Methods and compounds for preparing topoisomerase i inhibitor linker-payloads

Abstract

This specification relates to processes and intermediate compounds involved in the preparation of topoisomerase I inhibitor (TOPOl i) linker-payloads suitable for use in the synthesis of antibody conjugates. Formula (1)

Description

[0001] Cross-referencing of related patent applications

[0002] This specification claims priority to International Application No. PCT / CN2024 / 081246 (filed on March 12, 2024). The entire text of the aforementioned patent application is incorporated herein by reference. Technical Field

[0003] This specification relates to methods and intermediate compounds involved in the preparation of topoisomerase I inhibitor (TOPO1i) linker-loads suitable for the synthesis of antibody conjugates. Background Technology

[0004] Topoisomerase inhibitors are compounds that block the action of topoisomerases (topoisomerases I and II), enzymes that control changes in DNA structure by catalyzing the breaking and rejoining of the phosphodiester backbone of the DNA strand during the normal cell cycle. Antibody-drug conjugates (ADCs) containing TOPO1i linker-loads have been previously described. WO2020 / 200880 discloses certain linker-loads containing the TOPO1i drug payload AZ'0132.

[0005]

[0006] Example 1 of WO 2020 / 200880 is the Val-Ala–PEG8–TOPO1i linker-load (AZ'0133). AZ'0133 has been used to prepare the B7-H4-directed antibody-drug conjugate AZD8205 (Kinneer et al., Clin Cancer Res., 2023, 29(6), 1086-1101). ADCs containing AZ'0133 can undergo enzymatic cleavage in lysosomes to release the TOPO1i drug payload AZ'0132.

[0007]

[0008] WO 2020 / 200880 describes the synthetic route for AZ'0133 as outlined below. This route allows intermediate A to be prepared from 5-bromotetrahydronaphthalene-1-one (where "Alloc" refers to N-allyloxycarbonyl).

[0009]

[0010] Although the synthetic route disclosed in WO 2020 / 200880 provides a reliable method for the preparation of AZ'0133, there is a desire to improve the economics of large-scale manufacturing processes in order to minimize environmental impact and reduce commodity costs. Summary of the Invention

[0011] This article discloses a new synthetic route for the synthesis of AZ'0133. This includes a new route for the synthesis of intermediate A from naphthalene-1-amine 1.

[0012]

[0013] The conversion of compound 3 to compound 5 involves Buchwald–Hartwig amination followed by deprotection. This conversion proved sensitive to the choice of amine source. Using NH3 as the amine source in the presence of Cu2O or CuI did not produce the desired amination reaction. Using lithium bis(trimethylsilyl)amino (LiHMDS) as the amine source resulted in significant formation of the impurity Imp3, without the expected amination reaction being observed.

[0014]

[0015] Therefore, in the first aspect, a compound for preparing formula (I) is provided:

[0016] ,

[0017] A method using a salt thereof, the method comprising a compound of formula (II):

[0018] ,

[0019] The reaction of HZ or its salt with HZ or its salt, wherein the reaction is carried out in the presence of a palladium catalyst and a base.

[0020] Where X is Br, I, or Cl, and

[0021] Z is .

[0022] In another aspect, a compound for preparing formula (III) is provided.

[0023]

[0024] A method using its salt or a salt thereof, the method comprising

[0025] (i) preparing a compound of formula (I) or a salt thereof using the methods described above; and

[0026] (ii) Preparation of a compound of formula (III) or a salt thereof, including the reaction of a compound of formula (I) or a salt thereof with an acid.

[0027] In another aspect, tert-butyl (4-acetamido-5-oxo-5,6,7,8-tetrahydronaphth-1-yl)carbamate is provided.

[0028] , or its salt.

[0029] In another aspect, N-(4-((diphenylmethylene)amino)-8-oxo-5,6,7,8-tetrahydronaphth-1-yl)acetamide is provided.

[0030] , or its salt.

[0031] In another aspect, a method for preparing compounds of formula (IV) is provided.

[0032] ,

[0033] The method includes either the method described above (i) or (ii) the compound or a salt thereof.

[0034] In another aspect, a conjugate for preparing formula (V) is provided.

[0035] Ab – (LP) k (V)

[0036] The method of or a pharmaceutically acceptable salt thereof, either the method described above (i) or (ii) the compound thereof, wherein

[0037] Ab is an antibody or its antigen-binding fragment.

[0038] k is an integer from 1 to 10, and

[0039] LP is

[0040] .

[0041] To avoid any doubt, the formula in this instruction manual is " The use of "" indicates a covalent attachment point with a group.

