Process for preparing EGFR inhibitors

Abstract

This invention provides a method for preparing a compound of structural formula (I) or a pharmaceutically acceptable salt thereof:

Description

Prior Technology

[0001] EGFR (epidermal growth factor receptor) is a member of the erbB receptor family, which includes transmembrane protein tyrosine kinase receptors. By binding to its ligands, such as epidermal growth factor (EGF), EGFR can form homodimers on the cell membrane or heterodimers with other receptors in the family, such as erbB2, erbB3, or erbB4. This dimerization leads to phosphorylation of key tyrosine residues in EGFR cells, thereby activating many downstream signaling pathways in the cell. These intracellular signaling pathways play important roles in cell proliferation, survival, and anti-apoptosis. Disorders of the EGFR signaling pathway, including increased expression of ligands and receptors, EGFR gene amplification, and alterations (such as mutations, deletions, and similar changes), can promote malignant transformation of cells and play a significant role in tumor cell proliferation, invasion, metastasis, and angiogenesis. For example, alterations to the EGFR gene, such as mutations and deletions, are seen in non-small cell lung cancer (NSCLC) tumors. The two most frequent EGFR alterations seen in NSCLC tumors are short frame deletion in exon 19 (del19) and single missense mutation in exon 21, L858R (Cancer Discovery 2016 6(6) 601). These two alterations result in ligand-independent EGFR activation and primary or activating mutations known as EGFR mutant NSCLC (EGFR M+). Clinical experience shows that the objective response rate (ORR) of EGFR M+ NSCLC patients treated as first-line (1L) therapy with EGFR tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib, afatinib, and osimertinib is approximately 60% to 85% (Lancet Oncol. 2010, Vol. 11, 121; Lancet Oncol. 2016, Vol. 17, 577; N. Engl. J. Med. 2017 Nov 18 Doi:10.1056 / NEJMoa1713137; Lancet Oncol. (2011, Vol. 12, 735), thus confirming that EGFR mutant NSCLC tumors depend on oncogenic EGFR activity for survival and proliferation, and establishing del19 and L858R mutated EGFR as oncogenic drivers of the disease. Therefore, we can verify drug targets and biomarkers for the treatment of NSCLC.

[0002] However, resistance to these small molecule inhibitors has been observed in almost all NSCLC patients after an average of 10 to 12 months of treatment with first-generation (erlotinib and gefitinib) and second-generation (afatinib) EGFR TKIs (Lancet Oncol. Feb. 2010; 11(2):121-8.; Lancet Oncol. May 2016; 17(5):577-89; Lancet Oncol. Aug. 2011; 12(8):735-42). The most important resistance mechanism for first- and second-generation EGFR TKIs is due to the secondary mutation T790M in EGFR, which occurs in 50% to 70% of patients receiving first- and second-generation EGFR inhibitors (Cancer Discov; 2(10); 872–5, 2012; Cancer Res., 65:(16), 2005). This secondary mutation reduces the affinity of drugs for the target, thereby leading to drug resistance and causing tumor recurrence or disease progression.

[0003] Given the prevalence of this mutation leading to drug resistance in EGFR-targeted therapies for lung cancer, many companies are attempting to develop novel small-molecule EGFR inhibitors to treat patients with drug-resistant lung cancer by inhibiting the resistant mutant EGFR-T790M. For example, osimertinib (Tagrisso®), a third-generation EGFR TKI, has been developed to treat NSCLC patients whose cancer cells are positive for the primary EGFR mutation del19 or L858R in the gene encoding EGFR, with or without the T790M mutation.

[0004] Although the third-generation EGFR TKI osimertinib has shown efficacy in NSCLC patients, unfortunately, resistance mediated by exon 20 C797 mutations in EGFR typically develops within approximately 10 months (European Journal of Medicinal Chemistry 2017, Vol. 142: 32-47) and accounts for the majority of osimertinib resistance cases (Cancer Letters 2016, Vol. 385: 51-54). The EGFR del19 / L858R T790M C797S cis-mutant kinase variant typically appears in second-line (2L) patients after osimertinib treatment and is commonly referred to as a "triple mutant" EGFR that can no longer be inhibited by first-, second-, or third-generation EGFR inhibitors.

[0005] Compound (I) is a highly selective inhibitor of EGFR TKIs, which can inhibit triple mutant variants. Furthermore, the compound represented by this formula can highly selectively inhibit EGFR mutants with the triple mutant del19 / L858R T790M C797S, while exhibiting no or low activity against wild-type EGFR. . Summary of the Invention

[0006] This paper presents a novel method for the preparation and purification of compound (I). Additionally, a novel intermediate is disclosed herein. Implementation

[0007] [Cross-reference to related applications] [] This application claims priority to U.S. Provisional Application No. 63 / 214,069, filed June 23, 2021. The entire contents of the above application are incorporated herein by reference.

[0008] This article discloses a method for preparing compounds of formula (I). The method involves using a first starting material of formula (Ic): Or its salt and the second starting substance of formula (Id): Or its salt reaction. This article also discloses: i) a method for preparing the compound of formula (Ic) from readily available starting materials; and ii) intermediates obtained from the preparation of the compound of formula (Ic).

[0009] In one state, the reaction between the starting material of formula (Ic) and the starting material of formula (Id) is carried out in the presence of a palladium catalyst and a phosphine ligand. The palladium catalyst and the phosphine ligand are separate compounds. Alternatively, the complex comprises both the palladium catalyst and the phosphine ligand.

[0010] Non-limiting list of palladium catalysts includes Pd(dppe)2(bis[1,2-bis(diphenylphosphine)ethane]palladium(0)), CX-11(1,3-bis(2,6-diisopropylphenyl)imidazolium-2-ylidene(1,4-naphthoquinone)palladium(0) dimer), CX-12(1,3-bis(2,4,6-trimethylphenyl)imidazolium-2-ylidene(1,4-naphthoquinone)palladium(0) dimer), Pd(t-Bu3P)2(bis(tri-tert-butylphosphine)palladium(0)), Pd(PCy3)2(bis(tricyclohexylphosphine)palladium(0)), Pd(PPh3)4(tetra(triphenylphosphine)palladium(0)), Pd2(dba)3(dibenzylacetone)dipalladium(0)), Pd(OAc)2(palladium(II)acetate), PdCl 2(PPh 3) 2(dichlorobis(triphenylphosphine)palladium(II)), PdCl 2(Amphos) 2(bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)), Pd(MeCN) 2Cl 2(bis(acetonitrile)dichloropalladium(II)), PdCl 2(P(o-Tol) 3) 2(dichlorobis(tri-o-tolylphosphine)palladium(II)), Pd(dppf)Cl 2(1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium(II)), Pd(MeCN) 4(BF 4) 2(tetra(acetonitrile)tetrafluoroboratepalladium(II)), Pd-PEPPSI-IPent (dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)), Pd-PEPPSI-IPr ([1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)), Pd-PEPPSI-SIPr ((1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)(3-chloropyridyl)palladium(II)) and bis(dibenzylideneacetone)palladium(0) (Pd(dba) 2).

[0011] A non-limiting list of phosphine ligands and complexes comprising both palladium catalysts and phosphine ligands includes triphenylphosphine (PPh 3), bis(tri-o-tolylphosphine) (P(o-Tol) 3) 2, tritert-butoxyphosphine (Pt-Bu 3), tri-tert-butyltetrafluoroborate phosphonium (Pt-Bu 3HBF 4), bis(tricyclohexylphosphine) (PCy 3), bis(1-adamantyl)butylphosphine (n-BuP(AD) 2), 2,2′-bis(diphenylphosphine)-1,1′-binaphthyl (BINAP), (9,9-dimethyl-9H-α) Xantphos (-4,5-diyl)bis(diphenylphosphine), bis[(2-diphenylphosphine)phenyl] ether (DPEPhos), 1,1'-bis(diphenylphosphine)ferrocene (dppf), 1,1′-bis(di-tert-butylphosphine)ferrocene (dcypf), 1,3-bis(diphenylphosphine)propane (DPPP), (2-biphenyl)di-tert-butylphosphine (JohnPhos), chloro(2-dicyclohexylphosphine-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)] (CyJohnPhos), 2-dicyclohexylphosphine-2′-(N,N-dimethylamino)biphenyl (DavePhos), (2-dicyclohexylphosphine-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)] (RuPhos), 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos), [(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] (BrettPhos), 1,1'-bis(di-tert-butylphosphino)ferrocene (dtbpf), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (t-BuXPhos), [(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] ( t-BuBrettPhos), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl (Me 4- tBuXPhos), 5-(di-tert-butylphosphino)-1′,3′,5′-triphenyl-1′H-1,4′-bipyrazole (BippyPhos), di(1-adamantyl)-2-morpholinophenylphosphine (MorDalPhos), palladium / 1,3-bis-(2,6-diisopropylphenyl)chloroimidazoline (IPr .HCl), [2-(di-1-adamantylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl][2-(2′-amino-1,1′-biphenyl)]palladium methanesulfonate(II) (AdBrettPhos), (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium methanesulfonate(II) (RuPhos), [(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium methanesulfonate(II) (BrettPhos), [(2-{bis[3,5-bis(trifluoromethyl)phenyl]phosphine}-3,6-dimethoxy-2′,4′,6′-Triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (JackiePhos), [(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (t-BuBrettPhos), methanesulfonyl(2-(di-tert-butylphosphino)-1,1′-binaphthyl)[2-(2′-amino-1,1′-biphenyl)]palladium (TrixiePhos), (2-biphenyl)di-tert-butylphosphine, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine ( t-BuDavePhos), 2-di-tertiary butylphosphino-2′-methylbiphenyl (t-BuMePhos), chloro(2-dicyclohexylphosphino-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (CyJohnPhos), 2-Dicyclohexylphosphino-2′-methylbiphenyl (MePhos), 2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (PhDavePhos), 2-Dicyclohexylphosphino-2′-methoxy-4′,6′-di-tertiary butylbiphenyl (VPhos), 2-[(tertiary butyl)phenylphosphino]-2′,6′-bis(N,N-dimethylamino)biphenyl (PhCPhos), [(2-Dicyclohexylphosphino-2′,6′-bis(N,N-dimethylamino)-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium methanesulfonate(II) (CPhos), methanesulfonate-[2-diethylphosphino-2',6'-bis(dimethylamino)-1,1-biphenyl](2'-amino-1,1'-biphenyl-2-yl)palladium(II) (EtCPhos), 2-bis(tert-butyl)phosphino-2',4',6'-triisopropyl-3-methoxy-6-methylbiphenyl (RockPhos), di-1-adamantyl(4″-butyl-2',3',5',6'-tetrafluoro-2',4',6'-triisopropyl-2-methoxy-meta-triphenyl)phosphine (AlPhos), 2-(tert-butylphenylphosphino)-2',6'-dimethylamino-1,1'-biphenyl (( t-Bu)PhCPhos) and dicyclohexyl[2′,4′,6′-tris(propyl-2-yl)[1,1′-biphenyl]-2-yl]phosphonane (XPhos). The above list includes examples in which the palladium catalyst and phosphine ligand are part of the complex.

[0012] In one state, the palladium catalyst and phosphine ligand used to prepare compound (I) are not the complex methanesulfonate-(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (BrettPhos-Pd-G4).

