Processes and compounds for the preparation of topoisomerase i inhibitor linker-payloads
Patent Information
- Application Number
- AU2025235841
- Authority / Receiving Office
- AU · AU
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2024-03-12
- Filing Date
- 2025-03-11
- Publication Date
- 2026-10-29
Abstract
Description
Example 1 of WO 2020 / 200880 is a Val-Ala-PEG8-TOPOli linker-payload (AZ'0133). AZ'0133 has been used in the preparation of a B7-H4-directed antibody drug conjugate AZD8205 (Kinneer et al., Clin Cancer Res., 2023, 29(6), 1086-1101.) ADCs comprising AZ'0133 may undergo enzymatic cleavage in a cell lysosome to release TOPOli drug payload AZ'0132. WO 2020 / 200880 describes a synthetic route to AZ'0133 as summarised below. This route allows Intermediate A to be prepared from 5 bromotetralin-l-one (where "Alloc" means N-Allyloxycarbonyl). 5 Although the synthetic route disclosed in WO 2020 / 200880 provides a reliable method for producing AZ'0133, it is desirable to improve the economy of the process for large-scale manufacture to minimise environmental impact and reduce cost of goods. Summary Disclosed herein is a new synthetic route for the synthesis of AZ'0133. This includes a new route for 10 the synthesis of Intermediate A from naphthalen-l-amine 1. 4, R is NHC(O)CH3 4A, R is NHC(O)OC(CH3)3 4B, R is N=CPh2 Intermediate A The conversion of compound 3 into compound 5 involves a Buchwald-Hartwig amination followed by deprotection. This transformation proved to be sensitive to the choice of amine source. The use of NH3 as an amine source in the presence of CU2O or Cui did not result in the desired amination reaction. Using lithium bis(trimethylsilyl)amide (LiHMDS) as an amine source resulted in significant formation of Impurity Imp3 without observation of the desired amination reaction. 0.2 eq Cu2O or Cui, base NMP, 16h, 100 °C 20 eq nh3 not observed 1.2 eq LiHMDS (1Min THF) 0.025 eq Pd2dba3 0.1 eq Brettphos, 0.6 eq ZnCI2 THF, 16 h, 50 °C Br Impurity Imp3 14% Therefore, in a first aspect there is provided a process for the production of a compound of Formula o H H3C^.N or a salt thereof, comprising a reaction of a compound of Formula (II): o H H3C^,N (II) 10 or a salt thereof, and H-Z, or a salt thereof, wherein the reaction is performed in the presence of a palladium catalyst and a base, wherein X is Br, I or Cl, and f N CH3 Zis h 3 N OC(CH3)3 or In a further aspect there is provided a process for the production of a compound of Formula (III) or a salt thereof, comprising (i) the production of a compound of Formula (I), or a salt thereof, using a process as described above; and 5 (ii) the production of the compound of Formula (III), of a salt thereof, comprising the reaction of the compound of Formula (I), or a salt thereof, and an acid. In a further aspect there is provided tert-Butyl (4-acetamido-5-oxo-5,6,7,8-tetrahydronaphthalen-l- yl)carbamate, .. OC(CH3)3 h , or a salt thereof. 10 In a further aspect there is provided / V-(4-((Diphenylmethylene)amino)-8-oxo-5,6,7,8- tetrahydronaphthalen-l-yl)acetamide, In a further aspect there is provided a process for the production of a compound of Formula (IV) 15 comprising any of the (i) processes, or (ii) compounds, or salts thereof, described above. In a further aspect there is provided a process for the production of a conjugate of Formula (V) Ab-(LP)k (V) or a pharmaceutically acceptable salt thereof, any of the (i) processes, or (ii) compounds, or salts thereof, described above, wherein Ab is an antibody or antigen-binding fragment thereof, k is an integer from 1 to 10, and LP is For the avoidance of doubt, the use of " -L" in formulas of this specification denotes the point of covalent attachment to a group. For a process for the production of a compound of Formula (I), the term "molar equivalents" refers to molar equivalents relative to the compound of Formula (II), or salt thereof. Units, prefixes, and symbols are denoted in their International System of Units (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range. Unless defined otherwise, 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 is related. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary of Biochemistry and Molecular Biology, Revised, 2000, Oxford University Press, provide one of skill with a general dictionary of many of the terms used in this disclosure. Detailed Description As noted above, in a first aspect there is provided a process for the production of a compound of Formula (I): (I) > or a salt thereof, comprising a reaction of a compound of Formula (II): (II) or a salt thereof, and H-Z, or a salt thereof, wherein the reaction is performed in the presence of a palladium catalyst and a base, wherein X is Br, I or Cl, and In embodiments, there is provided a process for the production of a compound of Formula (I) wherein X is Br or Cl. In further embodiments, X is Br. In embodiments, there is provided a process for the production of a compound of Formula (I) wherein the reaction is performed in the presence of at least 1.0 equivalents of base. In further embodiments, the reaction is performed in the presence of at least 1.5 equivalents of base. In further embodiments, the reaction is performed in the presence of 1.0 to 5.0 equivalents of base. In further embodiments, the reaction is performed in the presence of 1.0 to 3.0 equivalents of base. In further embodiments, the reaction is performed in the presence of 1.0 to 2.5 equivalents of base. In further embodiments, the reaction is performed in the presence of 1.0 to 2.0 equivalents of base. In further embodiments, the reaction is performed in the presence of 1.5 to 2.5 equivalents of base. In further embodiments, the reaction is performed in the presence of 1.5 to 2.0 equivalents of base. In further embodiments, the reaction is performed