Process for preparing toll-like receptor modulator compounds - Patents.com

Abstract

To provide a process for preparing a Toll-like receptor modulator compound. SOLUTION: The present disclosure provides methods for preparing (7?)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol, or a salt thereof, as well as related key intermediates. Specifically, in one preferred embodiment of the present invention, for example, the present invention provides a process for preparing a Toll-like receptor modulator compound.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 868,662, filed June 28, 2019, which is incorporated herein in its entirety for all purposes. [Background technology]

[0002] The Toll-like receptor (TLR) family plays a fundamental role in pathogen recognition and innate immune activation. Toll-like receptor 8 (TLR-8) is primarily expressed by myeloid immune cells, and activation of this receptor stimulates a broad range of immune responses. TLR-8 agonists activate myeloid dendritic cells, monocytes, monocyte-derived dendritic cells, and Kupffer cells, leading to the production of proinflammatory cytokines and chemokines, such as interleukin-18 (IL-18), interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ). Such agonists also promote CD4+ production. 8+ It promotes increased expression of costimulatory molecules such as major histocompatibility complex molecules (MAITs, NK cells), and chemokine receptors. Collectively, activation of these innate and adaptive immune responses induces immune responses and provides therapeutic benefits in various conditions involving autoimmunity, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD), infectious diseases, cancer, and immunodeficiency. For example, with regard to hepatitis B, activation of TLR8 on professional antigen-presenting cells (pAPCs) and other intrahepatic immune cells is associated with the induction of IL-12 and proinflammatory cytokines, which are expected to enhance HBV-specific T cell responses, activate intrahepatic NK cells, and promote the reconstitution of antiviral immunity. See, e.g., Wille-Reece, U. et al., J Exp Med 203,1249-1258(2006), Peng,G.et al.,Science 309,1380-1 384(2005),Jo,J.et al.,PLoS See Pathogens 10, el004210 (2014) and Watashi, K. et al., J Biol Chem 288, 317 15-3 1727 (2013). Given their potential to treat a wide range of diseases, potent and selective modulators of TLR-8 with reduced potential for non-specific disease liability are particularly desirable. Toll-like receptor modulator compounds, such as diaminopyrido[3,2-d]pyrimidine compounds, and methods for making them are disclosed in WO 2016 / 141092. However, there remains a need for methods for preparing diaminopyrido[3,2-d]pyrimidine compounds. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2016 / 141092 [Non-patent literature]

[0004] [Non-Patent Document 1] Wille-Reece, U. et al., J Exp Med 203, 1249-1258 (2006) [Non-patent document 2] Peng,G.et al.,Science 309,1380-1 384(2005) [Non-patent document 3] Jo, J. et al., PLoS Pathogens 10, el004210(2014) [Non-patent document 4] Watashi, K. et al., J Biol Chem 288,317 15-3 1727(2013) Summary of the Invention [Means for solving the problem]

[0005] In one embodiment, the present disclosure provides a compound of formula I: [ka] or a salt thereof, the method comprising: a) Formula III: [ka] or a salt thereof, a compound having the formula PG-NHC(=NH)NH2 or a salt thereof, a first base, and a first solvent to form a first reaction mixture comprising a compound of formula II: [ka] or a salt thereof; and b) forming a second reaction mixture comprising the compound of formula II or a salt thereof, a deprotecting agent, and a second solvent to provide the compound of formula I or a salt thereof; In the formula, R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl or C 1~3 is alkoxy, and R 4 is hydrogen or methyl, and R 5 is C 3~6 alkyl, X is F, Cl, Br, I, or OTs, and PG is an amino protecting group.

[0006] In another embodiment, the present disclosure provides a compound of formula I: [ka] or a salt thereof, the method comprising: a) Formula III: [ka] or a salt thereof, a compound having the formula PG-NHC(=NH)NH2 or a salt thereof, a first transition metal catalyst, a first base, and a first solvent to form a first reaction mixture comprising a compound of formula II: [ka] or a salt thereof; and b) forming a second reaction mixture comprising the compound of formula II or a salt thereof, a deprotecting agent, and a second solvent to provide the compound of formula I or a salt thereof; In the formula, R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl or C 1~3 is alkoxy, and R 4 is hydrogen or methyl, and R 5 is C 3~6 alkyl, X is Cl, Br, I, or OTs, and PG is an amino protecting group.

[0007] In another embodiment, the present disclosure provides compounds of formula Ib: [ka] or a salt thereof, the method comprising: a4) Formula VIIIb: [ka] or a salt thereof, oxalyl chloride, N,N-dimethylformamide, and 2-methyltetrahydrofuran to form a seventh reaction mixture comprising a compound of Formula VIIb: [ka] or a salt thereof; and a3) a compound of formula VIIb or a salt thereof with a compound of formula VIb: [ka] forming a sixth reaction mixture comprising the compound of Formula Vb, aqueous potassium carbonate, 2-methyltetrahydrofuran, and water to form a compound of Formula Vc: [ka] or a salt thereof; and a2) forming a fourth reaction mixture comprising a compound of Formula Vb or a salt thereof, thionyl chloride, and 2-methyltetrahydrofuran to produce a compound of Formula IVb-1: [ka] or a salt thereof; and a1) forming a third reaction mixture comprising a compound of Formula IVb-1 or a salt thereof, aqueous sodium hydroxide, tetra-n-butylammonium hydrogen sulfate, and 2-methyltetrahydrofuran to form a compound of Formula IIIb: [ka] or a salt thereof; and a) combining a compound of formula IIIb or a salt thereof with a compound of formula IXa, wherein n is 0 to 1: [ka] , copper(II) acetate, tribasic potassium phosphate, cysteine, 2-methyltetrahydrofuran, and acetonitrile to form a first reaction mixture comprising the compound of formula IIb: [ka] or a salt thereof; and b) forming a second reaction mixture comprising a compound of Formula IIb or a salt thereof, trifluoroacetic acid, and dichloromethane to produce a compound of Formula Ib: [ka] preparing a trifluoroacetate salt of the compound of formula (I); c) forming a ninth reaction mixture comprising the trifluoroacetate salt of the compound of formula Ib, sodium hydroxide, ethanol, and water to provide the neutral form of the compound of formula Ib.

[0008] In some embodiments, the present disclosure provides a compound of formula II: [ka] or a salt thereof, the method comprising: a) Formula V: [ka] or a salt thereof, a compound having the formula PG-NHC(=NH)NH2 or a salt thereof, a first transition metal catalyst, a first base, and a first solvent to form a compound of Formula II or a salt thereof; In the formula, R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl, or C 1~3 may be alkoxy, and R 4 may be hydrogen or methyl, R 5 is C 3~6 X may be F, Cl, Br, I, or OTs, and PG may be an amino protecting group.

[0009] In another embodiment, the present disclosure provides a compound of formula I: [ka] or a salt thereof, the method comprising: a) Formula III: [ka] forming a first reaction mixture comprising a compound of Formula I, a compound having the formula HNC(=NH)NH or a salt thereof, a first base, and a first solvent to form a compound of Formula I or a salt thereof; In the formula, R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl or C 1~3 may be alkoxy, and R 4 may be hydrogen or methyl, R 5 is C 3~6 It may be alkyl, and X may be F, Cl, Br, I, or OTs.

[0010] In another embodiment, the present disclosure provides a compound of formula XVIII: [ka] or a salt thereof, the method comprising: a) Formula XV: [ka] with a compound of formula XVI-1: [ka] or a salt thereof, and a compound of formula R 7 forming a first reaction mixture comprising a compound having —NHC(═NH)NH or a salt thereof, a first transition metal catalyst, a first base, and a first solvent to form a compound of Formula XVIII or a salt thereof; In the formula, R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl or C1~3 is alkoxy, and R 4 is hydrogen or methyl, and R 5 is C 1~6 alkyl, and R 6 is hydrogen, OH, or O-PG1, and R 7 is hydrogen or PG, and X and X 1 are each independently F, Cl, Br, I, or OTs, PG is an amino protecting group, and PG1 is a hydroxy protecting group.

[0011] In another embodiment, the present disclosure provides a compound of formula I: [ka] or a salt thereof, the method comprising: a) Formula XI: [ka] or a salt thereof with a compound of formula VI: [ka] or a salt thereof, a first base, and a first solvent to form a first reaction mixture comprising a compound of formula X: [ka] or a salt thereof; and b) forming a second reaction mixture comprising a compound of Formula IX or a salt thereof, a compound of PG-NH2 or a salt thereof, a second base, and a second solvent to produce a compound of Formula II: [ka] or a salt thereof; and b) forming a third reaction mixture comprising the compound of Formula II or a salt thereof, a deprotecting agent, and a third solvent to provide the compound of Formula I or a salt thereof; In the formula, R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl, or C 1~3 is alkoxy, and R 4 is hydrogen or methyl, and R 5 is C 3~6 alkyl and PG is an amino protecting group.

[0012] In another embodiment, the present disclosure provides a compound of formula Ib: [ka] or a salt thereof, the method comprising: a) Formula XIb: [ka] or a salt thereof with a compound of formula VIb: [ka] , N,N-diisopropylethylamine, 2-methyltetrahydrofuran, and isopropyl acetate to form a compound of Formula Xb: [ka] or a salt thereof; and b) forming a second reaction mixture comprising a compound of Formula Xb or a salt thereof, 2,4-dimethoxybenzylamine, potassium carbonate, 2-methyltetrahydrofuran, and isopropyl acetate to produce a compound of Formula IIb: [ka] or a salt thereof; and c) forming a third reaction mixture comprising the compound of Formula IIb or a salt thereof, trifluoroacetic acid, and dichloromethane to produce a compound of Formula Ib: [ka] preparing a trifluoroacetate salt of the compound of formula (I); d) a mixture of the trifluoroacetate salt of the compound of formula Ib, sodium hydroxide, ethanol, and water and forming a fourth reaction mixture comprising:

[0013] In another embodiment, the present disclosure provides a compound of formula III: [ka] or a salt thereof, wherein R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl or C 1~3 is alkoxy, and R 4 is hydrogen or methyl, and R 5 is C 3~6 alkyl and X is F, Cl, Br, I, or OTs.

[0014] In another embodiment, the present disclosure provides a compound of formula III: [ka] or a salt thereof, wherein R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl or C 1~3 is alkoxy, and R 4 is hydrogen or methyl, and R 5 is C 3~6 alkyl and X is Cl, Br, I, or OTs.

[0015] In another embodiment, the present disclosure provides a compound of formula IV: [ka] or a salt thereof, wherein R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl, or C 1~3 is alkoxy, and R 4 is hydrogen or methyl, and R 5 is C 3~6 alkyl, X is F, Cl, Br, I, or OTs, AG 1 are Cl, Br, OSO3H, OSO3 - , OMs, OTs, or OTf.

[0016] In another embodiment, the present disclosure provides a compound of formula IV: [ka] or a salt thereof, wherein R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl, or C 1~3 is alkoxy, and R 4 is hydrogen or methyl, and R 5 is C 3~6 alkyl, X is F, Cl, Br, I, or OTs, AG 1 is Cl, Br, OMs, OTs, or OTf.

[0017] In another embodiment, the present disclosure provides a compound of formula V: [ka] or a salt thereof, wherein R 1 , R 2 , and R3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl, or C 1~3 is alkoxy, and R 4 is hydrogen or methyl, and R 5 is C 3~6 and X is F, Cl, Br, I, or OTs, with the proviso that the compound of formula V is 3-bromo-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide, 3-bromo-N-(1-hydroxy-3,3-dimethylbutan-2-yl)picolinamide, 3-bromo-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide, 3-bromo-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide, 3,6-dichloro-N-( 1-hydroxy-3-methylbutan-2-yl)picolinamide, 3,6-dichloro-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide, 3,4,5-trichloro-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide, 3,6-dichloro-N-(1-hydroxy-4,4-dimethylpentan-2-yl)picolinamide, or 3,4,5-trichloro-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide.

[0018] In another embodiment, the present disclosure provides a compound of formula V: [ka] or a salt thereof, wherein R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl, or C 1~3 is alkoxy, and R 4 is hydrogen or methyl, and R 5 is C 3~6and X is Cl, Br, I, or OTs, with the proviso that the compound of formula V is 3-bromo-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide, 3-bromo-N-(1-hydroxy-3,3-dimethylbutan-2-yl)picolinamide, 3-bromo-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide, 3-bromo-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide, 3,6-dichloro-N-(1 3,6-dichloro-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide, 3,4,5-trichloro-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide, 3,6-dichloro-N-(1-hydroxy-4,4-dimethylpentan-2-yl)picolinamide, or 3,4,5-trichloro-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide.

[0019] In another embodiment, the present disclosure provides a compound of formula XII: [ka] or a salt thereof, wherein R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl, or C 1~3 is alkoxy, and R 6 and R 7 are each independently hydrogen, C 1~4 Alkyl, or C 3~6 cycloalkyl, or R 6 and R 7 are combined to form a 3-6 membered N-linked heterocycloalkyl, optionally having 1-2 additional heteroatoms selected from O and S, with the proviso that R 1 , R 2 , and R 3 At least one of the following is F, Cl, CN, CF3, C 1~3 Alkyl, or C 1~3It is an alkoxy. [Brief explanation of the drawings]

[0020] [Figure 1] 1 illustrates the preparation of compound of formula Ib via transition metal-mediated coupling reaction of (R)-2-(3-bromo-5-fluoropyridin-2-yl)-4-butyl-4-methyl-4,5-dihydrooxazole (IIIb) with a protected guanidine compound to provide (R)-2-((2-((3,4-dimethylbenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (IIb), which is subsequently deprotected to form (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (Ib).

[0021] [Figure 2]

[0023] The preparation of compound of formula Ib is shown via two successive nucleophilic aromatic substitution reactions of 2,4-dichloro-7-fluoropyrido[3,2-d]pyrimidine (XIb) to provide (R)-2-((2-((3,4-dimethylbenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (IIb), which is subsequently deprotected to form (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (Ib).

[0022] [Figure 3A] 1 shows the preparation of compounds of formula VIb via the steps of condensation, alkylation / hydrolysis, salt formation, enzymatic resolution, BOC protection, reduction, and deprotection / TsOH salt formation. [Figure 3B] An alternative method for preparing isopropyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate is presented.

[0023] [Figure 4]1 shows the preparation of compounds of Formula VIb via the steps of cyclocondensation, nucleophilic addition, reduction, and hydrogenolysis / TsOH salt formation.

[0024] [Figure 5A] The preparation of compounds of formula VIIIb via halogen exchange, cyanation, and hydrolysis steps is shown. [Figure 5B] An alternative method for preparing 3-bromo-5-fluoro-2-iodopyridine is presented.

[0025] [Figure 6] The preparation of compounds of formula VIIIb via amidation, bromination, and hydrolysis steps is shown.

[0026] [Figure 7A] The preparation of compounds of formula XIb is shown via the steps of cyanation, cyclization with carbon dioxide, and chlorination. [Figure 7B] An alternative method for preparing 7-fluoropyrido[3,2-d]pyrimidine-2,4-diol via oxidation and cyclization steps with triphosgene is presented.

[0027] [Figure 8] 1 illustrates the preparation of compounds of formula IIIb from compounds of formula IIb via sulfonation, ion exchange, and cyclization steps.

[0028] [Figure 9] 1 shows the preparation of the compound of formula IIb from 3,5-difluoropicolinic acid (VIIIb-1) via the coupling reaction of (R)-2-(3-fluoro-5-fluoropyridin-2-yl)-4-butyl-4-methyl-4,5-dihydrooxazole (IIIb-1) with a protected guanidine compound.

[0029] [Figure 10]1 shows the preparation of compounds of formula IIb via a transition metal-mediated coupling reaction of (R)-3-bromo-5-fluoro-N-(1-hydroxy-2-methylhexan-2-yl)picolinamide (Vb) with protected guanidine compounds.

[0030] [Figure 11] 1 shows the preparation of compounds of formula Ib via a direct coupling reaction with the guanidine salt of (R)-2-(3-fluoro-5-fluoropyridin-2-yl)-4-butyl-4-methyl-4,5-dihydrooxazole (IIIb-1).

[0031] [Figure 12] 1 illustrates the preparation of compounds of formula Ib via a condensation reaction of 2-bromo-3,5-difluoropyridine, (R)-2-isocyano-2-methylhexan-1-ol, and a guanidine salt.

[0032] [Figure 13] 1 shows the preparation of isopropyl 2-amino-2-methylhexanoate from hexan-2-one via 2-amino-2-methylhexanenitrile.

[0033] [Figure 14] 1 shows the preparation of compounds of formula VIb via the steps of nucleophilic addition, Bz protection, reduction, and deprotection / TsOH salt formation.

[0034] [Figure 15] 1 shows the preparation of the compound of formula VIb via the steps of reduction of the salt of (R)-2-amino-2-methylhexanoate and TsOH salt formation.

[0035] [Figure 16] 1 shows the preparation of (R)-2-amino-2-methylhexanoic acid hydrochloride from (2S,4R)-3-benzoyl-4-methyl-2-phenyloxazolidin-5-one via alkylation and hydrolysis steps. DETAILED DESCRIPTION OF THE INVENTION

[0036] (Detailed Description of the Invention) I. Overview The present disclosure provides methods for preparing compounds of formula I or salts thereof, particularly (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol. The present disclosure also provides methods for preparing compounds of formulas III, IV, V, VI, VII, VIII, IX, and X. Additionally, the present disclosure provides compounds of formulas III, IV, V, and XI.

[0037] II. Definition The abbreviations used herein have their conventional meaning within the chemical and biological arts.

[0038] "Alkyl" has the number of carbon atoms indicated (i.e., C 1~6 refers to a straight or branched chain, saturated, aliphatic group of 1 to 6 carbons. Alkyl refers to any number of carbons, e.g., C 1~2 , C 1~3 , C 1~4 , C 1~5 , C 1~6 , C 1~7 , C 1~8 , C 1~9 , C 1~10 , C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 3~4 , C 3~5 , C 3~6 , C 4~5 , C 4~6 and C 5~6 For example, C1-6 alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, hexyl, and the like.

[0039] "Alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group to its point of attachment: alkyl-O-. The alkoxy group can have any suitable number of carbon atoms, such as C1 to C6. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, and the like.

[0040] "Cycloalkyl" refers to a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing 3 to 12 carbon ring atoms, or the number of atoms indicated. Cycloalkyl can be any number of carbons, e.g., C 3~6 , C 4~6 , C 5~6 , C 3~8 , C 4~8 , C 5~8 , C 6~8 , C 3~9 , C 3~10 , C 3~11 , and C 3~12 Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. Cycloalkyl groups can also be partially It may be partially unsaturated, having one or more double or triple bonds in the ring. Representative partially unsaturated cycloalkyl groups include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4-, and 1,5-isomers), norbornene, and norbornadiene. When cycloalkyl is a saturated monocyclic C3-C8 cycloalkyl, typical groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl ... 3~6When cycloalkyl, typical groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0041] "N-linked heterocycloalkyl" or "nitrogen-linked heterocycloalkyl" refers to a heterocycloalkyl group linked through the N-position on the ring. For example, N-linked aziridinyl is aziridin-1-yl, N-linked azetidinyl is azetidin-1-yl, N-linked pyrrolidinyl is pyrrolidin-1-yl, N-linked piperidinyl is piperidin-1-yl, N-linked pyrazolidinyl is pyrazolidin-1-yl or pyrazolidin-2-yl, and N-linked imidazolidinyl is imidazolidin-1-yl or imidazolidin-3-yl. wherein N-linked piperazinyl is piperazin-1-yl or piperazin-4-yl, N-linked oxazolidinyl is oxazolidin-3-yl, N-linked isoxazolidinyl is isoxazolidin-2-yl, N-linked thiazolidinyl is thiazolidin-3-yl, N-linked isothiazolidinyl is isothiazolidin-2-yl, and N-linked morpholinyl is 4-morpholinyl.

[0042] "OMs" refers to methanesulfonate, "OTs" refers to p-toluenesulfonate, and "OTf" refers to trifluoromethanesulfonate.

[0043] "Forming a reaction mixture" refers to the process of contacting at least two different species so that they can mix together and react to modify one of the original reactants or form a product that is a third, distinct species. However, it should be understood that the resulting reaction product may be produced directly from the reaction between the added reagents or from an intermediate derived from one or more of the added reagents that may be produced in the reaction mixture.