[0013] In another sample, the palladium catalyst used to prepare compound (I) is bis(dibenzylacetone)palladium(0) (Pd(dba)2). In another sample, the phosphine ligand is dicyclohexyl[2′,4′,6′-tris(prop-2-yl)[1,1′-biphenyl]-2-yl]phosphine (XPhos). In yet another sample, the palladium catalyst used to prepare compound (I) is bis(dibenzylacetone)palladium(0) (Pd(dba)2), and the phosphine ligand is dicyclohexyl[2′,4′,6′-tris(prop-2-yl)[1,1′-biphenyl]-2-yl]phosphine (XPhos).

[0014] In another state, the reaction mixture further comprises a base. Suitable bases include potassium carbonate (K₂CO₃), cesium carbonate (Cs₂CO₃), potassium hydroxide (KOH), and sodium tert-butoxide (NaO tBu). In another state, the base is either cesium carbonate (Cs₂CO₃) or sodium tert-butoxide (NaO tBu).

[0015] In another embodiment, the reaction is carried out in a solvent such as toluene, 1,4-dioxane, tetrahydrofuran (THF), methyltetrahydrofuran, anisole, water (H₂O), or mixtures thereof. In some examples, the reaction is carried out in 1,4-dioxane, tetrahydrofuran (THF), water (H₂O), or mixtures thereof. In some examples, the reaction is carried out in 1,4-dioxane, toluene, or mixtures thereof.

[0016] In one state, the compound of formula (I) can be purified by recrystallization in a solvent system such as dimethyl sulfoxide (DMSO) and ethanol. For example, the compound of formula (I) can be dissolved in dimethyl sulfoxide (DMSO), heated as appropriate, and then ethanol (or water) can be added, cooled as appropriate. In another state, seed crystals of the compound of formula (I) can be added to promote crystallization. In one state, the compound of formula (I) is obtained from the methods described above or in the examples and is separated from the reaction as, for example, a wet filter cake.

[0017] Example 4 provides specific conditions for preparing compound (I) from compounds of formula (Ic) and (Id).

[0018] The preparation of compound (Ic) is also revealed in this article. .

[0019] As specified above, compound (Ic) is the starting material for preparing compound (I). The method for preparing compound (Ic) includes, in the presence of a base, a palladium catalyst, and a phosphine ligand, reacting the first starting material of formula (Ia): Or its salt and the second starting substance of formula (Ib): Or its salts react to form compound of formula (Ic). Suitable palladium catalysts and phosphine coordination systems are as described above for the preparation of compound (I). Suitable base systems are as described above for the preparation of compound (I).

[0020] In one state sample, the base in the reaction between the starting materials (Ia) and (Ib) is cesium carbonate (Cs₂CO₃), the palladium catalyst is bis(dibenzylacetone)palladium(O) (Pd(dba)₂), and the phosphine ligand is (9,9-dimethyl-9H-α). -4,5-diyl)bis(diphenylphosphine) (Xantphos). In some instances, the reaction is carried out in a polar solvent, such as dioxane. The reaction can also be carried out under heating, such as at 90°C to 110°C, or at 92°C to 108°C, or at 95°C to 105°C.

[0021] In one state sample, the base in the reaction between the starting materials (Ia) and (Ib) is potassium hydroxide (KOH), the palladium catalyst is bis(dibenzylacetone)palladium(0) (Pd(dba)2), and the phosphine ligand is (9,9-dimethyl-9H-α). -4,5-diyl)bis(diphenylphosphine) (Xantphos). In some instances, the reaction is carried out in a nonpolar solvent, such as toluene. The reaction can also be carried out under heating, such as at 70°C to 110°C, or at 80°C to 100°C, or at 85°C to 95°C.

[0022] In a sample, the compound (Ic) prepared by the above method is reacted with the compound (Id) without separating the compound (Ic).

[0023] Example 4 provides specific conditions for the preparation of compound (Ic).

[0024] This article also discloses a method for preparing compound (Ia). As described above, compound (Ia) is a starting material for preparing compound (Ic). The preparation of compound (Ia) is a five-step procedure, each of which is described below. Each reaction step is considered an individual example. The combination of these reaction steps, including the five-step procedure for producing compound (Ia), is also considered an individual example.

[0025] The first step in preparing a compound of formula (Ia) is a method for preparing a compound of formula (III): .

[0026] The method includes, in the presence of a platinum hydride catalyst or a palladium hydride catalyst, using the starting material of formula (II): Hydrogenation is performed to form compound (III). Suitable hydrogenolysis catalysts include 20% palladium hydroxide supported on carbon (Perlman's catalyst), palladium chloride, palladium, wet palladium / carbon, and platinum oxide (PtO₂). In one state, the platinum hydrogenolysis catalyst is PtO₂ and the palladium hydrogenolysis catalyst is wet palladium / carbon. In another state, the reaction is carried out in ethyl acetate (EtOAc) at 20°C to 30°C, or at 22°C to 28°C. Compound (II) can be prepared from 4-bromo-iodophenone (see Example 1.1), a known compound (CAS 15115-60-3), which is also available from Sigma Aldrich (catalog number 644366). []

[0027] The second step in preparing a compound of formula (Ia) is a method for preparing a compound of formula (IV): .

[0028] This method includes using the starting material of formula (III): The compound is reacted with tert-BuONO nitrite and hydrogen chloride to form compound (IV). In one state, the reaction is carried out in tetrahydrofuran (THF) at 0°C to 10°C, and the hydrogen chloride is methanolic hydrogen chloride. In another state, the starting material of structure (III) is prepared as described in the first step.

[0029] The third step in preparing a compound of formula (Ia) is to prepare a compound of formula (V): Or the method of salting it.

[0030] This method includes using the starting material of formula (IV): Or its salt reacts with phosphine chloride (POCl 3), phosphorus pentachloride (PCl 5) and hydrogen chloride to form compound of formula (V).

[0031] In one state, the starting material of formula (IV) is combined with POCl3 and PCl5 at 0°C to 25°C, 5°C to 20°C, or 10°C to 15°C, followed by the addition of hydrogen chloride and heating to 50°C to 70°C or 55°C to 65°C. In another state, the reaction is carried out in dioxane. In another state, the starting material of formula (IV) is prepared as described in step two.

[0032] The fourth step in preparing a compound of formula (Ia) is a method for preparing a compound of formula (VI): .

[0033] This method involves using the starting material of formula (V) in the presence of an amine base, a hydride reducing agent, and a palladium catalyst: It can react with its salts to form a compound of formula (VI).

[0034] Amine bases are nitrogen-containing compounds that can accept protons. Examples include methylamine (CH3NH2), dimethylamine ((CH3)2NH), trimethylamine ((CH3)3N) and their C2-C6 alkylamine analogs, aniline (PhNH2) and its derivatives, N,N-diisopropylethylamine, dimethylaminopyridine (DMAP), tetramethylethylenediamine (TMEDA), and pyridine.

[0035] Hydride reducing agents are chemical compounds that can reduce the compound of interest by adding negatively charged hydrogen ions (H- ions). Examples include sodium hydride (NaH), lithium hydride (LiH), lithium aluminum hydride (LiAlH4), sodium triethylborohydride, and sodium borohydride (NaBH4).

[0036] The suitable palladium catalyst system is as described above for the first embodiment. In one state, the palladium catalyst is 1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (Pd(dba)2), the hydride reducing agent is sodium borohydride, and the amine base is tetramethylethylenediamine (TMEDA). In one state, the reaction is carried out in tetrahydrofuran at 20°C to 30°C. In another state, the starting material of formula (V) is prepared as described in the third step.

[0037] The fifth step in preparing the compound of formula (Ia) includes using the starting material of formula (VI): It reacts with a brominating agent in acid to form a compound of formula (Ia).

[0038] Suitable acids include (but are not limited to) sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid and similar acids.

[0039] The brominating agent is a compound capable of adding an electrophilic bromine atom (Br+) to the compound of interest. Suitable brominating agents are cyanogen bromide (CNBr), bromine (Br2), and N-bromosuccinimide (NBS). In one state, the brominating agent is N-bromosuccinimide (NBS) and the acid is sulfuric acid (H2SO4). In another state, the starting material of formula (VI) is prepared as described in step four.

[0040] Example 1 schematically illustrates a five-step procedure for preparing compound (Ia). Specific conditions for each of these reaction steps are provided in Example 1.

[0041] This article also discloses a method for preparing compound (Ib): .

[0042] As described above, compound (Ib) is the starting material for preparing compound (Ic). The preparation of compound (Ib) involves a five-step procedure, each of which is described below. Each reaction step is considered an individual example. The combination of these reaction steps, including the five-step procedure that produces compound (Ib), is also considered an individual example.

[0043] The first step in preparing a compound of formula (Ib) is a method for preparing a compound of formula (VII): . The following provides a definition of R. This method includes using the starting material of formula (VIIa): It reacts with sulfonyl chloride (e.g., ethanesulfonyl chloride (also known as esyl chloride or EsCl)) and amine bases (such as triethylamine (TEA)) to form compound (VII).

[0044] Sulfonyl chlorides have the general formula RSO₂Cl, where R is a C1-C4 straight-chain or branched alkyl group, or, depending on the case, a phenyl group substituted with a halogen, C1-C4 alkyl group, and / or a nitro group, or the like. Examples include benzenesulfonyl chloride, toluenesulfonyl chloride (p-toluenesulfonyl chloride), bromobenzenesulfonate chloride (p-bromobenzenesulfonyl chloride), nitrobenzenesulfonyl chloride (nosyl chloride / nitrophenyl sulfonyl chloride), mesyl chloride (mesyl chloride / methyl sulfonyl chloride), and esyl choride (esyl sulfonyl chloride). The sulfonyl group is represented by RSO₂⁻. In one state, the reaction is carried out in dichloromethane at 5°C to 20°C or at 10°C to 15°C.

[0045] Suitable amine-base systems are prepared as described above for compounds of formula (VI).

[0046] The starting material for formula (VIIa) can be obtained according to the procedure described in Frigola et al., J. Med. Chem., 38:1203 (1995) (the full teaching of which is incorporated herein by reference).

[0047] The second step in preparing a compound of formula (Ib) is a method for preparing a compound of formula (VIII): .

[0048] This method includes using the first starting material of formula (VII): (For example, ) or its salt and the second starting substance of formula (VIIIb): The mixture reacts with an alkali (such as potassium carbonate (K₂CO₃)) to form compound (VIII). R is as described above for compound (VII). In another sample, the starting material for formula (VII) is prepared as described in the first step.

[0049] The third step in preparing the compound of formula (Ib) is a method for preparing the second starting material of formula (VIIIb). This method includes reacting methyl 2-bromoacetate with... reaction.

[0050] The fourth step in preparing a compound of formula (Ib) is a method for preparing a compound of formula (IX): .

[0051] This method involves the presence of the starting material of formula (VIII) underwater: Or its salt reacts with lithium chloride (LiCl) to form compound (IX). For example, 0.4 to 0.6 mol equivalents of water can be used. In one state, the reaction is carried out in dimethylacetamide (DMAc) at 160 to 170 °C. In another state, the starting material of formula (VIII) is prepared as described in step three.

[0052] The fifth step in preparing a compound of formula (Ib) or a salt thereof includes using the starting material of formula (IX): Or its salt is hydrogenated in the presence of a palladium hydrolysis catalyst to form compound (Ib). In one state, the palladium hydrolysis catalyst is carbon-supported palladium hydroxide, 20% by weight dry basis (20% Pd(OH)₂ / C), and the reaction is carried out in methanol (MeOH) at 30°C to 50°C or 35°C to 45°C. In another state, the starting material of formula (IX) is prepared as described in step four.