in the presence of 1.7 to 1.9 equivalents of base. In further embodiments, the reaction is performed in the presence of about 1.8 equivalents of base. In embodiments, there is provided a process for the production of a compound of Formula (I) wherein the reaction is performed in the presence of at least 1.0 molar equivalents of base. In further embodiments, the reaction is performed in the presence of at least 1.5 molar equivalents of base. In further embodiments, the reaction is performed in the presence of 1.0 to 5.0 molar equivalents of base. In further embodiments, the reaction is performed in the presence of 1.0 to 3.0 molar equivalents of base. In further embodiments, the reaction is performed in the presence of 1.0 to 2.5 molar equivalents of base. In further embodiments, the reaction is performed in the presence of 1.0 to 2.0 molar equivalents of base. In further embodiments, the reaction is performed in the presence of 1.5 to 2.5 molar equivalents of base. In further embodiments, the reaction is performed in the presence of 1.5 to 2.0 molar equivalents of base. In further embodiments, the reaction is performed in the presence of 1.7 to 1.9 molar equivalents of base. In further embodiments, the reaction is performed in the presence of about 1.8 molar equivalents of base. In embodiments, there is provided a process for the production of a compound of Formula (I) wherein the base is caesium carbonate (CS2CO3), tripotassium phosphate (K3PO4), potassium tert-butoxide (KOCfCHsh), potassium carbonate (K2CO3), potassium hydrogen carbonate (KHCO3), sodium carbonate (Na2CO3), sodium hydrogen carbonate (NaHCOs), sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), caesium hydroxide (CsOH), calcium hydroxide (Ca(OH)2), calcium carbonate (CaCOs), or barium hydroxide (Ba(OH)2). In further embodiments, the base is caesium carbonate (CS2CO3). In further embodiments, the base is tripotassium phosphate (K3PO4). In embodiments, there is provided a process for the production of a compound of Formula (I) wherein the reaction is performed in the presence of at least 1.0 equivalents of K3PO4. In further embodiments, the reaction is performed in the presence of at least 1.5 equivalents of K3PO4. In further embodiments, the reaction is performed in the presence of 1.0 to 5.0 equivalents of K3PO4. In further embodiments, the reaction is performed in the presence of 1.0 to 3.0 equivalents of K3PO4. In further embodiments, the reaction is performed in the presence of 1.0 to 2.5 equivalents of K3PO4. In further embodiments, the reaction is performed in the presence of 1.0 to 2.0 equivalents of K3PO4. In further embodiments, the reaction is performed in the presence of 1.5 to 2.5 equivalents of K3PO4. In further embodiments, the reaction is performed in the presence of 1.5 to 2.0 equivalents of K3PO4. In further embodiments, the reaction is performed in the presence of 1.7 to 1.9 equivalents of K3PO4. In further embodiments, the reaction is performed in the presence of about 1.8 equivalents of K3PO4. In embodiments, there is provided a process for the production of a compound of Formula (I) wherein the reaction is performed in the presence of at least 1.0 molar equivalents of K3PO4. In further embodiments, the reaction is performed in the presence of at least 1.5 molar equivalents of K3PO4. In further embodiments, the reaction is performed in the presence of 1.0 to 5.0 molar equivalents of K3PO4. In further embodiments, the reaction is performed in the presence of 1.0 to 3.0 molar equivalents of K3PO4. In further embodiments, the reaction is performed in the presence of 1.0 to 2.5 molar equivalents of K3PO4. In further embodiments, the reaction is performed in the presence of 1.0 to 2.0 molar equivalents of K3PO4. In further embodiments, the reaction is performed in the presence of 1.5 to 2.5 molar equivalents of K3PO4. In further embodiments, the reaction is performed in the presence of 1.5 to 2.0 molar equivalents of K3PO4. In further embodiments, the reaction is performed in the presence of 1.7 to 1.9 molar equivalents of K3PO4. In further embodiments, the reaction is performed in the presence of about 1.8 molar equivalents of K3PO4. 10 In embodiments, there is provided a process for the production of a compound of Formula (I) wherein the reaction is performed using at least 1.0 molar equivalents of Z-H. In further embodiments, the reaction is performed using 1.0 to 2.0 molar equivalents of Z-H. In further embodiments, the reaction is performed using 1.0 to 1.4 molar equivalents of Z-H. In further embodiments, the reaction is performed using 1.1 to 1.3 molar equivalents of Z-H. In further embodiments, the reaction is performed using about 1.2 molar equivalents of Z-H. In embodiments, there is provided a process for the production of a compound of Formula (I) 0 0 0 ^N^CH3 ^N^OC(CH3)3 ^n^ch3 wherein Z is H or H . In further embodiments, Z is H .In further O ^N^OC(CH3)3 embodiments, Z is H . In embodiments, there is provided a process for the production of a compound of Formula (I) In embodiments, there is provided a process for the production of a compound of Formula (I) wherein the reaction is performed in the presence of a ligand. Example ligands include Ligand Chemical Name PPh3 triphenylphosphine PCy3HBF4 tricyclohexylphosphine tetrafluoroborate BuPAd3 di(l-adamantyl)-n-butylphosphine XPHOS 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl tBuXPHOS 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl BRETTPHOS dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[l,r-biphenyl]-2-yl)phosphine RUPHOS 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl JOHNPHOS (2-biphenyl)di-tert-butylphosphine JOSIPHOS (R)-l-[(SP)-2-(di-tert-butylphosphino)ferrocenyl]ethylbis(2-methylphenyl)phosphine DPPP l,3-bis(diphenylphosphino)propane DPPF l,l'-Ferrocenediyl-bis(diphenylphosphine) BINAP 2,2'-Bis(diphenylphosphino)-l,l'-binaphthalene XANTPHOS 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In embodiments, there is provided a process for the production of a compound of Formula (I) wherein the reaction is performed in the presence of a phosphine ligand. In embodiments, there is provided a process for the production of a compound of Formula (I) O ^n^ch3 wherein Z is H or O OC(CH3)3 , and the reaction is performed in the presence of dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[l,l'-biphenyl]-2-yl)phosphine or 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene In further embodiments, the reaction is performed in the presence of dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[l,l'-biphenyl]-2-yl)phosphine. 