[0044] "Acid" is defined as a compound that contains a proton (H +) or is an electron pair acceptor under the Lewis definition. Acids useful in this disclosure are Bronsted-Lowry acids, as defined herein, including, but not limited to, alkanoic or carboxylic acids (such as formic acid, acetic acid, citric acid, lactic acid, and oxalic acid), fluorinated carboxylic acids (trifluoroacetic acid), sulfonic acids, and mineral acids. Mineral acids are hydrogen halides (such as hydrofluoric acid, hydrochloric acid, and hydrobromic acid), halogen oxoacids (such as hypochlorous acid and perchloric acid), and inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, chromic acid, and boric acid. Sulfonic acids include, among others, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid.

[0045] "Lewis acid" refers to a compound or ionic species that can accept an electron pair from a donor compound. Lewis acids useful in the present disclosure include, but are not limited to, boron trifluoride diethyl etherate, lithium chloride, zinc chloride, titanium tetrachloride, silicon tetrachloride, aluminum chloride, samarium(II) iodide, cerium(III) chloride, and lanthanum(III) chloride lithium chloride complex.

[0046] "Base" refers to a functional group that deprotonates water to produce hydroxide ions. Bases useful in the present disclosure include organic and inorganic bases. Exemplary organic bases include amines, carboxylates, alkali alkoxides, metal amides, and alkyl or alkenyl metal compounds, as defined herein. Exemplary inorganic bases include alkali bicarbonates, alkali carbonates, tribasic alkali phosphates, dibasic alkali phosphates, alkali hydroxides, and alkali hydrides, as defined herein. Amines useful as bases in the present disclosure include tertiary amines, aromatic amine bases, and amidine-based compounds, as defined herein.

[0047] "Tertiary amine" refers to a compound having the formula N(R), where the R group can be, among others, alkyl, aryl, heteroalkyl, heteroaryl, or two R groups together can be an N-linked heterocycloalkyl. The R groups can be the same or different. Non-limiting examples of tertiary amines include triethylamine, tri-n-butylamine, N,N-diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine, dimethylaniline, diethylaniline, 1,8-bis(dimethylamino)naphthalene, quinuclidine, and 1,4-diazabicyclo[2.2.2]-octane (DABCO).

[0048] "Aromatic amine base" refers to an N-containing 5- to 10-membered heteroaryl compound or a tertiary amine having the formula N(R)3, where at least one R group is aryl or heteroaryl. Aromatic amine bases useful in the present application include, but are not limited to, pyridine, lutidine (e.g., 2,6-lutidine, 3,5-lutidine, and 2,3-lutidine), collidine (e.g., 2,3,4-collidine, 2,3,5-collidine, 2,3,6-collidine, 2,4,5-collidine, 2,4,6-collidine, and 3,4,5-collidine), 4-dimethylaminopyridine, imidazole, dimethylaniline, and diethylaniline.

[0049] As used herein, "amidine-based compounds" refers to a class of compounds that includes, but is not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).

[0050] "Carboxylate" refers to the combination of an alkali metal cation or phosphonium with a carboxylate anion (RC(O)O -), where the R group can be alkyl or aryl. Carboxylate salts useful in the present disclosure include, but are not limited to, lithium acetate (LiOC(O)CH3), sodium acetate (NaOC(O)CH3), potassium acetate (KOC(O)CH3), cesium acetate (CsOC(O)CH3), potassium trimethylacetate (KOC(O)C(CH3)3), and tetrabutylphosphonium malonate.

[0051] "Alkali bicarbonate" is a compound consisting of an alkali metal cation and a bicarbonate anion (HCO3 - Alkali carbonates useful in the present disclosure include lithium bicarbonate (LiHCO), sodium bicarbonate (NaHCO), potassium bicarbonate (KHCO), and cesium bicarbonate (CsHCO).

[0052] "Alkali carbonate" is a compound of alkali metal cation and carbonate anion (CO3 2- Alkali carbonates useful in the present disclosure include lithium carbonate (Li2CO3), sodium carbonate (Na2CO3), potassium carbonate (K2CO3), and cesium carbonate (Cs2CO3).

[0053] "Tribasic alkali phosphate" is a compound consisting of an alkali metal cation and a phosphate anion (PO4 3- The tribasic alkaline phosphate compounds useful in the present disclosure are Phosphates include tribasic sodium phosphate (Na3PO4) and tribasic potassium phosphate (K3PO4).

[0054] "Dibasic alkali phosphate" is a compound consisting of an alkali metal cation and a hydrogen phosphate anion (HPO4 2- Dibasic alkaline phosphates useful in the present disclosure include dibasic sodium phosphate (NaHPO), and dibasic potassium phosphate (KHPO).

[0055] "Alkali hydroxide" refers to a compound of an alkali metal cation and a hydroxide anion (OH - Alkali hydroxides useful in the present disclosure include lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), and cesium hydroxide (CsOH).

[0056] "Alkali alkoxide" refers to the combination of an alkali metal cation and an alkoxide anion (RO - ) and R is C 1~4 Alkyl alkoxides refer to a class of compounds in which the alkyl group is substituted. Alkyl alkoxides useful in the present disclosure include, but are not limited to, sodium isopropoxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, and potassium isopropoxide.

[0057] "Metal amide" refers to a class of coordination compounds composed of a metal center with an amide ligand of the form -NR2, where R is alkyl, cycloalkyl, or silyl. Metal amides useful in the present disclosure include, but are not limited to, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium 2,2,6,6-tetramethylpiperidide, 2,2,6,6-tetramethylpiperidinyl magnesium chloride, bis(2,2,6,6-tetramethylpiperidinyl)magnesium, and di-n-butyllithium (2,2,6,6-tetramethylpiperidinyl)magnesate).

[0058] "Alkyl and alkenyl metal compounds" refers to a class of compounds consisting of a metal center bonded to an alkyl or alkenyl. Alkyl and alkenyl metal compounds useful in the present disclosure include, but are not limited to, n-butyllithium, isopropylmagnesium chloride, tri-n-butyllithium magnesate, di-n-butylmagnesium, di-sec-butylmagnesium, and ethyl n-butylmagnesium.

[0059] "Alkali hydrides" are compounds formed by combining an alkali metal cation and a hydride anion (H - Alkali hydrides useful in the present disclosure include lithium hydride, sodium hydride, and potassium hydride.

[0060] A "protecting group" refers to a compound that renders a functional group unreactive to a particular set of reaction conditions, but which can then be removed in a later synthetic step to restore the functional group to its original state. Such protecting groups are well known to those skilled in the art and include those disclosed in "Protective Groups in Organic Synthesis," 4th edition, T.W. Greene and P.G.M. Butts, John Wiley & Sons, New York, 2006, which is incorporated herein by reference in its entirety.

[0061] "Amino-protecting group" refers to a protecting group used to protect an amino group. As used herein, and unless otherwise specified, "amino" refers to -NH2. Exemplary amino-protecting groups include carbobenzyloxy (Cbz) groups, p-methoxybenzylcarbonyl (p-Cbz) groups, and methylamino groups. These include, but are not limited to, carboxyl (Moz or MeOZ) groups, tert-butyloxycarbonyl (BOC) groups, 9-fluorenylmethyloxycarbonyl (Fmoc) groups, acetyl (Ac) groups, benzoyl (Bz) groups, benzyl (Bn) groups, carbamate groups, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMB), p-methoxyphenyl (PMP), tosyl (Ts) groups, Troc (trichloroethyl chloroformate) groups, and other sulfonamide (Nosyl and Nps) groups.

[0062] "Deprotecting agent" refers to one or more chemicals or agents that remove a protecting group, as defined above, so as to restore the functionality to its original state.

[0063] "Metal" refers to an element of the periodic table that is metallic and may be neutral, or may be negatively or positively charged as a result of having more or fewer electrons in its valence shell than are present in a neutral metal element. Metals useful in this disclosure include alkali metals and transition metals. Alkali metals in this disclosure include alkali metal cations. Alkali metal cations useful in this disclosure include Li + , Na + , K. + , and Cs + Transition metals useful in the present disclosure include Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag, Cd, La, Hf, Ta, W, Re, Os, Ir, Pt, Au, Hg, and Ac. Transition metals useful in the present disclosure include transition metal cations, such as Cd 2+ , Co 2+ , Co + , Cr 2+ , Cr + , Cu + (i.e., copper(I)), Cu 2+ (i.e., copper(II)), Fe 2+ , Fe + , Mn 2+ , Mn + , Ni 2+ , Ni + , Pd2+ (i.e., Pd(II)), and Zn 2+ Examples include:

[0064] A "catalyst" refers to a substance that increases the rate of a chemical reaction by reducing the activation energy, but remains unchanged by the reaction. Catalysts can be classified as either homogeneous or heterogeneous. Homogeneous catalysts are those whose molecules are dispersed in the same phase as the reactants. Heterogeneous catalysts are those whose molecules are not in the same phase as the reactants, and are typically gases or liquids that are adsorbed on the surface of a solid catalyst. Catalysts useful in the present disclosure are both homogeneous and heterogeneous catalysts.

[0065] "Transition metal catalyst" refers to a compound composed of a transition metal, as defined above, which may be neutral or positively charged.

[0066] "Ligand" refers to a molecule (functional group) that binds to a central metal atom to form a coordination complex. Bonding with the metal generally involves the formal donation of one or more of the ligand's electron pairs. The nature of the metal-ligand bond can range from covalent to ionic. Furthermore, the order of the metal-ligand bond can range from 1 to 3. Generally, the ligand is viewed as the electron donor and the metal as the electron acceptor. Exemplary ligands in the present disclosure are tertiary amines, as defined above, polypyridyl ligands, as defined herein, and amino acids, as defined herein.

[0067] "Polypyridyl ligand" refers to a class of compounds containing at least two pyridine moieties, which are linked by a bond (e.g., 2,2'-bipyridine compounds) or by part of a fused tricyclic aromatic ring assembly containing 14 ring atoms (e.g., 1,10-phenanthroline compounds). Exemplary polypyridyl ligands include, but are not limited to, 2,2'-bipyridine, 1,10-phenanthroline, 4,4'-dimethyl-2,2'-bipyridine, 6,6'-dimethyl-2,2'-bipyridine, 4,4'-di-tert-butyl-2,2-bipyridine, and 2,2'-bipyridine-4,4'-dicarboxylic acid.

[0068] "Amino acid" refers to naturally occurring synthetic amino acids, as well as amino acid analogs that function similarly to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, γ-carboxyglutamate, and O-phosphoserine.

[0069] A "phase transfer agent" or "phase transfer catalyst (PTC)" refers to a catalyst that promotes the transfer of reactants from one phase to another where a reaction occurs. Phase transfer catalysts are a special form of heterogeneous catalyst. Ionic reactants are often soluble in the aqueous phase but insoluble in the organic phase in the absence of a phase transfer catalyst. The catalyst functions like a surfactant to solubilize salts in the organic phase. Using a PTC process can achieve faster reactions, obtain higher conversions or yields, achieve fewer by-products, eliminate the need for expensive or hazardous solvents to dissolve all reactants in one phase, eliminate the need for expensive raw materials, and / or minimize waste issues. PTCs are not limited to systems with hydrophilic and hydrophobic reactants. PTCs may be used in liquid / solid and liquid / gas reactions. As the name implies, one or more of the reactants is transferred to a second phase containing both reactants. Phase transfer catalysts for anionic reactants, as defined herein, are often quaternary ammonium salts.

[0070] "Quaternary ammonium salt" refers to a salt of a quaternary ammonium cation, as defined herein. Quaternary ammonium cations, also known as quats, have the formula NR4 + where the R groups can be alkyl, aryl, or a combination thereof. + ), and unlike primary, secondary, or tertiary ammonium cations, quaternary ammonium cations are permanently charged regardless of the pH of the solution.

[0071] An "activating agent" refers to a reagent that can convert a less reactive functional group in a molecule into a more reactive functional group, increasing its propensity to undergo a particular chemical reaction. In some embodiments, for example, the activating agent converts the -OH group in a compound of Formula V into a reactive functional group (e.g., -Cl, -OMs, -OTs, or -OTf). In some embodiments, the activating agent is a peptide coupling agent known in the art that activates the -C(O)OH group (e.g., a compound of Formula VIII) and then reacts with an amine to form an amide (e.g., a compound of Formula V). Further non-limiting examples of reactive functional groups include -OSO3H and -OSO3 - Examples include:

[0072] "Chlorinating agent" refers to a reagent capable of adding a chloro group, -Cl, to a compound. Exemplary chlorinating agents include, but are not limited to, phosphorus oxychloride, thionyl chloride, oxalyl chloride, and sulfuryl chloride.

[0073] "Bromating agent" refers to a reagent capable of adding a bromo group, -Br, to a compound. Exemplary brominating agents include, but are not limited to, bromine, N-bromosuccinimide, triphenylphosphine dibromide, tetrabutylammonium tribromide, trimethylphenylammonium tribromide, N-bromoacetamide, pyridinium tribromide, dibromodimethylhydantoin, tribromoisocyanuric acid, N-bromosaccharin, and 1,2-dibromo-1,1,2,2-tetrachloroethane.

[0074] "Sulfonating agent" means a compound containing a sulfonate group, -OSO3 - Representative sulfonating agents include sulfur trioxide, sulfur trioxide complexes (e.g., dioxane, pyridine, polyvinylpyridine, trimethylamine, triethylamine, dimethylaniline, thioxane, bis(2-chloroethyl) ether, 2-methylpyridine, quinoline, N,N'-dimethylformamide, tri-n-propylamine, tri-n-butylamine, etc.). amine, N-alkylmorpholine (methyl, ethyl, n-butyl), pentamethylguanidine, 4'-methylacetanilide, N,N'-diethyl-4-toluenesulfonamide, tetramethylurea, tetramethyladipamide, N,N'-dimethylurethane, formylmorpholide, N,N'-dimethylbenzamide, dimethylcyanamide, n-propylpiperidine, n-isoamylpiperidine, N-benzylpiperidine, trimethylphosphine oxide, tetrahydrofuran, diethyl sulfide, anthraquinone, benzanthrone, benzonaphthone, or 2,6-dimethyl-γ-pyrone, chlorosulfonamide, chloroisothiazolinone ... Examples of suitable amines include, but are not limited to, benzoic acid, and sulfur dioxide.

[0075] "Promoter" refers to a substance added to a reactant (e.g., a chlorinating agent as defined above) to improve its performance in a chemical reaction (e.g., the formation of an acyl chloride of Formula VII from an acid of Formula VIII). A promoter itself has little or no catalytic effect on the reaction.

[0076] "Cyclizing agent" refers to one or more reagents (when used in combination) that are capable of promoting a cyclization reaction (e.g., 4,5-dihydrooxazole formation from a compound of formula V) via reactions known in the art.

[0077] A "solvent" refers to a substance, such as a liquid, capable of dissolving a solute. Solvents can be polar or nonpolar, protic or aprotic. Polar solvents typically have a dielectric constant greater than about 5 or a dipole moment greater than about 1.0, while nonpolar solvents have a dielectric constant less than about 5 or a dipole moment less than about 1.0. Protic solvents are characterized by having a proton available for removal, such as by having a hydroxy or carboxy group. Aprotic solvents lack such groups. Representative polar protic solvents include alcohols (e.g., methanol, ethanol, propanol, isopropanol), acids (e.g., formic acid, acetic acid), and water. Representative polar aprotic solvents include dichloromethane, chloroform, tetrahydrofuran, methyltetrahydrofuran, diethyl ether, 1,4-dioxane, acetone, ethyl acetate, dimethylformamide, acetonitrile, and dimethyl sulfoxide. Representative non-polar solvents include alkanes (pentane, hexane, etc.), cycloalkanes (cyclopentane, cyclohexane, etc.), benzene, and toluene. Other solvents are useful in the present disclosure.

[0078] Solvents can also be classified based on their chemical structure, for example, ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), ketones (e.g., acetone, methyl isobutyl ketone, etc.), esters (e.g., ethyl acetate, butyl acetate, isobutyl acetate, etc.), aromatic solvents (e.g., benzene, toluene, xylene, etc.), chlorinated solvents (e.g., dichloromethane, 1,2-dichloroethane, etc.), hydrocarbons (n-heptane, hexane, cyclohexane, methylcyclohexane, etc.), alcohols (methanol, ethanol, propanol, isopropanol, etc.), or acids (e.g., formic acid, acetic acid, etc.).

[0079] "Salt" refers to an acid or base salt of a compound used in the methods of the present disclosure. Salts useful in the present disclosure include, but are not limited to, hemisulfate, sulfate, chloride, bromide, carbonate, nitrate, and acetate. A hemisulfate refers to a compound in which only one of the two basic groups forms a salt with sulfate. Carbonate salts include hydrogen carbonate (or bicarbonate). Illustrative examples of pharmaceutically acceptable salts are salts with mineral acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), organic acids (such as acetic acid, propionic acid, glutamic acid, citric acid, etc.), and quaternary ammonium salts (such as methyl iodide, ethyl iodide, etc.). It is understood that pharmaceutically acceptable salts are non-toxic. For additional information regarding suitable pharmaceutically acceptable salts, see the references. The methods and methods for preparing medicaments for use in the preparation of pharmaceutical compositions can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0080] III. Methods for Preparing Compounds The present disclosure includes several methods for preparing compounds of formula I.

[0081] A. Methods for Preparing Compounds of Formula I from Formula III 1. Preparation of Formula I from Formula III In some embodiments, the present disclosure provides a compound of formula I: [ka] or a salt thereof, the method comprising: a) Formula III: [ka] or a salt thereof, a compound having the formula PG-NHC(=NH)NH2 or a salt thereof, a first base, and a first solvent to form a first reaction mixture comprising a compound of formula II: [ka] or a salt thereof; and b) forming a second reaction mixture comprising the compound of formula II or a salt thereof, a deprotecting agent, and a second solvent to provide the compound of formula I or a salt thereof; In the formula, R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl, or C 1~3 may be alkoxy, and R 4 may be hydrogen or methyl, R 5 is C 3~6 X may be F, Cl, Br, I, or OTs, and PG may be an amino protecting group.

[0082] In one embodiment, the present disclosure provides a compound of formula I: [ka] or a salt thereof, the method comprising: a) Formula III: [ka] or a salt thereof, a compound having the formula PG-NHC(=NH)NH2 or a salt thereof, a first transition metal catalyst, a first base, and a first solvent to form a first reaction mixture comprising a compound of formula II: [ka] or a salt thereof; and b) forming a second reaction mixture comprising the compound of formula II or a salt thereof, a deprotecting agent, and a second solvent to provide the compound of formula I or a salt thereof; In the formula, R 1 , R 2 , and R 3are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl or C 1~3 may be alkoxy, and R 4 may be hydrogen or methyl, R 5 is C 3~6 X may be F, Cl, Br, I, or OTs, and PG may be an amino protecting group.

[0083] In one embodiment, the present disclosure provides a compound of formula I: [ka] or a salt thereof, the method comprising: a) Formula III: [ka] or a salt thereof, a compound having the formula PG-NHC(=NH)NH2 or a salt thereof, a first transition metal catalyst, a first base, and a first solvent to form a first reaction mixture comprising a compound of formula II: [ka] or a salt thereof; and b) forming a second reaction mixture comprising the compound of formula II or a salt thereof, a deprotecting agent, and a second solvent to provide the compound of formula I or a salt thereof; In the formula, R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl or C 1~3 may be alkoxy, and R 4 may be hydrogen or methyl, R 5 is C 3~6 X may be Cl, Br, I, or OTs, and PG may be an amino protecting group.

[0084] The compound having the formula PG-NHC(=NH)NH2 may be in any suitable form. In some embodiments, the compound having the formula PG-NHC(=NH)NH2 may be in neutral form. In some embodiments, the compound having the formula PG-NHC(=NH)NH2 may be in salt form. In some embodiments, the compound having the formula PG-NHC(=NH)NH2 may be its hemisulfate, sulfate, chloride, bromide, carbonate, nitrate, or acetate salt. In some embodiments, the compound having the formula PG-NHC(=NH)NH2 has formula IX: [ka] where n can be 0 to 1. In some embodiments, the compound of formula IX can be a hemisulfate salt, where n can be ½, a sulfate salt, where n can be 1, or a combination thereof. In some embodiments, the compound of formula IX can be a hemisulfate salt, where n can be ½.