[0053] Example 2 schematically illustrates a five-step procedure for preparing compound (Ib). Specific conditions for each of these reaction steps are provided in Example 2.

[0054] Another embodiment of the present invention comprises compounds selected from the following: (where R is defined as in this paper, for example) (Es is ethyl sulfonyl) , and , or salt of any of the above.

[0055] These compounds possess basic groups and therefore can react with inorganic and organic acids to form salts. Examples of such salts include sulfates, pyrosulfates, bisulfates, sulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propiolates, oxalates, malonates, succinates, octanoates, sebacic acid salts, and fumarates. Salts, maleates, butyn-1,4-diacidates, hexyn-1,6-diacidates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and similar salts.

[0056] [] [Example] [] [Preparation of Exemplary Compounds] [] [definition] [] ACN Acetonitrile C degrees Celsius Cs2CO3 cesium carbonate DCM dichloromethane DMAc dimethylacetamide DMSO (dimethylamine) EsCl (Ethylsulfonyl chloride) EtOAc (ethyl acetate) EtOH (ethanol) g gram h hours H2 hydrogen gas H₂O water H₂SO₄ sulfuric acid HCl (hydrogen chloride) HPLC (High Performance Liquid Chromatography) IC50 inhibition concentration 50% LC-MS (Liquid Chromatography-Mass Spectrometry) LiCl (lithium chloride) K₂CO₃ (potassium carbonate) kg mbar MeOH (methanol) min minutes MTBE (Methyl Tertiary Butyl Ether) N2 nitrogen gas Sodium borohydride (NaBH4) NaHSO3 (sodium bisulfite) Sodium sulfate (Na₂SO₄) NLT not less than NMT no more than PtO 2 platinum oxide R1 First Reactor R2 Second Reactor RT (Retention Time) rt room temperature SiO₂ (silicon dioxide) t-BuONO tert-butyl nitrite TEA Triethylamine TLC (Thin Layer Chromatography) TMEDA Tetramethylethylenediamine THF Tetrahydrofuran * 3 Number of repetitions (e.g., 3 times)

[0057] [LC-MS]: Liquid chromatography-mass spectrometry (LC-MS) data (for samples for purity and identity analysis) were obtained using an Agilent 6120 mass spectrometer with an Agilent Poroshel 120 (EC-C18, 2.7 µm particle size, 3.0 x 50 mm) reverse-phase column on an Agilent 1260 LC system. Data were obtained using ES-API ionization at 22.4 °C. The mobile phase consisted of a mixture of 0.1% formic acid / water and 0.1% formic acid / acetonitrile. A constant gradient was used from a 95% aqueous / 5% organic mobile phase to a 5% aqueous / 95% organic mobile phase over a 4-minute process. The flow rate was kept constant at 1 mL / min.

[0058] Alternatively, liquid chromatography-mass spectrometry (LC-MS) data (for samples undergoing purity and identity analysis) were obtained using a Shimadzu LCMS system with an Agilent (Poroshel HPH-C18, 2.7 µm particle size, 3.0 x 50 mm) reverse-phase column, via ESI ionization at 22.4 °C. The mobile phase consisted of a mixture of 5 mM NH₄HCO₃ (or 0.05% TFA) solvent, water, and acetonitrile. A constant gradient was used from 90% aqueous solution / 10% organic to 5% aqueous solution / 95% organic mobile phase over a 2-minute process. The flow rate was kept constant at 1.5 mL / min.

[0059] [Silicone Chromatography:] Silicone chromatography is performed on a Teledyne Isco CombiFlash® Rf unit, a Biotage® Isolera Four unit, or a Biotage® Isolera Prime unit.

[0060] [Proton] [NMR]: ¹H NMR spectra were obtained using a Varian 400MHz Unity Inova 400 MHz NMR instrument (acquisition time = 3.5 s with a 1 s delay; 16 to 64 scans) or an Avance 400MHz Unity Inova 400 MHz NMR instrument (acquisition time = 3.99 s with a 1 s delay; 4 to 64 scans) or an Avance 300MHz Unity Inova 300 MHz NMR instrument (acquisition time = 5.45 s with a 1 s delay; 4 to 64 scans). Unless otherwise specified, all protons were reported in DMSO-d6 solvent in parts per million (ppm) relative to residual DMSO (2.50 ppm).

[0061] GC: Gas chromatography was performed using an Agilent 7890C gas chromatography system or a similar DB-1 15 m x 0.25 mm x 1.0 µm or equivalent column, with a syringe temperature of 250 °C, a detector temperature of 325 °C, and a constant flow rate of nitrogen carrier gas of 1.6 mL / min.

[0062] [Crafting Example:] [] [Example] [1] [:synthesis] [8-] [bromine] [-3-] [chlorine] [-5-] [Isopropylisoquinoline] [(Ia)] [] [] [1.1] [preparation] [4-(] [C] [-1-] [ene] [-2-] [base] [)-2,3-] [Dihydrogen] [-1,H- , ] [Indigo] [-1-] [ketone] [(II)] At 25°C, a mixture containing dioxane (2500 mL) and H₂O (500 mL) was prepared. [Compound] Add to the solution of [(IIa)](500 g, 2.37 mol, 1.00 eq) [Compound] [(IIb)] (398 g, 2.37 mol, 1.00 eq), Pd(dppf)Cl₂ (17.3 g, 23.6 mmol, 0.01 eq), and TEA (719 g, 7.11 mol, 989 mL, 3.00 eq). The reaction mixture was stirred at 80 °C for 12 hours. LCMS showed... [Compound] [(IIa)] Complete consumption and determination to the desired mass (RT = 0.885 min). The three batches were combined. The mixture was filtered through diatomaceous earth and the filter cake was washed with ethyl acetate (500 mL * 3). H₂O (4000 mL) was added to the filtrate and extracted with ethyl acetate (1000 mL * 3). The organic phase was washed with brine (2000 mL), dried over Na₂SO₄, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 50 / 1 to 10 / 1, Rf = 0.4). A pale yellow solid was obtained. [Compound] [(II)] (1.05 kg, 6.05 mol, 85.1% yield, 99.0% purity) and confirmed by 1H NMR and LCMS. [LC-MS]: Product: RT = 0.885 min, m / z = 173.0 (M+H)+. [, 1 , ] [HNMR]: (400 MHz, CDCl 3) [ppm] δ 7.68 (dd, J= 7.6, 0.8 Hz, 1H), 7.49 (dd, J= 8.0, 1.2 Hz, 1H), 7.34 - 7.38 (m, 1H), 5.30 - 5.31 (m, 1H), 5.10 (d, J= 1.2, 0.8 Hz, 1H), 3.15 - 3.18 (m, 2H), 2.67 - 2.71 (m, 2H), 2.14 - 2.15 (m, 3H).

[0063] [1.2] [preparation] [4-] [Isopropyl] [-2,3-] [Dihydrogen] [-1, H , - ] [Indigo] [-1-] [ketone] [(III)] [] At 25°C and under N₂ conditions, the solution contained in EtOAc (10.5 L) was... [Compound] [(II)] A solution of 1.05 kg (6.04 mol, 1.00 eq) was supplemented with wet Pd / C (210 g, 10% Pd content). The suspension was degassed under vacuum and purified several times with H₂. The mixture was stirred at 25°C for 12 hours with H₂ (20 psi). LCMS showed... [Compound] [(II)] Complete consumption and determination of the desired mass (RT = 0.802 min). The mixture was filtered through diatomaceous earth and washed with ethyl acetate (2000 mL * 3). The filtrate was concentrated to obtain the residue. This residue was used in the next step without further purification. A white solid was obtained. [Compound] [(III)] (1.08 kg, crude product) and verified by LCMS. [LC-MS]: Product: RT = 0.858 min, m / z = 175.1 (M+H)+.

[0064] [] [1.3] [preparation] [( , E , )-2-( ] [Hydroxyimino group] [)-4-] [Isopropyl] [-2,3-] [Dihydrogen] [-1H-] [Indigo] [-1-] [ketone] [(IV)] At 0 to 10°C, under N2 conditions, the solution contained in THF (750 mL) was... [Compound] t-BuONO (262 g, 2.54 mol, 302 mL, 1.50 eq) was added to a solution of [(III)] (295 g, 1.69 mol, 1.00 eq). Then, HCl / MeOH (4 M, 110 mL, 0.26 eq) was added dropwise to the mixture at 0 to 10 °C. After the addition, the reaction mixture was stirred at 0 °C for 2 hours. LCMS showed... [Compound] [(III)] Consumption and determination of the desired mass (RT = 0.774 min). The reaction mixture was concentrated to obtain a residue. The residue was slurried with petroleum ether / ethyl acetate = 7 / 1 (800 mL) and filtered. The filter cake was collected to give a pale yellow solid. A pale yellow solid was obtained. [Compound] [(IV)](205 g, 1.00 mol, 59.2% yield, 99.4% purity), confirmed by LCMS and 1H NMR. [LC-MS]: Product: RT = 0.773 min, m / z = 204.1 (M+H)+. [, 1 , ] [H NMR]: (400 MHz, DMSO) δ [ppm] 12.65 (s, 1H), 7.65 (d, J= 7.6 Hz, 1H), 7.58 (d, J= 7.2 Hz, 1H), 7.46 (t, J= 7.6 Hz, 1H), 3.77 (s, 2H), 3.06 - 3.36 (m, 1H), 1.24 (d, J= 6.8 Hz, 6H).

[0065] [1.4] [preparation] [1,3-] [Dichloro] [-5-] [Isopropylisoquinoline] [(V)] [] At 25°C, the solution contained in dioxane (650 mL) was... [Compound] POCl3 (151 g, 984 mmol, 91.5 mL, 1.51 eq) was added to a solution of [(IV)] (133 g, 650 mmol, 1.00 eq). Then, PCl5 (203 g, 976 mmol, 1.50 eq) was added fractionally to the mixture at 0–20 °C. The mixture was stirred at 0–20 °C for 0.5 h. Then, HCl / dioxane (4 M, 16.3 mL, 0.10 eq) was added to the mixture at 0–20 °C, and the mixture was stirred at 60 °C for 11 h. LCMS showed… [Compound] [(IV)] Complete consumption and determination to the desired mass (RT = 1.074 min). The mixture was stopped with H₂O (1500 mL) and extracted with dichloromethane (300 mL * 3). The organic phase was washed with brine (300 mL), dried over Na₂SO₄, filtered, and concentrated to obtain the residue. The residues were combined and purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0 to 100 / 1, Rf = 0.35). The residues were detected by TLC (petroleum ether / ethyl acetate = 1 / 0, Rf = 0.35). A yellow oil was obtained. [Compound] [(V)] (138 g, 575 mmol, 64.5% yield) and confirmed by LCMS. [LC-MS]: Products: RT = 1.074 min, m / z = 239.9 (M+H) +

[0066] [1.5] [preparation] [3-] [chlorine] [-5-] [Isopropylisoquinoline] [(VI)] [] [] At 25°C, under nitrogen atmosphere, the solution contained in THF (850 mL) was... [Compound] Pd(dppf)Cl₂ (4.25 g, 5.81 mmol, 0.01 eq) was added to a solution of [(V)] (170 g, 581 mmol, 1.00 eq). Then, TMEDA (101 g, 872 mmol, 132 mL, 1.50 eq) and NaBH₄ (81.6 g, 2.16 mol, 3.71 eq) were added to the mixture. The reaction mixture was stirred at 25 °C for 1 hour. TLC (petroleum ether / ethyl acetate = 10 / 1) showed... [Compound] [(V)] (R f = 0.8) was completely consumed and detected at the major point (R f = 0.6). The mixture was poured into a cooled 1N HCl aqueous solution (1000 mL) and extracted with ethyl acetate (500 mL * 3). The organic phase was filtered through diatomaceous earth and the filtrate was washed with brine (200 mL), dried over Na₂SO₄, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0 to 100 / 1, R f = 0.6). A yellow oil was obtained. [Compound] [(VI)] (137 g, crude product) and confirmed by 1H NMR and LCMS. [LC-MS]: Product: RT = 0.901 min, m / z = 206.1 (M+H)+. [] [, 1 , ] [H NMR]: (400 MHz, CDCl 3) δ [ppm] 9.06 (s, 1H), 7.94 (s, 1H), 7.82 (d, J= 8.0 Hz, 1H), 7.64 (d, J= 6.8 Hz, 1H), 7.55 - 7.58 (m, 1H), 3.55 - 3.65 (m, 1H), 1.40 (d, J= 6.8 Hz, 6H).