[0042] For methods used to prepare compounds of formula (I), the term "molar equivalent" refers to the molar equivalent of a compound of formula (II) or a salt thereof.

[0043] Units, prefixes, and symbols are represented in their internationally recognized (SI) form. Numerical ranges include the values ​​that define that range.

[0044] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd edition, 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd edition, 1999, Academic Press; and the Oxford Dictionary of Biochemistry and Molecular Biology, revised edition, 2000, Oxford University Press provide a general dictionary for those skilled in the art of the use of many terms in this disclosure. Detailed Implementation

[0045] As described above, in a first aspect, a compound for preparing formula (I) is provided:

[0046] ,

[0047] A method using a salt thereof, the method comprising a compound of formula (II):

[0048] ,

[0049] The reaction of HZ or its salt with HZ or its salt, wherein the reaction is carried out in the presence of a palladium catalyst and a base.

[0050] Where X is Br, I, or Cl, and

[0051] Z is .

[0052] In one embodiment, a method for preparing a compound of formula (I) is provided, wherein X is Br or Cl. In another embodiment, X is Br.

[0053] In one embodiment, a method for preparing a compound of formula (I) is provided, wherein the reaction is carried out in the presence of at least 1.0 equivalents of base. In another embodiment, the reaction is carried out in the presence of at least 1.5 equivalents of base. In another embodiment, the reaction is carried out in the presence of 1.0 to 5.0 equivalents of base. In another embodiment, the reaction is carried out in the presence of 1.0 to 3.0 equivalents of base. In another embodiment, the reaction is carried out in the presence of 1.0 to 2.5 equivalents of base. In another embodiment, the reaction is carried out in the presence of 1.0 to 2.0 equivalents of base. In another embodiment, the reaction is carried out in the presence of 1.5 to 2.5 equivalents of base. In another embodiment, the reaction is carried out in the presence of 1.5 to 2.0 equivalents of base. In another embodiment, the reaction is carried out in the presence of 1.7 to 1.9 equivalents of base. In another embodiment, the reaction is carried out in the presence of about 1.8 equivalents of base.

[0054] In one embodiment, a method for preparing a compound of formula (I) is provided, wherein the reaction is carried out in the presence of at least 1.0 molar equivalent of a base. In another embodiment, the reaction is carried out in the presence of at least 1.5 molar equivalents of a base. In another embodiment, the reaction is carried out in the presence of 1.0 to 5.0 molar equivalents of a base. In another embodiment, the reaction is carried out in the presence of 1.0 to 3.0 molar equivalents of a base. In another embodiment, the reaction is carried out in the presence of 1.0 to 2.5 molar equivalents of a base. In another embodiment, the reaction is carried out in the presence of 1.0 to 2.0 molar equivalents of a base. In another embodiment, the reaction is carried out in the presence of 1.5 to 2.5 molar equivalents of a base. In another embodiment, the reaction is carried out in the presence of 1.5 to 2.0 molar equivalents of a base. In another embodiment, the reaction is carried out in the presence of 1.7 to 1.9 molar equivalents of a base. In another embodiment, the reaction is carried out in the presence of about 1.8 molar equivalents of a base.

[0055] In one embodiment, a method for preparing a compound of formula (I) is provided, wherein the base is cesium carbonate (Cs₂CO₃), tripotassium phosphate (K₃PO₄), potassium tert-butoxide (KOC(CH₃)₃), potassium carbonate (K₂CO₃), potassium bicarbonate (KHCO₃), sodium carbonate (Na₂CO₃), sodium bicarbonate (NaHCO₃), sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), cesium hydroxide (CsOH), calcium hydroxide (Ca(OH)₂), calcium carbonate (CaCO₃), or barium hydroxide (Ba(OH)₂). In another embodiment, the base is cesium carbonate (Cs₂CO₃). In yet another embodiment, the base is tripotassium phosphate (K₃PO₄).

[0056] In one embodiment, a method for preparing a compound of formula (I) is provided, wherein the reaction is carried out in the presence of at least 1.0 equivalents of K3PO4. In another embodiment, the reaction is carried out in the presence of at least 1.5 equivalents of K3PO4. In another embodiment, the reaction is carried out in the presence of 1.0 to 5.0 equivalents of K3PO4. In another embodiment, the reaction is carried out in the presence of 1.0 to 3.0 equivalents of K3PO4. In another embodiment, the reaction is carried out in the presence of 1.0 to 2.5 equivalents of K3PO4. In another embodiment, the reaction is carried out in the presence of 1.0 to 2.0 equivalents of K3PO4. In another embodiment, the reaction is carried out in the presence of 1.5 to 2.5 equivalents of K3PO4. In another embodiment, the reaction is carried out in the presence of 1.5 to 2.0 equivalents of K3PO4. In another embodiment, the reaction is carried out in the presence of 1.7 to 1.9 equivalents of K3PO4. In another embodiment, the reaction is carried out in the presence of approximately 1.8 equivalents of K3PO4.