[0085] PG can be an amino-protecting group. Suitable amino-protecting groups include carbobenzyloxy (Cbz) group, p-methoxybenzylcarbonyl (Moz or MeOZ) group, tert-butyloxycarbonyl (BOC) group, 2-trimethylsilylethoxymethyl (SEM) group, 9-fluorenylmethyloxycarbonyl (Fm Examples of suitable PGs include, but are not limited to, PG (oc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate, p-methoxybenzyl (PMB), 2,4-dimethoxybenzyl (DMB), 1-(2,4-dimethoxyphenyl)ethyl, 3,4-dimethoxybenzyl (DMPB), p-methoxyphenyl (PMP), tosyl (Ts), Troc (trichloroethyl chloroformate), and other sulfonamide (Nosyl and Nps) groups. In some embodiments, PG can be 2,4-dimethoxybenzyl.

[0086] In some embodiments, the compound of formula IX has formula IXa: [ka] wherein n can be 0 to 1. In some embodiments, the compound of formula IXa can be a hemisulfate salt, where n can be ½, a sulfate salt, where n can be 1, or a combination thereof. In some embodiments, the compound of formula IXa can be a compound of formula IXb: [ka] It may be a hemisulfate salt having the formula:

[0087] The first transition metal catalyst may be a compound containing one or more transition metals or transition metal cations. Suitable transition metals include, but are not limited to, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag, Cd, La, Hf, Ta, W, Re, Os, Ir, Pt, Au, Hg, and Ac. Suitable transition metal cations include Cd 2+ , Co 2+ , Co + , Cr 2+ , Cr + , Cu + (i.e., copper(I)), Cu 2+ (i.e., copper(II)), Fe 2+ , Fe + , Mn 2+ , Mn + , Ni 2+ , Ni + , Pd 2+ (i.e., Pd(II)) , and Zn 2+In some embodiments, the first transition metal catalyst includes, but is not limited to, copper metal, copper oxide, a copper(I) salt, a copper(II) salt, or a combination thereof. In some embodiments, the first transition metal catalyst includes a copper(I) salt. In some embodiments, the first transition metal catalyst includes a copper(II) salt. In some embodiments, the first transition metal catalyst may be copper(I) iodide, copper(I) bromide, copper(I) chloride, copper(I) acetate, copper(I) carbonate, copper(I) nitrate, copper(I) sulfate, copper(I) phosphate, copper(I) 3-methylsalicylate, copper(I) thiophene-2-carboxylate, copper(I) oxide, copper(II) iodide, copper(II) bromide, copper(II) chloride, copper(II) acetate, copper(II) carbonate, copper(II) nitrate, copper(II) sulfate, copper(II) pyrophosphate, copper(II) phosphate, copper(II) tartrate, copper(II) oxide, or a combination thereof. In some embodiments, the first transition metal catalyst may be copper(II) iodide, copper(II) bromide, copper(II) chloride, copper(II) acetate, copper(II) carbonate, copper(II) nitrate, copper(II) sulfate, copper(II) pyrophosphate, copper(II) phosphate, copper(II) tartrate, copper(II) oxide, or a combination thereof. In some embodiments, the first transition metal catalyst includes copper(II) acetate. In some embodiments, the first transition metal catalyst may be copper(II) acetate.

[0088] The first base may be an alkali carbonate, alkali bicarbonate, tribasic alkali phosphate, carboxylate, amidine-based compound, or a combination thereof. Suitable alkali carbonates include lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Suitable alkali bicarbonates include lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate. Suitable tribasic alkali phosphates include tribasic sodium phosphate and tribasic potassium phosphate. Suitable carboxylates include, but are not limited to, lithium acetate, sodium acetate, potassium acetate, cesium acetate, potassium trimethylacetate, and tetrabutylphosphonium malonate. Suitable amidine-based compounds include, but are not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN). In some embodiments, the first base can be lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, tribasic sodium phosphate, tribasic potassium phosphate, potassium acetate, potassium trimethylacetate, tetrabutylphosphonium malonate, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, or a combination thereof. In some embodiments, the first base includes tribasic potassium phosphate. In some embodiments, the first base can be tribasic potassium phosphate.

[0089] The first solvent may be any suitable polar or non-polar, protic or aprotic solvent. In some embodiments, the first solvent may be acetonitrile, propionitrile, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, isopropanol, 2-methylbutan-2-ol, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, toluene, trifluorotoluene, xylene, or a combination thereof. In some embodiments, the first solvent includes 2-methyltetrahydrofuran. In some embodiments, the first solvent includes acetonitrile. In some embodiments, the first solvent includes 2-methyltetrahydrofuran and acetonitrile. In some embodiments, the first solvent may be 2-methyltetrahydrofuran and acetonitrile.

[0090] In some embodiments, the first reaction mixture further comprises a first ligand. In some embodiments, the first ligand is an amino acid, a polypyridyl ligand, or a tertiary amino acid. Suitable amino acids include naturally occurring synthetic amino acids, as well as amino acid analogs that function similarly to the naturally occurring amino acids. Suitable polypyridyl ligands include, but are not limited to, 2,2'-bipyridine, 1,10-phenanthroline, 4,4'-dimethyl-2,2'-bipyridine, 6,6'-dimethyl-2,2'-bipyridine, 4,4'-di-tert-butyl-2,2-bipyridine, 2,2'-bipyridine-4,4'-dicarboxylic acid, and 2,2':6'2"-terpyridine. Suitable tertiary amines include triethylamine, tri-n-butylamine, N,N-diisopropylethylamine, N-methyl- In some embodiments, the first ligand is an amino acid sequence selected from the group consisting of arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, thiamin ... In some embodiments, the amine may be methylamino, tryptophan, α-(methylamino)isobutyric acid, (4-methyl-1-piperazinyl)acetic acid, N-acetyl-cysteine, 2,2'-bipyridine, 1,10-phenanthroline, 4,4'-dimethyl-2,2'-bipyridine, 6,6'-dimethyl-2,2'-bipyridine, 4,4'-di-tert-butyl-2,2-bipyridine, 2,2'-bipyridine-4,4'-dicarboxylic acid, N,N,N',N'-tetramethylethylenediamine, or a combination thereof. In some embodiments, the first ligand includes cysteine, selenocysteine, N-acetyl-cysteine, or homocysteine. In some embodiments, the first ligand includes cysteine. In some embodiments, the first ligand includes L-cysteine. In some embodiments, the first ligand may be cysteine, selenocysteine, N-acetyl-cysteine, or homocysteine. In some embodiments, the first ligand may be cysteine.In some embodiments, the first ligand may be L-cysteine.

[0091] Generally, the first reaction (i.e., step a)) can be carried out at ambient to elevated temperatures. For example, the first reaction mixture can be at a temperature of 30°C to 110°C, or can be heated to reflux. In some embodiments, the first reaction mixture can be at a temperature of 40°C to 100°C, 50°C to 100°C, 50°C to 90°C, 60°C to 90°C, 70°C to 90°C, or about 80°C. In some embodiments, the first reaction mixture can be at a temperature of 55°C to reflux. In some embodiments, the first reaction mixture can be heated to reflux.

[0092] Once the first reaction is complete, the first transition metal catalyst can be removed from the reaction mixture with a second ligand, such as ethylenediaminetetraacetic acid (EDTA) or EDTA disodium salt. In some embodiments, once the first reaction is complete, the first transition metal catalyst can be removed from the first reaction mixture using a second ligand. In some embodiments, the second ligand includes ethylenediaminetetraacetic acid or a salt thereof. In some embodiments, once the first reaction is complete, the first transition metal catalyst can be removed from the first reaction mixture using ethylenediaminetetraacetic acid or a salt thereof. In some embodiments, once the first reaction is complete, copper(II) can be removed from the first reaction mixture using ethylenediaminetetraacetic acid disodium salt.

[0093] The compound of formula II can be deprotected by various methods known in the art to provide the compound of formula I or a salt thereof. When PG is 2,4-dimethoxybenzyl, the compound of formula II can be deprotected by various methods, for example, under acidic, reductive (hydrogenolysis), or oxidative conditions, to provide the compound of formula I or a salt thereof.

[0094] In some embodiments, the deprotecting agent can be an acid. In some embodiments, the acid can be trifluoroacetic acid, trichloroacetic acid, acetic acid, formic acid, hydrochloric acid, sulfuric acid, phosphoric acid, or a combination thereof. In some embodiments, the acid includes trifluoroacetic acid. In some embodiments, the acid can be trifluoroacetic acid.

[0095] In some embodiments, the deprotecting agent can be a hydrogen source, and the second reaction mixture further comprises a second transition metal catalyst. In some embodiments, the hydrogen source can be ammonium formate, formic acid, hydrogen gas, or a combination thereof. In some embodiments, the hydrogen source includes hydrogen gas. In some embodiments, the hydrogen source includes ammonium formate. In some embodiments, the hydrogen source includes formic acid. In some embodiments, the second transition metal catalyst can be palladium hydroxide on carbon, palladium on carbon, or platinum oxide. In some embodiments, the second transition metal catalyst includes palladium hydroxide on carbon. In some embodiments, the second transition metal catalyst includes palladium on carbon. In some embodiments, the second transition metal catalyst includes platinum oxide. In some embodiments, the deprotecting agent can be hydrogen gas, and the second reaction mixture further comprises palladium hydroxide on carbon, palladium on carbon, or platinum oxide. In some embodiments, the deprotecting agent includes ammonium formate, and the second reaction mixture further comprises palladium hydroxide on carbon, palladium on carbon, or platinum oxide. In some embodiments, the deprotecting agent includes formic acid and the second reaction mixture further includes palladium hydroxide on carbon, palladium on carbon, or platinum oxide. In some embodiments, the deprotecting agent includes formic acid and the second solvent includes formic acid.

[0096] In some embodiments, the hydrogen source can be hydrogen gas. In some embodiments, the hydrogen source can be ammonium formate. In some embodiments, the hydrogen source can be formic acid. In some embodiments, the second transition metal catalyst can be palladium hydroxide on carbon. In some embodiments, the second transition metal catalyst can be palladium on carbon. In some embodiments, the second transition metal catalyst can be platinum oxide. In some embodiments, the deprotecting agent can be ammonium formate, and the second reaction mixture further comprises palladium hydroxide on carbon, palladium on carbon, or platinum oxide. In some embodiments, the deprotecting agent can be formic acid, and the second reaction mixture further comprises palladium hydroxide on carbon, palladium on carbon, or platinum oxide. In some embodiments, the deprotecting agent can be formic acid, and the second solvent can be formic acid.

[0097] In some embodiments, the deprotecting agent can be boron tribromide, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, ceric ammonium nitrate, or a combination of trifluoromethanesulfonic acid and 1,3-dimethoxybenzene.

[0098] The second solvent may be any suitable polar or non-polar, protic or aprotic solvent. In some embodiments, the second solvent may be ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, benzene, xylene, trifluorotoluene, anisole, dimethyl sulfoxide, propionitrile, butyronitrile, dichloromethane, 1,2-dichloroethane, chlorobenzene, methanol, ethanol, isopropanol, water, formic acid, acetic acid, trichloroacetic acid, or a combination thereof. In some embodiments, the second solvent includes formic acid. In some embodiments, the second solvent includes dichloromethane. In some embodiments, the second solvent may be formic acid. In some embodiments, the second solvent may be dichloromethane.

[0099] Generally, the second reaction (i.e., step b)) can be carried out at any suitable temperature, for example, from -10°C to 80°C. In some embodiments, the second reaction mixture is The second reaction mixture may be at a temperature of 20°C to 40°C. In some embodiments, the second reaction mixture may be at a temperature of about 30°C. In some embodiments, the second reaction mixture may be at a temperature of about 40°C. In some embodiments, the second solvent includes dichloromethane, and the second reaction mixture may be heated to reflux. In some embodiments, the second solvent may be dichloromethane, and the second reaction mixture may be heated to reflux.

[0100] 2. Preparation of Formula III from Formula IV In some embodiments, the method further comprises, prior to step a), a1) Formula IV: [ka] or a salt thereof, a second base, and a third solvent to form a compound of formula III or a salt thereof; 1 are Cl, Br, OSO3H, OSO3 - , OMs, OTs, or OTf.

[0101] In some embodiments, the method further comprises, prior to step a), a1) Formula IV: [ka] or a salt thereof, a second base, and a third solvent to form a compound of formula III or a salt thereof; 1 is Cl, Br, OMs, OTs, or OTf.

[0102] The second base may be a tertiary amine, an aromatic amine base, an alkali carbonate, an alkali bicarbonate, a tribasic alkali phosphate, an alkali hydroxide, or a combination thereof. Suitable tertiary amines include, but are not limited to, triethylamine, tri-n-butylamine, N,N-diisopropylethylamine, N-methylpyrrolidine, and N-methylmorpholine. Suitable aromatic amine bases include, but are not limited to, pyridine, lutidine (e.g., 2,6-lutidine, 3,5-lutidine, and 2,3-lutidine), collidine (e.g., 2,3,4-collidine, 2,3,5-collidine, 2,3,6-collidine, 2,4,5-collidine, 2,4,6-collidine, and 3,4,5-collidine), and 4-dimethylaminopyridine. Suitable alkali carbonates include, but are not limited to, pyridine, lutidine (e.g., 2,6-lutidine, 3,5-lutidine, and 2,3-lutidine), collidine (e.g., 2,3,4-collidine, 2,3,5-collidine, 2,3,6-collidine, 2,4,5-collidine, 2,4,6-collidine, and 3,4,5-collidine), and 4-dimethylaminopyridine. Suitable alkali bicarbonates include lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate. Suitable tribasic alkali phosphates include tribasic sodium phosphate and tribasic potassium phosphate. Suitable alkali hydroxides include lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide. In some embodiments, the second base may be triethylamine, tri-n-butylamine, N,N-diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, tribasic potassium phosphate, sodium hydroxide, potassium hydroxide, or a combination thereof. The second base may be in an aqueous solution. In some embodiments, the second base includes an aqueous solution of sodium hydroxide. In some embodiments, the second base may be an aqueous solution of sodium hydroxide.

[0103] The third solvent may be any suitable polar aprotic solvent or non-polar solvent. In some embodiments, the third solvent may be tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, xylene, or a combination thereof. In some embodiments, the third solvent includes 2-methyltetrahydrofuran. In some embodiments, the third solvent may be 2-methyltetrahydrofuran.

[0104] The third reaction (i.e., step a1) can be carried out with or without a phase transfer agent. In some embodiments, the third reaction mixture further comprises a phase transfer agent. In some embodiments, the phase transfer agent can be a quaternary ammonium salt. In some embodiments, the quaternary ammonium salt can be tetra-n-butylammonium hydrogen sulfate, tetra-n-butylammonium bromide, tetra-n-butylammonium chloride, benzyltributylammonium bromide, benzyltriethylammonium chloride, benzalkonium chloride, or dodecylethyldimethylammonium bromide. In some embodiments, the quaternary ammonium salt includes tetra-n-butylammonium hydrogen sulfate. In some embodiments, the quaternary ammonium salt can be tetra-n-butylammonium hydrogen sulfate. In some embodiments, the phase transfer agent can be tetra-n-butylammonium hydrogen sulfate.

[0105] Generally, the third reaction (i.e., step a1)) can be carried out at any suitable temperature. For example, the third reaction mixture can be at a temperature of 0°C to 80°C. In some embodiments, the third reaction mixture can be at a temperature of 0°C to 80°C, 10°C to 60°C, 10°C to 50°C, 15°C to 50°C, 20°C to 50°C, or about 35°C. In some embodiments, the third reaction mixture can be at a temperature of 15°C to 50°C. In some embodiments, the third reaction mixture can be at a temperature of about 35°C.

[0106] In some embodiments, the compound of formula IV has the formula: [ka] It has. In some embodiments, the compound of formula IV has the formula: [ka] and In the formula, Y + is the metal ion M + , or ammonium salt HA + Any suitable metal ion M, including but not limited to lithium, sodium, potassium, calcium, or cesium, + Any suitable ammonium salt HA can be used, including, but not limited to, trimethylammonium, triethylammonium, or dicyclohexylammonium. + In some embodiments, Y + is sodium. In some embodiments, Y + is HNMe3 + In some embodiments, the compound of formula IV has the formula: [ka] It has.

[0107] In some embodiments, the third solvent includes acetonitrile, propionitrile, butyronitrile, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, 2-methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, toluene, trifluorotoluene, xylene, benzonitrile, dichloromethane, 1,2-dichloroethane, chlorobenzene, methanol, ethanol, n-butanol, 1-hexanol, 2-propanol, and 2-methyl-2-butanol. In some embodiments, the third solvent includes 2-methyl-2-butanol. In some embodiments, the third solvent can be 2-methyl-2-butanol.

[0108] In some embodiments, the third reaction mixture further comprises an additive. Suitable additives include Examples of suitable additives include, but are not limited to, thionyl chloride, oxalyl chloride, phosphorus(V) oxychloride, phosphorus(V) pentachloride, methanesulfonyl chloride, para-toluenesulfonic acid, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, water, acetic anhydride, 4-dimethylaminopyridine, or tetra-butylammonium salts (e.g., hydrogen sulfate, chloride, bromide, or iodide salts). In some embodiments, no additive is present.

[0109] 3. Preparation of Formula IV from Formula V In some embodiments, prior to step a1), the method further comprises: a2) Formula V: [ka] or a salt thereof, a first activating agent, and a fourth solvent to form a fourth reaction mixture comprising a compound of Formula IV: [ka] or a salt thereof.

[0110] In some embodiments, the AG 1 may be Cl, and the first activating agent may be a first chlorinating agent. The first chlorinating agent converts the —OH group of formula V to the corresponding —Cl group (i.e., AG in formula IV). 1 The first chlorinating agent may be any suitable chlorinating agent capable of converting HCl to HCl (which may be Cl). In some embodiments, the first chlorinating agent may be oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, or chlorosulfonic acid. In some embodiments, the first chlorinating agent includes oxalyl chloride. In some embodiments, the first chlorinating agent includes thionyl chloride. In some embodiments, the first chlorinating agent may be oxalyl chloride. In some embodiments, the first chlorinating agent may be thionyl chloride.

[0111] In some embodiments, the AG 1 may be Br, and the first activating agent may be a first brominating agent. The brominating agent converts the —OH group of formula V to the corresponding —Br group (i.e., AG in formula IV). 1 wherein R 1 is Br. In some embodiments, the brominating agent may be triphenylphosphine dibromide or tribromoisocyanuric acid.

[0112] In some embodiments, the AG 1 may be OMs, OTs, or OTf, and the first activating agent may be methanesulfonyl chloride, methanesulfonic anhydride, para-toluenesulfonyl chloride, The compound may be selected from the group consisting of toluenesulfonic acid, toluenesulfonic acid anhydride, trifluoromethanesulfonic acid anhydride, toluenesulfonic acid dian ... 1 may be OMs, and the first activating agent may be methanesulfonyl chloride or methanesulfonic anhydride. In some embodiments, AG 1 may be OMs, and the first activating agent may include methanesulfonyl chloride. In some embodiments, AG 1may be OTs, and the first activating agent may include para-toluenesulfonyl chloride. In some embodiments, AG 1 may be OTf, and the first activating agent may include trifluoromethanesulfonic anhydride. In some embodiments, AG 1 may be OTs and the first activating agent may be para-toluenesulfonyl chloride. In some embodiments, AG 1 may be OTf and the first activating agent may be trifluoromethanesulfonic anhydride.

[0113] The fourth solvent may be any suitable polar aprotic solvent and / or nonpolar solvent. In some embodiments, the fourth solvent may be tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, xylene, or a combination thereof. In some embodiments, the fourth solvent includes 2-methyltetrahydrofuran. In some embodiments, the fourth solvent may be 2-methyltetrahydrofuran.

[0114] Generally, when the first activating agent can be a first chlorinating agent, the fourth reaction (i.e., step a2) can be carried out at any suitable temperature. For example, the fourth reaction mixture can be at a temperature of 0°C to 80°C. In some embodiments, the fourth reaction mixture can be at a temperature of 0°C to 80°C, 10°C to 80°C, 20°C to 70°C, 30°C to 60°C, 40°C to 60°C, 15°C to 50°C, or about 50°C. In some embodiments, the fourth reaction mixture can be at a temperature of 15°C to 50°C. In some embodiments, the fourth reaction mixture can be at a temperature of about 50°C.

[0115] In some embodiments, prior to step a1), the method further comprises: a2) Formula V: [ka] or a salt thereof, a first activating agent, and a fourth solvent to form a fourth reaction mixture comprising a compound of formula IV-2: [ka] and forming The compound of formula IV-2 or a salt thereof is treated with an ion exchange reagent in a fourth solvent to provide a compound of formula IV: [ka] or a salt thereof, 1 is OSO3H or OSO3 - is.