[0067] [1.6] [preparation] [3-] [chlorine] [-5-] [Isopropylisoquinoline] [(Ia)] [] At -10 to 0°C, [Compound] [(VI)] (93.8 g, 392 mmol, 1.00 eq) was added to a solution of H₂SO₄ (500 mL). After the addition, the mixture was cooled to -10 to -20 °C, and at -10 to -20 °C, NBS (90.7 g, 510 mmol, 1.30 eq) was added to the mixture. The reaction mixture was then stirred at 25 °C for 2 hours. TLC (petroleum ether / ethyl acetate = 20 / 1) showed... [Compound] [(VI)] (R f = 0.6) Residue and major formation point (R f = 0.9). The mixture was poured into ice (1500 g) at 0 to 10 °C and adjusted to pH = 9 with ammonium hydroxide (1800 mL), then extracted with ethyl acetate (500 mL * 2). The organic phase was washed with brine (1000 mL), dried over Na₂SO₄, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0 to 50 / 1, R f = 0.9). A grayish-white solid was obtained. [Compound] [(VI)] (70.03 g, 230 mmol, 58.7% yield, 93.6% purity) and confirmed by 1H NMR, LCMS and HPLC. [LC-MS]: Product: RT = 1.149 min, m / z = 283.9 (M+H)+. [] [HPLC]: Product: RT = 2.863 min, 93.6% purity, at 220 nm. [, 1 , ] [HNMR]: (400 (MHz, CDCl 3) δ [ppm] 9.43 (s, 1H), 7.91 (s, 1H), 7.78 (d, J= 7.6 Hz, 1H), 7.46 (d, J= 7.6 Hz, 1H), 3.51 - 3.62 (m, 1H), 1.38 (d, J= 7.2 Hz, 6H).

[0068] [Example] [2] [:] [synthesis] [( , 2R,3S , )-2- ] [methyl] [-3-((] [Methylsulfonylurea] [)] [methyl] [)] [Azacyclobutane hydrochloride] [(Ib)] [] [] [] [2.1] [preparation] [2-(] [Methylsulfonylurea] [)] Methyl acetate [(VIIIb)] [:] [] [] Sodium methanesulfinate (153.19 kg, 1500 mol, 1.2 eq) and acetone (760.00 kg) were added to a 3000 L reactor in a single-component manner. [Acetic acid] [2-] [Methyl bromide] [(BMA)](190.00 kg, 1250 mol, 1.0 eq). The reaction mixture was heated to 55–60 °C and stirred at 55–60 °C for 12–16 hours. After the reaction was complete (GC monitoring), the reaction mixture was cooled to 15–20 °C. The reaction mixture was filtered, and the filter cake was washed once with acetone (50 L). The combined filtrates were concentrated to a volume of 300–350 L under vacuum. Heptane (200 L) was added, and the mixture was further concentrated to a volume of 300–350 L. This process was repeated twice to remove residual acetone.

[0069] Add 400 L of n-heptane and stir the mixture at 20 to 30 °C for 1 to 2 hours. Filter the mixture and wash the filter cake once with 60 L of n-heptane. Dry the wet filter cake at 35 to 40 °C for 6 to 10 hours to obtain a white solid. [Compound] [(VIIIb)] (167.60 kg, 88.2% yield), GCAP: 100%. [GC] Purity: 100% (a / a), RT = 3.79 min. [, 1 , ] [H NMR]: (400 MHz, CDCl 3) δ [ppm] 4.02 (s, 2H), 3.85 (s, 3H), 3.16 (s, 2H).

[0070] [] [2.2] [preparation] [(((2 ,R , , 3 , S , )-1- ] [Diphenylmethyl] [-] [Methylazacyclobutane] [-3-] [base] [)] [Oxygen group] [)] [Ethyl sulfonate] [(VIIc)] [] [] Add to a 2000 L reactor [Compound] [(VIIa)] (215.00 kg, 848.7 mol, 1.0 eq) and DCM (1144.00 kg). After stirring for 5 minutes, TEA (111.64 kg, 1103.3 mol, 1.3 eq) was added. The reaction mixture was cooled to 0 to 10 °C under nitrogen protection. EsCl (120.03 kg, 933.5 mol, 1.1 eq) was slowly added to the reaction over 2 to 3 hours while maintaining the temperature <10 °C. A white solid formed during the addition. After the addition, the reaction was stirred for another 1 to 2 hours.

[0071] The reaction mixture was stopped and stirred for 15 minutes with H₂O (645 L). The organic layer was separated, and the aqueous phase was extracted once with DCM (215 L). The combined organic phases were washed with 10% brine (215 L). The organic fraction was concentrated to a volume of 450 to 500 L under vacuum at 40 to 45 °C. 645 L of n-heptane was added, and the mixture was distilled to a volume of 450 to 500 L. This process was repeated twice to remove residual DCM. 645 L of n-heptane was added, and the mixture was stirred at 20 to 30 °C for 1 to 2 hours. The mixture was filtered, and the filter cake was washed once with n-heptane (88 L). The wet filter cake was dried under vacuum at 45 to 55 °C for 6 to 10 hours to obtain a yellow solid. [Compound] [(VIIc)](284.20 kg, 96.9% yield). [HPLC] Purity: 99.7% (a / a), RT = 6.70 min. [, 1 , ] [H NMR]: (400 MHz, CDCl 3) δ [ppm] 7.45-7.33 (m, 4H), 7.30-7.21 (m, 6H), 4.66-4.61 (ddd, 1H), 4.43 (s, 1H), 3.77-3.73 (dd, 1H), 3.43-3.36 (dq, 1H), 3.43-3.37 (q, 2H), 2.91-2.87 (dd, 1H), 1.43-1.40 (t, 3H), 0.84-0.83 (d, 3H).

[0072] [2.3] [preparation] [(S)2-(2, R , ,3 , S , )-1- ] [Diphenylmethyl] [-2-] [Methylazacyclobutane] [-3-] [base] [)-2-((] [Methylsulfonylurea] [)] Methyl acetate [) (VIII)] [] [] Add to 2000 L reactor [Compound] [(VIIc)] (142.2 kg, 411.6 mol, 1.0 eq) and acetonitrile (665.50 kg). After stirring for 5 minutes, methyl 2-(methanesulfonyl)acetate was added separately. [Compound] [(VIIIb)] (75.16 kg, 494.0 mol, 1.2 eq) and K₂CO₃ (113.78 kg, 823.3 mol, 2.0 eq). The reaction mixture was heated to 68–72 °C and stirred at 68–72 °C for 16 hours. K₂CO₃ (28.45 kg, 205.8 mol, 0.5 eq) was added to the reaction mixture, and it was stirred at 68–72 °C for 24 hours. After the reaction was complete (as monitored by HPLC), the reaction mixture was cooled to 15–20 °C. The reaction mixture was centrifuged, the filtrate was concentrated to a volume of 150–200 L, and the filtrate was combined with the filtrate from the next step.

[0073] The centrifuged filter cake was suspended in ethyl acetate (570 L) and stirred for 1 to 2 hours. The slurry was centrifuged. The filtrate was combined with the filtrate from the previous step. A 10% NaCl aqueous solution (156 L) was added to the combined liquid and stirred for 15 minutes. The organic layer was separated, and the aqueous phase was extracted with ethyl acetate (142 L). The combined organic phase was washed twice with 10% brine (142 L x 2). The organic phase was concentrated under reduced pressure at 45 to 55 °C.

[0074] MTBE (284 L) was added to the residue and stirred for 1 to 2 hours, followed by slow addition of n-heptane (383 L) at 15 to 20 °C for 2 to 3 hours. The resulting slurry was filtered, and the filter cake was washed once with n-heptane (50 L). The wet filter cake was dried under vacuum at 45 to 55 °C for 6 to 10 hours to obtain a yellow solid. [Compound] [(VIII)](125.70 kg, 78.9% yield). [HPLC] Purity: 97.7% (a / a), RT = 6.30 min. [, 1 , ] [H NMR]: (400 MHz, DMSO-d 6) δ [ppm] 7.43-7.27 (m, 4H), 7.25-7.18 (m, 6H), 4.69-4.59 (dd, 1H), 4.50 (s, 1H), 3.74 (s, 3H), 3.45-3.40 (ddd, 1H), 3.35-3.15 (m, 1H), 3.05 (d, 3H), 2.73-2.55 (m, 2H), 0.76-0.58 (dd, 3H).

[0075] [] [2.4] [preparation] [(2, R , ,3 , S , )-1- ] [Diphenylmethyl] [-2-] [methyl] [-3-((] [Methylsulfonylurea] [)] [methyl] [)] [Azacyclobutane] [(IX)] [] [] Put into the reactor [Compound] [(VIII)] (120.8 kg, 311.7 mol, 1.0 eq) and DMAc (849.00 kg) were added, followed by the addition of LiCl (19.82 kg, 467.6 mol, 1.5 eq) and H₂O (3.00 kg, 166.7 mol, 0.53 eq), and the mixture was stirred until dissolved. The mixture was then reacted in a flow reactor at 170–175 °C for 17 minutes. The reaction mixture was monitored by HPLC every 1–2 hours. Water (725 L) and ethyl acetate (966 L) were added to the reaction mixture and stirred for 15 minutes. The organic layer was separated, and the aqueous phase was extracted once with ethyl acetate (725 L).

[0076] The combined organic phases were washed twice with 10% brine (725 L x 1, 483 L x 1), and then concentrated under reduced pressure at 45 to 55 °C. MTBE (242 L) was added to the residue and stirred for 1 to 2 hours, followed by the slow addition of n-heptane (121 L) at 15 to 25 °C for 2 to 3 hours. The resulting slurry was filtered, and the filter cake was washed once with MTBE (30 L). The wet filter cake was dried under vacuum at 45 to 55 °C for 6 to 10 hours to obtain a yellow solid. [Compound] [(IX)](74.70 kg, 72.7% yield). [HPLC] Purity: 98.8% (a / a), RT = 8.81 min. [, 1 , ] [H NMR]: (400 MHz, CDCl 3) δ [ppm] 7.45-7.40 (m, 4H), 7.32-7.19 (m, 6H), 4.35 (s, 1H), 3.70-3.65 (m, 1H), 3.26-3.10 (m, 3H), 2.85 (s, 3H), 2.65-2.57 (m, 2H), 0.85-0.82 (d, 3H).