10 In embodiments, there is provided a process for the production of a compound of Formula (I) wherein Z is Bis(diphenylphosphino)-l,r-binaphthalene In embodiments, there is provided a process for the production of a compound of Formula (I) wherein the reaction is performed in the presence of at least 0.01 molar equivalents of a ligand. In further embodiment, the reaction is performed in the presence of at least 0.02 molar equivalents of a ligand. In further embodiments, there the reaction is performed in the presence of 0.01 to 0.15 molar equivalents of a ligand. In further embodiment, the reaction is performed in the presence of 0.01 to 0.10 molar equivalents of a ligand. In further embodiment, the reaction is performed in the presence of 0.01 to 0.06 molar equivalents of a ligand. In further embodiment, the reaction is performed in the presence of 0.02 to 0.06 molar equivalents of a ligand. In further embodiment, the reaction is performed in the presence of 0.03 to 0.05 molar equivalents of a ligand. In further embodiment, the reaction is performed in the presence of about 0.04 molar equivalents of a ligand. In embodiments, there is provided a process for the production of a compound of Formula (I) O 0 ^N^CH3 ^N^OC(CH3)3 wherein Z is H or H , and the reaction is performed in the presence of at least 0.01 molar equivalents of dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[l,l'-biphenyl]-2-yl)phosphine. In further embodiment, the reaction is performed in the presence of 0.01 to 0.15 molar equivalents of dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[l,r-biphenyl]-2-yl)phosphine. In further embodiment, the reaction is performed in the presence of 0.01 to 0.10 molar equivalents of dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[l,r-biphenyl]-2-yl)phosphine. In further embodiment, the reaction is performed in the presence of 0.01 to 0.06 molar equivalents of dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[l,r-biphenyl]-2-yl)phosphine. In further embodiment, the reaction is performed in the presence of 0.02 to 0.06 molar equivalents of a dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[l,r-biphenyl]-2-yl)phosphine. In further embodiment, the reaction is performed in the presence of 0.03 to 0.05 molar equivalents of dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[l,r-biphenyl]-2-yl)phosphine. In further embodiment, the reaction is performed in the presence of about 0.04 molar equivalents of dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[l,l'-biphenyl]-2-yl)phosphine. In embodiments, there is provided a process for the production of a compound of Formula (I) wherein Z is and the reaction is performed in the presence of at least 0.02 molar equivalents of 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl. In further embodiments, the reaction is performed in the presence of 0.02 to 0.4 molar equivalents of 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl. In embodiments, there is provided a process for the production of a compound of Formula (I) wherein the palladium catalyst is a palladium(O) catalyst. Examples of palladium(O) catalysts include tris(dibenzylideneacetone)dipalladium(0), tetrakis(triphenylphosphine)palladium(0) and bis(tri-tert-butylphosphine)palladium(O). In embodiments, there is provided a process for the production of a compound of Formula (I) wherein the palladium catalyst is a palladium(11) catalyst. Examples of palladium(II) catalysts include palladium(ll) acetate, [l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium (II), palladium (II) chloride, Bis(triphenylphosphine)palladium (II) dichloride, palladium (II) hydroxide and palladium (II) acetylacetonate In embodiments, the palladium catalyst contains at least 0.001 molar equivalents of palladium. In further embodiments, the palladium catalyst contains at least 0.002 molar equivalents of palladium. In further embodiments, the palladium catalyst contains 0.001 to 0.05 molar equivalents of palladium. In further embodiments, the palladium catalyst contains 0.002 to 0.003 molar equivalents of palladium. In further embodiments, the palladium catalyst contains about 0.0025 molar equivalents of palladium. In embodiments, there is provided a process for the production of a compound of Formula (I) O 0 ^N^CHa ^N^OC(CH3)3 wherein Z is H or H , and the palladium catalyst is tris(dibenzylideneacetone)dipalladium(0). In embodiments, there is provided a process for the production of a compound of Formula (I) 0 wherein Z is and wherein the palladium catalyst is palladium(ll) acetate. In embodiments, there is provided a process for the production of a compound of Formula (I) O O / x / x CH3 OC(CH3)3 wherein Z is H or H , and the reaction is performed in the presence of at least 0.005 molar equivalents of tris(dibenzylideneacetone)dipalladium(0). In further embodiments, the reaction is performed in the presence of at least 0.01 molar equivalents of tris(dibenzylideneacetone)dipalladium(0). In further embodiments, the reaction is performed in the