[0057] In one embodiment, a method for preparing a compound of formula (I) is provided, wherein the reaction is carried out in the presence of at least 1.0 molar equivalent of K3PO4. In another embodiment, the reaction is carried out in the presence of at least 1.5 molar equivalents of K3PO4. In another embodiment, the reaction is carried out in the presence of 1.0 to 5.0 molar equivalents of K3PO4. In another embodiment, the reaction is carried out in the presence of 1.0 to 3.0 molar equivalents of K3PO4. In another embodiment, the reaction is carried out in the presence of 1.0 to 2.5 molar equivalents of K3PO4. In another embodiment, the reaction is carried out in the presence of 1.0 to 2.0 molar equivalents of K3PO4. In another embodiment, the reaction is carried out in the presence of 1.5 to 2.5 molar equivalents of K3PO4. In another embodiment, the reaction is carried out in the presence of 1.5 to 2.0 molar equivalents of K3PO4. In another embodiment, the reaction is carried out in the presence of 1.7 to 1.9 molar equivalents of K3PO4. In yet another embodiment, the reaction is carried out in the presence of approximately 1.8 molar equivalents of K3PO4.

[0058] In one embodiment, a method for preparing a compound of formula (I) is provided, wherein the reaction is carried out using at least 1.0 molar equivalent of ZH. In another embodiment, the reaction is carried out using 1.0 to 2.0 molar equivalents of ZH. In another embodiment, the reaction is carried out using 1.0 to 1.4 molar equivalents of ZH. In another embodiment, the reaction is carried out using 1.1 to 1.3 molar equivalents of ZH. In another embodiment, the reaction is carried out using about 1.2 molar equivalents of ZH.

[0059] In the embodiments, a method for preparing a compound of formula (I) is provided, wherein Z is or In another implementation, Z is... In another implementation, Z is... .

[0060] In the embodiments, a method for preparing a compound of formula (I) is provided, wherein Z is .

[0061] In one embodiment, a method for preparing a compound of formula (I) is provided, wherein the reaction is carried out in the presence of a ligand. Exemplary ligands include...

[0062]

[0063] In one embodiment, a method for preparing a compound of formula (I) is provided, wherein the reaction is carried out in the presence of a phosphine ligand.

[0064] In the embodiments, a method for preparing a compound of formula (I) is provided, wherein Z is or The reaction occurs in the presence of dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine. Or 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene The reaction is carried out in the presence of dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine.

[0065] In the embodiments, a method for preparing a compound of formula (I) is provided, wherein Z is The reaction occurs in the presence of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl This will be carried out under certain circumstances.

[0066] In one embodiment, a method for preparing a compound of formula (I) is provided, wherein the reaction is carried out in the presence of at least 0.01 molar equivalents of a ligand. In another embodiment, the reaction is carried out in the presence of at least 0.02 molar equivalents of a ligand. In another embodiment, the reaction is carried out in the presence of 0.01 to 0.15 molar equivalents of a ligand. In another embodiment, the reaction is carried out in the presence of 0.01 to 0.10 molar equivalents of a ligand. In another embodiment, the reaction is carried out in the presence of 0.01 to 0.06 molar equivalents of a ligand. In another embodiment, the reaction is carried out in the presence of 0.02 to 0.06 molar equivalents of a ligand. In another embodiment, the reaction is carried out in the presence of 0.03 to 0.05 molar equivalents of a ligand. In another embodiment, the reaction is carried out in the presence of about 0.04 molar equivalents of a ligand.

[0067] In the embodiments, a method for preparing a compound of formula (I) is provided, wherein Z is or The reaction is carried out in the presence of at least 0.01 molar equivalents of dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine. In another embodiment, the reaction is carried out in the presence of 0.01 to 0.15 molar equivalents of dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine. In yet another embodiment, the reaction is carried out in the presence of 0.01 to 0.10 molar equivalents of dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine. In another embodiment, the reaction is carried out in the presence of 0.01 to 0.06 molar equivalents of dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine. In another embodiment, the reaction is carried out in the presence of 0.02 to 0.06 molar equivalents of dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine. In another embodiment, the reaction is carried out in the presence of 0.03 to 0.05 molar equivalents of dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine. In another embodiment, the reaction is carried out in the presence of about 0.04 molar equivalents of dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine.