[0116] In some embodiments, the AG 1 is OSO3H or OSO3 - and the first activating agent may be a sulfonating agent, which converts the -OH group of formula V to the corresponding -OSO3H or -OSO3 -In some embodiments, the sulfonating agent may be sulfur trioxide, chlorosulfonic acid, sulfur dioxide, or sulfur trioxide complex. In some embodiments, the sulfur trioxide complex may be sulfur trioxide complexed with dioxane, pyridine, polyvinylpyridine, trimethylamine, triethylamine, dimethylaniline, thioxane, bis(2-chloroethyl)ether, 2-methylpyridine, quinoline, N,N'-dimethylformamide, tri-n-propylamine, tri-n-butylamine, N-alkylmorpholine (methyl, ethyl, n-butyl), pentamethylguanidine, 4'-methylacetanilide, N,N'-diethyl-4-toluenesulfonamide, tetramethylurea, tetramethyladipamide, N,N'-dimethylurethane, formylmorpholide, N,N'-dimethylbenzamide, dimethylcyanamide, n-propylpiperidine, n-isoamylpiperidine, N-benzylpiperidine, trimethylphosphine oxide, tetrahydrofuran, diethylsulfide, anthraquinone, benzanthrone, benzonaphthone, or 2,6-dimethyl-γ-pyrone. In some embodiments, the sulfonating agent includes sulfur trioxide trimethylamine complex. In some embodiments, the sulfonating agent can be sulfur trioxide trimethylamine complex.

[0117] In some embodiments of the compound of formula IV-2, Y + is hydrogen, pyridinium, trimethylammonium, triethylammonium, methylpyridinium, quinolinium, tri-n-propylammonium, tri-n-butylammonium, morpholinium, optionally methyl, ethyl, or n-butyl, pentamethylguanidinium, N,N'-dimethylethylenediammonium, dimethylcyanamide, or benzoyl In some embodiments of Formula IV-2, Y is substituted with dipiperidinium. + is trimethylammonium.

[0118] In some embodiments, the ion exchange reagent is an ion exchange resin (e.g., ion exchanger I, II, III, IV, or V; Amberlite® IR-120, e.g., H + Type, Na + type, IRA-67, IRA-402, IRA-410, 15; and Dowex®, e.g., 50WX4, 50W-XZ8, 1-X8; mineral acids (e.g., hydrochloric acid, or hydrobromic acid); carboxylic acid salts (e.g., disodium sebacate, sodium hexanoate, sodium 2-ethylhexanoate, calcium 2-ethylhexanoate, or potassium 2-ethylhexanoate); hydroxides or alkoxides (e.g., lithium The ion exchange reagent may be sodium tert-butoxide, sodium tert-pentoxide, potassium tert-pentoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, or cesium hydroxide; an amine (e.g., dicyclohexylamine or N-methylcyclohexylamine); or others (e.g., sodium tetrafluoroborate, dibasic potassium phosphate, calcium sulfate, or ferrocyanine acid). In some embodiments, the ion exchange reagent includes sodium 2-ethylhexanoate. In some embodiments, the ion exchange reagent may be sodium 2-ethylhexanoate.

[0119] In some embodiments, the compound of formula IV has the formula: [ka] In the acid form, In some embodiments, the compound of formula IV has the formula: [ka] and in the form of a salt having the formula In the formula, Y + is the metal ion M + , or ammonium salt HA +Any suitable metal ion M, such as, but not limited to, lithium, sodium, potassium, calcium, or cesium, + Any suitable ammonium salt HA can be used, such as, but not limited to, trimethylammonium, triethylammonium, or dicyclohexylammonium. + In some embodiments, Y + is sodium. In some embodiments, the compound of formula IV has the formula: [ka] It has.

[0120] In some embodiments, the fourth solvent can be any suitable polar aprotic and / or non-polar solvent. In some embodiments, the fourth solvent is acetonitrile, The fourth solvent may be propionitrile, butyronitrile, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, 2-methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, isopropyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, acetone, methyl isobutyl ketone, toluene, trifluorotoluene, xylene, benzonitrile, dichloromethane, 1,2-dichloroethane, chlorobenzene, or a combination thereof. In some embodiments, the fourth solvent includes acetonitrile, 2-methyltetrahydrofuran, or a combination thereof. In some embodiments, the fourth solvent includes acetonitrile and 2-methyltetrahydrofuran. In some embodiments, the fourth solvent may be acetonitrile, 2-methyltetrahydrofuran, or a combination thereof. In some embodiments, the fourth solvent may be acetonitrile and 2-methyltetrahydrofuran.

[0121] Generally, the sulfonation and ion exchange step of the fourth reaction (i.e., step a2) can be carried out at any suitable temperature. For example, the sulfonation reaction mixture can be at a temperature of 0°C to 100°C. In some embodiments, the sulfonation reaction mixture can be at a temperature of 20°C to 100°C, 30°C to 100°C, 40°C to 100°C, 40°C to 100°C, 50°C to 100°C, 60°C to 100°C, 60°C to 90°C, or 60°C to 80°C. In some embodiments, the sulfonation reaction mixture can be at a temperature of 60°C to 80°C. For example, the ion exchange reaction mixture can be at a temperature of 0°C to 50°C. In some embodiments, the ion exchange reaction mixture can be at a temperature of 10°C to 40°C, 15°C to 40°C, 15°C to 30°C, or about 20°C. In some embodiments, the ion exchange reaction mixture can be at a temperature of about 20°C.

[0122] 4. Preparation of Formula III from Formula V In some embodiments, the method further comprises, prior to step a), a1-2) Formula V: [ka] or a salt thereof, one or more cyclizing agents, and a fifth solvent to form a compound of Formula III or a salt thereof.

[0123] The one or more cyclizing agents may be any suitable reagent capable of forming a 4,5-dihydrooxazole moiety from a compound of Formula V by cyclization. The one or more cyclizing agents may be a reagent combined with triphenylphosphine, such as 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) / triphenylphosphine, diethyl azodicarboxylate (DEAD) / triphenylphosphine, diisopropyl azodicarboxylate (DIAD) / triphenylphosphine, or carbon tetrabromide / triphenylphosphine. The one or more cyclizing agents may be a dehydrating agent used alone, such as methyl N-(triethylammoniosulfonyl)-carbamate (also known as Burgess's reagent). The one or more cyclizing agents may be diethylaminosulfur trifluoride (DAST), which mediates cyclization to form a 4,5-dihydrooxazole moiety. In some embodiments, The one or more cyclizing agents are a combination of 2,3-dichloro-5,6-dicyano-p-benzoquinone and triphenylphosphine, a combination of diethyl azodicarboxylate and triphenylphosphine, a combination of diisopropyl azodicarboxylate and triphenylphosphine, a combination of carbon tetrabromide and triphenylphosphine, methyl N-(triethylammoniosulfonyl)-carbamate, or diethylaminosulfur trifluoride.

[0124] The fifth solvent may be any suitable polar aprotic solvent and / or nonpolar solvent. In some embodiments, the fifth solvent may be tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, xylene, or a combination thereof. In some embodiments, the fifth solvent includes 2-methyltetrahydrofuran. In some embodiments, the fifth solvent may be 2-methyltetrahydrofuran.

[0125] 5. Preparation of Formula V from Formula VII and Formula VI In some embodiments, the method further comprises, prior to step a2) or a1-2), a3) Formula VII: [ka] or a salt thereof with a compound of formula VI: [ka] or a salt thereof, a third base, and a sixth solvent to form a compound of Formula V or a salt thereof.

[0126] The compound of formula VI may be in any suitable form. In some embodiments, the compound of formula VI may be in neutral form. In some embodiments, the compound of formula VI may be in salt form. In some embodiments, the compound of formula VI may be its tosylate salt.

[0127] The third base may be a tertiary amine, an aromatic amine base, an alkali carbonate, an alkali bicarbonate, a tribasic alkali phosphate, an alkali hydroxide, or a combination thereof. Suitable tertiary amines include, but are not limited to, triethylamine, tri-n-butylamine, N,N-diisopropylethylamine, N-methylpyrrolidine, and N-methylmorpholine. Suitable aromatic amine bases include, but are not limited to, pyridine, lutidine (e.g., 2,6-lutidine, 3,5-lutidine, and 2,3-lutidine), collidine (e.g., 2,3,4-collidine, 2,3,5-collidine, 2,3,6-collidine, 2,4,5-collidine, 2,4,6-collidine, and 3,4,5-collidine), and 4-dimethylaminopyridine. Suitable alkali carbonates include lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Suitable Suitable alkali bicarbonates include lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate. Suitable tribasic alkali phosphates include tribasic sodium phosphate and tribasic potassium phosphate. Suitable alkali hydroxides include lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide. In some embodiments, the third base may be triethylamine, tri-n-butylamine, N,N-diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, tribasic potassium phosphate, sodium hydroxide, potassium hydroxide, or a combination thereof. In some embodiments, the third base may be in an aqueous solution. In some embodiments, the third base may include potassium carbonate. In some embodiments, the third base may include an aqueous solution of potassium carbonate. In some embodiments, the third base may be potassium carbonate. In some embodiments, the third base can be an aqueous solution of potassium carbonate.

[0128] The sixth solvent may be any suitable polar aprotic solvent and / or nonpolar solvent. In some embodiments, the sixth solvent further comprises water. In these embodiments, the sixth reaction (i.e., step a3)) may be a biphasic reaction. In some embodiments, the sixth solvent may be tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, xylene, water, or a combination thereof. In some embodiments, the sixth solvent includes 2-methyltetrahydrofuran. In some embodiments, the sixth solvent includes 2-methyltetrahydrofuran and water. In some embodiments, the sixth solvent may be 2-methyltetrahydrofuran. In some embodiments, the sixth solvent may be 2-methyltetrahydrofuran and water.

[0129] Generally, the sixth reaction (i.e., step a3) can be carried out at any suitable temperature. For example, the fourth reaction mixture can be at a temperature of 0°C to 60°C. In some embodiments, the fourth reaction mixture can be at a temperature of 0°C to 60°C, 10°C to 50°C, 10°C to 40°C, 20°C to 40°C, 20°C to 30°C, or about 20°C. In some embodiments, the third reaction mixture can be at a temperature of 20°C to 30°C. In some embodiments, the third reaction mixture can be at a temperature of about 20°C.

[0130] 6. Preparation of Formula VII from Formula VIII In some embodiments, the method further comprises, prior to step a3), a4) Formula VIIIb: [ka] or a salt thereof, a second chlorinating agent, a promoter, and a seventh solvent to form a compound of Formula VII or a salt thereof.

[0131] The second chlorinating agent can be any suitable chlorinating agent capable of converting the —C(O)OH group of formula VIII to the —C(O)Cl group of formula VII. In some embodiments, the second The chlorinating agent may be oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, or (chloromethylene)dimethyliminium chloride. In some embodiments, the second chlorinating agent includes oxalyl chloride. In some embodiments, the second chlorinating agent includes thionyl chloride. In some embodiments, the second chlorinating agent may be oxalyl chloride. In some embodiments, the second chlorinating agent may be thionyl chloride.

[0132] In some embodiments, the promoter may be N,N-dimethylformamide, N,N-dimethylacetamide, or dichloromethylene-dimethyliminium chloride. In some embodiments, the promoter includes N,N-dimethylformamide. In some embodiments, the promoter may be N,N-dimethylformamide.

[0133] The seventh solvent may be any suitable polar aprotic solvent and / or nonpolar solvent. In some embodiments, the seventh solvent may be tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, xylene, or a combination thereof. In some embodiments, the seventh solvent includes 2-methyltetrahydrofuran. In some embodiments, the seventh solvent may be 2-methyltetrahydrofuran.

[0134] Generally, the seventh reaction (i.e., step a4)) can be carried out at any suitable temperature. For example, the seventh reaction mixture can be at a temperature of 0°C to 60°C. In some embodiments, the seventh reaction mixture can be at a temperature of 0°C to 60°C, 10°C to 50°C, 10°C to 40°C, 20°C to 40°C, 20°C to 30°C, or about 20°C. In some embodiments, the seventh reaction mixture can be at a temperature of 20°C to 30°C. In some embodiments, the seventh reaction mixture can be at a temperature of about 20°C.

[0135] 7. Preparation of Formula V from Formula VIII and Formula VI In some embodiments, the method further comprises, prior to step a2) or a1-2), a3-1) Formula VIII: [ka] or a salt thereof with a compound of formula VI: [ka] or a salt thereof, a second activating agent, a fourth base, and an eighth solvent to form a compound of Formula V or a salt thereof.

[0136] The compound of formula VI can be in any suitable form. In some embodiments, the compound of formula VI can be in neutral form. In some embodiments, the compound of formula VI can be in salt form. In some embodiments, the compound of formula VI may be its tosylate salt.

[0137] The second activating agent can be any peptide coupling reagent that can activate an acid group (e.g., the acid group of Formula III) and thereby react with an amine (e.g., a compound of Formula VI) to form an amide bond (e.g., the amide group of Formula V). Peptide coupling reagents include isobutyl chloroformate, 1,1'-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), hydroxybenzotriazole (HOBt), and 1-hydroxy-7-azabenzotriazole (HOAt). In some embodiments, the second activating agent can be isobutyl chloroformate or 1,1'-carbonyldiimidazole.

[0138] The fourth base may be a tertiary amine, an aromatic amine base, or a combination thereof. Suitable tertiary amines include, but are not limited to, triethylamine, tri-n-butylamine, N,N-diisopropylethylamine, N-methylpyrrolidine, and N-methylmorpholine. Suitable aromatic amine bases include, but are not limited to, pyridine, lutidine (e.g., 2,6-lutidine, 3,5-lutidine, and 2,3-lutidine), collidine (e.g., 2,3,4-collidine, 2,3,5-collidine, 2,3,6-collidine, 2,4,5-collidine, 2,4,6-collidine, and 3,4,5-collidine), and 4-dimethylaminopyridine. In some embodiments, the fourth base can be triethylamine, tri-n-butylamine, N,N-diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, or a combination thereof. In some embodiments, the fourth base includes N,N-diisopropylethylamine. In some embodiments, the fourth base can be N,N-diisopropylethylamine.

[0139] The eighth solvent may be any suitable polar aprotic solvent and / or nonpolar solvent. In some embodiments, the eighth solvent may be N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, acetonitrile, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, xylene, or a combination thereof. In some embodiments, the eighth solvent includes N,N-dimethylformamide. In some embodiments, the eighth solvent includes 2-methyltetrahydrofuran. In some embodiments, the eighth solvent includes N,N-dimethylformamide and 2-methyltetrahydrofuran. In some embodiments, the eighth solvent may be N,N-dimethylformamide. In some embodiments, the eighth solvent may be 2-methyltetrahydrofuran. In some embodiments, the eighth solvent can be N,N-dimethylformamide and 2-methyltetrahydrofuran.

[0140] The neutral form of the compound of Formula I can be produced by contacting a salt of the compound of Formula I with a base. In some embodiments, the method further includes c) forming a ninth reaction mixture comprising the salt of the compound of Formula I, a fifth base, and a ninth solvent to provide the neutral form of the compound of Formula I.

[0141] The fifth base can be an alkali carbonate or an alkali hydroxide. Suitable alkali carbonates include sodium carbonate and potassium carbonate. Suitable alkali hydroxides include sodium hydroxide and potassium hydroxide. In some embodiments, the fifth base can be sodium hydroxide or potassium hydroxide. In some embodiments, the fifth base can include sodium hydroxide. In some embodiments, the fifth base can be in an aqueous solution. In some embodiments, the fifth base can include an aqueous solution of sodium hydroxide. In some embodiments, the fifth base can be sodium hydroxide. In some embodiments, the fifth base can be an aqueous solution of sodium hydroxide.

[0142] The ninth solvent may be any suitable alcohol solvent, ester solvent, and / or water. In some embodiments, the ninth solvent may be methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, water, or a combination thereof. In some embodiments, the ninth solvent includes i) ethanol and water, or ii) ethyl acetate and water. In some embodiments, the ninth solvent includes ethanol and water. In some embodiments, the ninth solvent includes ethyl acetate and water. In some embodiments, the ninth solvent may be i) ethanol and water, or ii) ethyl acetate and water. In some embodiments, the ninth solvent may be ethanol and water. In some embodiments, the ninth solvent may be ethyl acetate and water.

[0143] If the ninth solvent comprises an ester solvent (eg, ethyl acetate or isopropyl acetate), once the reaction is complete, the reaction mixture after partition can be further treated with an aqueous solution of sodium bicarbonate.

[0144] Generally, the ninth reaction (i.e., step c)) can be carried out at any suitable temperature. For example, the ninth reaction mixture can be at a temperature of 0°C to 60°C. In some embodiments, the ninth reaction mixture can be at a temperature of 0°C to 60°C, 10°C to 60°C, 10°C to 50°C, or 20°C to 40°C. In some embodiments, the ninth reaction mixture can be at a temperature of 20°C to 40°C. In some embodiments, the ninth reaction mixture can be at a temperature of about 20°C. In some embodiments, the ninth reaction mixture can be at a temperature of about 40°C.

[0145] 8. Preparation of Formula II from Formula III In some embodiments, the present disclosure provides a compound of formula II: [ka] or a salt thereof, the method comprising: a) Formula III: [ka] or a salt thereof, a compound having the formula PG-NHC(=NH)NH2 or a salt thereof, and a first solvent to form a first reaction mixture comprising a compound of formula II: [ka] or a salt thereof, In the formula, R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl, or C 1~3 may be alkoxy, and R 4 may be hydrogen or methyl, R 5 is C 3~6 X may be F, and PG may be an amino protecting group.

[0146] The compound having the formula PG-NHC(=NH)NH2 may be in any suitable form. In some embodiments, the compound having the formula PG-NHC(=NH)NH2 may be in neutral form. In some embodiments, the compound having the formula PG-NHC(=NH)NH2 may be in salt form. In some embodiments, the compound having the formula PG-NHC(=NH)NH2 may be its hemisulfate, sulfate, chloride, bromide, carbonate, nitrate, or acetate salt. In some embodiments, the compound having the formula PG-NHC(=NH)NH2 has formula IXc: [ka] It may be.

[0147] In some embodiments, PG can be an amino-protecting group. Suitable amino-protecting groups include, but are not limited to, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, acetyl, trifluoroacetyl, 2,2,5,7,8-pentamethyl-chroman-6-sulfonyl chloride, para-toluenesulfonyl, 4-methoxy-2,3,6-trimethylbenzenesulfonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-chlorobenzyl. In some embodiments, PG can be 2,4-dimethoxybenzyl.

[0148] In some embodiments, the first reaction mixture further comprises a first base. The first base can be selected from the group consisting of a carbonate (e.g., cesium carbonate, lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, magnesium carbonate, calcium carbonate, strontium carbonate, barium carbonate, nickel carbonate, zinc carbonate, silver carbonate, and ammonium carbonate), a metal oxide (e.g., magnesium oxide), a hydroxide (e.g., potassium hydroxide, sodium hydroxide, lithium hydroxide, cesium hydroxide, barium hydroxide, ammonium hydroxide, and tetra-n-butylammonium hydroxide), an alkoxide (e.g., lithium phenoxide), a silanolate (e.g., potassium trimethylsilanolate, sodium trimethylsilanolate, lithium silanolate, and tetra-n-butylammonium hydroxide). silanolate, or sodium dimethylphenylsilanolate), phosphates (e.g., tribasic potassium phosphate, tribasic calcium phosphate, tribasic magnesium phosphate, tribasic sodium phosphate, dibasic sodium phosphate, or dibasic potassium phosphate), hydrides (e.g., sodium hydride or potassium hydride), amines (e.g., N,N-diisopropylethylamine, triethylamine, N,N,N',N'-tetramethylethylenediamine, 1,4-diazabicyclo[2.2.2]octane, 1-azabicyclo[2.2.2]octane, 1,8-diaza[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-enepyridine, 1,1,3,3-tetramethylguanidine, 4-methylmorpholine, 2-tert-butyl-1,1,3,3-tetramethylguanidine, 1,3,4,6,7,8-hexahydro-1-methyl-2H-pyrimido[1,2-a]pyrimidine, 1,8-bis(dimethylamino)naphthalene, or N,N,N'N'-tetramethyl-1,8-naphthalenediamine), amides (e.g., lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, sodium diisopropylamide, or lithium dicyclohexylamide), alkyl metals (e.g., For example, n-butyllithium, tert-butyllithium, methyllithium, phenyllithium, lithium naphthalenide, or sodium naphthalenide), an alkoxide (e.g., magnesium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, sodium tert-pentoxide, or potassium tert-pentoxide), a phosphorane (e.g., tert-butylimino-tri(pyrrolidino)phospholene, 2-tert-butylimino-tri(pyrrolidino)phospholene, or 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphorene), or a combination thereof. In some embodiments, the first base includes cesium carbonate. In some embodiments, the first base can be cesium carbonate.