presence of 0.005 to 0.04 molar equivalents of tris(dibenzylideneacetone)dipalladium(0). In further embodiments, the reaction is performed in the presence of 0.01 to 0.04 molar equivalents of tris(dibenzylideneacetone)dipalladium(0). In further embodiments, the reaction is performed in the presence of 0.01 to 0.02 molar equivalents of tris(dibenzylideneacetone)dipalladium(0). In further embodiments, the reaction is performed in the presence of 0.010 to 0.013 molar equivalents of tris(dibenzylideneacetone)dipalladium(0). In further embodiments, the reaction is performed in the 5 presence of about 0.015 molar equivalents tris(dibenzylideneacetone)dipalladium(0). In embodiments, there is provided a process for the production of a compound of Formula (I) 0 AN 10 wherein Z is and wherein the reaction is performed in the presence of at least 0.01 molar equivalents of palladium(11) acetate. In further embodiments, the reaction is performed in the presence of 0.01-0.2 molar equivalents of palladium(II) acetate. 10 In embodiments, there is provided a process for the production of a compound of Formula (I) wherein the reaction is performed in the presence of a solvent. In further embodiments, the solvent is toluene, 1,4-dioxane, 2-methylbutan-2-ol (tAmylOH), dimethylformamide or 2-methyltetrahydrofuran. In embodiments, there is provided a process for the production of a compound of Formula (I) O O ^N^CHa ^N^OC(CH3)3 15 wherein Z is H or H , and the reaction is performed in the presence of toluene or 2-methyltetrahydrofuran. In further embodiments, is performed in the presence of toluene. In embodiments, there is provided a process for the production of a compound of Formula (I) wherein Z is and the reaction is performed in the presence of 1,4-dioxane. 20 In embodiments, there is provided a process for the production of a compound of Formula (I) wherein the reaction is performed at a temperature of at least 60 °C. In embodiments, there is provided a process for the production of a compound of Formula (I) O O ^N^CH3 ^N^OC(CH3)3 wherein Z is H or H , and the reaction is performed at a temperature of at least 60 °C. In further embodiments, the reaction is performed at a temperature of 60 to 100 °C. In further embodiments, the reaction is performed at a temperature of 70 to 90 °C. In further embodiments, the reaction is performed at a temperature of about 80 °C. In embodiments, there is provided a process for the production of a compound of Formula (I) wherein Z is , and the reaction is performed at a temperature of at least 60 °C. In further embodiments, the reaction is performed at a temperature of at least 80 °C. In further embodiments, the reaction is performed at a temperature of 80 to 120 °C. In further embodiments, the reaction is performed at a temperature of 90 to 110 °C. In further embodiments, the reaction is performed at a temperature of about 100 °C. In a further aspect, there is provided a process for the production of a compound of Formula (III) H2N nh2 (HI) or a salt thereof, comprising (i) the production of a compound of Formula (I), or a salt thereof, using any process described herein; and (ii) the production of the compound of Formula (III), of a salt thereof, comprising the reaction of the compound of Formula (I), or a salt thereof, and an acid. In embodiments, there is provided a process for the production of a compound of Formula (III), wherein the acid is a mineral acid. In further embodiments, acid is hydrochloric acid, sulfuric acid or phosphoric acid. In further embodiments, the acid is hydrochloric acid. In a further aspect there is provided a compound that is tert-Butyl (4-acetamido-5-oxo-5,6,7,8-tetrahydronaphthalen-l-yl)carbamate, H , or a salt thereof. In embodiments, there is provided tert-Butyl (4- acetamido-5-oxo-5,6,7,8-tetrahydronaphthalen-l-yl)carbamate. In a further aspect there is provided a compound that is / V-(4-((Diphenylmethylene)amino)-8-oxo- 5,6,7,8-tetrahydronaphthalen-l-yl)acetamide, , or a salt thereof. In embodiments, there is provided / V-(4- ((Diphenylmethylene)amino)-8-oxo-5,6,7,8-tetrahydronaphthalen-l-yl)acetamide. In a further aspect there is provided a process for the production of a compound of Formula (IV) comprising (i) any process described herein, or (ii) the use of tert-Butyl (4-acetamido-5-oxo-5,6,7,8-tetrahydronaphthalen-l-yl)carbamate, ora salt thereof, or N-(4-((Diphenylmethylene)amino)-8-oxo-5,6,7,8-tetrahydronaphthalen-l-yl)acetamide, ora salt thereof. In a further aspect there is provided a process for the production of a conjugate of Formula (V) Ab-(LP)k (V) or a pharmaceutically acceptable salt thereof, comprising (i) any process described herein or (ii) the use of tert-Butyl (4-acetamido-5-oxo-5,6,7,8-tetrahydronaphthalen-l-yl)carbamate, or a salt thereof, or N-(4-((Diphenylmethylene)amino)-8-oxo-5,6,7,8-tetrahydronaphthalen-l-yl)acetamide, or a salt thereof, wherein Ab is an antibody or antigen-binding fragment thereof, k is an integer from 1 to 10, and LP is In embodiments, there is provided a process for the production of a conjugate of Formula (V), wherein k is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In further embodiments k is an integer from 2 to 10. In further embodiments k is an integer from 2 to 8. In further embodiments k is 4. In further embodiments k is 8. Examples The specification will now be illustrated by the following non-limiting Examples. Abbreviations: EtOH - Ethanol DCM - Dichloromethane HCI - Hydrochloric acid THF - Tetrahydrofuran DMSO - Dimethylsulfoxide MTBE - Methyl tert-butyl ether t-BuOH - tert-Butanol 2-MeTHF - 2-Methyltetrahydrofuran MeOH - Methanol 2-PrOH - 2-Propanol 1,2-DME - 1,2-Dimethoxyethane DMF - / V, / V-Dimethylformamide w / w - weight / weight weq. - weight equivalents v / v - volume / volume veq. - volume equivalents IUPAC names