[0068] In the embodiments, a method for preparing a compound of formula (I) is provided, wherein Z is The reaction is carried out in the presence of at least 0.02 molar equivalents of 2,2'-bis(diphenylphosphino)-1,1'-binaphthylene. In another embodiment, the reaction is carried out in the presence of 0.02 to 0.4 molar equivalents of 2,2'-bis(diphenylphosphino)-1,1'-binaphthylene.

[0069] In an embodiment, a method for preparing a compound of formula (I) is provided, wherein the palladium catalyst is a palladium (0) catalyst. Examples of palladium (0) catalysts include tris(dibenzylacetone)dipalladium (0), tetra(triphenylphosphine)palladium (0), and bis(tri-tert-butylphosphine)palladium (0).

[0070] In an embodiment, a method for preparing a compound of formula (I) is provided, wherein the palladium catalyst is a palladium (II) catalyst. Examples of palladium (II) catalysts include palladium (II) acetate, [1,1'-bis(diphenylphosphine)ferrocene]palladium (II) chloride, palladium (II) chloride, bis(triphenylphosphine)palladium (II) chloride, palladium (II) hydroxide, and palladium (II) acetylacetone.

[0071] In one embodiment, the palladium catalyst contains at least 0.001 molar equivalents of palladium. In another embodiment, the palladium catalyst contains at least 0.002 molar equivalents of palladium. In yet another embodiment, the palladium catalyst contains from 0.001 to 0.05 molar equivalents of palladium. In yet another embodiment, the palladium catalyst contains from 0.002 to 0.003 molar equivalents of palladium. In yet another embodiment, the palladium catalyst contains about 0.0025 molar equivalents of palladium.

[0072] In the embodiments, a method for preparing a compound of formula (I) is provided, wherein Z is or Furthermore, the palladium catalyst is tris(dibenzylacetone)dipalladium(0).

[0073] In the embodiments, a method for preparing a compound of formula (I) is provided, wherein Z is Furthermore, the palladium catalyst is palladium(II) acetate.

[0074] In the embodiments, a method for preparing a compound of formula (I) is provided, wherein Z is or The reaction is carried out in the presence of at least 0.005 molar equivalents of tris(dibenzylacetone)dipalladium(0). In another embodiment, the reaction is carried out in the presence of at least 0.01 molar equivalents of tris(dibenzylacetone)dipalladium(0). In another embodiment, the reaction is carried out in the presence of 0.005 to 0.04 molar equivalents of tris(dibenzylacetone)dipalladium(0). In another embodiment, the reaction is carried out in the presence of 0.01 to 0.04 molar equivalents of tris(dibenzylacetone)dipalladium(0). In another embodiment, the reaction is carried out in the presence of 0.01 to 0.02 molar equivalents of tris(dibenzylacetone)dipalladium(0). In another embodiment, the reaction is carried out in the presence of 0.010 to 0.013 molar equivalents of tris(dibenzylacetone)dipalladium(0). In another embodiment, the reaction is carried out in the presence of about 0.015 molar equivalents of tris(dibenzylacetone)dipalladium(0).

[0075] In the embodiments, a method for preparing a compound of formula (I) is provided, wherein Z is The reaction is carried out in the presence of at least 0.01 molar equivalents of palladium(II) acetate. In another embodiment, the reaction is carried out in the presence of 0.01 to 0.2 molar equivalents of palladium(II) acetate.

[0076] In one embodiment, a method for preparing a compound of formula (I) is provided, wherein the reaction is carried out in the presence of a solvent. In another embodiment, the solvent is toluene, 1,4-di(II)-methyl-2-ethylhexylene, ... Alkane, 2-methylbut-2-ol (tAmylOH), dimethylformamide or 2-methyltetrahydrofuran.

[0077] In the embodiments, a method for preparing a compound of formula (I) is provided, wherein Z is or The reaction is carried out in the presence of toluene or 2-methyltetrahydrofuran. In another embodiment, the reaction is carried out in the presence of toluene.

[0078] In the embodiments, a method for preparing a compound of formula (I) is provided, wherein Z is And the reaction occurs in the presence of 1,4-di This is carried out in the case of alkane.

[0079] In one embodiment, a method for preparing a compound of formula (I) is provided, wherein the reaction is carried out at a temperature of at least 60°C.