[0077] [] [2.5] [preparation] [(2, R , ,3 , S , )-2- ] [methyl] [-3-((] [Methylsulfonylurea] [)] [methyl] [)] [Azacyclobutane hydrochloride] [(Ib)] [] [] Add to a 1000 L reactor [Compound] [(IX)] (143.9 kg, 436.8 mol, 1.0 eq) and MeOH (447.50 kg) were added separately, followed by the addition of 20% Pd(OH)₂ / C (28.78 kg, 20% w / w%) and AcOH (26.21 kg, 436.8 mol, 1.0 eq). The mixture was subjected to hydrogenolysis at 0.5 to 1.0 MPa H₂ and 25 to 35 °C for 8 to 12 hours. After the reaction was complete (HPLC monitoring), the reaction mixture was filtered, and the filter cake was washed once with MeOH (144 L). 4M HCl / MeOH was added to the filtrate to adjust the pH to the target range of 1 to 2. The mixture was concentrated to a volume of 400 L under vacuum at 45 to 55 °C. The residue was washed twice with n-heptane (288 L x 2), and the n-heptane phase was discarded. The residue was then concentrated under reduced pressure at 45 to 55°C. MeOH (144 L) was added to the residue and the mixture was stirred at 45 to 55°C for 0.5 to 1 hour, followed by the slow addition of THF (864 L) to the mixture at 45 to 55°C for 2 to 3 hours. The mixture was cooled to 20 to 30°C over 5 hours and stirred again for 4 to 5 hours. The resulting slurry was filtered, and the filter cake was washed once with THF (32 L). The wet filter cake was dried under vacuum at 45 to 55°C for 6 to 10 hours to obtain a white solid. [Compound] [(Ib)](76.20 kg, 87.7% yield). [GC] Purity: 98.9% (a / a), RT = 18.98 min. [, 1 , ] [H NMR]: (400 MHz, DMSO-d 6) δ [ppm] 9.22-9.13 (m, 2H), 4.32-4.25 (m, 1H), 3.90 (m, 1H), 3.75 (m, 1H), 3.55 (m, 2H), 2.95 (m, 4H), 1.48-1.46 (d, 3H).

[0078] [Example] [3a] [:synthesis] [2-((3s, 4R)-3-] [fluorine] [-4-] [Methoxypiperidine] [-1-] [base] [)] [Pyrimidine] [-4-] [amine] [(Id)] [] [] [3.1] [synthesis] [(3S,4R)-3-] [fluorine] [-4-] [Hydroxypiperidine] [-1-] [Tributyl formate] [(i)] [] [Compound] [(i)]((3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester) was synthesized according to the method described in J. Org. Chem., 2013, 78, 8892-8897.

[0079] [] [3.2] [synthesis] [(3S,4R)-3-] [fluorine] [-4-] [Methoxypiperidine] [-1-] [Tributyl formate] [(ii)] Sodium hydride (218.90 mg, 9.122 mmol, 4 equiv.) was added to a solution containing ((3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester) at 0 °C. [Compound] [(i)] (500 mg, 2.280 mmol, 1 equiv.) of THF (10 mL). After stirring for 20 minutes, methyl iodide (1294.73 mg, 9.122 mmol, 4 equiv.) was added. The resulting solution was stirred at 0 °C for another 1 hour. The reaction was then stopped by adding 10 mL of water. The solid was removed by filtration. The resulting solution was extracted with EA and concentrated under vacuum. This yielded 500 mg (94.1%) of the title compound as a pale yellow oil. [LC-MS]: (ES, m / z) = 178 [M+1-56].

[0080] [3.3] [synthesis] [(3S,4R)-3-] [fluorine] [-4-] [Methoxypiperidine] [(iii)] The (3S,4R)-3-fluoro-4-methoxypiperidine-1-carboxylic acid tert-butyl ester contained in TFA / DCM (3 / 10 mL) [Compound] A solution of [(ii)] (500 mg, 2.143 mmol, 1 equiv.) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum to obtain 500 mg (crude product) as a solid. [Compound] [(iii)].

[0081] [3.4] [synthesis] [2-((3S,4R)-3-] [fluorine] [-4-] [Methoxypiperidine] [-1-] [base] [)] [Pyrimidine] [-4-] [amine] [(Id)] (3S,4R)-3-fluoro-4-methoxypiperidine contained in IPA (3 mL) [Compound] [(iii)](3 g, 22.528 mmol, 1 equiv.), 2-chloropyrimidine-4-amine [Compound] A mixture of [(iv)] (2.33 g, 0.018 mmol, 0.8 equiv.) and TEA (6.84 g, 0.068 mmol, 3 equiv.) was stirred at 100 °C for 12 hours. The solvent was removed under vacuum, and the residue was purified by FLASH (5% MeOH / DCM) to obtain 3.3 g (66%) of a pale yellow solid. [Compound] [(Id)]. [LC-MS]: (ES, m / z) = 227 [M+1]. [, 1 , ] [H-NMR](400 MHz, 6d-DMSO) δ ppm 7.72 (d, 1H, J=5.6 Hz), 6.39 (s, 2H), 5.71 (d, 1H, J=5.6 Hz), 4.83 (d, 1H, J=49.3 Hz), 4.60 - 4.49 (m, 1H), 4.29 (d, 1H, J=13.3 Hz), 3.55 - 3.42 (m, 1H), 3.28 (d, 1H, J=13.3 Hz), 3.20 - 3.04 (m, 1H), 1.76 - 1.48 (m, 2H).

[0082] [Example] [3b] [:synthesis] [2-((3s,4R)-3-] [fluorine] [-4-] [Methoxypiperidine] [-1-] [base] [)] [Pyrimidine] [-4-] [amine] [(Id)] [] [] [step] [1] [and] [2] [:synthesis] [(3S,4R)-3-] [fluorine] [-4-] [Methoxypiperidine] [(iii)] Precisely mix 75 mL of tetrahydrofuran and 30.0 g (0.1368 mol) of N-Boc-(3S,4R)-3-fluoro-4-hydroxypiperidine. [Compound] [(i)] Place the mixture into a 250 mL three-necked round-bottom flask equipped with a top stirrer and a nitrogen inlet / outlet. Then add 5 g (6.4 mL) of tributanol and rinse the glass funnel with 2.5 g (2.8 mL) of tetrahydrofuran (note: toluene / THF can also be used). Add 26 g (0.20 mol, 1.5 mol eq) of dimethyl sulfate (note: CH3I can also be used) and stir the resulting mixture for 5 minutes. Add 20% potassium tributate (26.5 g, 0.24 mol, 1.75 mol eq) to THF via an addition funnel over a period of 1 hour, maintaining the internal temperature between 20 and 30 °C. This addition is exothermic, and the temperature is controlled by the rate of addition. The reaction mixture initially thickens and then thins as the addition proceeds. After the addition is complete, rinse the addition funnel with 3 mL of THF. The reaction mixture was stirred at 20 to 30°C for 30 minutes, and then samples were taken to indicate complete reaction. When < 2.0 %-a / a [Compound] [(i)] When residual, determine that the reaction system is complete. The reaction can be maintained at 20 to 40 °C for 24 hours without negatively affecting the yield or quality. Then add 30 mL of water to the reaction mixture while stirring.

[0083] Add 850 mL of deionized water and 100 g of 25% ammonia solution to a 2 L Erlenmeyer flask and stir the resulting solution for 5 minutes. Then add 32 mL of this solution to the reaction mixture, followed by 15 mL of water, maintaining the temperature between 20 and 30 °C. Stir the resulting mixture at this temperature for 2 hours and then sample for complete consumption of dimethyl sulfate. Dimethyl sulfate is considered completely quenched when < 5 ppm remains. Transfer the mixture to a 250 mL separatory funnel and allow the layers to separate for 30 minutes. Discard the lower wastewater phase. Combine any rag layer with the organic layer. Allow the product-rich organic layer to stand for 5 minutes, then discard any remaining wastewater layer. Transfer the product-rich organic layer back to a 3-necked round-bottom flask. Then add 4.5 g of acetic acid to the mixture, followed by 45 mL of water. Stir the resulting two-phase mixture at 20 to 30 °C for 30 minutes. Stop stirring and transfer the two-phase mixture back to a 250 mL separatory funnel. Allow the layers to separate for 30 minutes, then remove and discard the lower wastewater layer. Let the organic layer stand for another 5 minutes, then remove and discard any remaining water layer. Transfer the organic layer back to a 250 mL three-necked flask and heat the mixture under slight house vacuum to 40-50°C until slight reflux is achieved and approximately 20 mL of the THF / water azeotrope is removed by distillation. Then add 75 mL of toluene and heat the mixture under slight house vacuum to 40-50°C until slight reflux is achieved and approximately 20 mL of the THF / toluene / water azeotrope is removed by distillation. [step] [1] Mixture sampling was used for Karl-Fischer analysis (KF). The KF endpoint was reached at < 0.25 %-w / w. [step] [1] The mixture can be kept at 20 to 30°C for 72 hours without negatively affecting yield or quality. [step] [1] Transfer the mixture to a glass jar and add 20 mL of toluene.

[0084] Accurately place 80 g (100 mL) of isopropanol into a 500 mL three-necked flask equipped with a top stirrer and a nitrogen inlet / outlet. Add 25 g (100%) of hydrogen chloride into the reactor via the gas inlet tube and with gentle stirring, ensuring the gas inlet tube is below the surface of the isopropanol. This addition is highly exothermic. Stir the hydrochloric acid solution containing toluene under nitrogen at 0–15°C for 1 hour. Adjust the temperature of the hydrochloric acid solution containing isopropanol to 20–30°C and add it dropwise via an addition funnel over 90 minutes. [step] [1] Mixture. Observe the CO2 exhaust gas, which is controlled by the addition rate. After the addition is complete, rinse the addition funnel with 10 mL of toluene and stir the resulting slurry at 20 to 30 °C for 3 to 4 hours. When < 0.5 %-a / a [step] [1] When the mixture remains, the reaction is considered complete. The slurry can be kept at 20 to 30 °C for 24 hours without negatively affecting the yield or quality. The slurry is heated to 40 to 50 °C under slight vacuum until slight reflux is obtained and about 70 to 80 mL of isopropanol / toluene is distilled off. Another 100 mL of toluene is added, and distillation is performed simultaneously to maintain a constant volume in the 3-necked flask and to remove about 100 mL of solvent (repeat twice). The slurry is cooled to 20 to 30 °C and sampled to evaluate solvent exchange. The endpoint is reached when < 2 %-a / a isopropanol remains. 9 mL of isopropanol is added to the slurry and stirred for another hour. Crystals are collected by filtration and the filter cake is washed with two filter cake volumes (about 50 mL) of toluene. The filter cake is dehydrated under nitrogen for 1 hour and then dried under vacuum at 45 to 50 °C for 24 hours.