[0149] The first solvent may be any suitable polar or non-polar protic or aprotic solvent. The first solvent may be a polar aprotic solvent (e.g., N,N'-dimethylformamide, N,N'-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, sulfolane, acetonitrile, propionitrile, butyronitrile, nitromethane, or nitroethane), an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, methyl tert-butyl ether, or cyclopentyl methyl ether), an alcohol (e.g., methanol, ethanol, n- The first solvent may be butanol, 2-butanol, tert-butanol, 2-methylbutan-2-ol, 2,2,2-trifluoroethanol, or hexafluoro-2-propanol), a ketone (e.g., methyl isobutyl ketone or methyl ethyl ketone), an ester (e.g., isopropyl acetate or n-butyl acetate), a chlorinated solvent (e.g., 1,2-dichloroethane, chlorobenzene, or trifluorotoluene), an aromatic solvent (e.g., toluene, xylene, or anisole), water, or a combination thereof. In some embodiments, the first solvent includes 2-methyltetrahydrofuran. In some embodiments, the first solvent may be 2-methyltetrahydrofuran.

[0150] In some embodiments, the first reaction mixture further comprises an additive. The additive may be 4-dimethylaminopyridine, 4-piperidinopyridine, 4-pyrrolidinopyridine, imidazole, N-methylimidazole, or 9-azajulolidine. In some embodiments, no additive is present.

[0151] Generally, the first reaction (i.e., step a)) can be carried out at ambient to elevated temperatures. For example, the first reaction mixture can be at a temperature of 30°C to 150°C. In some embodiments, the first reaction mixture can be at a temperature of 40°C to 100°C, 40°C to 90°C, 40°C to 80°C, or about 80°C. In some embodiments, the first reaction mixture can be at a temperature of 40°C to 80°C. In some embodiments, the first reaction mixture can be at a temperature of about 80°C.

[0152] In some embodiments, the method further comprises, prior to step a), a1) Formula IV: [ka] or a salt thereof, a second base, and a third solvent to form a compound of formula III or a salt thereof, wherein X is F and AG 1 is Cl.

[0153] The second base may be an aprotic amine (e.g., triethylamine, tri-n-butylamine, N,N'-diisopropylethylamine, N-methylpyrrolidine, or N-methylmorpholine), an aromatic amine (e.g., pyridine, 2,6-lutidine, or collidine), or an inorganic base (e.g., sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, cesium carbonate, or potassium phosphate). The second base may be in an aqueous solution. In some embodiments, the second base includes an aqueous solution of sodium hydroxide. In some embodiments, the second base may be an aqueous solution of sodium hydroxide.

[0154] The third solvent may be any suitable polar aprotic or nonpolar solvent. The third solvent may be an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, or 1,4-dioxane), a halogenated solvent (e.g., dichloromethane or 1,2-dichloroethane), an aromatic solvent (benzene, toluene, or xylene), water, or a combination thereof. In some embodiments, the third solvent includes 2-methyltetrahydrofuran. In some embodiments, the third solvent includes 2-methyltetrahydrofuran and water. In some embodiments, the third solvent may be 2-methyltetrahydrofuran. In some embodiments, the third solvent may be 2-methyltetrahydrofuran and water.

[0155] The third reaction (i.e., step a1)) can be carried out with or without a phase transfer agent. In some embodiments, the third reaction mixture further comprises a phase transfer agent. The phase transfer agent can be an ammonium salt (e.g., tetra-n-butylammonium hydrogen sulfate, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, benzalkonium chloride, or dodecylethyldimethylammonium bromide). In some embodiments, the phase transfer agent includes tetra-n-butylammonium hydrogen sulfate. In some embodiments, the phase transfer agent can be tetra-n-butylammonium hydrogen sulfate.

[0156] Generally, the third reaction (i.e., step a1) can be carried out at any suitable temperature. For example, the third reaction mixture can be at a temperature of 20°C to 80°C. In some embodiments, the third reaction mixture can be at a temperature of 20°C to 70°C, 20°C to 60°C, 20°C to 50°C, or 20°C to 40°C. In some embodiments, the third reaction mixture can be at a temperature of 20°C to 40°C.

[0157] In some embodiments, prior to step a1), the method further comprises: a2) Formula V: [ka] or a salt thereof, a first activating agent, and a fourth solvent to form a fourth reaction mixture comprising a compound of Formula IV: [ka] or a salt thereof, wherein X is F and AG 1 is Cl.

[0158] In some embodiments, the first activating agent can be a first chlorinating agent, which converts the —OH group of formula V to the corresponding —Cl group (i.e., AG 1 The first chlorinating agent may be any suitable chlorinating agent capable of converting HCl to HCl (which may be Cl). In some embodiments, the first chlorinating agent may be thionyl chloride, oxalyl chloride, phosphorus(V) oxychloride, phosphorus(V) pentachloride, methanesulfonyl chloride, para-toluenesulfonic acid, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, or chlorosulfonic acid. In some embodiments, the first chlorinating agent includes oxalyl chloride. In some embodiments, the first chlorinating agent includes thionyl chloride. In some embodiments, the first chlorinating agent may be oxalyl chloride. In some embodiments, the first chlorinating agent may be thionyl chloride.

[0159] The fourth solvent may be any suitable polar aprotic solvent and / or non-polar solvent. The fourth solvent may be an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, or 1,4-dioxane), a halogenated solvent (e.g., dichloromethane or 1,2-dichloroethane), an aromatic solvent (e.g., benzene, toluene, or xylene), or a combination thereof. In some embodiments, the fourth solvent includes 2-methyltetrahydrofuran. In some embodiments, the fourth solvent may be 2-methyltetrahydrofuran.

[0160] Generally, the fourth reaction (i.e., step a2) can be carried out at any suitable temperature. For example, the fourth reaction mixture can be at a temperature of 0°C to 80°C. In some embodiments, the fourth reaction mixture can be at a temperature of 20°C to 80°C, 30°C to 80°C, 40°C to 80°C, 50°C to 80°C, or 50°C to 70°C. In some embodiments, the fourth reaction mixture can be at a temperature of 50°C to 70°C.

[0161] In some embodiments, the method further comprises, prior to step a2) or a1-2), a3) Formula VII: [ka] or a salt thereof with a compound of formula VI: [ka] or a salt thereof, a third base, and a sixth solvent to form a compound of Formula V or a salt thereof, wherein X is F.

[0162] The compound of formula VI may be in any suitable form. In some embodiments, the compound of formula VI may be in neutral form. In some embodiments, the compound of formula VI may be in salt form. In some embodiments, the compound of formula VI may be its tosylate salt.

[0163] The third base may be a tertiary amine (e.g., triethylamine, tri-n-butylamine, N,N-diisopropylethylamine, N-methylpyrrolidine, or N-methylmorpholine), an aromatic amine (e.g., pyridine, 2,6-lutidine, or collidine), or an inorganic base (e.g., sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, or tribasic potassium phosphate). In some embodiments, the third base may be in an aqueous solution. In some embodiments, the third base includes potassium carbonate. In some embodiments, the third base includes an aqueous solution of potassium carbonate. In some embodiments, the third base may be potassium carbonate. In some embodiments, the third base may be an aqueous solution of potassium carbonate.

[0164] The sixth solvent may be any suitable polar aprotic and / or non-polar solvent. In some embodiments, the sixth solvent further comprises water. The reaction of 6 (i.e., step a3)) can be a biphasic reaction. In some embodiments, the sixth solvent can be an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, or 1,4-dioxane), a halogenated solvent (e.g., dichloromethane or 1,2-dichloroethane), an aromatic solvent (e.g., benzene, toluene, or xylene), water, or a combination thereof. In some embodiments, the sixth solvent includes 2-methyltetrahydrofuran. In some embodiments, the sixth solvent includes 2-methyltetrahydrofuran and water. In some embodiments, the sixth solvent can be 2-methyltetrahydrofuran. In some embodiments, the sixth solvent can be 2-methyltetrahydrofuran and water.

[0165] Generally, the sixth reaction (i.e., step a3)) can be carried out at any suitable temperature. For example, the sixth reaction mixture can be at a temperature of 0°C to 60°C. In some embodiments, the sixth reaction mixture can be at a temperature of 0°C to 60°C, 10°C to 50°C, 10°C to 40°C, 20°C to 40°C, 20°C to 30°C, or about 20°C. In some embodiments, the sixth reaction mixture can be at a temperature of 20°C to 30°C. In some embodiments, the sixth reaction mixture can be at a temperature of about 20°C.

[0166] In some embodiments, the method further comprises, prior to step a3), a4) Formula VIIIb: [ka] or a salt thereof, a second chlorinating agent, a promoter, and a seventh solvent to form a compound of Formula VII or a salt thereof, wherein X is F.

[0167] The second chlorinating agent can be any suitable chlorinating agent capable of converting the —C(O)OH group of Formula VIII to the —C(O)Cl group of Formula VII. In some embodiments, the second chlorinating agent can be oxalyl chloride, thionyl chloride, phosphorus(V) oxychloride, phosphorus(V) pentachloride, (chloromethylene)dimethyliminium chloride, 1,1′-carbonyldiimidazole, or isobutyl chloroformate. In some embodiments, the second chlorinating agent includes oxalyl chloride. In some embodiments, the second chlorinating agent includes thionyl chloride. In some embodiments, the second chlorinating agent can be oxalyl chloride. In some embodiments, the second chlorinating agent can be thionyl chloride.

[0168] In some embodiments, the promoter may be N,N-dimethylformamide or dichloromethylene-dimethyliminium chloride. In some embodiments, the promoter includes N,N-dimethylformamide. In some embodiments, the promoter may be N,N-dimethylformamide.

[0169] The seventh solvent can be any suitable polar aprotic and / or non-polar solvent. In some embodiments, the seventh solvent is an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, or 1,4-dioxa The seventh solvent may be a methyl hexane, a halogenated solvent (e.g., dichloromethane, or 1,2-dichloroethane), an aromatic solvent (e.g., benzene, toluene, or xylene), water, or a combination thereof. In some embodiments, the seventh solvent includes 2-methyltetrahydrofuran. In some embodiments, the seventh solvent may be 2-methyltetrahydrofuran.

[0170] Generally, the seventh reaction (i.e., step a4)) can be carried out at any suitable temperature. For example, the seventh reaction mixture can be at a temperature of 0°C to 60°C. In some embodiments, the seventh reaction mixture can be at a temperature of 0°C to 60°C, 10°C to 50°C, 10°C to 40°C, 20°C to 40°C, 20°C to 30°C, or about 20°C. In some embodiments, the seventh reaction mixture can be at a temperature of 20°C to 30°C. In some embodiments, the seventh reaction mixture can be at a temperature of about 20°C.

[0171] The compound of formula II can be deprotected by various methods known in the art to provide the compound of formula I, or a salt thereof. In some embodiments, when PG is 2,4-dimethoxybenzyl, the compound of formula II can be deprotected by various methods, for example, under acidic, reductive (hydrogenolysis), or oxidative conditions, as described herein, to provide the compound of formula I, or a salt thereof.

[0172] 9. Embodiments of Formulas I, II, III, IV, V, VII, and VIII In some embodiments of any one of Formulas I, II, III, IV, V, VII, and VIII, R 2 are Cl, F, CN, CF3, C 1~3 Alkyl or C 1~3 may be alkoxy, and R 1 and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl or C 1~3 It may be alkoxy. 1~3 Alkyl may be methyl, ethyl, n-propyl, or isopropyl. 1~3 Alkoxy can be methoxy, ethoxy, n-propoxy, or isopropoxy. In some embodiments of any one of Formulas I, II, III, IV, V, VII, and VIII, R 2 may be Cl, F, CN, CF, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; R 1 and R 3 may each independently be hydrogen, F, Cl, CN, CF, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy. In some embodiments of any one of Formulas I, II, III, IV, V, VII, and VIII, R 2 may be Cl, F, CN, CF, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; R 1 and R 3 In some embodiments of any one of Formulas I, II, III, IV, V, VII, and VIII, R 2 may be F, and R 1 and R 3 may each be hydrogen.

[0173] In some embodiments of any one of Formulas I, II, III, IV, V, and VI, R4 In some embodiments of any one of Formulas I, II, III, IV, V, and VI, R 4 may be methyl.

[0174] In some embodiments of any one of Formulas I, II, III, IV, V, and VI, R 5 is C 3~6 In some embodiments of any one of Formulas I, II, III, IV, V, and VI, R 5 In some embodiments of any one of Formulas I, II, III, IV, V, and VI, R may be n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or hexyl. 5 may be n-butyl.

[0175] Some embodiments of any one of Formulas I, II, III, IV, V, and VI So, R 4 may be methyl, R 5 is C 3~6 In some embodiments of any one of Formulas I, II, III, IV, V, and VI, R 4 may be methyl, R 5 In some embodiments of any one of Formulas I, II, III, IV, V, and VI, R may be n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or hexyl. 4 may be methyl, R 5 may be n-butyl.

[0176] In some embodiments of any one of Formulas III, IV, V, VII, and VIII, X can be F, Br, I, or OTs. In some embodiments of any one of Formulas III, IV, V, VII, and VIII, X can be Br. In some embodiments of any one of Formulas III, IV, V, VII, and VIII, X can be F.

[0177] In some embodiments, the compound of Formula I has Formula Ia: [ka] or a salt thereof, and R 2 and R 5 is as defined and explained herein.

[0178] In some embodiments, the compound of Formula I has Formula Ib: [ka] or a salt thereof.

[0179] In some embodiments, the compound of Formula II has Formula IIa: [ka] or a salt thereof, and R 2 and R 5 is as defined and explained herein.

[0180] In some embodiments, the compound of Formula II has Formula IIb: [ka] or a salt thereof.

[0181] In some embodiments, the compound of Formula III has Formula IIIa: [ka] or a salt thereof, and R2 and R 5 is as defined and explained herein.

[0182] In some embodiments, the compound of Formula III has the formula IIIa-1: [ka] or a salt thereof, and R 2 and R 5 is as defined and explained herein.

[0183] In some embodiments, the compound of Formula III has Formula IIIb: [ka] or a salt thereof.

[0184] In some embodiments, the compound of formula III has formula IIIb-1: [ka] or a salt thereof.

[0185] In some embodiments, the compound of formula IV has formula IV-1: [ka] or a salt thereof, and R 1 , R 2 , R 3 , R 4 , R 5 , and X are as defined and explained herein.

[0186] In some embodiments, the compound of formula IV-1 has formula IVa-1: [ka] or a salt thereof, and R 2 and R 5 is as defined and explained herein.

[0187] In some embodiments, the compound of formula IV-1 has formula IVa-2: [ka] or a salt thereof, and R 2 and R 5 is as defined and explained herein.

[0188] In some embodiments, the compound of formula IV-1 has formula IVb-1: [ka] or a salt thereof.

[0189] In some embodiments, the compound of formula IV-1 has formula IVb-2: [ka] or a salt thereof.

[0190] In some embodiments, the compound of formula V has formula Va: [ka] or a salt thereof, and R 2 and R 5 is as defined and explained herein.

[0191] In some embodiments, the compound of formula V has formula Va-1: [ka] or a salt thereof, and R 2 and R 5 is as defined and explained herein.

[0192] In some embodiments, the compound of formula V has formula Vb: [ka] or a salt thereof.

[0193] In some embodiments, the compound of formula V has formula Vb-1: [ka] or a salt thereof.

[0194] In some embodiments, the compound of formula VI has formula VIa: [ka] or a salt thereof, and R 5 is as defined and explained herein.

[0195] In some embodiments, the compound of formula VI has formula VIb: [ka] It may be.

[0196] In some embodiments, the compound of Formula VII has Formula VIIa: [ka] or a salt thereof, and R 2 is as defined and explained herein.

[0197] In some embodiments, the compound of Formula VII has Formula VIIa-1: [ka] or a salt thereof, and R 2 is as defined and explained herein.

[0198] In some embodiments, the compound of formula VII has formula VIIb: [ka] or a salt thereof.

[0199] In some embodiments, the compound of formula VII has formula VIIb-1: [ka] or a salt thereof.

[0200] In some embodiments, the compound of Formula VIII has Formula VIIIa: [ka] or a salt thereof, and R 2 is as defined and explained herein.

[0201] In some embodiments, the compound of Formula VIII has Formula VIIIa-1: [ka] or a salt thereof, and R 2 is as defined and explained herein.

[0202] In some embodiments, the compound of Formula VIII has Formula VIIIb: [ka] or a salt thereof.

[0203] In some embodiments, the compound of Formula VIII has Formula VIIIb-1: [ka] or a salt thereof.

[0204] In some embodiments, the present disclosure provides compounds of formula Ib: [ka] or a salt thereof, the method comprising: a4) Formula VIIIb: [ka] or a salt thereof, oxalyl chloride, N,N-dimethylformamide, and 2-methyltetrahydrofuran to form a seventh reaction mixture comprising a compound of Formula VIIb: [ka] or a salt thereof; and a3) a compound of formula VIIb or a salt thereof with a compound of formula VIb: [ka] forming a sixth reaction mixture comprising the compound of Formula Vb, aqueous potassium carbonate, 2-methyltetrahydrofuran, and water to form a compound of Formula Vc: [ka] or a salt thereof; and a2) forming a fourth reaction mixture comprising a compound of Formula Vb or a salt thereof, thionyl chloride, and 2-methyltetrahydrofuran to produce a compound of Formula IVb-1: [ka] or a salt thereof; and a1) forming a third reaction mixture comprising a compound of Formula IVb-1 or a salt thereof, aqueous sodium hydroxide, tetra-n-butylammonium hydrogen sulfate, and 2-methyltetrahydrofuran to form a compound of Formula IIIb: [ka] or a salt thereof; and a) combining a compound of formula IIIb or a salt thereof with a compound of formula IXa, wherein n is 0 to 1: [ka] , copper(II) acetate, tribasic potassium phosphate, cysteine, 2-methyltetrahydrofuran, and acetonitrile to form a first reaction mixture comprising the compound of formula IIb: [ka] or a salt thereof; and b) forming a second reaction mixture comprising a compound of Formula IIb or a salt thereof, trifluoroacetic acid, and dichloromethane to produce a compound of Formula Ib: [ka] preparing a trifluoroacetate salt of the compound of formula (I); c) forming a ninth reaction mixture comprising the trifluoroacetate salt of the compound of formula Ib, sodium hydroxide, ethanol, and water to provide the neutral form of the compound of formula Ib.

[0205] In some embodiments, the compound of formula IXa has formula IXb: [ka] It may be.

[0206] In some embodiments, the present disclosure provides compounds of formula Ib: [ka] or a salt thereof, the method comprising: a4) Formula VIIIb-1: [ka] or a salt thereof, oxalyl chloride, N,N-dimethylformamide, and 2-methyltetrahydrofuran to form a seventh reaction mixture comprising a compound of Formula VIIb-1: [ka] or a salt thereof; and a3) a compound of formula VIIb-1 or a salt thereof with a compound of formula VIb: [ka] forming a sixth reaction mixture comprising the compound of Formula Vb-1, aqueous potassium carbonate, 2-methyltetrahydrofuran, and water to produce a compound of Formula Vb-2: [ka] or a salt thereof; and a2) forming a fourth reaction mixture comprising a compound of Formula Vb-1 or a salt thereof, thionyl chloride, and 2-methyltetrahydrofuran to produce a compound of Formula IVb-2: [ka] or a salt thereof; and a1) forming a third reaction mixture comprising a compound of Formula IVb-2 or a salt thereof, aqueous sodium hydroxide, tetra-n-butylammonium hydrogen sulfate, and 2-methyltetrahydrofuran to form a compound of Formula IIIb-1: [ka] or a salt thereof; and a) combining a compound of formula IIIb-1 or a salt thereof with a compound of formula IXc: [ka] forming a first reaction mixture comprising a compound of Formula IIb: [ka] or a salt thereof; and b) forming a second reaction mixture comprising a compound of Formula IIb or a salt thereof, trifluoroacetic acid, and dichloromethane to produce a compound of Formula Ib: [ka] preparing a trifluoroacetate salt of the compound of formula (I); c) forming a ninth reaction mixture comprising the trifluoroacetate salt of the compound of formula Ib, sodium hydroxide, ethanol, and water to provide the neutral form of the compound of formula Ib.

