessel. The mixture was stirred, and under nitrogen protection, the reaction temperature was adjusted to 10–20 °C. Compound D (214.3 g, 0.53 mol) was then added while maintaining the temperature at 0–10 °C. DIPEA (2.0 eq) (129.1 g) was added dropwise, and the reaction was carried out for 2–3 hours under HPLC control. After the reaction was complete, column chromatography was performed, and the crude product was concentrated.

[0154] MTBE (12.62 kg) was added to a crystallization container, stirring was started, and the temperature was controlled at 15 ± 5 °C. The crude product's DCM solution (dissolved by diluting 4.50 kg of DCM) was slowly added dropwise. After the addition was complete, the mixture was stirred at 15 ± 5 °C for 2 ± 0.5 h to allow crystallization. The mixture was filtered under nitrogen protection, and the filter cake was washed with MTBE (1.74 kg) and dried under vacuum at 20 ± 5 °C for 10 ± 2 h. After drying, intermediate B-2 (356.0 g, 0.37 mol) was obtained, with a yield of 72.5% and an HPLC purity of 98.2%. [M+Na] + (Measured value m / z = 980.3).

[0155] 1 H NMR (400MHz, DMSO-d6) δ8.10(ov,3H),8.00(ov,2H),7.61~7.41(m,2H),7.35~7.27(ov,3H),7.2 7~7.05(ov,10H),6.66(d,J=19.2Hz,1H),5.23(s,1H),5.05(dd,J=14.0,7.6Hz,1H),4.63(ov,2H ),4.53(m,1H),3.90(s,2H),3.60(ov,2H),3.52~3.41(ov,12H),3.36(ov,3H),3.24(m,3H),2.96 (m,2H),2.73(m,1H),2.37(m,3H),2.09(m,1H),1.85(m,1H),1.62(m,1H),1.30(d,J=7.2Hz,2H).

[0156] Step Four

[0157] Compound B-2 (333.0 g, 0.35 mol) and DMF (2.48 kg) were added to the reaction flask, stirred and dissolved, and then purged with nitrogen for protection. EDCI (85.9 g, 0.45 mol) and HOBt (61.2 g, 0.45 mol) were added at room temperature, and the mixture was stirred for about 15 min. The temperature was lowered to below 10 °C, and eczema mesylate (178.5 g, 0.34 mol) (eczema was previously suspended in DMF) was added. DIPEA (89.3 g, 0.69 mol) was added dropwise while maintaining an internal temperature ≤10 °C. After the addition was complete, the mixture was stirred vigorously at below 10 °C for 16-20 h.

[0158] After the reaction was complete, water was added dropwise to quench the reaction, and the internal temperature was kept below 20°C. The quenched reaction solution was transferred to a separatory funnel, diluted with DCM, stirred, and allowed to stand for separation. The organic phase was collected. DCM was added to the aqueous phase for extraction (5.95 kg * 2), the organic phases were combined, and water was added for washing (7.27 kg * 3). The organic phase was collected and dried with anhydrous sodium sulfate. After filtration, the solution was transferred to a rotary evaporator and concentrated under reduced pressure at 25–35°C until no obvious fraction was observed. The concentrated solution was purified by reversed-phase preparative chromatography (10 μm C18 silica gel reversed-phase column), and the target component was collected. The solution was lyophilized to obtain 201.51 g of a white solid compound A-2, with a yield of 42.2% and an HPLC purity of 99.5%. [M+H]+ (measured value m / z = 1375.5).

[0159] 1 H NMR (400MHz, DMSO-d6) δ8.63(t,J=6.4Hz,1H),8.49(d,J=8.8Hz,1H),8.30(t,J= 5.2Hz,1H),8.16(t,J=5.2Hz,1H),8.11(d,J=8.0Hz,1H),8.00(t,J=5.6Hz,1H),7 .75(ov,1H),7.74(ov,1H),7.67(d,J=7.2Hz,1H),7.60(d,J=7.2Hz,1H),7.51~7. 40(ov,3H),7.40~7.11(ov,9H),6.51(s,1H),5.58(m,1H),5.41(s,2H),5.14(dd, J=32.0,19.2Hz,2H),5.01(d,J=14.0Hz,1H),4.64(s,2H),4.47(m,1H),4.03(s,2 H),3.81~3.65(ov,5H),3.65~3.52(ov,4H),3.50~3.40(ov,12H),3.29(t,J=5.2H z,2H),3.25~2.97(ov,5H),2.78(dd,J=13.6,10.0Hz,1H),2.57(m,1H),2.38(ov, 5H),2.20(ov,3H),2.00(m,1H),1.85(m,2H),1,75(m,1H),0.87(t,J=7.2Hz,3H).