were generated using Biovia Draw 2020 version 20.1 All NMR data were recorded on a Bruker Avance Neo spectrometer fitted with a QCI cryoprobe with an operating frequency of 499.90 MHz for proton. LC-MS data were collected using a a Water ACQUITY UPLC H-Class system, equipped with a single quad mass spectrometer. Reagent charges, weight equivalents and volume equivalents are relative to the limiting reagent which is the starting material in each process description. Example 1: Preparation of Intermediate A Preparation of / V-(8-bromotetralin-5-yl)acetamide 2 Naphthalen-l-amine 1 (80.0 kg, 559 mol) and EtOH (1200 L) were heated to 45-65°C and then acetic anhydride (62.7 kg, 615 mol) was added. The mixture was stirred until reaction completion, then cooled and purged with nitrogen to reach an oxygen content <0.1%. Raney nickel (80.0 kg, 1.0 wt equivalents) was added and then the mixture was purged with hydrogen and pressurised to 2.5-3.5 MPa. Upon reaction completion the mixture was filtered, and the filter cake was washed with EtOH. / V-Bromosuccinimide (109.4 kg, 615 mol) was added portionwise to the combined filtrate. Upon reaction completion water (1600 L) was added and the mixture stirred at 0-10°C for 2 hours. The mixture was filtered and the filter cake was washed with water. The isolated product was dried to give / V-(8-bromotetralin-5-yl)acetamide 2 as a solid in approximately 85% yield. 1H NMR (500 MHz, DMSO, 27°C) 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 Preparation of / V-(8-Bromo-4-oxo-tetralin-5-yl)acetamide 3 / V-(8-bromotetralin-5-yl)acetamide 2 (80.0 kg, 298 mol) was mixed with acetonitrile (800 L) and t-BuOH (800 L) and cooled to 15-25°C before addition of 15% aqueous MgSO4 (49.6 kg, 412 mol). KMnO4 (165.0 kg, 1044 mol) was then added portionwise over 2-3 hours. Upon reaction completion, 20% (w / w) aqueous H2SO4 (584.8 kg, 1194 mol) and oxalic acid dihydrate (150.4 kg, 1194 mol) were added until absence of oxidation by starch-KI test and pH <7 was reached. The mixture was filtered, and the isolated solid was washed with water then dissolved in DCM (800 L). Water (400 L) was added, and the mixture was stirred for 2 hours and filtered. The separated organic layer was washed sequentially with aqueous NaHCOs and saturated aqueous NaCI 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 / V-(8-Bromo-4-oxo-tetralin-5-yl)acetamide 3 as a solid in approximately 67% yield. XH NMR (500 MHz, DMSO, 27°C) 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 Preparation of / V-(8-Acetamido-l-oxo-tetralin-5-yl)acetamide 4 / V-(8-Bromo-4-oxo-tetralin-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 eq) and purged with nitrogen to an oxygen content <0.1%. Dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[l,l'-biphenyl]-2-yl)phosphine (4.34 kg, 8.1 mol, 0.04 eq) and tris(dibenzylideneacetone)dipalladium(0) (2.28 kg, 3.03 mol, 0.015 eq) were added and the mixture was heated to 80°C. Upon reaction completion, the mixture was cooled and then water (570 L) was added and the mixture stirred for 2 hours. The resulting suspension was filtered, and the filter cake washed with water. After drying, the isolated solid was stirred in EtOH (142.5 L) at 60°C for 2 hours then cooled. The resulting suspension was filtered, and the isolated product was washed with ethanol (114 L) and dried to give N-(8-Acetamido-l-oxo-tetralin-5-yl)acetamide 4 as a solid in approximately 77% yield. 1H NMR (500 MHz, DMSO, 27°C) 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. Preparation of 5,8-diaminotetralin-l-one 5 / V-(8-Acetamido-l-oxo-tetralin-5-yl)acetamide 4 (40.3 kg, 154.9 mol) was mixed with 36% aqueous HCI (123.3 kg, 1214 mol) then heated to 70-75°C. Upon reaction completion the mixture was cooled to 20-30°C and then water (80 L) and SMA905 (palladium scavenger, 2.4 kg, 0.06 w / w) were added. The mixture was stirred for 3 hours and additional SMA905 added if required. The mixture was filtered and the filter cake washed with water (40 L). The pH of the filtrate was adjusted to 8-10 at 010°C with 30% (w / w) aqueous NaOH (63.6 kg, 1595 mol). The resulting suspension was filtered, washed with water and the isolated product dried to give 5,8-Diaminotetralin-l-one 5 as a solid in approximately 87% yield XH NMR (500 MHz, DMSO, 27°C) 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. Preparation of allyl ((S)-l-(((S)-l-((4-amino-5-oxo-5,6,7,8-tetrahydronaphthalen-l-yl)amino)-l-oxopropan-2-yl)amino)-3-methyl-l-oxobutan-2-yl)carbamate Intermediate A Intermediate A Intermediate A may be prepared from compound 5 according to the process described in WO 2020 / 200880, the contents of which are incorporated by reference. Example 2: Reaction Screening of Buchwald-Hartwig amination with acetamide, B0C-NH2 and 10 ammonium sulfate General procedure 4, R is NHC(O)CH3 4A, R is NHC(O)OC(CH3)3 4C, R is NH2 The starting material 3 (20mg, 0.083mmol, 1 eq) was charged to a vial followed by acetamide or (N^hSCU or B0CNH2 (1.2 eq), base (1.5 eq), catalyst, e.g. Pdjdbas (0.025 eq) and either monodentate 15 ligand (0.1 eq) or bidentate ligand (0.05 eq) under a nitrogen atmosphere. Solvent (10 vol, degassed) was added at 20°C and the mixture was heated to 100°C for 16h. The reaction mixture was diluted with a mixture of acetonitrile and water, then sampled for HPLC analysis. Tables 1 to 3 set out the HPLC area% of starting material, product and impurities. Tables 1 to 3 make reference to the following impurities; Imp1 Imp2 Imp3 Imp4 Imp5 Imp6 Table 1: Reaction screening with acetamide Ligand Base Solvent 3 / % 4 / % lmpl / % lmp2 / % Imp3% Imp4% PPh3 CS2CO3 Toluene 43.68 0.00 14.64 9.67 20.38 6.77 PCy3HBF4 CS2CO3 Toluene 41.66 0.00 5.61 10.98 22.53 15.94 BuPAd3 CS2CO3 Toluene 45.74 0.00 5.78 1.57 1.70 1.66 Xphos CS2CO3 Toluene 67.15 0.00 3.89 7.06 19.83 