[0207] In some embodiments, the compound of Formula Vb or Vb-1 or a salt thereof is isolated in a solution containing 2-methyltetrahydrofuran and can be used in the subsequent step a2) without purification and / or removal of 2-methyltetrahydrofuran. In some embodiments, the compound of Formula IVb-1 or IVb-2 or a salt thereof is isolated in a solution containing 2-methyltetrahydrofuran and can be used in the subsequent step a1) without purification and / or removal of 2-methyltetrahydrofuran. In some embodiments, the compound of Formula IIIb or IIIb-1 or a salt thereof is isolated in a solution containing 2-methyltetrahydrofuran and can be used in the subsequent step a) without purification and / or removal of 2-methyltetrahydrofuran. In some embodiments, the compound of Formula Vb or Vb-1 or a salt thereof, the compound of Formula IVb-1 or IVb-2 or a salt thereof, and the compound of Formula IIIb or IIIb-1 or a salt thereof are each isolated in a solution containing 2-methyltetrahydrofuran and can be used in the subsequent step without purification and / or removal of 2-methyltetrahydrofuran. In some embodiments, the compound of Formula Vb or Vb-1 or a salt thereof is isolated in a solution containing 2-methyltetrahydrofuran and can be used in the subsequent step a2) without removing the 2-methyltetrahydrofuran. In some embodiments, the compound of Formula IVb-1 or IVb-2 or a salt thereof is isolated in a solution containing 2-methyltetrahydrofuran and can be used in the subsequent step a1) without removing the 2-methyltetrahydrofuran. In some embodiments, the compound of Formula IIIb or IIIb-1 or a salt thereof is isolated in a solution containing 2-methyltetrahydrofuran and can be used in the subsequent step a) without removing the 2-methyltetrahydrofuran. In some embodiments, the compound of Formula Vb or Vb-1 or a salt thereof, the compound of Formula IVb-1 or IVb-2 or a salt thereof, and the compound of Formula IIIb or IIIb-1 or a salt thereof are each isolated in a solution containing 2-methyltetrahydrofuran and can be used in the subsequent step without removing the 2-methyltetrahydrofuran.

[0208] In some embodiments, the compound of formula Vb or a salt thereof is isolated in a solution containing 2-methyltetrahydrofuran and can be used in the subsequent step a2) without purification and / or removal of 2-methyltetrahydrofuran. In some embodiments, the compound of formula IVb-1 or a salt thereof is isolated in a solution containing 2-methyltetrahydrofuran and can be used in the subsequent step a1) without purification and / or removal of 2-methyltetrahydrofuran. In some embodiments, the compound of formula IIIb or a salt thereof is isolated in a solution containing 2-methyltetrahydrofuran and can be used in the subsequent step a1) without purification and / or removal of 2-methyltetrahydrofuran. In some embodiments, the compound of Formula Vb or a salt thereof, the compound of Formula IVb-1 or a salt thereof, and the compound of Formula IIIb or a salt thereof are each isolated in a solution containing 2-methyltetrahydrofuran and can be used in a subsequent step a) without purification and / or removal of 2-methyltetrahydrofuran. In some embodiments, the compound of Formula Vb or a salt thereof is isolated in a solution containing 2-methyltetrahydrofuran and can be used in a subsequent step a2) without removal of 2-methyltetrahydrofuran. In some embodiments, the compound of Formula IVb-1 or a salt thereof is isolated in a solution containing 2-methyltetrahydrofuran and can be used in a subsequent step a1) without removal of 2-methyltetrahydrofuran. In some embodiments, the compound of Formula IIIb or a salt thereof is isolated in a solution containing 2-methyltetrahydrofuran and can be used in a subsequent step a) without removal of 2-methyltetrahydrofuran. In some embodiments, the compound of Formula Vb or a salt thereof, the compound of Formula IVb-1 or a salt thereof, and the compound of Formula IIIb or a salt thereof are each isolated in a solution containing 2-methyltetrahydrofuran and can be used in a subsequent step without removing 2-methyltetrahydrofuran.

[0209] In some embodiments, the compound of Formula VIIb or VIIb-1 or a salt thereof is formed in situ and can be used in subsequent step a3) without purification and / or removal of 2-methyltetrahydrofuran. In some embodiments, the compound of Formula VIIb or VIIb-1 or a salt thereof is formed in situ and can be used in subsequent step a3) without removal of 2-methyltetrahydrofuran.

[0210] In some embodiments, the compound of Formula VIIb or a salt thereof is formed in situ and can be used in subsequent step a3) without purification and / or removal of 2-methyltetrahydrofuran. In some embodiments, the compound of Formula VIIb or a salt thereof is formed in situ and can be used in subsequent step a3) without removal of 2-methyltetrahydrofuran.

[0211] In some embodiments, the compound of Formula VIIb or VIIb-1 or a salt thereof, the compound of Formula Vb or Vb-1 or a salt thereof, the compound of Formula IVb-1 or IVb-2 or a salt thereof, and the compound of Formula IIIb or IIIb-1 or a salt thereof are each isolated in a solution containing 2-methyltetrahydrofuran and can be used in a subsequent step without purification and / or removal of 2-methyltetrahydrofuran. In some embodiments, the compound of Formula VIIb or VIIb-1 or a salt thereof, the compound of Formula Vb or Vb-1 or a salt thereof, the compound of Formula IVb-1 or IVb-2 or a salt thereof, and the compound of Formula IIIb or IIIb-1 or a salt thereof are each isolated in a solution containing 2-methyltetrahydrofuran and can be used in a subsequent step without removal of 2-methyltetrahydrofuran.

[0212] In some embodiments, the compound of Formula VIIb or a salt thereof, the compound of Formula Vb or a salt thereof, the compound of Formula IVb-1 or a salt thereof, and the compound of Formula IIIb or a salt thereof are each isolated in a solution containing 2-methyltetrahydrofuran and can be used in a subsequent step without purification and / or removal of 2-methyltetrahydrofuran. In some embodiments, the compound of Formula VIIb or a salt thereof, the compound of Formula Vb or a salt thereof, the compound of Formula IVb-1 or a salt thereof, and the compound of Formula IIIb or a salt thereof are each isolated in a solution containing 2-methyltetrahydrofuran and can be used in a subsequent step without removal of 2-methyltetrahydrofuran.

[0213] B. Methods for Preparing Compounds of Formula I from Formula V In some embodiments, the present disclosure provides a compound of formula II: [ka] or a salt thereof, the method comprising: a) Formula V: [ka] or a salt thereof, a compound having the formula PG-NHC(=NH)NH2 or a salt thereof, a first transition metal catalyst, a first base, and a first solvent to form a compound of Formula II or a salt thereof; In the formula, R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl, or C 1~3 may be alkoxy, and R 4 may be hydrogen or methyl, R 5 is C 3~6 X may be F, Cl, Br, I, or OTs, and PG may be an amino protecting group.

[0214] The compound having the formula PG-NHC(=NH)NH2 may be in any suitable form. In some embodiments, the compound having the formula PG-NHC(=NH)NH2 may be in neutral form. In some embodiments, the compound having the formula PG-NHC(=NH)NH2 may be in salt form. In some embodiments, the compound having the formula PG-NHC(=NH)NH2 may be its hemisulfate, sulfate, chloride, bromide, carbonate, nitrate, or acetate salt. In some embodiments, the compound having the formula PG-NHC(=NH)NH2 has formula IX: [ka] where n can be 0 to 1. In some embodiments, the compound of formula IX can be a hemisulfate salt, where n can be ½, a sulfate salt, where n can be 1, or a combination thereof. In some embodiments, the compound of formula IX can be a hemisulfate salt, where n can be ½.

[0215] In some embodiments, PG can be an amino-protecting group. Suitable amino-protecting groups include carbobenzyloxy (Cbz) group, p-methoxybenzylcarbonyl (Moz or MeOZ) group, tert-butyloxycarbonyl (BOC) group, 2-trimethylsilyl Ethoxymethyl (trimethylsilylethyoxymethyl) (SEM) group, 9-fluorenylmethyl Examples of suitable PGs include, but are not limited to, phenyloxycarbonyl (Fmoc) groups, acetyl (Ac) groups, benzoyl (Bz) groups, benzyl (Bn) groups, carbamate groups, p-methoxybenzyl (PMB) groups, 2,4-dimethoxybenzyl (DMB) groups, 1-(2,4-dimethoxyphenyl)ethyl, 3,4-dimethoxybenzyl (DMPB) groups, p-methoxyphenyl (PMP) groups, tosyl (Ts) groups, Troc (trichloroethyl chloroformate) groups, and other sulfonamide (Nosyl and Nps) groups. In some embodiments, PG can be 2,4-dimethoxybenzyl.

[0216] In some embodiments, the compound of formula IX has formula IXa: [ka] wherein n can be 0 to 1. In some embodiments, the compound of formula IXa can be a hemisulfate salt, where n can be ½, a sulfate salt, where n can be 1, or a combination thereof. In some embodiments, the compound of formula IXa can be a compound of formula IXb: [ka] It may be a hemisulfate salt having the formula:

[0217] In some embodiments, X can be Br. In some embodiments, the compound of formula V can be a compound of formula Vb.

[0218] In some embodiments, the first transition metal catalyst can be a compound containing one or more transition metals or transition metal cations. Suitable transition metals include, but are not limited to, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag, Cd, La, Hf, Ta, W, Re, Os, Ir, Pt, Au, Hg, and Ac. Suitable transition metal cations include Cd 2+ , Co 2+ , Co + , Cr 2+ , Cr + , Cu + (i.e., copper(I)), Cu 2+ (i.e., copper(II)), Fe 2+ , Fe + , Mn 2+ , Mn + , Ni 2+ , Ni + , Pd 2+ (i.e., Pd(II)), and Zn 2+In some embodiments, the first transition metal catalyst includes, but is not limited to, copper metal, copper oxide, a copper(I) salt, a copper(II) salt, or a combination thereof. In some embodiments, the first transition metal catalyst includes a copper(I) salt. In some embodiments, the first transition metal catalyst can be a copper(I) salt. In some embodiments, the first transition metal catalyst includes a copper(II) salt. In some embodiments, the first transition metal catalyst can be a copper(II) salt. In some embodiments, the first transition metal catalyst is selected from the group consisting of copper(I) iodide, copper(I) bromide, copper(I) chloride, copper(I) acetate, copper(I) carbonate, copper(I) nitrate, copper(I) sulfate, copper(I) phosphate, copper(I) 3-methylsalicylate, copper(I) thiophene-2-carboxylate, copper(I) oxide, copper(II) iodide, copper(II) bromide, copper(II) chloride, copper(II) acetate, copper(II) carbonate, copper(II) nitrate, copper(II) sulfate, copper(II) pyrophosphate, The first transition metal catalyst may be copper(II) phosphate, copper(II) tartrate, copper(II) oxide, or a combination thereof. In some embodiments, the first transition metal catalyst may be copper(II) iodide, copper(II) bromide, copper(II) chloride, copper(II) acetate, copper(II) carbonate, copper(II) nitrate, copper(II) sulfate, copper(II) pyrophosphate, copper(II) phosphate, copper(II) tartrate, copper(II) oxide, or a combination thereof. In some embodiments, the first transition metal catalyst includes copper(I) iodide. In some embodiments, the first transition metal catalyst may be copper(I) iodide.

[0219] The first base may be an alkali carbonate, alkali bicarbonate, tribasic alkali phosphate, carboxylate, amidine-based compound, or a combination thereof. Suitable alkali carbonates include lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Suitable alkali bicarbonates include lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate. Suitable tribasic alkali phosphates include tribasic sodium phosphate and tribasic potassium phosphate. Suitable carboxylates include, but are not limited to, lithium acetate, sodium acetate, potassium acetate, cesium acetate, potassium trimethylacetate, and tetrabutylphosphonium malonate. Suitable amidine-based compounds include, but are not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN). In some embodiments, the first base can be lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, tribasic sodium phosphate, tribasic potassium phosphate, potassium acetate, potassium trimethylacetate, tetrabutylphosphonium malonate, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, or a combination thereof. In some embodiments, the first base includes tribasic potassium phosphate. In some embodiments, the first base can be tribasic potassium phosphate.

[0220] The first solvent may be any suitable polar or non-polar, protic or aprotic solvent. In some embodiments, the first solvent may be acetonitrile, propionitrile, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, isopropanol, 2-methylbutan-2-ol, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, toluene, trifluorotoluene, xylene, or a combination thereof. In some embodiments, the first solvent includes acetonitrile. In some embodiments, the first solvent may be acetonitrile.

[0221] In some embodiments, the first reaction mixture further comprises a first ligand. In some embodiments, the first ligand can be an amino acid, a polypyridyl ligand, or a tertiary amine. Suitable amino acids include naturally occurring synthetic amino acids, as well as amino acid analogs that function similarly to naturally occurring amino acids. Suitable polypyridyl ligands include, but are not limited to, 2,2'-bipyridine, 1,10-phenanthroline, 4,4'-dimethyl-2,2'-bipyridine, 6,6'-dimethyl-2,2'-bipyridine, 4,4'-di-tert-butyl-2,2-bipyridine, 2,2'-bipyridine-4,4'-dicarboxylic acid, and 2,2':6'2"-terpyridine. Suitable tertiary amines include, but are not limited to, triethylamine, tri-n-butylamine, N,N-diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine, 1,4-diazabicyclo[2.2.2]-octane, and N,N,N',N'-tetramethylethylenediamine. In some embodiments, the first ligand is selected from the group consisting of arginine, histidine, lysine, aspartic acid, glutamic acid, serine, sucrose, sorbitan, sorbitol ... The amino acid sequence may be leonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, α-(methylamino)isobutyric acid, (4-methyl-1-piperazinyl)acetic acid, N-acetyl-cysteine, 2,2′-bipyridine, 1,10-phenanthroline, 4,4′-dimethyl-2,2′-bipyridine, 6,6′-dimethyl-2,2′-bipyridine, 4,4′-di-tert-butyl-2,2-bipyridine, 2,2′-bipyridine-4,4′-dicarboxylic acid, N,N,N′,N′-tetramethylethylenediamine, or a combination thereof. In some embodiments, the first ligand includes 2,2'-bipyridine, 1,10-phenanthroline, 4,4'-dimethyl-2,2'-bipyridine, 6,6'-dimethyl-2,2'-bipyridine, 4,4'-di-tert-butyl-2,2-bipyridine, 2,2'-bipyridine-4,4'-dicarboxylic acid, and 2,2':6'2"-terpyridine. In some embodiments, the first ligand includes 2,2'-bipyridine. In some embodiments, the first ligand can be 2,2'-bipyridine.

[0222] In some embodiments, the first reaction mixture further comprises a dehydrating agent or additive. In some embodiments, the dehydrating agent or additive can be a 3 Å sieve, a 4 Å sieve, a 5 Å sieve, or silica gel. In some embodiments, the dehydrating agent or additive can be a 3 Å sieve.

[0223] Generally, the first reaction (i.e., step a)) can be carried out at ambient to elevated temperatures. For example, the first reaction mixture can be at a temperature of 30°C to 110°C, or can be heated to reflux. In some embodiments, the first reaction mixture can be at a temperature of 40°C to 100°C, 50°C to 100°C, 50°C to 90°C, 60°C to 90°C, 70°C to 90°C, or about 80°C. In some embodiments, the first reaction mixture can be at a temperature of 50°C to reflux. In some embodiments, the first reaction mixture can be heated to reflux.

[0224] Once the first reaction is complete, the first transition metal catalyst can be removed from the reaction mixture with a second ligand, such as ethylenediaminetetraacetic acid (EDTA) or EDTA disodium salt. In some embodiments, once the first reaction is complete, the first transition metal catalyst can be removed from the first reaction mixture using a second ligand. In some embodiments, the second ligand includes ethylenediaminetetraacetic acid or a salt thereof. In some embodiments, once the first reaction is complete, the first transition metal catalyst can be removed from the first reaction mixture using ethylenediaminetetraacetic acid or a salt thereof. In some embodiments, once the first reaction is complete, copper(I) can be removed from the first reaction mixture using ethylenediaminetetraacetic acid disodium salt.

[0225] The compound of Formula II can be deprotected by various methods known in the art to provide the compound of Formula I or a salt thereof. When PG is 2,4-dimethoxybenzyl, the compound of Formula II can be deprotected by various methods, for example, under acidic, reductive (hydrogenolysis), or oxidative conditions, as described in Section A, Section 1, to provide the compound of Formula I or a salt thereof.

[0226] C. Method for Preparing Compounds of Formula I from Compounds of Formula III via Unprotected Guanidine In some embodiments, the present disclosure provides a compound of formula I: [ka] or a salt thereof, the method comprising: a) Formula III: [ka] forming a first reaction mixture comprising a compound of Formula I, a compound having the formula HNC(=NH)NH or a salt thereof, a first base, and a first solvent to form a compound of Formula I or a salt thereof; In the formula, R1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl or C 1~3 may be alkoxy, and R 4 may be hydrogen or methyl, R 5 is C 3~6 It may be alkyl, and X may be F, Cl, Br, I, or OTs.

[0227] In some embodiments, X can be F.

[0228] The compound having the formula HNC(=NH)NH2 can be in any suitable form. In some embodiments, the compound having the formula HNC(=NH)NH2 can be in neutral form. In some embodiments, the compound having the formula HNC(=NH)NH2 can be in salt form. In some embodiments, the compound having the formula HNC(=NH)NH2 can be its hemisulfate, sulfate, chloride, bromide, carbonate, nitrate, or acetate salt. In some embodiments, the compound having the formula HNC(=NH)NH2 has formula XIV: [ka] where n can be 0 to 1. In some embodiments, the compound of formula XIV can be a hemisulfate salt, where n can be ½, a sulfate salt, where n can be 1, or a combination thereof. In some embodiments, the compound of formula XIV can be a hemisulfate salt, where n can be ½.

[0229] In some embodiments, the first base may be absent or present. If present, the first base may be a carbonate (e.g., cesium carbonate, sodium carbonate, potassium carbonate, charcoal, etc.). and / or ammonium carbonate), metal oxides (e.g., magnesium oxide), hydroxides (e.g., potassium hydroxide, sodium hydroxide, lithium hydroxide, cesium hydroxide, barium hydroxide, ammonium hydroxide, or tetra-n-butylammonium hydroxide), lithium phenoxide, silanolates (e.g., potassium trimethylsilanolate, sodium trimethylsilanolate, lithium silanolate, or sodium dimethylphenylsilanolate), phosphates (e.g., tribasic potassium phosphate, tribasic calcium phosphate, tribasic magnesium phosphate, tribasic sodium phosphate, dibasic sodium phosphate, or dibasic potassium phosphate), hydrides (e.g., sodium hydride or potassium hydride), amines (e.g., 1,4-diazabicyclo[2.2.2]octane, 1-azabicyclo[2.2.2]octane, 1,8-diaza[5.4.0]undec-7-ene, and 1,5-diazabicyclo[4.3.0]non-5-enepyridine, 1,1,3,3-tetramethylguanidine, 4-methylmorpholine, 2-tert-butyl-1,1,3,3-tetramethylguanidine, 1,3,4,6,7,8-hexahydro-1-methyl-2H-pyrimido[1,2-a]pyrimidine, 1,8-bis(dimethylamino)naphthalene, or N,N,N'N'-tetramethyl-1,8-naphthalenediamine), amides (e.g., lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, sodium diisopropylamide, or lithium dicyclohexylamide), alkyl metals (e.g., For example, n-butyllithium, tert-butyllithium, methyllithium, phenyllithium, lithium naphthalenide, or sodium naphthalenide), alkoxides (e.g., magnesium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, sodium tert-pentoxide, or potassium tert-pentoxide), phosphoranes (e.g., tert-butylimino-tri(pyrrolidino)phospholene, 2-tert-butylimino-tri(pyrrolidino)phospholene, or 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphorene), or combinations thereof. In some embodiments, the first base can be lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, tribasic sodium phosphate, tribasic potassium phosphate, potassium acetate, potassium trimethylacetate, tetrabutylphosphonium malonate, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, or a combination thereof. In some embodiments, the first base is present and includes cesium carbonate. In some embodiments, the first base can be cesium carbonate.