[0080] In the embodiments, a method for preparing a compound of formula (I) is provided, wherein Z is or The reaction is carried out at a temperature of at least 60°C. In another embodiment, the reaction is carried out at a temperature of 60°C to 100°C. In another embodiment, the reaction is carried out at a temperature of 70°C to 90°C. In another embodiment, the reaction is carried out at a temperature of about 80°C.

[0081] In the embodiments, a method for preparing a compound of formula (I) is provided, wherein Z is The reaction is carried out at a temperature of at least 60°C. In another embodiment, the reaction is carried out at a temperature of at least 80°C. In another embodiment, the reaction is carried out at a temperature of 80°C to 120°C. In another embodiment, the reaction is carried out at a temperature of 90°C to 110°C. In another embodiment, the reaction is carried out at a temperature of about 100°C.

[0082] In another aspect, a compound for preparing formula (III) is provided.

[0083]

[0084] A method using its salt or a salt thereof, the method comprising

[0085] (i) preparing a compound of formula (I) or a salt thereof using any of the methods described herein; and

[0086] (ii) Preparation of a compound of formula (III) or a salt thereof, including the reaction of a compound of formula (I) or a salt thereof with an acid.

[0087] In one embodiment, a method for preparing a compound of formula (III) is provided, wherein the acid is an inorganic acid. In another embodiment, the acid is hydrochloric acid, sulfuric acid, or phosphoric acid. In yet another embodiment, the acid is hydrochloric acid.

[0088] In another aspect, a compound is provided, which is (4-acetamido-5-oxo-5,6,7,8-tetrahydronaphth-1-yl)tert-butyl carbamate.

[0089] Or its salts. In the embodiments, tert-butyl (4-acetamido-5-oxo-5,6,7,8-tetrahydronaphth-1-yl)carbamate is provided.

[0090] In another aspect, a compound is provided, which is N-(4-((diphenylmethylene)amino)-8-oxo-5,6,7,8-tetrahydronaphth-1-yl)acetamide.

[0091] Or, or a salt thereof. In the embodiments, N-(4-((diphenylmethylene)amino)-8-oxo-5,6,7,8-tetrahydronaphth-1-yl)acetamide is provided.

[0092] In another aspect, a method for preparing compounds of formula (IV) is provided.

[0093] ,

[0094] The method includes (i) any of the methods described herein or (ii) the use of tert-butyl (4-acetamido-5-oxo-5,6,7,8-tetrahydronaphth-1-yl)carbamate or a salt thereof or N-(4-((diphenylmethylene)amino)-8-oxo-5,6,7,8-tetrahydronaphth-1-yl)acetamide or a salt thereof.

[0095] In another aspect, a conjugate for preparing formula (V) is provided.

[0096] Ab – (LP)k (V)

[0097] Methods using (i) any of the methods described herein or (ii) tert-butyl (4-acetamido-5-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)carbamate or salts thereof, wherein

[0098] Ab is an antibody or its antigen-binding fragment.

[0099] k is an integer from 1 to 10, and

[0100] LP is

[0101] .

[0102] In one embodiment, a method for preparing a conjugate of formula (V) is provided, wherein k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In another embodiment, k is an integer from 2 to 10. In another embodiment, k is an integer from 2 to 8. In another embodiment, k is 4. In another embodiment, k is 8.

[0103] Example

[0104] This specification will now be illustrated by the following non-limiting examples.

[0105] abbreviation :

[0106] EtOH – Ethanol

[0107] DCM – dichloromethane

[0108] HCl – hydrochloric acid

[0109] THF – Tetrahydrofuran

[0110] DMSO – dimethyl sulfoxide

[0111] MTBE – Methyl tert-butyl ether

[0112] t-BuOH–tert-butanol

[0113] 2-MeTHF–2-methyltetrahydrofuran

[0114] MeOH – Methanol

[0115] 2-PrOH–2-propanol

[0116] 1,2-DME–1,2-dimethoxyethane

[0117] DMF–N,N-dimethylformamide

[0118] w / w – weight / weight

[0119] weq.-Weight equivalent

[0120] v / v – Volume / Volume

[0121] veq. - volume equivalent

[0122] The IUPAC name was generated using Biovia Draw 2020 version 20.1.

[0123] All NMR data were recorded on a Bruker Avance Neo spectrometer equipped with a QCI cryopreservation probe at a proton operating frequency of 499.90 MHz.

[0124] LC-MS data were collected using a Water ACQUITY UPLC H-Class system equipped with a single quadrupole mass spectrometer.

[0125] The reagent dosage, weight equivalent, and volume equivalent are relative to the limiting reagents used as starting materials in each method description.