1.68 tBuXphos CS2CO3 Toluene 71.75 0.00 2.56 6.28 16.52 1.07 Brettphos CS2CO3 Toluene 0.58 75.93 2.43 3.01 0.00 0.25 Ruphos CS2CO3 Toluene 78.10 0.00 3.07 4.80 16.31 1.36 Johnphos CS2CO3 Toluene 70.57 0.00 2.67 7.81 22.50 0.44 Josiphos CS2CO3 Toluene 74.44 0.17 3.01 6.37 17.02 0.85 DPPP CS2CO3 Toluene 73.09 0.00 0.19 7.51 17.86 0.00 DPPF CS2CO3 Toluene 70.14 0.15 1.90 3.78 16.19 0.76 r-Binap CS2CO3 Toluene 78.00 0.22 0.35 3.66 14.21 0.28 Xantphos CS2CO3 Toluene 36.45 4.45 12.30 0.64 15.92 28.84 PPh3 K3PO4 Toluene 41.28 0.00 17.77 10.20 15.42 20.35 PCy3HBF4 k3po4 Toluene 61.13 0.00 6.46 2.94 6.52 15.90 BuPAd3 k3po4 Toluene 5.27 0.00 6.15 7.05 1.23 0.00 Xphos k3po4 Toluene 59.15 0.00 3.03 16.04 20.10 0.87 tBuXphos k3po4 Toluene 70.29 0.00 3.14 10.90 13.41 1.29 Brettphos k3po4 Toluene 0.32 78.98 1.87 2.79 0.00 0.00 Ruphos k3po4 Toluene 62.15 0.00 3.84 13.14 16.99 2.87 Johnphos K3PO4 Toluene 60.80 0.00 2.92 14.57 19.17 0.93 Josiphos k3po4 Toluene 62.15 0.00 3.04 13.98 15.09 1.28 DPPP k3po4 Toluene 61.19 0.00 0.20 15.87 17.17 0.39 DPPF k3po4 Toluene 63.27 0.00 1.90 17.49 16.56 1.49 r-Binap k3po4 Toluene 63.43 0.12 0.38 14.03 17.50 0.54 Xantphos k3po4 Toluene 17.16 7.83 19.05 3.48 9.02 37.37 PPh3 CS2CO3 Dioxane 30.80 0.00 18.53 4.34 36.34 19.97 PCy3HBF4 CS2CO3 Dioxane 40.78 0.00 9.41 1.78 12.67 31.10 BuPAd3 CS2CO3 Dioxane 15.47 0.00 1.11 0.38 1.91 3.10 Xphos CS2CO3 Dioxane 50.69 0.34 3.33 5.79 38.83 2.20 tBuXphos CS2CO3 Dioxane 6.10 0.42 0.89 4.42 25.17 21.20 Brettphos CS2CO3 Dioxane 0.20 55.05 4.86 0.56 0.00 1.23 Ruphos CS2CO3 Dioxane 57.12 0.23 2.75 4.74 32.19 1.72 Johnphos CS2CO3 Dioxane 56.54 0.24 2.89 4.69 33.27 0.91 Josiphos CS2CO3 Dioxane 61.64 1.24 3.75 3.49 24.28 1.14 DPPP CS2CO3 Dioxane 59.83 0.00 0.00 4.40 28.18 0.19 DPPF CS2CO3 Dioxane 57.65 0.31 1.43 7.79 32.68 1.27 r-Binap CS2CO3 Dioxane 63.78 0.48 0.58 4.09 32.71 0.64 Xantphos CS2CO3 Dioxane 2.62 15.03 27.75 2.29 0.00 36.93 PPh3 K3PO4 Dioxane 47.09 0.00 13.97 8.91 23.34 20.93 PCy3HBF4 K3PO4 Dioxane 52.74 0.00 10.23 7.51 3.77 22.07 BuPAd3 K3PO4 Dioxane 0.00 0.00 4.73 1.01 0.00 0.29 Xphos k3po4 Dioxane 53.41 0.33 2.17 9.88 38.97 1.49 tBuXphos k3po4 Dioxane 54.66 2.87 4.12 7.44 29.44 6.02 Brettphos k3po4 Dioxane 0.00 55.03 3.78 0.91 0.26 0.57 Ruphos k3po4 Dioxane 51.77 0.40 2.65 7.32 30.67 1.73 Johnphos k3po4 Dioxane 63.35 0.29 2.33 10.63 41.12 0.72 Josiphos k3po4 Dioxane 56.12 1.33 2.95 6.59 33.06 2.07 DPPP k3po4 Dioxane 52.15 0.00 0.00 11.63 39.38 0.46 DPPF k3po4 Dioxane 11.77 0.27 1.10 14.43 16.27 16.14 r-Binap k3po4 Dioxane 55.33 0.79 0.00 0.38 28.41 0.59 Xantphos k3po4 Dioxane 25.22 8.64 24.63 3.89 0.00 44.40 PPh3 CS2CO3 tAmylOH 10.67 0.21 3.88 3.66 47.83 1.75 PCy3HBF4 CS2CO3 tAmylOH 15.36 0.10 11.72 2.85 30.76 33.53 BuPAch CS2CO3 tAmylOH 7.24 0.00 0.94 1.34 20.98 4.16 Xphos CS2CO3 tAmylOH 17.64 0.34 1.27 4.19 52.03 2.14 tBuXphos CS2CO3 tAmylOH 14.19 5.15 4.47 3.05 59.20 2.88 Brettphos CS2CO3 tAmylOH 1.22 39.80 6.91 1.60 4.53 1.69 Ruphos CS2CO3 tAmylOH 21.26 0.36 1.15 0.15 44.14 1.06 Johnphos CS2CO3 tAmylOH 21.87 0.76 1.94 5.04 41.41 0.66 Josiphos CS2CO3 tAmylOH 10.49 1.14 7.27 2.09 38.75 11.48 DPPP CS2CO3 tAmylOH 23.63 0.00 0.00 5.12 43.66 0.15 DPPF CS2CO3 tAmylOH 22.86 0.13 0.00 7.87 47.34 0.30 r-Binap CS2CO3 tAmylOH 18.30 0.16 0.00 4.01 37.76 0.22 Xantphos CS2CO3 tAmylOH 5.06 0.96 3.70 2.90 42.92 0.61 PPh3 K3PO4 tAmylOH 18.92 0.00 15.96 6.55 41.20 20.70 PCy3HBF4 k3po4 tAmylOH 28.05 0.00 12.41 5.98 18.07 31.06 BuPAd3 k3po4 tAmylOH 0.00 0.00 1.72 4.13 0.00 0.57 Xphos k3po4 tAmylOH 47.45 0.62 2.58 11.58 40.65 2.23 tBuXphos k3po4 tAmylOH 41.51 7.09 5.60 8.86 32.14 4.93 Brettphos k3po4 tAmylOH 0.41 52.79 6.09 0.44 0.13 2.15 Ruphos k3po4 tAmylOH 19.20 0.31 1.74 10.57 30.39 11.25 Johnphos k3po4 tAmylOH 44.92 0.70 2.52 12.58 45.05 0.95 Josiphos k3po4 tAmylOH 34.94 0.75 6.25 9.84 38.85 10.30 DPPP k3po4 tAmylOH 42.46 0.00 0.00 12.82 43.54 0.75 DPPF k3po4 tAmylOH 43.02 0.00 0.00 11.90 37.73 0.35 r-Binap k3po4 tAmylOH 32.81 0.29 1.53 8.88 3.66 9.51 Xantphos k3po4 tAmylOH 32.30 2.12 10.38 1.17 35.43 23.60 PPh3 CS2CO3 DMF 2.67 0.65 13.82 27.19 36.24 22.53 PCy3HBF4 CS2CO3 DMF 7.67 0.00 16.31 14.79 15.98 54.07 BuPAd3 CS2CO3 DMF 4.83 0.16 0.88 9.36 3.15 6.82 Xphos CS2CO3 DMF 9.89 0.41 10.46 24.26 27.48 21.75 tBuXphos CS2CO3 DMF 10.17 3.85 13.68 22.64 17.13 26.57 Brettphos CS2CO3 DMF 0.00 31.54 14.69 2.94 0.35 1.06 Ruphos CS2CO3 DMF 0.00 0.24 0.00 23.23 12.50 0.26 Johnphos CS2CO3 DMF 3.10 0.48 7.86 24.43 43.56 9.33 Josiphos CS2CO3 DMF 1.26 1.74 20.32 12.03 25.31 31.43 DPPP CS2CO3 DMF 3.55 0.12 9.06 26.28 48.68 1.18 DPPF CS2CO3 DMF 4.93 0.17 9.79 31.19 47.34 1.12 r-Binap CS2CO3 DMF 4.32 0.37 10.95 24.58 45.57 3.11 Xantphos CS2CO3 DMF 2.44 0.91 10.21 10.50 43.71 14.00 PPh3 K3PO4 DMF 1.74 0.00 24.07 2.60 10.72 44.71 PCy3HBF4 k3po4 DMF 17.35 0.00 15.47 3.57 16.94 45.60 BuPAd3 k3po4 DMF 1.06 0.00 1.32 4.62 0.53 0.38 Xphos k3po4 DMF 24.34 0.74 8.95 5.65 15.10 17.31 tBuXphos k3po4 DMF 9.64 1.09 17.88 4.67 3.61 22.60 Brettphos k3po4 DMF 0.52 15.51 19.69 7.52 0.44 1.36 Ruphos k3po4 DMF 35.25 0.31 3.85 4.03 24.01 5.31 Johnphos k3po4 DMF 28.84 0.54 6.77 4.62 30.62 9.14 Josiphos k3po4 DMF 4.30 0.21 34.77 5.73 0.00 54.60 DPPP k3po4 DMF 29.33 0.00 4.59 8.71 36.22 1.46 DPPF k3po4 DMF 30.83 0.18 6.21 8.80 34.05 1.41 r-Binap k3po4 DMF 0.25 0.40 0.00 2.93 26.71 16.57 Xantphos k3po4 DMF 0.00 10.15 25.55 1.83 0.21 38.75 PPh3 CS2CO3 2-MeTHF 66.89 0.00 3.00 1.81 18.74 6.20 PCy3HBF4 CS2CO3 2-MeTHF 68.19 0.00 8.35 0.00 3.63 21.45 BuPAd3 CS2CO3 2-MeTHF 50.55 0.00 0.62 0.74 2.32 2.13 Xphos CS2CO3 2-MeTHF 64.94 0.36 2.37 1.61 14.79 1.92 tBuXphos CS2CO3 2-MeTHF 75.42 3.40 3.51 2.04 18.29 4.41 Brettphos CS2CO3 2-MeTHF 0.54 70.40 2.63 0.42 0.00 0.50 Ruphos CS2CO3 2-MeTHF 122.80 0.24 1.77 2.48 21.42 1.77 Johnphos CS2CO3 2-MeTHF 69.65 0.35 2.28 2.78 20.01 1.50 Josiphos CS2CO3 2-MeTHF 72.56 0.70 1.45 1.84 19.99 0.91 DPPP