[0230] The first solvent may be any suitable polar or non-polar protic or aprotic solvent. The first solvent may be a polar aprotic solvent (e.g., N,N'-dimethylformamide, N,N'-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, sulfolane, acetonitrile, propionitrile, butyronitrile, nitromethane, or nitroethane), an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, methyl tert-butyl ether, or cyclopentyl methyl ether), an alcohol (e.g., methanol, ethanol, n- The first solvent may be butanol, 2-butanol, tert-butanol, 2-methylbutan-2-ol, 2,2,2-trifluoroethanol, or hexafluoro-2-propanol), a ketone (e.g., methyl isobutyl ketone or methyl ethyl ketone), an ester (e.g., isopropyl acetate or n-butyl acetate), a chlorinated solvent (e.g., 1,2-dichloroethane, chlorobenzene, or trifluorotoluene), an aromatic solvent (e.g., toluene, xylene, or anisole), water, or a combination thereof. In some embodiments, the first solvent is acetonitrile, propionitrile, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, tetrahydrofuran, 2-methylpropanol, ... The first solvent may be N,N'-dimethylacetamide, ...

[0231] In some embodiments, the first reaction mixture further comprises an additive. The additive may be 4-dimethylaminopyridine, 4-piperidinopyridine, 4-pyrrolidinopyridine, imidazole, N-methylimidazole, or 9-azajulolidine. In some embodiments, no additive is present.

[0232] Generally, the first reaction (i.e., step a)) can be carried out at ambient to elevated temperatures. For example, the first reaction mixture can be at a temperature of 20°C to 150°C. In some embodiments, the first reaction mixture can be at a temperature of 30°C to 100°C, 40°C to 100°C, 50°C to 90°C, 50°C to 80°C, 60°C to 80°C, or about 80°C. In some embodiments, the first reaction mixture can be at a temperature of 60°C to 80°C. In some embodiments, the first reaction mixture can be at a temperature of about 80°C.

[0233] Compounds of Formula III can be prepared according to any one of the methods described herein. Embodiments of Formulas I, III, IV, V, VII, and VIII are as described in Section A, Section 9.

[0234] In some embodiments, the present disclosure provides compounds of formula Ib: [ka] or a salt thereof, the method comprising: a) Formula IIIb-1: [ka] or a salt thereof with a compound of formula XIVa: [ka] forming a first reaction mixture comprising the compound of Formula Ib, cesium carbonate, and N,N'-dimethylacetamide to form a compound of Formula Ib or a salt thereof.

[0235] D. Methods for Preparing Compounds of Formula I via Guanidine Salts In some embodiments, the present disclosure provides a compound of formula XVIII: [ka] or a salt thereof, the method comprising: a) Formula XV: [ka] with a compound of formula XVI-1: [ka] or a salt thereof, and a compound of formula R 7 forming a first reaction mixture comprising a compound having —NHC(═NH)NH or a salt thereof, a first transition metal catalyst, a first base, and a first solvent to form a compound of Formula XVIII or a salt thereof; During the ceremony, R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl or C 1~3 is an alkoxy, R 4 is hydrogen or methyl, R 5 is C 1~6 is alkyl, R 6 is hydrogen, OH, or O-PG 1 and R 7 is hydrogen or PG, X and X 1 are each independently F, Cl, Br, I, or OTs; PG is an amino protecting group, PG1 is a hydroxy protecting group.

[0236] In some embodiments, R 6 may be hydrogen. In some embodiments, R 6 may be OH.

[0237] In some embodiments, the compound of Formula XVIII has Formula I: [ka] or a salt thereof, wherein R 5 is C 3~6 It is alkyl.

[0238] In some embodiments, the compound of Formula XVI has Formula XVIa: [ka] It may be.

[0239] In some embodiments, PG 1 may be a hydroxy-protecting group. Suitable hydroxy-protecting groups include silyl groups (e.g., trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, phenyldimethylsilyl, di-tert-butylsilyl, [2-(trimethylsilyl)ethoxy]methyl, or 2-trimethylsilyl)ethoxycarbonyl), acyl groups (e.g., acetyl, propionyl, isobutyryl, trimethylacetyl, or trifluoroacetyl), aryl groups (e.g., phenyl, 4-methoxyphenyl, or 4-bromophenyl), alkyl or heterocycloalkyl groups (e.g., allyl, tert-butyl, or tertahydropyranyl), arylalkyl groups (e.g., benzyl, para-methoxybenzyl, or 2-trimethylsilyl)ethoxycarbonyl), and the like. ,4-dimethoxybenzyl). In some embodiments, PG 1 may be 2,4-dimethoxybenzyl.

[0240] In some embodiments, R 7 may be hydrogen. In some embodiments, 7-NHC(=NH)NH2 can be of the formula H2NC(=NH)NH2. The compound having the formula H2NC(=NH)NH2 can be in any suitable form. In some embodiments, the compound having the formula H2NC(=NH)NH2 can be in a neutral form. In some embodiments, the compound having the formula H2NC(=NH)NH2 can be in a salt form. In some embodiments, the compound having the formula H2NC(=NH)NH2 can be its hemisulfate, sulfate, chloride, bromide, carbonate, nitrate, or acetate salt. In some embodiments, the compound having the formula H2NC(=NH)NH2 has formula XIV: [ka] where n can be 0 to 1. In some embodiments, the compound of formula XIV can be a hemisulfate salt, where n can be ½, a sulfate salt, where n can be 1, or a combination thereof. In some embodiments, the compound of formula XIV can be a hemisulfate salt, where n can be ½.

[0241] In some embodiments, R 7 may be PG. In some embodiments, the formula R 7 -NHC(=NH)NH2 can be of the formula PG-NHC(=NH)NH2. The compound having the formula PG-NHC(=NH)NH2 can be in any suitable form. In some embodiments, the compound having the formula PG-NHC(=NH)NH2 can be in a neutral form. In some embodiments, the compound having the formula PG-NHC(=NH)NH2 can be in a salt form. In some embodiments, the compound having the formula PG-NHC(=NH)NH2 can be its hemisulfate, sulfate, chloride, bromide, carbonate, nitrate, or acetate salt. In some embodiments, the compound having the formula PG-NHC(=NH)NH2 has formula IX: [ka] where n can be 0 to 1. In some embodiments, the compound of formula IX can be a hemisulfate salt, where n can be ½, a sulfate salt, where n can be 1, or a combination thereof. In some embodiments, the compound of formula IX can be a hemisulfate salt, where n can be ½.

[0242] In some embodiments, PG can be an amino-protecting group. Suitable amino-protecting groups include, but are not limited to, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, acetyl, trifluoroacetyl, 2,2,5,7,8-pentamethyl-chroman-6-sulfonyl chloride, para-toluenesulfonyl, 4-methoxy-2,3,6-trimethylbenzenesulfonyl, 4-methoxybenzyl, 2-chlorobenzyl, or 2,4-dimethoxybenzyl. In some embodiments, PG can be 2,4-dimethoxybenzyl.

[0243] In some embodiments, the compound of formula IX has formula IXa: [ka] wherein n can be 0 to 1. In some embodiments, the compound of formula IXa can be a hemisulfate salt, where n can be ½, a sulfate salt, where n can be 1, or a combination thereof. In some embodiments, the compound of formula IXa can be a compound of formula IXb: [ka] It may be a hemisulfate salt having the formula:

[0244] The first transition metal catalyst may be a compound containing one or more transition metals or transition metal cations. Suitable transition metals include, but are not limited to, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag, Cd, La, Hf, Ta, W, Re, Os, Ir, Pt, Au, Hg, and Ac. Suitable transition metal cations include Cd 2+ , Co 2+ , Co + , Cr 2+ , Cr + , Cu + (i.e., copper(I)), Cu 2+ (i.e., copper(II)), Fe 2+ , Fe + , Mn 2+ , Mn + , Ni 2+ , Ni + , Pd 2+ (i.e., Pd(II)), and Zn 2+In some embodiments, the first transition metal catalyst includes, but is not limited to, a Pd catalyst. In some embodiments, the first transition metal catalyst can be a Pd catalyst. In some embodiments, the first transition metal catalyst includes a Pd(II) catalyst. In some embodiments, the first transition metal catalyst can be a Pd(II) catalyst. In some embodiments, the Pd(II) catalyst is selected from the group consisting of palladium(II) acetate, palladium(II) pivorate, palladium(II) propionate, palladium(II) trifluoroacetate, palladium(II) bromide, palladium(II) chloride, tris(dibenzylideneacetone)dipalladium(0); bis(acetonitrile)palladium(II) dichloride, (2-dicyclohexylphosphino-1,1'-biphenyl)[2-(2'-amino-1,1'- biphenyl)]palladium(II) methanesulfonate, (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(I I) Methanesulfonate, (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, [(di(1-adamantyl)-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1 '-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, [(1,3,5,7-tetramethyl-6-phenyl-2,4,6-trioxa-6-phosphaadamantane)-2-(2'-amino-1,1'-biphenyl)]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)]palladium(II) methanesulfonate, (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) Nyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, [(2-di-tert-butylphosphino-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate, [2-(di-1-adamantylphosphino)-2',4',6'-triisopropyl-3,6-dimeth, In some embodiments, the first transition metal catalyst may be palladium(II) acetate, such as 2-(2'-amino-1,1'-biphenyl)-2-(2'-aminobiphenyl)-[(di-tert-butylneopentylphosphine)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate, [(di-tert-butylneopentylphosphine)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate, mesyl(2-(di-tert-butylphosphino)-1,1'-binaphthyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), methanesulfonato(di-tert-butyl)methylphosphino(2'-amino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonato2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl(2'-amino-1,1'-biphenyl-2-yl)palladium(II), or a combination thereof. In some embodiments, the first transition metal catalyst may be palladium(II) acetate. In some embodiments, the first transition metal catalyst can be palladium(II) acetate.

[0245] In some embodiments, the first base can be any suitable inorganic or organic base. In some embodiments, the first base is a carbonate (e.g., cesium carbonate, lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, strontium carbonate, barium carbonate, or ammonium carbonate), a hydroxide (e.g., potassium hydroxide, sodium hydroxide, lithium hydroxide, cesium hydroxide, barium hydroxide, ammonium hydroxide, or tetra-n-butylammonium hydroxide), a silanolate (e.g., potassium trimethylsilanolate, sodium trimethylsilanolate, lithium silanolate, or sodium dimethylphenylsilanolate), a phosphate (e.g., tribasic potassium phosphate, tribasic calcium phosphate, tribasic magnesium phosphate, tribasic sodium phosphate, dibasic sodium phosphate, or dibasic potassium phosphate), a carboxylate (e.g., sodium acetate, potassium acetate, potassium trimethylacetate, or potassium propionate), an alkoxide (e.g., sodium tert-butoxide, potassium tert-butoxide, or sodium tert-pentoxide). , amines (e.g., N,N-diisopropylethylamine, triethylamine, N,N,N',N'-tetramethylethylenediamine, 1,4-diazabicyclo[2.2.2]octane, 1-azabicyclo[2.2.2]octane, 1,8-diaza[5.4.0]undec-7-ene, and 1,5-diazabicyclo[4.3.0]non-5-enepyridine, 1,1,3,3-tetramethylguanidine, 4-methylmorpholine, 2-tert-butyl-1,1,3,3-tetramethylguanidine, 1,3,4, 6,7,8-hexahydro-1-methyl-2H-pyrimido[1,2-a]pyrimidine, 1,8-bis(dimethylamino)naphthalene, or N,N,N'N'-tetramethyl-1,8-naphthalenediamine), an amide (e.g., lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, sodium diisopropylamide, lithium dicyclohexylamide), or a combination thereof.In some embodiments, the first base can be cesium carbonate, lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, strontium carbonate, barium carbonate, or ammonium carbonate, or a combination thereof. In some embodiments, the first base can be lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, or a combination thereof. In some embodiments, the first base includes cesium carbonate. In some embodiments, the first base can be cesium carbonate.

[0246] In some embodiments, the first solvent can be any suitable polar or non-polar protic or aprotic solvent. In some embodiments, the first solvent can be a polar aprotic solvent (e.g., N,N'-dimethylformamide, N,N'-dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, sulfolane, acetonitrile, propionitrile, butyronitrile, nitromethane, or nitroethane), an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, methyl tert-butyl ether, or cyclopentyl methyl ether), The first solvent may be an alcohol (e.g., 2-propanol, 2-butanol, tert-butanol, 2-methylbutan-2-ol, 2,2,2-trifluoroethanol, or hexafluoro-2-propanol), a ketone (e.g., methyl isobutyl ketone or methyl ethyl ketone), an ester (e.g., isopropyl acetate or n-butyl acetate), a chlorinated solvent (1,2-dichloroethane, chlorobenzene, or trifluorotoluene), an aromatic solvent (toluene, xylene, or anisole), or a combination thereof. In some embodiments, the first solvent may be toluene, trifluorotoluene, chlorobenzene, xylene, anisole, or a combination thereof. In some embodiments, the first solvent includes toluene. In some embodiments, the first solvent may be toluene.

[0247] In some embodiments, the first reaction mixture further comprises a first ligand, such as 1,3-bis(dicyclohexylphosphino)propane, 1,2-bis(dimethylphosphino)ethane, bis(diphenylphosphino)methane, di(1-adamantyl)-n-butylphosphine, 2-(dicyclohexylphosphino)biphenyl, triphenylphosphine, tri-ortho-tolylphosphine, tri-tert-butylphosphine, di-tert-butyl-(methyl)phosphine, di-tert-butyl(phenyl)phosphine, tricyclohexylphosphine, tri-isopropylphosphine, di ... isopropylphosphine, n-butyldiadamantylphosphine, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, bis[(2-diphenylphosphino)phenyl]ether, 1,1'-bis(diphenylphosphino)ferrocene, (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene, 1,3-bis(diphenylphosphino)propane, 5-(di-te rt-butylphosphino)-1',3',5'-triphenyl-1'H-[1,4']bipyrazole, di(1-adamantyl)-2-morpholinophenylphosphine, N,N'-(2,6-diisopropylphenyl)dihydroimidazolium chloride, (2-biphenyl)di-tert-butylphosphine, (2-biphenylyl)di-tert-butylphosphine, 2-(di-tert-butylphosphino)biphenyl, (2-biphenyl)dicyclohexylphosphine, 2-dicyclohexylphosphino-2'-(N,N-dimethyl amino)biphenyl, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, 2-(di-tert-butylphosphino)-2',4',The first ligand may be 6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl, or a tetrafluoroborate salt thereof. In some embodiments, the first ligand includes 1,3-bis(dicyclohexylphosphino)propane. In some embodiments, the first ligand may be 1,3-bis(dicyclohexylphosphino)propane.

[0248] Generally, the first reaction (i.e., step a)) can be carried out at ambient to elevated temperatures. For example, the first reaction mixture can be at a temperature of 50°C to 120°C. In some embodiments, the first reaction mixture can be at a temperature of 40°C to 120°C, 50°C to 120°C, 60°C to 120°C, 60°C to 110°C, 70°C to 110°C, or about 90°C. In some embodiments, the first reaction mixture can be at a temperature of 70°C to 110°C. In some embodiments, the first reaction mixture can be at about 90°C.

[0249] In some embodiments, once the first reaction is complete, the first transition metal catalyst may be removed from the reaction mixture by filtration through silica gel.

[0250] In some embodiments, the compound of Formula I has Formula Ia: [ka] or a salt thereof, and R 2 and R 5 is as defined and explained herein.

[0251] In some embodiments, the compound of Formula I has Formula Ib: [ka] or a salt thereof.

[0252] In some embodiments, the compound of formula XV has formula XVa: [ka] or a salt thereof, and R 2 and X are as defined and explained herein.

[0253] In some embodiments, the compound of formula XV has formula XVb: [ka] or a salt thereof.

[0254] In some embodiments, the compound of formula XVI-1 or XVI-2 has formula XVIa: [ka] or a salt thereof, and R 4 and R 5 is as defined and explained herein.

[0255] In some embodiments, the compound of formula XVI-1 or XVI-2 has formula XVIb: [ka] or a salt thereof, and R 5 is as defined and explained herein.

[0256] In some embodiments, the compound of formula XVI-1 or XVI-2 has formula XVIc: [ka] or a salt thereof.

[0257] In some embodiments, the present disclosure provides compounds of formula Ib: [ka] or a salt thereof, the method comprising: a) Formula XVb: [ka] or a salt thereof with a compound of formula XVIc: [ka] or a salt thereof with a compound of formula XIVa: [ka] forming a first reaction mixture comprising the compound of Formula Ib, palladium(II) acetate, cesium carbonate, 1,3-bis(dicyclohexylphosphino)propane, and toluene to form a compound of Formula Ib or a salt thereof.

[0258] E. Methods for Preparing Compounds of Formula I from Formula XI In another embodiment, the present disclosure provides a compound of formula I: [ka] or a salt thereof, the method comprising: a) Formula XI: [ka] or a salt thereof with a compound of formula VI: [ka] or a salt thereof, a first base, and a first solvent to form a first reaction mixture comprising a compound of formula X: [ka] or a salt thereof; and b) forming a second reaction mixture comprising a compound of formula X or a salt thereof, a compound of PG-NH2 or a salt thereof, a second base, and a second solvent to produce a compound of formula II: [ka] or a salt thereof; and c) forming a third reaction mixture comprising the compound of Formula II or a salt thereof, a deprotecting agent, and a third solvent to provide the compound of Formula I or a salt thereof; In the formula, R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl or C 1~3 may be alkoxy, and R 4 may be hydrogen or methyl, R 5 is C 3~6 It may be alkyl and PG may be an amino protecting group.

[0259] The compound of formula VI may be in any suitable form. In some embodiments, the compound of formula VI may be in neutral form. In some embodiments, the compound of formula VI may be in salt form. In some embodiments, the compound of formula VI may be its tosylate salt.

[0260] The first base may be a tertiary amine, an aromatic amine base, an amidine-based compound, an alkali carbonate, an alkali bicarbonate, a tribasic alkali phosphate, a dibasic alkali phosphate, or a combination thereof. Suitable tertiary amines include, but are not limited to, triethylamine, tri-n-butylamine, N,N-diisopropylethylamine, N,N,N',N'-tetramethylethylenediamine, N-methylmorpholine, N-methylpiperidine, quinuclidine, and 1,4-diazabicyclo[2.2.2]-octane. Suitable aromatic amine bases include, but are not limited to, pyridine, lutidine (e.g., 2,6-lutidine, 3,5-lutidine, and 2,3-lutidine), collidine (e.g., 2,3,4-collidine, 2,3,5-collidine, 2,3,6-collidine, 2,4,5-collidine, 2,4,6-collidine, and 3,4,5-collidine), 4-dimethylaminopyridine, imidazole, and 1,8-bis(dimethylamino)naphthalene. Suitable amidine compounds include, but are not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN). Suitable alkali carbonates include lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Suitable alkali bicarbonates include lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate. Suitable tribasic alkaline phosphates include tribasic sodium phosphate and tribasic potassium phosphate. Suitable dibasic alkaline phosphates include dibasic sodium phosphate and dibasic potassium phosphate. In some embodiments, the first base is selected from the group consisting of triethylamine, tri-n-butylamine, N,N-diisopropylethylamine, N,N,N',N'-tetramethylethylenediamine, N-methylmorpholine, N-methylpiperidine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminobenzoate, 2,6-diisopropyl ... The first base may be aminopyridine, imidazole, 1,8-bis(dimethylamino)naphthalene, sodium bicarbonate, sodium carbonate, tribasic sodium phosphate, dibasic sodium phosphate, potassium bicarbonate, potassium carbonate, tribasic potassium phosphate, dibasic potassium phosphate, cesium carbonate, or a combination thereof. In some embodiments, the first base includes N,N-diisopropylethylamine. In some embodiments, the first base may be N,N-diisopropylethylamine.

[0261] The first solvent may be any suitable polar aprotic solvent and / or nonpolar solvent. In some embodiments, the first solvent may be ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, benzene, xylene, trifluorotoluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, butyronitrile, dichloromethane, 1,2-dichloroethane, chlorobenzene, or a combination thereof. In some embodiments, the first solvent includes isopropyl acetate and 2-methyltetrahydrofuran. In some embodiments, the first solvent may be isopropyl acetate and 2-methyltetrahydrofuran.

[0262] The PG-NH2 compound can be in any suitable form. In some embodiments, the PG-NH2 compound can be in a neutral form. In some embodiments, the PG-NH2 compound can be in a salt form. In some embodiments, the PG-NH2 compound can be its hemisulfate, sulfate, chloride, bromide, carbonate, nitrate, or acetate salt.