[0085] [step] [3.] [synthesis] [2-((3S,4R)-3-] [fluorine] [-4-] [Methoxypiperidine] [-1-] [base] [)] [Pyrimidine] [-4-] [amine] [(Id)] Precisely measure 80 g (78 mL) of dioxane and 31.0 g (0.183 mol, 1.09 mol eq). [Compound] [(iii)] 21.6 g (0.167 mol, 1.0 mol eq) of 4-amino-2-chloropyrimidine, 14.5 g (0.027 mol, 0.16 mol eq) of 25% ZnCl₂ in 2-methyltetrahydrofuran solution, and 44.0 g (60.0 mL, 0.43 mol) of triethylamine were placed in a 500 mL three-necked flask equipped with a top stirrer and a nitrogen inlet / outlet. The resulting mixture was heated to reflux (90 to 100 °C) and stirred at this temperature for 16 hours. The reaction mixture was cooled to 50 to 60 °C and samples were taken to indicate complete reaction. The reaction was considered complete when < 1.0 %-a / a 4-amino-2-chloropyrimidine residue was observed. The reaction was cooled to 20 to 30 °C, and then 43 mL of water and 110 g of 30% NaOH were added. Stir the resulting two-phase mixture at 20–30°C for 20 minutes. Stop stirring and allow the layers to separate for 30 minutes. Discard the lower wastewater phase. Remove any boundary layer and the lower wastewater phase, then sample it for pH determination. The pH of the wastewater layer should be > 12. Allow the upper organic-rich stream to stand for another 5 minutes. Discard any wastewater layer. Add 40 g of 30% NaOH and 16 g of water to the product-rich organic layer. Stir the resulting two-phase mixture at 20–30°C for 20 minutes. Stop stirring and allow the layers to separate for 30 minutes. Discard the lower wastewater layer. Remove any boundary layer and discard it. Allow the product-rich upper organic layer to stand for another 5 minutes. Discard any wastewater layer. Polish and filter the product-rich organic phase into a second 500 mL three-necked flask equipped with a top stirrer and nitrogen inlet / outlet. Rinse the first flask with 28 mL of 1,4-dioxane and transfer the rinsing solution to the second flask. Heat the solution under vacuum to 40–60 °C until slight reflux is achieved and filter out 100–120 mL of 1,4-dioxane. Then add 130 mL of toluene to the mixture and heat the resulting solution under vacuum to 40–60 °C until slight reflux is achieved. Remove the 1,4-dioxane / toluene solvent mixture by distillation. Add an additional 200 mL of toluene during distillation to maintain a constant volume. Remove a total of 180–220 mL of 1,4-dioxane / toluene distillate. Determine that the solvent exchange system is complete when < 5%-a / a of 1,4-dioxane residue remains. Heat the resulting slurry to 65–75 °C, stir at this temperature for 30 minutes, cool to 20–30 °C and then to 0–10 °C. Hold the slurry at this temperature for 30 minutes. The crystals were collected by filtration, washed with 30 mL of toluene, and then dehydrated under nitrogen for 30 minutes. [LC-MS]: (ES, m / z) = 227 [M+1]. [,1 , ] [H-NMR](400 MHz, 6d-DMSO) δ ppm 7.72 (d, 1H, J=5.6 Hz), 6.39 (s, 2H), 5.71 (d, 1H, J=5.6 Hz), 4.83 (d, 1H, J=49.3 Hz), 4.60 - 4.49 (m, 1H), 4.29 (d, 1H, J=13.3 Hz), 3.55 - 3.42 (m, 1H), 3.28 (d, 1H, J=13.3 Hz), 3.20 - 3.04 (m, 1H), 1.76 - 1.48 (m, 2H).

[0086] [] [Example] [4a] [:synthesis] [, N , ] [-(2-((3 , S , ,4 , R , )-3- ] [fluorine] [-4-] [Methoxypiperidine] [-1-] [base] [)] [Pyrimidine] [-4-] [base] [)-5-] [Isopropyl] [-8-((2 , R , ,3 , S , )-2- ] [methyl] [-3-((] [Methylsulfonylurea] [)] [methyl] [)] [Azacyclobutane] [-1-] [base] [)] [Isoquinoline] [-3-] [amine] [(I)] [] At 20 to 30°C, 1,4-dioxane (18.0 L, 4.0 vol) was added to the glass-jacketed reactor (R1). [Compound] [(Ia)](6.0 kg, 1.0 eq), [Compound] [(Ib)] (4.5 kg, 1.05 eq) and Cs₂CO₃ (23.6 kg, 3.4 eq). R1 ​​was inert with N₂ and vacuum (2 cycles), followed by the addition of Pd(dba)₂ (364 g, 0.03 eq) and XantPhos (366 g, 0.03 eq). R1 ​​was again inert with N₂ and vacuum (2 cycles), and the batch was heated to 100°C for 4 to 8 hours, then cooled to 40 to 50°C. Then, [(Ib)] (4.5 kg, 1.05 eq) and Cs₂CO₃ (23.6 kg, 3.4 eq) were added. [Compound] The reaction mixture of [(Ic)] is cooled to 20 to 30°C and used directly in the next step. [, 1 , ] [H NMR (CDCl , 3, ): ]δ [ppm] = 9.43 (s, 1H), 7.91 (s, 1H), 7.78 (d, 1H, 7.8 Hz), 7.45 (d, 1H, 7.8 Hz), 3.56 (hept, 1H, 6.9 Hz), 1.38 (d, 6H, 6.9 Hz). []

[0087] To contain [Compound] Add to the reaction mixture of [(Ic)] [Compound] [(Id)] (4.2 kg, 1.05 eq), Pd(dba)₂ (352 g, 0.04 eq), XPhos (501 g, 0.06 eq), and 1,4-dioxane (5 L, 0.83 vol) as a rinsing agent were added. The batch was heated to 100°C for 4 hours, then cooled to 50°C, and additional Pd(dba)₂ (241 g, 0.024 eq) and 1,4-dioxane (1 L, 0.15 vol) as a rinsing agent were added. The reaction was stirred at 100°C for another 4 hours.

[0088] Cool the batch to 50-60°C, dilute with water (12 L, 2 vol), stir at 55-65°C for 30 minutes, and remove the aqueous layer (maintaining 50°C during layer separation). Add water (9 L, 1.50 vol) and 38% (w / w) NaHSO₃ (10.4 kg, 2.2 eq), stir the batch at 55-65°C for 2 hours, and then dilute with 1,4-dioxane (72 L, 12 vol). Azeotropically dry the batch by distillation (40-50°C, 200 mbar) to remove 14 volumes of distillate. Continue azeotropic distillation by adding another 72 L, 12 vol of 1,4-dioxane, followed by distillation to remove another 12 volumes of distillate. Check the water content of the batch (water is NMT 1.0%), and if the water content is high, repeat the process of adding more 1,4-dioxane and distillation. After reaching NMT 1.0% water, the batch was diluted with 1,4-dioxane (84 L, 14 vol) and stirred at 65 to 75 °C for NLT 1 hour. The batch was cooled to 25 °C and filtered (R1 to R2) to remove the Pd bisulfite precipitate. R1 was washed with 1,4-dioxane (5 L, 0.80 vol) and passed through a filter to R2. The filtrate was concentrated (50 to 60 °C, 150 mbar) to remove 16.3 volumes (approximately 98 L) of distillate.

[0089] Add the previously synthesized [material] at 50 to 60°C. [Compound] [(I)] Seed crystals (0.15% w / w) were added, followed by slow addition of EtOH (60 L, 10 vol) as an antisolvent at 50–60 °C for 1 NLT. The ratio of 1,4-dioxane to EtOH (1,4-dioxane NMT 15%) was checked, and the reaction was then slowly cooled to 15–25 °C and stirred for another 3 NLT. The resulting compound (I) solid was separated by filtration, washed with EtOH (9 L, 1.4 vol), followed by two slurry washes with water (2 x 18 L, 2 x 2.8 vol), and then three washes with EtOH (3 x 6 L, 3 x 0.9 vol). [Compound] [(I)] was dried under vacuum (50 mbar, 65 to 75 °C) to obtain [Compound] [(I)] Crude product (5.6 kg, 37% yield, by HPLC, purity 94% a / a). [HPLC] [:]93.7% (a / a). [] [, 1 , ] [¹H NMR (DMSO-d₆, δ, ppm): ] δ [ppm] = 9.94 (1H, bs), 9.07 (1H, bs), 8.65 (1H, bs), 8.01 (1H, d, J = 5.67), 7.42 (1H, d, J = 8.08), 6.56 (1H, d, J = 8.08), 6.49 (1H, d, J = 5.67), 4.94 (1H, dddd, J = 50.0, 4.95, 2.17, 2.17), 4.74 (1H, dddd, J = 14.35, 9.53, 5.31, 1.57), 4.67 (1H, dd, J = 7.25, 7.25), 4.49 (1H, bd, J = 12.46), 4.20 (1H, dq, J = 6.25, 6.25), 3.64 (1H, dd, J = 7.25, 7.25), 3.59 (1H, dddd, J = 24.88, 10.15, 4.44, 2.26), 3.57 (1H, dd, J = 14.34, 6.33), 3.53 - 3.48 (1H, bm), 3.52 - 3.44 (1H, m), 3.51 (1H, dd, J = 14.34, 8.33), 3.37 (3H, s), 3.29 (1H, ddd, J = 12.46, 10.12, 3.13), 3.00 (3H, s), 2.90 (1H, dddd, J = 7.80, 7.80, 7.80, 7.80), 1.82 (1H, dddd, J = 12.95, 4.27, 4.27, 3.99), 1.​​​​​​​​​​​​​​​​​​​​​ [-4-] [Methoxypiperidine] [-1-] [base] [)] [Pyrimidine] [-4-] [base] [)-5-] [Isopropyl] [-8-((2 , R , ,3 , S , )-2- ] [methyl] [-3-((] [Methylsulfonylurea] [)] [methyl] [)] [Azacyclobutane] [-1-] [base] [)] [Isoquinoline] [-3-] [amine] [(I)] [] Under nitrogen atmosphere, precisely mix 44 g (45 mL) of toluene and 12.3 g (43.2 mmol, 1.0 eq) of 8-bromo-3-chloro-5-isoquinoline (… [Compound] [(Ia)]), 9.1 g (45.6 mmol, 1.05 mol eq) (2R,3S)-2-methyl-3-((methanesulfonyl)methyl)azacyclobutane HCl ( [Compound] [(Ib)]), 110 mg (0.2 mmol, 0.005 mol eq) bis(dibenzylacetone)palladium(0) (Pd(dba) 2), 110 mg (0.2 mmol, 0.005 mol eq) Xantphos were placed in a 250 mL three-necked flask equipped with a top stirrer and a reflux condenser. The flask was evacuated twice under room vacuum and then the vacuum was broken with nitrogen. Then 11.8 g (7.7 mL, 105 mmol, 2.65 mol eq) 50% potassium hydroxide and 8.0 mL deionized water were added. The flask was evacuated again under room vacuum and then the vacuum was broken with nitrogen. The resulting two-phase mixture was heated to 85 to 95 °C and held at this temperature for 10 hours. The reaction mixture was cooled to 55 to 65 °C. When <1.0 %-a / a [Compound] [(Ia)] When residual, the reaction system is determined to be complete. Cool the reaction mixture to 20-30°C and then add 9 mL of deionized water, followed by 9 mL of toluene. Stir the two-phase mixture for another 0.5 hours. Stop stirring and transfer the mixture to a separatory funnel, allowing the layers to separate for 0.5 hours. Discard the wastewater stream along with any interface layer. Let the product-rich organic phase stand for 5 minutes and discard the aqueous layer. Transfer the product-rich organic stream back to a 3-necked flask. Add 9 mL of deionized water and 30 mg (30 µL) of acetic acid to a separate 25 mL Erlenmeyer flask. Add the aqueous acetic acid solution to the organic layer and stir the two-phase mixture for 30 minutes. Stop stirring and transfer the two-phase mixture to a separatory funnel, allowing the layers to separate for 0.5 hours. Discard the wastewater stream along with any interface layer. Let the product-rich organic stream stand for 5 minutes and discard any aqueous layer. Transfer the product-rich toluene stream back to a three-necked flask and heat to reflux to distill off 15 to 25 mL of the toluene / water azeotrope. Add another 40 mL of toluene to the three-necked flask and heat to reflux to distill off the remaining 40 mL of the toluene / water azeotrope. Cool the product-rich toluene stream to 20 to 30 °C and sample for KF. When KF is < 0.2 % w / w, the mixture ( [Compound] [Ic]) Polish and filter through a diatomaceous earth pad, then rinse the pad with about 2 mL of toluene and mix thoroughly.