[0160] This disclosure uses compound F-2 as the starting material and obtains the target product through four steps, resulting in fewer reaction steps and a higher yield. Compared to the process in CN113264983A, the high-cost, highly active substance eczema is added in the final step, and only the final step needs to be carried out in a high-activity workshop, further reducing costs and improving safety, making it suitable for large-scale industrial production. The target product produced using the process route of this disclosure can achieve a purity of 99.5%, with a maximum single impurity of less than 0.15%, which meets the requirements for drug registration. In contrast, the final product purity reported by the route in CN113264983A is only 98.6%, which cannot meet the registration requirements.

[0161] Furthermore, this disclosure optimizes the reaction route from F-2 to C-2, achieving a total two-step yield of 77.9%, significantly higher than the 30% yield in Example 28 (steps 8 and 9) of WO2023025256, achieving unexpected results. Through in-depth research, we found that the poor stability of reaction intermediate E-2' in the reaction solution is the main reason for the low C-2 yield in the prior art route.

[0162] Compound F-2 (15g, 15.3mmol, 1.0eq) and DCM (300mL) were added to a reaction vessel and stirred. DBU (0.8eq) was added dropwise while maintaining the temperature at -10 to 0℃. After the addition was complete, the temperature was maintained at -10 to 0℃ with stirring, and the reaction was monitored by HPLC. After 1 hour of reaction, samples were taken for analysis. Compound F-2 had reacted completely, but the purity of the main peak of the target intermediate E-2' was only 33.48%. After another 3 hours of reaction, samples were taken for analysis, and the purity of the main peak of E-2' had decreased to 0.31%. Intermediate E-2' slowly decomposes in the reaction solution, exhibiting poor stability. Due to the long intermediate control time in industrial production, this route is not suitable for large-scale industrial production. The inventors obtained the process route disclosed in this paper through route adjustment, which significantly improves the overall yield without increasing cost or route complexity.

[0163] Those skilled in the art will understand that the foregoing description is exemplary and illustrative in nature, and is intended to illustrate the invention and its preferred embodiments. Through conventional experimentation, those skilled in the art will understand that obvious modifications and variations can be made without departing from the spirit of the invention. All such modifications are intended to be included within the scope of the appended claims. Therefore, the invention is intended to be defined not by the foregoing description but by the scope of the following claims and their equivalents.

[0164] All publicly available publications cited in this specification are incorporated herein by reference.

Claims

1. A method for preparing a compound of formula (A) or a stereoisomer thereof, said method comprising the step of reacting a compound of formula (B) with eczema or a salt thereof to obtain a compound of formula (A): in, n is an integer selected from 0 to 20; R1 and R2 are each independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyl, amino, cyano and nitro; or, R1 and R2 together with the carbon atom they are attached to form a 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl or carbonyl; The alkyl, alkoxy, cycloalkyl, and heterocycloalkyl groups are each optionally and independently further substituted with groups selected from deuterium, halogen, hydroxyl, amino, cyano, and nitro groups.

2. The preparation method according to claim 1, wherein R1 and R2 are each independently selected from hydrogen, deuterium, halogen, and C. 1-6 Alkyl, C 3-6 Cycloalkyl and 3-6-membered heterocycloalkyl, or R1 and R2 together with the carbon atoms they are attached to form 3-6-membered cycloalkyl or 3-6-membered heterocycloalkyl; each of the alkyl, cycloalkyl and heterocycloalkyl is optionally further substituted independently by a group selected from deuterium, halogen, hydroxyl and amino.

3. The preparation method according to claim 1 or 2, wherein R1 and R2 are each independently selected from hydrogen, deuterium, halogen, and C. 1-6 Alkyl and C 3-6 The cycloalkyl group, or R1 and R2 together with the carbon atom attached to them, forms a 3-6 membered cycloalkyl group; each of the alkyl and cycloalkyl groups is optionally further substituted independently by a group selected from deuterium, halogen, hydroxyl and amino groups.

4. The preparation method according to any one of claims 1-3, wherein R1 and R2 are both hydrogen.

5. The preparation method according to any one of claims 1-4, further comprising the step of reacting compound (C) and compound (D) to obtain compound (B): in, R1, R2, and n are defined as described above.