CS2CO3 2-MeTHF 70.37 0.00 0.00 2.37 19.27 0.55 DPPF CS2CO3 2-MeTHF 69.87 0.00 0.00 7.81 23.50 0.74 r-Binap CS2CO3 2-MeTHF 66.12 0.23 0.00 2.65 20.95 0.75 Xantphos CS2CO3 2-MeTHF 65.21 1.77 5.75 1.23 13.09 9.70 PPh3 K3PO4 2-MeTHF 69.60 0.00 3.03 3.55 11.99 6.13 PCy3HBF4 k3po4 2-MeTHF 65.34 0.00 7.27 1.64 2.91 18.72 BuPAdz K3PO4 2-MeTHF 26.68 0.00 1.01 0.18 0.43 3.89 Xphos k3po4 2-MeTHF 73.19 0.52 2.66 3.91 9.91 2.10 tBuXphos k3po4 2-MeTHF 70.66 4.06 4.93 1.87 4.86 6.61 Brettphos k3po4 2-MeTHF 0.41 70.83 2.33 1.82 0.00 0.57 Ruphos k3po4 2-MeTHF 75.78 0.29 1.89 3.17 10.33 1.76 Johnphos k3po4 2-MeTHF 78.49 0.62 3.88 2.74 7.18 1.80 Josiphos k3po4 2-MeTHF 68.86 0.69 1.43 3.84 13.14 0.95 DPPP k3po4 2-MeTHF 80.41 0.00 0.00 3.31 12.62 0.73 DPPF k3po4 2-MeTHF 62.58 0.16 0.00 9.32 10.24 0.76 r-Binap k3po4 2-MeTHF 71.72 0.26 0.00 4.18 14.96 0.82 Xantphos k3po4 2-MeTHF 45.79 7.09 17.93 0.39 0.15 34.69 Table 2: Reaction Screening with B0C-NH2 Imp1 Imp2 Imp3 Imp7 (unknown structure) Ligand Base Solvent 3 / % 4a / % lmpl / % lmp2 / % lmp3 / % lmp7 / % PPh3 K3PO4 Toluene 58.39 0.00 13.04 0.00 5.79 19.87 PCy3HBF4 k3po4 Toluene 54.29 0.00 9.05 0.00 2.00 11.59 BuPAd3 k3po4 Toluene 10.96 0.26 2.09 0.00 0.51 1.25 Xphos k3po4 Toluene 0.80 71.00 1.68 0.00 0.00 0.00 tBuXphos k3po4 Toluene 0.00 68.68 1.61 0.00 0.00 0.00 Brettphos k3po4 Toluene 0.00 81.10 0.31 0.00 0.00 0.00 Ruphos k3po4 Toluene 0.91 64.61 3.53 0.34 0.00 0.00 Johnphos k3po4 Toluene 22.38 41.39 4.35 0.00 0.66 0.27 Josiphos k3po4 Toluene 78.44 3.94 3.29 0.40 3.23 0.38 DPPP k3po4 Toluene 83.72 0.00 0.47 0.55 4.18 0.00 DPPF k3po4 Toluene 83.39 0.86 0.96 0.37 4.15 0.14 r-Binap k3po4 Toluene 68.16 4.39 1.19 0.00 2.87 0.00 Xantphos k3po4 Toluene 44.24 4.24 13.90 0.00 3.55 24.14 PPh3 K3PO4 Dioxane 52.31 0.00 10.77 1.31 18.61 23.30 PCy3HBF4 k3po4 Dioxane 44.62 0.00 7.40 0.00 7.64 16.25 BuPAd3 k3po4 Dioxane 20.38 0.00 1.21 0.00 1.81 2.28 Xphos k3po4 Dioxane 3.37 43.60 6.61 0.00 0.00 0.00 tBuXphos k3po4 Dioxane 54.05 9.36 3.67 0.56 4.15 1.62 Brettphos k3po4 Dioxane 1.03 71.54 1.29 0.00 0.00 0.00 Ruphos k3po4 Dioxane 9.70 32.98 7.62 0.24 0.00 0.31 Johnphos k3po4 Dioxane 57.85 7.52 4.52 0.66 5.58 0.69 Josiphos k3po4 Dioxane 69.68 1.03 5.11 1.12 16.01 0.77 DPPP k3po4 Dioxane 79.28 0.00 0.31 1.33 16.22 0.26 DPPF k3po4 Dioxane 77.96 0.26 1.28 1.24 16.68 0.27 r-Binap k3po4 Dioxane 72.24 0.42 0.00 0.76 12.39 0.61 Xantphos k3po4 Dioxane 11.71 3.22 27.89 0.00 1.26 60.99 PPh3 k3po4 tAmylOH 32.93 0.00 3.41 11.73 54.69 7.97 PCy3HBF4 k3po4 tAmylOH 26.66 0.00 11.77 4.67 26.72 16.16 BuPAd3 k3po4 tAmylOH 17.69 0.00 1.54 3.35 24.25 1.75 Xphos k3po4 tAmylOH 24.44 14.66 7.11 2.25 12.49 0.00 tBuXphos k3po4 tAmylOH 22.49 28.99 6.76 2.95 12.89 0.89 Brettphos k3po4 tAmylOH 0.66 65.70 2.85 0.00 0.00 0.00 Ruphos k3po4 tAmylOH 36.69 2.45 3.44 6.50 38.66 0.00 Johnphos k3po4 tAmylOH 27.02 22.70 5.85 2.78 16.15 0.33 Josiphos k3po4 tAmylOH 36.80 0.16 1.69 10.42 43.30 0.26 DPPP k3po4 tAmylOH 37.12 0.00 0.49 12.24 47.83 0.00 DPPF k3po4 tAmylOH 38.68 0.00 0.35 11.80 47.75 0.00 r-Binap k3po4 tAmylOH 40.78 0.00 0.73 11.29 46.84 0.34 Xantphos k3po4 tAmylOH 33.88 0.00 1.70 12.53 62.21 0.68 PPh3 k3po4 DMF 44.89 0.00 7.36 1.46 14.52 11.22 PCy3HBF4 k3po4 DMF 52.86 0.00 5.01 1.35 13.77 3.44 BuPAd2 k3po4 DMF 3.39 0.00 4.97 0.00 1.33 5.91 Xphos k3po4 DMF 12.71 0.00 18.81 0.00 1.65 26.32 tBuXphos k3po4 DMF 12.15 0.00 16.30 2.40 0.00 17.92 Brettphos k3po4 DMF 7.17 0.00 12.65 1.58 0.00 12.16 Ruphos k3po4 DMF 30.95 0.00 8.09 0.00 3.94 10.74 Johnphos K3PO4 DMF 18.51 0.00 22.29 2.36 1.54 34.09 Josiphos k3po4 DMF 49.15 0.00 4.59 1.74 17.29 1.65 DPPP k3po4 DMF 46.81 0.00 5.71 2.12 18.83 1.06 DPPF k3po4 DMF 51.30 0.00 4.78 1.57 14.31 0.97 r-Binap k3po4 DMF 46.93 0.00 6.99 1.75 14.48 1.54 Xantphos k3po4 DMF 34.76 0.00 12.80 1.06 12.34 17.40 PPh3 k3po4 2-MeTHF 70.41 0.00 7.87 0.39 4.54 21.50 PCy3HBF4 k3po4 2-MeTHF 66.43 0.00 5.33 0.00 2.22 11.70 BuPAd3 k3po4 2-MeTHF 59.00 0.00 0.49 0.23 2.33 1.19 Xphos k3po4 2-MeTHF 53.21 13.08 4.01 0.00 1.21 1.97 tBuXphos k3po4 2-MeTHF 44.37 30.47 2.12 0.19 0.34 0.94 Brettphos k3po4 2-MeTHF 2.20 79.33 0.89 0.00 0.00 0.00 Ruphos k3po4 2-MeTHF 33.30 20.86 4.45 0.00 0.00 0.00 Johnphos k3po4 2-MeTHF 53.38 22.13 3.41 0.00 0.27 1.58 Josiphos k3po4 2-MeTHF 80.53 0.54 1.42 0.51 5.97 0.98 DPPP k3po4 2-MeTHF 76.55 0.00 0.00 0.00 4.17 1.58 DPPF k3po4 2-MeTHF 78.82 0.00 0.00 0.00 3.16 0.00 r-Binap k3po4 2-MeTHF 74.90 0.00 0.00 0.00 3.77 0.00 Xantphos k3po4 2-MeTHF 67.81 0.00 6.09 0.00 5.75 10.87 Table 3: Reaction Screening with Ammonium Sulfate ((NhkhSCk) 3 4C Ligand Base Solvent 3 / % 4C / % Imp5% Imp6% lmpl / % Imp3% PPh3 KOtBu Dioxane 0.00 34.63 0.00 0.00 0.00 102.59 PCy3HBF4 KOtBu Dioxane 0.00 13.21 0.00 1.36 0.16 110.90 BuPAd3 KOtBu Dioxane 0.23 15.75 0.00 9.28 0.00 100.25 Xphos KOtBu Dioxane 0.00 22.29 0.00 8.27 0.00 107.10 tBuXphos KOtBu Dioxane 0.00 21.30 4.60 1.69 0.00 112.43 Brettphos KOtBu Dioxane 0.00 18.65 18.36 16.99 0.00 56.19 Ruphos KOtBu Dioxane 0.00 21.56 0.00 11.66 0.00 72.88 Johnphos KOtBu Dioxane 0.00 21.54 1.75 3.13 0.00 101.96 Josiphos KOtBu Dioxane 0.00 62.81 0.00 2.51 0.00 66.18 DPPP KOtBu Dioxane 0.00 37.59 0.00 0.10 0.14 112.97 DPPF KOtBu Dioxane 0.00 29.22 0.00 0.06 0.00 85.45 r-Binap KOtBu Dioxane 0.00 22.72 0.00 0.37 0.00 132.52 Xantphos KOtBu Dioxane 0.00 38.28 0.00 2.26 0.00 100.68 PPh3 K3PO4 Dioxane 33.12 0.69 0.00 1.88 22.93 5.79 PCy3HBF4 k3po4 Dioxane 47.40 0.63 0.00 0.08 9.72 5.51 BuPAd3 k3po4 Dioxane 38.82 0.00 0.00 0.00 0.00 5.15 Xphos k3po4 Dioxane 38.43 0.74 0.00 0.00 2.97 49.16 tBuXphos k3po4 Dioxane 49.51 0.61 0.00 0.00 2.48 41.79 Brettphos k3po4 Dioxane 30.55 0.00 0.00 0.14 3.82 2.81 Ruphos k3po4 Dioxane 48.35 0.46 0.00 0.00 2.63 37.91 Johnphos k3po4 Dioxane 54.44 0.55 0.00 0.00 3.61 31.56 Josiphos k3po4 Dioxane 46.94 1.00 0.00 0.00 3.93 46.52 DPPP k3po4 Dioxane 49.88 0.00 0.00 0.00 0.43 46.53 DPPF