[0091] The above-prepared solution contained 15.06 g (0.041 mol, 1.03 eq) (analytical 35.95%) in an exact 42 mL volume. [Compound] The [Ic] solution was placed in a 250 mL three-necked round-bottom flask equipped with a top stirrer and a nitrogen inlet / outlet. Then, 9.0 g (0.0398 mol, 1.00 eq) was added. [Compound] [(Id)], 46 mg (0.08 mmol, 0.02 mol eq) bis(dibenzylacetone)palladium, 39 mg (0.08 mmol, 0.02 mol eq) Xphos and 7.5 mL toluene were placed in a flask. The reactor was purged twice under a vacuum. The vacuum was then broken with nitrogen. 29 g (0.06 mol, 1.5 mol eq) of 20% wt% sodium tributyrate in THF solution was then added to the flask, followed by 3 mL of toluene. The resulting mixture was heated to 45°C and held for 15 minutes, then slowly heated to 80-95°C. The reaction mixture was held at this temperature for 6 hours. The mixture was cooled to 55-60°C. When < 4%-a / a [Compound] [(Ic)] or [Compound] When [(Id)] remains, the reaction system is determined to be complete. 63 mL of 1,4-dioxane was added to the reaction mixture, followed by 3.5 mL (3.67 g, 0.061 mol) of acetic acid. []

[0092] In a separate 500 mL Erlenmeyer flask, add 23 g (0.141 mol) of N-acetycysteine, 284 mL of deionized water, and 20 mL of 30 wt% sodium hydroxide. Stir the mixture at room temperature for 15 minutes. Add 25 mL of this solution to the reaction mixture. Heat the mixture to 55-60 °C and stir at this temperature for 30 minutes. Stop stirring, transfer the mixture to a 250 mL separatory funnel, and allow the layers to separate for 30 minutes. Discard the lower dark brown wastewater layer. Combine the interface layer with the product-rich organic phase and allow the organic phase to stand for 15 minutes. Discard the remaining wastewater layer. Transfer the reaction mixture back to a three-necked round-bottom flask and add 25 mL of N-acetycysteine ​​solution. Heat the resulting two-phase mixture to 55-60 °C and stir at this temperature for 30 minutes. Stop stirring, transfer the mixture to a 250 mL separatory funnel, and allow the layers to separate for 30 minutes. Discard the lower dark brown wastewater layer. Combine the boundary layer with the product-rich organic phase and allow the upper organic phase to stand for 15 minutes. Discard the remaining wastewater layer. Transfer the organic phase back to a 3-necked round-bottom flask and add 25 mL of N-acetylglucosamine solution. Heat the resulting two-phase mixture to 55-60°C and stir at this temperature for 30 minutes. Stop stirring, transfer the mixture to a 250 mL separatory funnel, and allow the layers to separate for 30 minutes. Discard the lower dark brown wastewater layer. Combine the boundary layer with the product-rich organic phase and allow the upper organic phase to stand for 15 minutes. Discard the remaining wastewater layer. Add 27 mL of deionized water to the reaction mixture. Add 10 g of 1,4-dioxane (without peroxide) to the reaction mixture, heat to 55-60°C, and maintain this temperature for 30 minutes. Stop stirring, transfer the mixture to a separatory funnel, and allow the layers to separate for 30 minutes. Discard the lower dark brown wastewater layer. Combine the boundary layer with the product-rich organic phase and allow the upper organic phase to stand for 15 minutes. Discard the additional wastewater layer. Return the reaction mixture to a three-necked round-bottom flask and add 50 mL of toluene to the mixture. Heat the mixture to reflux (80 to 120 °C) and distill off 50 mL of the toluene / dioxane / water azeotrope. Add another 90 to 110 mL of toluene to the mixture to maintain a constant volume during distillation. Cool the product-rich toluene stream to 70 to 90 °C and examine for crystallization. Cool the crystal slurry to 15 to 25 °C over 4 hours, maintaining an inert atmosphere using nitrogen. Stir the crystal slurry at this temperature for another 2 hours. Collect the crystals by filtration. Wash the filter cake with approximately 30 mL of toluene via displacement washing. Wash the filter cake twice with approximately 30 mL of toluene-denatured ethanol and dehydrate the filter cake to obtain the crude compound (I). [LC-MS]: (ES, m / z) = 557 [M+1]. [, 1 , ] [¹H NMR (DMSO-d₆, 600 MHz):] δ [ppm] = 9.94 (1H, bs), 9.07 (1H, bs), 8.65 (1H, bs), 8.01 (1H, d, J = 5.67), 7.42 (1H, d, J = 8.08), 6.56 (1H, d, J = 8.08), 6.49 (1H, d, J = 5.67), 4.94 (1H, dddd, J = 50.0, 4.95, 2.17, 2.17), 4.74 (1H, dddd, J = 14.35, 9.53, 5.31, 1.57), 4.67 (1H, dd, J = 7.25, 7.25), 4.49 (1H, bd, J = 12.46), 4.20 (1H, dq, J = 6.25, 6.25), 3.64 (1H, dd, J = 7.25, 7.25), 3.59 (1H, dddd, J = 24.88, 10.15, 4.44, 2.26), 3.57 (1H, dd, J = 14.34, 6.33), 3.53 - 3.48 (1H, bm), 3.52 - 3.44 (1H, m), 3.51 (1H, dd, J = 14.34, 8.33), 3.37 (3H, s), 3.29 (1H, dddd, J = 12.46, 10.12, 3.13), 3.00 (3H, s), 2.90 (1H, dddd, J = 7.80, 7.80, 7.80, 7.80), 1.82 (1H, dddd, J = 12.95, 4.27, 4.27, 3.99), 1.75 (1H, ddddd, J = 10.56, 10.56, 10.56, 4.22, 1.64), 1.43 (3H, d, J = 6.09), 1.31 (3H, d, J = 6.95), 1.30 (3H, d, J = 6.92).

[0093] [Example] [5a] [:] [N-(2-((3, S ,,4, R , )-3-] [Fluoro] [-4-] [Methoxypiperidine] [-1-] [base] [)] [Pyrimidine] [-4-] [base] [)-5-] [Isopropyl] [-8-((2 , R , ,3 , S , )-2- ] [methyl] [-3-((] [Methylsulfonylurea] [)] [methyl] [)] [Azacyclobutane] [-1-] [base] [)] [Isoquinoline] [-3-] [amine] [(I)] [Recrystallization] [] The crude material obtained from Example 4 [Compound] [(I)] (6.3 kg) dissolved in DMSO (10 L, 1.5 vol) and treated with Pd scavenger Quadrasil MP (850 g, based on [Compound] [(I)]14% w / w equivalent) treatment. After stirring at 70°C for 1.5 hours, the cleaning agent was removed by filtration (50°C). The silicone cleaning agent solids were washed with DMSO (5 L, 0.8 vol), and all filtrates were combined. The batch was heated to 55°C and EtOH (95 L, 15.0 vol) was slowly added over NLT 3 hours. (After adding 2 vol of EtOH, the mixture was mixed with the previously synthesized...) [Compound] [(I)] Seed crystals were then introduced, and the batch was cooled to 45°C. The batch was then slowly cooled to 10°C while stirring for 2 hours. The batch was then filtered and... [Compound] [(I)] The solid was washed twice with EtOH replacement washing solution (3 x 6.3 L, 3 x 1.0 vol). [Compound] [(I)] The solid was dried under vacuum (50°C, 35 mbar) for NLT 16 hours to obtain recrystallized [the solid]. [Compound] [(I)](4.9 kg, 78% yield, 99.3% purity a / a by HPLC) [HPLC] 99.3% (a / a) [, 1 , ] [¹H NMR (DMSO-d₆, δ, ppm): ] δ [ppm] = 9.94 (1H, bs), 9.07 (1H, bs), 8.65 (1H, bs), 8.01 (1H, d, J = 5.67), 7.42 (1H, d, J = 8.08), 6.56 (1H, d, J = 8.08), 6.49 (for 1H, d, J = 5.67), 4.94 (1H, dddd, J = 50.0, 4.95, 2.17, 2.17), 4.74 (1H, dddd, J = 14.35, 9.53, 5.31, 1.57), 4.67 (1H, dd, J = 7.25, 7.25), 4.49 (1H, bd, J = 12.46), 4.20 (1H, dq, J = 6.25, 6.25), 3.64 (1H, dd, J = 7.25, 7.25), 3.59 (1H, dddd, J = 24.88, 10.15, 4.44, 2.26), 3.57 (1H, dd, J = 14.34, 6.33), 3.53 - 3.48 (1H, bm), 3.52 - 3.44 (1H, m), 3.51 (1H, dd, J = 14.34, 8.33), 3.37 (3H, s), 3.29 (1H, dddd, J = 12.46, 10.12, 3.13), 3.00 (3H, s), 2.90 (1H, dddd, J = 7.80, 7.80, 7.80, 7.80), 1.82 (1H, dddd, J = 12.95, 4.27, 4.27, 3.99), 1.75 (1H, ddddd, J = 10.56, 10.56, 10.56, 4.22, 1.64), 1.43 (3H, d, J = 6.09), 1.31 (3H, d, J = 6.95), 1.30 (3H, d, J = 6.92).

[0094] [] [Example] [5b] [:] [N-(2 - ((3, S ,,, 4, R , ) - 3 - ] [Fluorine] [-4-] [Methoxypiperidine] [-1-] [base] [)] [Pyrimidine] [-4-] [base] [)-5-] [Isopropyl] [-8-((2 , R , ,3 , S , )-2- ] [methyl] [-3-((] [Methylsulfonylurea] [)] [methyl] [)] [Azacyclobutane] [-1-] [base] [)] [Isoquinoline] [-3-] [amine] [(I)] [Recrystallization] [] Add 65 mL of dimethyl sulfoxide (DMSO), 5.4 g of Quadrasil MP (scavenger), 2.8 g of SiliaMetS diamine, and 23 g (0.0413 mol) of Compound I to a 500 mL jacketed three-necked flask equipped with a top stirrer, nitrogen inlet / outlet, and bottom valve. Heat the resulting suspension to 85–95 °C and maintain this temperature for 2 hours. Cool the suspension to 65–75 °C and filter. Wash the waste Quadrasil / SiliaMetS diamine filter cake with 25 mL of hot (65–75 °C) DMSO. Heat the combined filtrate and wash solution to 85–95 °C. Then, slowly add 23 mL of deionized water over 10 minutes, followed by 2 g of seed crystals. Finally, add 8 mL of water over 20 minutes. Stir the resulting slurry at 85–95 °C for 2 hours, then cool it to 15–25 °C over 4 hours and maintain this temperature for at least 3 hours. The crystals were collected by filtration, washed with 60 mL of anhydrous ethanol, dehydrated under nitrogen for 1 hour, and dried under vacuum at 50 to 55 °C for 24 hours. [LC-MS]:(ES, m / z) = 557 [M+1]。 [ , 1 , ] [H NMR (DMSO-d , 6, ): ]δ [ppm] = 9.94 (1H, bs), 9.07 (1H, bs), 8.65 (1H, bs), 8.01 (1H, d, J=5.67), 7.42 (1H, d, J=8.08), 6.56 (1H, d, J=8.08), 6.49 (1H, d, J=5.67), 4.94 (1H, dddd, J=50.0, 4.95, 2.17, 2.17), 4.74 (1H, dddd, J=14.35, 9.53, 5.31, 1.57), 4.67 (1H, dd, J=7.25, 7.25), 4.49 (1H, bd, J=12.46), 4.20 (1H, dq, J=6.25, 6.25), 3.64 (1H, dd, J=7.25, 7.25), 3.59 (1H, dddd, J=24.88, 10.15, 4.44, 2.26), 3.57 (1H, dd, J=14.34, 6.33), 3.53-3.48 (1H, bm), 3.52-3.44 (1H, m), 3.51 (1H, dd, J=14.34, 8.33), 3.37 (3H, s), 3.29 (1H, ddd, J=12.46, 10.12, 3.13), 3.00 (3H, s), 2.90 (1 H, dddd, J=7.80, 7.80, 7.80, 7.80), 1.82 (1H, dddd, J=12.95, 4.27, 4.27, 3.99), 1.75 (1H, ddddd, J=10.56, 10.56, 10.56, 4.22, 1.64), 1.43 (3H, d, J=6.09), 1.31 (3H, d, J=6.95), 1.30 (3H, d, J=6.92)。