6. The preparation method according to any one of claims 1-5, further comprising the step of reacting the compound of formula (E) to obtain the compound of formula (C): in, R1, R2, and n are defined as described above. R3 is an amino protecting group. For example, R3 can be selected from fluorenemethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), p-methoxybenzyl (PMB), benzyl (Bn), triphenylmethyl (Trt), p-toluenesulfonyl (Tos), phthaloyl (Pht), and allyloxycarbonyl (Alloc). Preferably, R3 is fluorenemethyloxycarbonyl (Fmoc).

7. The preparation method according to any one of claims 1-6, further comprising the step of reacting the compound of formula (F) to obtain the compound of formula (E): in, R1, R2, R3 and n are as defined above.

8. The preparation method according to any one of claims 1-7, further comprising the step of reacting the compound of formula (G) preferably with benzyl glycolate to obtain the compound of formula (F): in, R1, R2, R3 and n are as defined above.

9. The preparation method according to any one of claims 1-8, further comprising the step of reacting the compound of formula (H) to obtain the compound of formula (G): in, R1, R2, R3 and n are as defined above.

10. The preparation method according to claim 9, wherein the compound of formula (G) is obtained by reacting the compound of formula (H) with lead tetraacetate.

11. The preparation method according to any one of claims 1-10, further comprising the step of reacting the compound of formula (I) to obtain the compound of formula (H): in, R1, R2, R3, and n are defined as described above, and R4 is a carboxyl protecting group.

12. The preparation method according to claim 11, wherein, R4 is selected from methyl, ethyl, allyl, benzyl and tert-butyl, preferably tert-butyl.

13. The preparation method according to any one of claims 1-12, further comprising the step of reacting the compound of formula (J) with the compound of formula (K) to obtain the compound of formula (I): in, R1, R2, R3, R4 and n are as defined above.

14. The preparation method according to any one of claims 1-13, further comprising the step of reacting the compound of formula (L) to obtain the compound of formula (J): in, R1, R2, and R4 are as defined above; R5 is an amino protecting group, for example, R5 can be selected from fluorenemethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), p-methoxybenzyl (PMB), benzyl (Bn), triphenylmethyl (Trt), p-toluenesulfonyl (Tos), phthaloyl (Pht), and allyloxycarbonyl (Alloc), preferably, R3 is fluorenemethyloxycarbonyl (Fmoc).

15. A method for preparing a compound of formula (C) or a stereoisomer thereof, comprising the step of reacting a compound of formula (E) to obtain a compound of formula (C): in, R1, R2, and n are defined as described above.

16. The preparation method according to claim 15, further comprising the step of reacting the compound of formula (F) to obtain the compound of formula (E): in, R1, R2, R3 and n are as defined above.

17. A method for preparing a compound of formula (F) or a stereoisomer thereof, comprising the step of reacting a compound of formula (G) preferably with benzyl glycolate to obtain a compound of formula (F): in, R1, R2, R3 and n are as defined above.

18. The preparation method according to claim 17, further comprising the step of reacting the compound of formula (H) to obtain the compound of formula (G): in, R1, R2, R3 and n are as defined above.

19. The preparation method according to claim 17 or 18, further comprising the step of reacting the compound of formula (I) to obtain the compound of formula (H): in, R1, R2, R3, R4 and n are as defined above.

20. The preparation method according to any one of claims 17-19, further comprising the step of reacting the compound of formula (J) with the compound of formula (K) to obtain the compound of formula (I): in, R1, R2, R3, R4 and n are as defined above.

21. The preparation method according to any one of claims 17-20, further comprising the step of reacting the compound of formula (L) to obtain the compound of formula (J): in, R1, R2, R4, and R5 are as defined above.

22. A method for preparing a compound of formula (A) or a stereoisomer thereof, comprising the step of reacting a compound of formula (E) to obtain a compound of formula (C): ;in, R1, R2, R3, and n are as defined above; and The steps to obtain compound (E) from compound (F): R1, R2, R3 and n are as defined above.

23. The compound shown in formula (J-1), its salts, or stereoisomers:

24. The compound shown in formula (I-1), its salts, or stereoisomers: in, n is as defined above.

25. The compound shown in formula (H-1), its salts, or stereoisomers: in, n is as defined above.

26. The compound shown in formula (G-1), its salts, or stereoisomers: in, n is as defined above.

27. The compound shown in formula (E-1), its salts, or stereoisomers: in, n is as defined above.

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