[0126] Example 1: Preparation of Intermediate A

[0127] Preparation of N-(8-bromotetrahydronaphthalene-5-yl)acetamide 2

[0128]

[0129] Naphthalene-1-amine 1 (80.0 kg, 559 mol) and EtOH (1200 L) were heated to 45°C–65°C, and then acetic anhydride (62.7 kg, 615 mol) was added. The mixture was stirred until the reaction was complete, then cooled and purged with nitrogen to achieve an oxygen content of ≤0.1%. Raney nickel (80.0 kg, 1.0 wt equivalent) was added, and the mixture was then purged with hydrogen and pressurized to 2.5 MPa–3.5 MPa. When the reaction was complete, the mixture was filtered, and the filter cake was washed with EtOH. N-bromosuccinimide (109.4 kg, 615 mol) was added in portions to the combined filtrate. When the reaction was complete, water (1600 L) was added, and the mixture was stirred at 0°C–10°C for 2 hours. The mixture was filtered, and the filter cake was washed with water. The separated product was dried to give N-(8-bromotetrahydronaphthalene-5-yl)acetamide 2 as a solid in about 85% yield. 1H NMR (500MHz, DMSO, 27℃) 9.20 (1H, s), 7.38 (1H, d), 7.19 (1H, d), 2.65 (2H, t), 2.58 (2H, q), 2.04 (3H, s), 1.70 (4H, dddd); m / z (ES + [M+H] + =268

[0130] Preparation of N-(8-bromo-4-oxo-tetrahydronaphthalene-5-yl)acetamide 3

[0131]

[0132] N-(8-bromotetrahydronaphthyl-5-yl)acetamide 2 (80.0 kg, 298 mol) was mixed with acetonitrile (800 L) and t-BuOH (800 L) and cooled to 15°C-25°C. Then, 15% MgSO4 aqueous solution (49.6 kg, 412 mol) was added. KMnO4 (165.0 kg, 1044 mol) was then added in portions over 2-3 hours. At the end of the reaction, 20% (w / w) H2SO4 aqueous solution (584.8 kg, 1194 mol) and oxalic acid dihydrate (150.4 kg, 1194 mol) were added until no oxidation was detected by starch-KI test and pH ≤ 7 was reached. The mixture was filtered, and the separated solids were washed with water and then dissolved in DCM (800 L). Water (400 L) was added, and the mixture was stirred for 2 hours and then filtered. The separated organic layer was washed sequentially with aqueous NaHCO3 solution and saturated NaCl solution, and then concentrated to a volume of approximately 200-240 L. MeOH (720 L) was added, and the subsequent precipitate was collected by filtration and dried to give N-(8-bromo-4-oxo-tetrahydronaphthalene-5-yl)acetamide 3 as a solid in approximately 67% yield. 1 H NMR (500MHz, DMSO, 27℃) 11.95 (1H, s), 8.42 (1H, d), 7.83 (1H, d), 2.96 (2H, t), 2.66 – 2.74 (2H, m), 2.15 (3H, s), 2.03 (2H, p); m / z (ES + [M+H] + =282

[0133] Preparation of N-(8-acetamido-1-oxo-tetrahydronaphthalene-5-yl)acetamide 4

[0134]

[0135] N-(8-bromo-4-oxo-tetrahydronaphthyl-5-yl)acetamide 3 (57.0 kg, 202 mol) was mixed with toluene (1140 L), K3PO4 (77.2 kg, 363.6 mol), and acetamide (14.3 kg, 242 mol, 1.2 equivalents) and purged with nitrogen to an oxygen content ≤0.1%. Dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (4.34 kg, 8.1 mol, 0.04 equivalents) and tris(dibenzylideneacetone)dipalladium(0) (2.28 kg, 3.03 mol, 0.015 equivalents) were added, and the mixture was heated to 80 °C. Upon completion of the reaction, the mixture was cooled, and then water (570 L) was added, and the mixture was stirred for 2 hours. The resulting suspension was filtered, and the filter cake was washed with water. After drying, the separated solid was stirred in EtOH (142.5 L) at 60 °C for 2 hours, and then cooled. The resulting suspension was filtered, and the separated product was washed with ethanol (114 L) and dried to give N-(8-acetamido-1-oxo-tetrahydronaphthalene-5-yl)acetamide 4 as a solid in about 77% yield. 1 H NMR (500MHz, DMSO, 27℃) 11.95 (1H, s), 9.46 (1H, s), 8.41 (1H, d), 7.51 (1H, d), 2.80 (2H, t), 2.64 – 2.71 (2H, m), 2.14 (3H, s), 2.05 (3H, s),1.95 (2H, p); m / z (ES + [M+H] + =261.