Claims

1. A method for preparing a compound of formula (Ic): The method comprises reacting a first starting material of formula (Ia): or a salt thereof, with a second starting material of formula (Ib): or a salt thereof, in the presence of a base, a palladium catalyst, and a phosphine ligand to form the compound of formula (Ic), wherein: (i) The base is cesium carbonate (Cs2CO3) or potassium hydroxide (KOH), the palladium catalyst is bis(dibenzylideneacetone)palladium(O) (Pd(dba)2), and the phosphine ligand is (9,9-dimethyl-9H-α-4,5-diyl)bis(diphenylphosphine) (Xantphos); and / or (ii) the reaction is carried out in dioxane at 90°C to 110°C.

2. A method for preparing a compound of formula (I): comprising reacting a first starting material of formula (Ic) or a salt thereof with a second starting material of formula (Id) or a salt thereof in the presence of a palladium catalyst and a phosphine ligand to form a compound of formula (I), wherein the palladium catalyst and the phosphine ligand are separate compounds or complexes comprising both the palladium catalyst and the phosphine ligand.

3. As in request item 2, wherein: (i) The palladium catalyst and phosphine ligand are non-miscible compounds of methanesulfonato (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (BrettPhos-Pd-G4); or (ii) The palladium catalyst is selected from the group consisting of: Pd(dppe)2 (bis[1,2-bis(diphenylphosphino)ethane]palladium(0)), CX-11 (1,3-bis(2,6-diisopropylphenyl)imidazolium-2-ylidene(1,4-naphthoquinone)palladium(0) dimer), CX-12 (1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene(1,4-naphthoquinone)palladium(0) dimer), Pd(t-Bu3P)2 (bis(tri-tert-butylphosphine)palladium(0)), Pd(PCy3)2 (bis(tricyclohexylphosphine)palladium(0)), Pd(PPh3)4 (tetra(triphenylphosphine)palladium(0)), Pd2(dba)3 (dibenzylacetone)palladium(0)), Pd(OAc)2 (palladium(II) acetate), PdCl2(PPh3)2 (dichlorobis(triphenylphosphine)palladium(II)), PdCl2(Amphos)2 (bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)), Pd(MeCN)2Cl2 (bis(acetonitrile)dichloropalladium(II)), PdCl2(P(o-Tol)3)2 (Dichlorobis(tri-o-tolylphosphine)palladium(II)), Pd(dppf)Cl2 ([1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium(II)), Pd(MeCN)4(BF4)2 (tetra(acetonitrile)tetrafluoroboratepalladium(II)), Pd-PEPPSI-IPent (dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazolium-2-ylidene](3-chloropyridyl)palladium(II)), Pd-PEPPSI-IPr ([1,3-bis(2,6-diisopropylphenyl)imidazolium-2-ylidene](3-chloropyridyl)palladium(II)), Pd-PEPPSI-SIPr ((1,3-bis(2,6-diisopropylphenyl)imidazolium-2-ylidene](3-chloropyridyl)palladium(II)), Pd-PEPPSI-SIPr ((1,3-bis(2,6-diisopropylphenyl)imidazolium-2-ylidene)) (3-chloropyridyl)palladium dichloride (II) and bis(dibenzylacetone)palladium (O) (Pd(dba)2); or (iii) the phosphine ligand or the complex comprising the palladium catalyst and the phosphine ligand is selected from the group consisting of: triphenylphosphine (PPh3), bis(tri-o-tolylphosphine) (P(o-Tol)3)2, tri-tert-butoxyphosphine (Pt-Bu3), tri-tert-butyltetrafluoroborate phosphonium (Pt-Bu3HBF4), bis(tricyclohexylphosphine (PCy3), bis(1-adamantyl)butylphosphine (n-BuP(AD)2), 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), (9,9-dimethyl-9H-α-4,5-diyl)bis(diphenylphosphine) (Xantphos), bis[(2-diphenylphosphino)phenyl] ether (DPEPhos), 1,1′-bis(diphenylphosphino)ferrocene (dppf), 1,1′-bis(di-tert-butylphosphino)ferrocene (dcypf), 1,3-bis(diphenylphosphino)propane (DPPP), (2-biphenyl)di-tert-butylphosphine (JohnPhos), chloro(2-dicyclohexylphosphino-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)] (CyJohnPhos), 2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (DavePhos), (2-Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)] (RuPhos), 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos), [(2-Dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] (BrettPhos), 1,1'-bis(di-tert-butylphosphino)ferrocene (dtbpf), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (t-BuXPhos), [(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] (t-BuBrettPhos), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl (Me4-tBuXPhos), 5-(di-tert-butylphosphino)-1′, 3′, 5′-Triphenyl-1′H-1,4′-Bipyrazole (BippyPhos), Di(1-adamantyl)-2-morpholinophenylphosphine (MorDalPhos), Palladium / 1,3-bis-(2,6-diisopropylphenyl)imidazolinium chloride (IPr.HCl), [2-(di-1-adamantylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl][2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (AdBrettPhos), (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (RuPhos), [(2-Dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,Palladium(II) methanesulfonate [(2-{bis[3,5-bis(trifluoromethyl)phenyl]phosphine}-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]methanesulfonate (JackiePhos) Palladium(II) methanesulfonate [(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]methanesulfonate (II) (t-BuBrettPhos), methanesulfonyl(2-(di-tert-butylphosphino)-1,1′-binaphthyl)[2-(2′-amino-1,1′-biphenyl)]palladium (TrixiePhos), (2-biphenyl)di-tert-butylphosphine, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine (t-BuDavePhos), 2-di-tert-butylphosphino-2′-methylbiphenyl (t-BuMePhos), chloro(2-dicyclohexylphosphino-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium (II) (CyJohnPhos), 2-Dicyclohexylphosphino-2′-methylbiphenyl (MePhos), 2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (PhDavePhos), 2-Dicyclohexylphosphino-2′-methoxy-4′,6′-di-tertiary butylbiphenyl (VPhos), 2-[(tertiary butyl)phenylphosphino]-2′,6′-bis(N,N-dimethylamino)biphenyl (PhCPhos), [(2-Dicyclohexylphosphino-2′,6′-bis(N,N-dimethylamino)-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium methanesulfonate(II) (CPhos), methanesulfonate-[2-diethylphosphino-2',6'-bis(dimethylamino)-1,1-biphenyl](2'-amino-1,1'-biphenyl-2-yl)palladium(II) (EtCPhos), 2-bis(tert-butyl)phosphino-2′,4′,6′-triisopropyl-3-methoxy-6-methylbiphenyl (RockPhos), di-1-adamantyl(4″-butyl-2″,3″,5″,6″-tetrafluoro-2′,4′,6′-triisopropyl-2-methoxy-meta-triphenyl)phosphine (AlPhos), 2-(tert-butylphenylphosphino)-2',6'-dimethylamino-1,1'-biphenyl ((t-Bu)PhCPhos), and dicyclohexyl[2′,4′,6′-tris(propyl-2-yl)[1,1′-biphenyl]-2-yl]phosphine (XPhos).

4. The method of claim 3, wherein the palladium catalyst is bis(dibenzylideneacetone)palladium(0) (Pd(dba)2) and the phosphine ligand is dicyclohexyl[2′,4′,6′-tris(prop-2-yl)[1,1′-biphenyl]-2-yl]phosphonane (XPhos).

5. The method of any one of claims 2 to 4, wherein the reaction mixture further comprises a base.

6. The method of claim 5, wherein the base is selected from the group consisting of potassium carbonate (K2CO3), cesium carbonate (Cs2CO3), potassium hydroxide (KOH), and sodium tributoxide (NaOtBu).

7. The method of any one of claims 2 to 4, wherein the reaction is carried out in a solvent selected from toluene, 1,4-dioxane, tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF), anisole, water (H2O), or mixtures thereof.

8. The method of claim 2, further comprising purifying the compound of formula (I) to form a crystalline product, comprising recrystallizing the compound of formula (I) in a solvent system.

9. The method of claim 8, wherein the solvent system comprises dimethyl sulfoxide (DMSO) and ethanol, or the solvent system comprises dimethyl sulfoxide (DMSO) and water.

10. The method of claim 2, wherein the compound of formula (Ic) is prepared by a method comprising reacting a first starting material of formula (Ia): or a salt thereof, with a second starting material of formula (Ib): or a salt thereof, in the presence of a base, a palladium catalyst and a phosphine ligand to form the compound of formula (Ic).

11. The method of claim 10, wherein the compound of formula (Ia) is prepared by a method comprising reacting the starting material of formula (VI) with a brominating agent in an acid to form the compound of formula (Ia).

12. The method of claim 11, wherein the compound of formula (VI) is prepared by a method comprising reacting a starting material of formula (V) or a salt thereof in the presence of an amine base, a hydride reducing agent and a palladium catalyst to form the compound of formula (VI).

13. The method of claim 12, wherein the compound of formula (V) or a salt thereof is prepared by a method comprising reacting the starting material of formula (IV) or a salt thereof with phosphine chloride (POCl3), phosphorus pentachloride (PCl5) and hydrogen chloride to form the compound of formula (V).

14. The method of claim 13, wherein the compound of formula (IV) is prepared by a method comprising reacting the starting material of formula (III) with tert-BuONO nitrite and hydrogen chloride to form the compound of formula (IV).

15. The method of claim 14, wherein the compound of formula (III) is prepared by a method comprising hydrogenating the starting material of formula (II) in the presence of a platinum hydrocatalyst or a palladium hydrocatalyst to form the compound of formula (III).

16. The method of claim 10, wherein the compound of formula (Ib) is prepared by a method comprising hydrogenating the starting material of formula (IX) or a salt thereof in the presence of a palladium hydride catalyst to form the compound of formula (Ib).

17. The method of claim 16, wherein the compound of formula (IX) is prepared by a method comprising reacting the starting material of formula (VIII) or a salt thereof with lithium chloride (LiCl) to form the compound of formula (IX).

18. The method of claim 17, wherein the compound of formula (VIII) is prepared by a method comprising reacting a first starting material of formula (VIIc): or a salt thereof with a second starting material of formula (VIIIb): and potassium carbonate (K2CO3) to form the compound of formula (VIII).