k3po4 Dioxane 56.96 0.00 0.00 0.00 2.43 23.95 r-Binap k3po4 Dioxane 49.27 0.14 0.00 0.00 1.49 13.40 Xantphos k3po4 Dioxane 18.22 0.22 0.00 2.62 26.82 2.38 Example 3: Buchwald-Hartwig amination with benzophenone imine N-(8-bromo-4-oxo-tetralin-5-yl)acetamide 3 (3.5g, 12.4mmol) was mixed with benzophenone imine 5 (2.7g, 14.9 mmol, 1.2 eq), K3PO4 (3.9g, 18.6mmol, 1.5 eq), Pd(0Ac)2 (0.28g, 1.24 mmol, 0.1 eq) and BINAP (2.48mmol, 1.54g, 0.2 eq) in 1,4-dioxane (35 mL) and heated to reflux for 18 h. The mixture was concentrated in vacuo then partitioned between water (10 vol) and ethyl acetate (10 vol). The separated organic layer was dried over sodium sulfate and concentrated under vacuum then purified by silica gel chromatography to give N-[8-(benzhydrylideneamino)-4-oxo-tetralin-5-yl]acetamide 4B (3.5g) in 65% yield. XH NMR (500 MHz, DMSO, 27°C) 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. 5 The above description of illustrative embodiments is intended only to acquaint others skilled in the art with the Applicant's specification, its principles, and its practical application so that others skilled in the art may readily adapt and apply the specification in its numerous forms, as they may be best suited to the requirements of a particular use. This description and its specific examples, while 10 indicating embodiments of this specification, are intended for purposes of illustration only. This specification, therefore, is not limited to the illustrative embodiments described in this specification, and may be variously modified. In addition, it is to be appreciated that various features of the specification that are, for clarity reasons, described in the context of separate embodiments, also may be combined to form a single embodiment. Conversely, various features of the specification 15 that are, for brevity reasons, described in the context of a single embodiment, also may be combined to form sub-combinations thereof.
Claims
1. A process for the production of a compound of Formula (I):(I)or a salt thereof, comprising a reaction of a compound of Formula (II):or a salt thereof, and H-Z, or a salt thereof, wherein the reaction is performed in the presence of apalladium catalyst and a base,wherein X is Br, I or Cl, and2. A process as claimed in claim 1, wherein X is Br.
3. A process as claimed in claim 1 or claim 2, wherein the reaction is performed in the presenceof 1.0 to 3.0 equivalents of base.
4. A process as claimed in any one of claims 1 to 3, wherein the base is K3PO4.
5. A process as claimed in any one of claims 1 to 4, wherein the reaction is performed using 1.0to 1.4 molar equivalents of Z-H.0 ^N^CHa6. A process as claimed in any one of claims 1 to 5, wherein Z is H .7.A process as claimed in any one of claims 1 to 5, wherein Z isOC(CH3)38. A process as claimed in claim 6 or claim 7, wherein the reaction is performed in the presenceof dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[l,r-biphenyl]-2-yl)phosphine.
9. A process as claimed in any one of claims 6 to 8, wherein the reaction is performed in the presence of 0.01 to 0.15 molar equivalents of dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[l,l'-biphenyl]-2-yl)phosphine.
10. A process as claimed in any one of claims 6 to 9, wherein the palladium catalyst is tris(dibenzylideneacetone)dipalladium(0).
11. A process as claimed in any one of claims 6 to 10, wherein the reaction is performed in the presence of 0.01 to 0.04 molar equivalents of tris(dibenzylideneacetone)dipalladium(0).
12. A process as claimed in any one of claims 6 to 11, wherein the reaction is performed in thepresence of toluene.
13. A process as claimed in any one of claims 6 to 12, wherein the reaction is performed at atemperature of 60 to 100 °C.14.
15. A process as claimed in claim 14, wherein the reaction is performed in the presence of 2,2'-Bis(diphenylphosphino)-l,l'-binaphthalene.
16. A process as claimed in claim 14 or claim 15, wherein the reaction is performed in the presence of 0.02 to 0.4 molar equivalents of 2,2'-Bis(diphenylphosphino)-l,l'-binaphthalene.
17. A process as claimed in any one of claims 14 to 16, wherein the palladium catalyst is palladium(II) acetate.
18. A process as claimed in any one of claims 14 to 17, wherein the reaction is performed in the presence of 0.01-0.2 molar equivalents of palladium(II) acetate.
19. A process as claimed in any one of claims 14 to 18, wherein the reaction is performed in thepresence of dioxane.
20. A process as claimed in any one of claims 14 to 19, wherein the reaction is performed at atemperature of 80 to 120 °C.
21. A process for the production of a compound of Formula (III)or a salt thereof, comprising(i) the production of a compound of Formula (I), or a salt thereof, using a process as claimed in any one of claims 1 to 20; and(ii) the production of the compound of Formula (III), of a salt thereof, comprising the reaction of the compound of Formula (I), or a salt thereof, and an acid.
22. A process as claimed in claim 21, wherein the acid is hydrochloric acid.
23. A compound that is tert-Butyl (4-acetamido-5-oxo-5,6,7,8-tetrahydronaphthalen-l-5 yl)carbamate,OH N, or a salt thereof.
24. A compound that is / V-(4-((Diphenylmethylene)amino)-8-oxo-5,6,7,8-tetrahydronaphthalen-l-yl)acetamide,1025. A process for the production of a compound of Formula (IV)15 comprising a process as claimed in any one of claims 1 to 22, or a compound, or a salt thereof, asclaimed in claim 23 or claim 24.
26. A process for the production of a conjugate of Formula (V)Ab-(LP)k(V)or a pharmaceutically acceptable salt thereof, comprising a process as claimed in any one of claims 1 to 22, or a compound, or a salt thereof, as claimed in claim 23 or claim 24, whereinAb is an antibody or antigen-binding fragment thereof, k is an integer from 1 to 10, and5 LP isHO O .