[0136] Preparation of 5,8-diaminotetrahydronaphthalene-1-one

[0137]

[0138] N-(8-acetamido-1-oxo-tetrahydronaphthyl-5-yl)acetamide 4 (40.3 kg, 154.9 mol) was mixed with a 36% aqueous HCl solution (123.3 kg, 1214 mol) and heated to 70-75°C. Upon completion of the reaction, the mixture was cooled to 20-30°C, and water (80 L) and SMA905 (palladium scavenger, 2.4 kg, 0.06 w / w) were added. The mixture was stirred for 3 hours, with additional SMA905 added if necessary. The mixture was filtered, and the filter cake was washed with water (40 L). The pH of the filtrate was adjusted to 8-10 at 0-10°C with a 30% (w / w) aqueous NaOH solution (63.6 kg, 1595 mol). The resulting suspension was filtered, washed with water, and the separated product was dried to give solid 5,8-diaminotetrahydronaphthyl-1-one 5 in approximately 87% yield. 1 H NMR (500MHz, DMSO, 27℃) 6.77 (1H, d), 6.52 – 6.84 (2H, m), 6.43 (1H,d), 4.17 (2H, s), 2.56 (2H, t), 2.46 (2H, dd), 1.90 (2H, p); m / z (ES + [M+H] + =177.

[0139] ((S)-1-(((S)-1-((4-amino-5-oxo-5,6,7,8-tetrahydronaphthyl-1-yl)amino)-1-oxopropyl-2- Preparation of intermediate A of 3-methyl-1-oxobut-2-yl)carbamate

[0140]

[0141] Intermediate A can be prepared from compound 5 according to the method described in WO 2020 / 200880, the contents of which are incorporated herein by reference.

[0142] Example 2: Screening of Buchwald–Hartwig amination reactions using acetamide, Boc-NH2, and ammonium sulfate

[0143] General Procedure

[0144]

[0145] Under a nitrogen atmosphere, starting material 3 (20 mg, 0.083 mmol, 1 equivalent) was placed in a vial, followed by acetamide or (NH4)2SO4 or BocNH2 (1.2 equivalents), a base (1.5 equivalents), a catalyst (e.g., Pd2dba3 (0.025 equivalents)), and a monodentate ligand (0.1 equivalents) or a bidentate ligand (0.05 equivalents). Solvent (10 volumes, degassed) was added at 20 °C, and the mixture was heated to 100 °C for 16 hours.

[0146] The reaction mixture was diluted with a mixture of acetonitrile and water, and then samples were taken for HPLC analysis. Tables 1 to 3 list the HPLC area percentages of starting materials, products, and impurities.

[0147] The following impurities are mentioned in Tables 1 to 3;

[0148] .

[0149] Table 1: Screening using acetamide reaction

[0150]

[0151]

[0152]

[0153]

[0154]

[0155] Table 2: Reaction screening using Boc-NH2

[0156]

[0157]

[0158]

[0159] Table 3: Reaction screening using ammonium sulfate ((NH4)2SO4)

[0160]

[0161]

[0162] Example 3: Buchwald–Hartwig amination with benzophenone imine

[0163]

[0164] N-(8-bromo-4-oxo-tetrahydronaphthyl-5-yl)acetamide 3 (3.5 g, 12.4 mmol) was reacted with benzophenone imine (2.7 g, 14.9 mmol, 1.2 equivalence), K3PO4 (3.9 g, 18.6 mmol, 1.5 equivalence), Pd(OAc)2 (0.28 g, 1.24 mmol, 0.1 equivalence), and BINAP (2.48 mmol, 1.54 g, 0.2 equivalence) in a 1,4-dioxane-2 ... The mixture was mixed in alkane (35 mL) and heated to reflux for 18 hours. The mixture was concentrated under vacuum and then partitioned between water (10 v / v) and ethyl acetate (10 v / v). The separated organic layer was dried over sodium sulfate and concentrated under vacuum, and then purified by silica gel chromatography to give N-[8-(diphenylmethyleneamino)-4-oxo-tetrahydronaphthalene-5-yl]acetamide 4B (3.5 g) in 65% yield. 1 H NMR (500MHz, DMSO, 27℃) 1.98 (2H, p), 2.08 (3H, s), 2.65 (2H, t), 2.83 (2H, t), 6.69 (1H, d),7.15 (2H, dd), 7.3 – 7.39 (3H, m), 7.48 (2H, t), 7.51 – 7.58 (1H, m), 7.68 –7.73 (2H, m), 8.17 (1H, d), 11.77 (1H, s); m / z (ES+) [M+H]+=383.

[0165] The above description of the illustrative embodiments is intended only to familiarize others skilled in the art with the applicant's specification, its principles, and its practical applications, enabling them to readily adapt and apply this specification in various forms to best suit the requirements of a particular application. This description and its specific examples are intended for illustrative purposes only when indicating embodiments of this specification. Therefore, this specification is not limited to the illustrative embodiments described herein, and various modifications are possible. Furthermore, it should be understood that, for clarity, the various features of the specification described in the case of individual embodiments may be combined to form a single embodiment. Conversely, for brevity, the various features of the specification described in the case of individual embodiments may be combined to form sub-combinations.

Claims

1. A compound for preparation of formula (I): ， A method using a salt thereof, the method comprising a compound of formula (II): ， The reaction of HZ or its salt with HZ or its salt, wherein the reaction is carried out in the presence of a palladium catalyst and a base. Where X is Br, I, or Cl, and Z is .

2. The method according to claim 1, wherein X is Br.

3. The method according to claim 1 or claim 2, wherein the reaction is carried out in the presence of 1.0 to 3.0 equivalents of base.

4. The method according to any one of claims 1 to 3, wherein the base is K3PO4.

5. The method according to any one of claims 1 to 4, wherein the reaction is carried out using 1.0 to 1.4 molar equivalents of ZH.

6. The method according to any one of claims 1 to 5, wherein Z is .

7. The method according to any one of claims 1 to 5, wherein Z is .

8. The method according to claim 6 or claim 7, wherein the reaction is carried out in the presence of dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine.

9. The method according to any one of claims 6 to 8, wherein the reaction is carried out in the presence of 0.01 to 0.15 molar equivalents of dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine.

10. The method according to any one of claims 6 to 9, wherein the palladium catalyst is tris(dibenzylacetone)dipalladium(O).

11. The method according to any one of claims 6 to 10, wherein the reaction is carried out in the presence of 0.01 molar equivalent to 0.04 molar equivalent of tris(dibenzylacetone)palladium(0).

12. The method according to any one of claims 6 to 11, wherein the reaction is carried out in the presence of toluene.

13. The method according to any one of claims 6 to 12, wherein the reaction is carried out at a temperature of 60°C to 100°C.

14. The method according to any one of claims 1 to 5, wherein Z is .

15. The method according to claim 14, wherein the reaction is carried out in the presence of 2,2'-bis(diphenylphosphino)-1,1'-binaphthylene.

16. The method according to claim 14 or claim 15, wherein the reaction is carried out in the presence of 0.02 to 0.4 molar equivalents of 2,2'-bis(diphenylphosphino)-1,1'-binaphthylene.

17. The method according to any one of claims 14 to 16, wherein the palladium catalyst is palladium(II) acetate.

18. The method according to any one of claims 14 to 17, wherein the reaction is carried out in the presence of 0.01 molar equivalent to 0.2 molar equivalent of palladium(II) acetate.

19. The method according to any one of claims 14 to 18, wherein the reaction occurs in the presence of two This is carried out in the case of alkane.

20. The method according to any one of claims 14 to 19, wherein the reaction is carried out at a temperature of 80°C to 120°C.

21. A compound for preparation of formula (III) A method for using its salt or a salt thereof, the method comprising (i) preparing a compound of formula (I) or a salt thereof using the method according to any one of claims 1 to 20; and (ii) Preparing a compound of formula (III) or a salt thereof, comprising the reaction of a compound of formula (I) or a salt thereof with an acid.

22. The method of claim 21, wherein the acid is hydrochloric acid.

23. A compound, said compound being (4-acetamido-5-oxo-5,6,7,8-tetrahydronaphth-1-yl) tert-butyl carbamate. , or its salt.

24. A compound, said compound being N-(4-((diphenylmethylene)amino)-8-oxo-5,6,7,8-tetrahydronaphth-1-yl)acetamide , or its salt.

25. A method for preparing compounds of formula (IV). ， The method comprises the method according to any one of claims 1 to 22 or the compound or salt thereof according to claim 23 or claim 24.

26. A conjugate for preparing formula (V) Ab – (LP) k (V) A method comprising, or a pharmaceutically acceptable salt thereof, the method comprising, according to any one of claims 1 to 22, or according to claim 23 or 24, the compound thereof, wherein... Ab is an antibody or its antigen-binding fragment. k is an integer from 1 to 10, and LP is 。

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