[0263] PG can be an amino-protecting group. Suitable amino-protecting groups include, but are not limited to, a carbobenzyloxy (Cbz) group, a p-methoxybenzylcarbonyl (Moz or MeOZ) group, a tert-butyloxycarbonyl (BOC) group, a 2-trimethylsilylethoxymethyl (SEM) group, a 9-fluorenylmethyloxycarbonyl (Fmoc) group, an acetyl (Ac) group, a benzoyl (Bz) group, a benzyl (Bn) group, a carbamate group, a p-methoxybenzyl (PMB) group, a 2,4-dimethoxybenzyl (DMB) group, a 1-(2,4-dimethoxyphenyl)ethyl, 3,4-dimethoxybenzyl (DMPB) group, a p-methoxyphenyl (PMP) group, a tosyl (Ts) group, a Troc (trichloroethyl chloroformate) group, and other sulfonamide (Nosyl and Nps) groups. In some embodiments, PG can be 2,4-dimethoxybenzyl.

[0264] In some embodiments, the compound PG-NH2 can be 2,4-dimethoxybenzylamine.

[0265] The second base may be a tertiary amine, an aromatic amine base, an amidine-based compound, an alkali carbonate, an alkali bicarbonate, a tribasic alkali phosphate, a dibasic alkali phosphate, or a combination thereof. Suitable tertiary amines include, but are not limited to, triethylamine, tri-n-butylamine, N,N-diisopropylethylamine, N,N,N',N'-tetramethylethylenediamine, N-methylmorpholine, N-methylpiperidine, quinuclidine, and 1,4-diazabicyclo[2.2.2]-octane. Suitable aromatic amine bases include, but are not limited to, pyridine, lutidine (e.g., 2,6-lutidine, 3,5-lutidine, and 2,3-lutidine), collidine (e.g., 2,3,4-collidine, 2,3,5-collidine, 2,3,6-collidine, 2,4,5-collidine, 2,4,6-collidine, and 3,4,5-collidine), 4-dimethylaminopyridine, imidazole, and 1,8-bis(dimethylamino)naphthalene. Suitable amidine compounds include 1,8-diazabicyclo[5.4.0]undecane, 1,8-bis(dimethylamino)naphthalene ... Suitable alkali carbonates include, but are not limited to, 1,5-diazabicyclo-4.3.0]non-5-ene (DBN). Suitable alkali carbonates include lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Suitable alkali bicarbonates include lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate. Suitable tribasic alkali phosphates include tribasic sodium phosphate and tribasic potassium phosphate. Suitable dibasic alkali phosphates include dibasic sodium phosphate and dibasic potassium phosphate. In some embodiments, the second base may be triethylamine, tri-n-butylamine, N,N-diisopropylethylamine, N,N,N',N'-tetramethylethylenediamine, N-methylmorpholine, N-methylpiperidine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo-4.3.0]non-5-ene, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, imidazole, 1,8-bis(dimethylamino)naphthalene, sodium bicarbonate, sodium carbonate, tribasic sodium phosphate, dibasic sodium phosphate, potassium bicarbonate, potassium carbonate, tribasic potassium phosphate, dibasic potassium phosphate, cesium carbonate, or a combination thereof. In some embodiments, the second base includes potassium carbonate. In some embodiments, the second base may be potassium carbonate.

[0266] The second solvent may be any suitable polar aprotic solvent and / or nonpolar solvent. In some embodiments, the second solvent may be ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, benzene, xylene, trifluorotoluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, butyronitrile, dichloromethane, 1,2-dichloroethane, chlorobenzene, or a combination thereof. In some embodiments, the second solvent includes isopropyl acetate and 2-methyltetrahydrofuran. In some embodiments, the second solvent may be isopropyl acetate and 2-methyltetrahydrofuran.

[0267] Generally, the first reaction (i.e., step a)) can be carried out at ambient to elevated temperatures. For example, the first reaction mixture can be at a temperature of 20°C to 100°C, or can be heated to reflux. In some embodiments, the first reaction mixture can be at a temperature of 30°C to 100°C, 40°C to 100°C, 50°C to 100°C, 60°C to 90°C, 70°C to 90°C, or about 80°C. In some embodiments, the first reaction mixture can be at a temperature of 50°C to reflux. In some embodiments, the first reaction mixture can be at a temperature of about 80°C. In some embodiments, the first reaction mixture can be heated to reflux.

[0268] Generally, the second reaction (i.e., step b)) can be carried out at ambient to elevated temperatures. For example, the second reaction mixture can be at a temperature of 20°C to 100°C, or can be heated to reflux. In some embodiments, the second reaction mixture can be at a temperature of 30°C to 100°C, 40°C to 100°C, 50°C to 100°C, 60°C to 90°C, 60°C to 80°C, or about 70°C. In some embodiments, the second reaction mixture can be at a temperature of 50°C to reflux. In some embodiments, the second reaction mixture can be at a temperature of about 70°C. In some embodiments, the second reaction mixture can be heated to reflux.

[0269] The compound of formula II or a salt thereof can be deprotected by various methods known in the art to provide the compound of formula I or a salt thereof. When PG is 2,4-dimethoxybenzyl, the compound of formula II can be deprotected by various methods, for example, acidic, reductive (hydrogenolysis), or can be deprotected under oxidative conditions to provide a compound of Formula I or a salt thereof.

[0270] In some embodiments, the deprotecting agent can be an acid. In some embodiments, the acid can be trifluoroacetic acid, trichloroacetic acid, acetic acid, formic acid, hydrochloric acid, sulfuric acid, phosphoric acid, or a combination thereof. In some embodiments, the acid includes trifluoroacetic acid. In some embodiments, the acid can be trifluoroacetic acid.

[0271] In some embodiments, the deprotecting agent can be a hydrogen source, and the third reaction mixture further comprises a transition metal catalyst. In some embodiments, the hydrogen source can be ammonium formate, formic acid, hydrogen gas, or a combination thereof. In some embodiments, the hydrogen source includes hydrogen gas. In some embodiments, the hydrogen source includes ammonium formate. In some embodiments, the hydrogen source includes formic acid. In some embodiments, the transition metal catalyst can be palladium hydroxide on carbon, palladium on carbon, or platinum oxide. In some embodiments, the transition metal catalyst includes palladium hydroxide on carbon. In some embodiments, the transition metal catalyst includes palladium on carbon. In some embodiments, the transition metal catalyst includes platinum oxide. In some embodiments, the deprotecting agent can be hydrogen gas, and the third reaction mixture further comprises palladium hydroxide on carbon, palladium on carbon, or platinum oxide. In some embodiments, the deprotecting agent includes ammonium formate, and the third reaction mixture further comprises palladium hydroxide on carbon, palladium on carbon, or platinum oxide. In some embodiments, the deprotecting agent includes formic acid, and the third reaction mixture further includes palladium hydroxide on carbon, palladium on carbon, or platinum oxide.

[0272] In some embodiments, the hydrogen source can be ammonium formate. In some embodiments, the hydrogen source can be formic acid. In some embodiments, the transition metal catalyst can be palladium hydroxide on carbon. In some embodiments, the transition metal catalyst can be palladium on carbon. In some embodiments, the transition metal catalyst can be platinum oxide. In some embodiments, the deprotecting agent can be ammonium formate, and the third reaction mixture further comprises palladium hydroxide on carbon, palladium on carbon, or platinum oxide. In some embodiments, the deprotecting agent can be formic acid, and the third reaction mixture further comprises palladium hydroxide on carbon, palladium on carbon, or platinum oxide.

[0273] In some embodiments, the deprotecting agent can be boron tribromide, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, ceric ammonium nitrate, or a combination of trifluoromethanesulfonic acid and 1,3-dimethoxybenzene.

[0274] The third solvent may be any suitable polar or non-polar, protic or aprotic solvent. In some embodiments, the third solvent may be ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, benzene, xylene, trifluorotoluene, anisole, dimethyl sulfoxide, propionitrile, butyronitrile, dichloromethane, 1,2-dichloroethane, chlorobenzene, methanol, ethanol, isopropanol, water, formic acid, acetic acid, trichloroacetic acid, or a combination thereof. In some embodiments, the third solvent includes formic acid. In some embodiments, the deprotecting agent may be formic acid, and the third solvent may be formic acid. In some embodiments, the third solvent includes dichloromethane. In some embodiments, the third solvent may be dichloromethane.

[0275] Generally, the third reaction (i.e., step c)) can be carried out at any suitable temperature, for example, from -10°C to 80°C. In some embodiments, the third reaction mixture is The third reaction mixture may be at a temperature of 20°C to 40°C. In some embodiments, the third reaction mixture may be at a temperature of about 30°C. In some embodiments, the third reaction mixture may be at a temperature of about 40°C. In some embodiments, the third solvent may be dichloromethane, and the third reaction mixture may be heated to reflux.

[0276] In some embodiments, the method further includes d) forming a fourth reaction mixture comprising the salt of the compound of Formula I, a third base, and a fourth solvent to provide the neutral form of the compound of Formula I.

[0277] The third base can be an alkali carbonate or an alkali hydroxide. Suitable alkali carbonates include sodium carbonate and potassium carbonate. Suitable alkali hydroxides include sodium hydroxide and potassium hydroxide. In some embodiments, the third base can be sodium hydroxide or potassium hydroxide. In some embodiments, the third base can include sodium hydroxide. In some embodiments, the third base can be in an aqueous solution. In some embodiments, the third base can include an aqueous solution of sodium hydroxide. In some embodiments, the third base can be an aqueous solution of sodium hydroxide.

[0278] The fourth solvent may be any suitable alcohol solvent, ester solvent, and / or water. In some embodiments, the fourth solvent may be methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, water, or a combination thereof. In some embodiments, the fourth solvent includes i) ethanol and water, or ii) ethyl acetate and water. In some embodiments, the fourth solvent includes ethanol and water. In some embodiments, the fourth solvent includes ethyl acetate and water. In some embodiments, the fourth solvent may be i) ethanol and water, or ii) ethyl acetate and water. In some embodiments, the fourth solvent may be ethanol and water. In some embodiments, the fourth solvent may be ethyl acetate and water.

[0279] If the fourth solvent comprises an ester solvent (eg, ethyl acetate or isopropyl acetate), once the reaction is complete, the reaction mixture after partition can be further treated with an aqueous solution of sodium bicarbonate.

[0280] Generally, the fourth reaction (i.e., step d)) can be carried out at any suitable temperature. For example, the fourth reaction mixture can be at a temperature of 0°C to 60°C. In some embodiments, the fourth reaction mixture can be at a temperature of 0°C to 60°C, 10°C to 60°C, 10°C to 50°C, or 20°C to 40°C. In some embodiments, the fourth reaction mixture can be at a temperature of 20°C to 40°C. In some embodiments, the fourth reaction mixture can be at a temperature of about 20°C. In some embodiments, the fourth reaction mixture can be at a temperature of about 40°C.

[0281] In some embodiments of any one of Formulas I, II, X, and XI, R 2 are Cl, F, CN, CF3, C 1~3 Alkyl or C 1~3 may be alkoxy, and R 1 and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl or C 1~3 It may be alkoxy. 1~3 Alkyl may be methyl, ethyl, n-propyl, or isopropyl. 1~3 Alkoxy can be methoxy, ethoxy, n-propoxy, or isopropoxy. In some embodiments of any one of Formulas I, II, X, and XI, R 2 is Cl, F, CN, CF3, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropyl R may be epoxy; 1 and R 3 may each independently be hydrogen, F, Cl, CN, CF, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy. In some embodiments of any one of Formulas I, II, X, and XI, R 2 may be Cl, F, CN, CF, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; R 1 and R 3In some embodiments of any one of Formulas I, II, X, and XI, R 2 may be F, and R 1 and R 3 may each be hydrogen.

[0282] In some embodiments of any one of Formulas I, II, VI, and X, R 4 In some embodiments of any one of Formulas I, II, VI, and X, R 4 may be methyl.

[0283] In some embodiments of any one of Formulas I, II, VI, and X, R 5 is C 3~6 In some embodiments, R 5 In some embodiments of any one of Formulas I, II, VI, and X, R may be n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or hexyl. 5 may be n-butyl.

[0284] In some embodiments of any one of Formulas I, II, VI, and X, R 4 may be methyl, R 5 is C 3~6 In some embodiments of any one of Formulas I, II, VI, and X, R 4 may be methyl, R 5 In some embodiments of any one of Formulas I, II, VI, and X, R may be n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or hexyl. 4 may be methyl, R 5 may be n-butyl.

[0285] In some embodiments, the compound of Formula I has Formula Ia: [ka] or a salt thereof, and R 2 and R 5 is as defined and explained herein.

[0286] In some embodiments, the compound of Formula I has Formula Ib: [ka] or a salt thereof.

[0287] In some embodiments, the compound of formula XI has formula XIa: [ka] or a salt thereof, and R 2 is as defined and explained herein.

[0288] In some embodiments, the compound of formula XI has formula Xb: [ka] or a salt thereof.

[0289] In some embodiments, the compound of formula VI has formula VIa: [ka] R may be 5 is as defined and explained herein.

[0290] In some embodiments, the compound of formula VI has formula VIb: [ka] It may be.

[0291] In some embodiments, the compound of formula X has formula IXa: [ka] or a salt thereof, and R 2 and R 5 is as defined and explained herein.

[0292] In some embodiments, the compound of formula X has formula IXb: [ka] or a salt thereof.

[0293] In some embodiments, the present disclosure provides compounds of formula Ib: [ka] or a salt thereof, the method comprising: a) Formula XIb: [ka] or a salt thereof with a compound of formula VIb: [ka] , N,N-diisopropylethylamine, 2-methyltetrahydrofuran, and isopropyl acetate to form a compound of Formula Xb: [ka] or a salt thereof; and b) forming a second reaction mixture comprising a compound of Formula Xb or a salt thereof, 2,4-dimethoxybenzylamine, potassium carbonate, 2-methyltetrahydrofuran, and isopropyl acetate to produce a compound of Formula IIb: [ka] or a salt thereof; and c) forming a third reaction mixture comprising the compound of Formula IIb or a salt thereof, trifluoroacetic acid, and dichloromethane to produce a compound of Formula Ib: [ka] preparing a trifluoroacetate salt of the compound of formula (I); d) forming a fourth reaction mixture comprising the trifluoroacetate salt of the compound of formula Ib, sodium hydroxide, ethanol, and water to provide the compound of formula Ib in salt-free form.

[0294] In some embodiments, the compound of formula Xb or a salt thereof is isolated in a solution comprising 2-methyltetrahydrofuran and isopropyl acetate and can be used in the subsequent step b) without purification and / or removal of the 2-methyltetrahydrofuran and isopropyl acetate. In some embodiments, the compound of formula Xb or a salt thereof is isolated in a solution comprising 2-methyltetrahydrofuran and isopropyl acetate and can be used in the subsequent step b) without ... The compound of formula Xb or a salt thereof can be precipitated by adding n-heptane to a solution comprising 2-methyltetrahydrofuran and isopropyl acetate and isolated in a solid form. In some embodiments, the compound of formula Xb or a salt thereof can be precipitated by adding n-heptane to a solution comprising 2-methyltetrahydrofuran and isopropyl acetate and isolated in a solid form, and can be used in the subsequent step b) without purification.

[0295] F. Methods for Preparing Intermediates The intermediates used in the methods of the present disclosure can be prepared by a variety of methods.

[0296] 1. Preparation of salts of (R)-2-amino-2-methylhexan-1-ol, Route 1 In some embodiments, the present disclosure provides (R)-2-amino-2-methylhexan-1-ol: [ka] and a method for preparing a salt of This method is 1) Formula: [ka] C with 1~4 forming a first reaction mixture comprising an alkyl alaninate or a salt thereof, an aldehyde, a first base, a drying agent, and a first solvent; [ka] C 1~4 forming an imine of the alkyl alanina; 2a)C 1~4 an alkyl alaninate, an electrophile, and a second base; and a second solvent to form a second mixture comprising: [ka] C 1~4 forming an imine of alkyl 2-amino-2-methylhexanoate; 2b)C 1~4 forming a third reaction mixture comprising the imine of alkyl 2-amino-2-methylhexanoate, the first acid, and a third solvent to form C 1~4 Alkyl 2-amino-2-methylhexanoate: [ka] forming a first salt of 2c)C 1~4forming a fourth reaction mixture comprising the first salt of alkyl 2-amino-2-methylhexanoate, a third base, a fourth solvent, and water to produce a neutral form of C 1~4 forming an alkyl 2-amino-2-methylhexanoate; 3) C 1~4 forming a fifth reaction mixture comprising alkyl 2-amino-2-methylhexanoate, a second acid, and a fifth solvent to produce C 1~4 forming a second salt of an alkyl 2-amino-2-methylhexanoate; and 4) C 1~4 forming a sixth reaction mixture comprising a second salt of alkyl 2-amino-2-methylhexanoate, an enzyme, a fourth base, and a sixth solvent; 1~4 Alkyl (R)-2-amino-2-methylhexanoate: [ka] or a salt thereof; 5) C 1~4 forming a seventh reaction mixture comprising alkyl (R)-2-amino-2-methylhexanoate or a salt thereof, a BOC-protected reagent, and a seventh solvent to form C 1~4 Alkyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate: [ka] and forming 6) C 1~4 forming an eighth reaction mixture comprising alkyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate, a reductant, a promoter, and an eighth solvent to produce tert-butyl (R)-(1-hydroxy-2-methylhexan-2-yl)carbamate: [ka] and forming 7) forming a ninth reaction mixture comprising tert-butyl (R)-(1-hydroxy-2-methylhexan-2-yl)carbamate, a third acid, and a ninth solvent to form (R providing a salt of 2-amino-2-methylhexan-1-ol; wherein R can be unsubstituted or substituted aryl, or unsubstituted or substituted aryl -CH=CH-.

[0297] In some embodiments, (R)-2-amino-2-methylhexan-1-ol can be prepared according to steps 1-7 as shown in the scheme in Figure 3A.

[0298] In some embodiments, C in any one of the formulas or compounds of steps 1, 2a, 2b, 2c, and 3-6 1~4 Alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments, C in any one of the formulas or compounds of steps 1, 2a, 2b, 2c, and 3-6 1~4 The alkyl may be isopropyl.

[0299] Regarding step 1, C 1~4 Alkyl alaninate or a salt thereof, an aldehyde, a first base, a drying agent, a first solvent, C 1~4 The alkylalaninate imines and reaction temperatures are described herein.

[0300] In some embodiments, C 1~4 Alkyl alaninate is C 1~4 Alkyl L-alaninate, C 1~4 In some embodiments, C may be alkyl D-alaninato, alkyl D-alaninato, or mixtures thereof. 1~4 The alkyl alaninato may be methyl alaninato, ethyl alaninato, n-propyl alaninato, isopropyl alaninato, n-butyl alaninato, sec-butyl alaninato, or tert-butyl alaninato. 1~4The alkyl alaninate may be isopropyl alaninate. In some embodiments, C 1~4 The alkyl alaninate may be isopropyl L-alaninate. The isopropyl L-alaninate may be in any suitable form, for example, in a neutral form or a salt form. In some embodiments, the isopropyl L-alaninate may be its HCl salt.

[0301] Aldehyde can be any suitable aldehyde that can form imine with amine.For example, aldehyde can be benzaldehyde, 2-chlorobenzaldehyde, 4-chlorobenzaldehyde, 3-hydroxybenzaldehyde, 4-hydroxybenzaldehyde, 3-phenylprop-2-enal, 3-(4-methylphenyl)prop-2-enal, 3-(4-hydroxy-3-methoxyphenyl)prop-2-enal, 2-methylbenzaldehyde, 4-methylbenzaldehyde or 4-methoxybenzaldehyde.In some embodiments, aldehyde can be benzaldehyde.

[0302] The first base can be a tertiary amine (e.g., trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylpiperidine, or tri-n-butylamine), a carboxylate (e.g., sodium acetate or potassium acetate), or an inorganic base (e.g., sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, tribasic sodium phosphate, or tribasic potassium phosphate). In some embodiments, the first base includes trimethylamine. In some embodiments, the first base can be trimethylamine.

[0303] The desiccant can be any suitable agent or method capable of removing the water formed by condensation. For example, the desiccant can be sodium sulfate, magnesium sulfate, trialkyl orthoformate (e.g., trimethyl orthoformate), molecular sieves, or azeotropic removal of water (e.g., using a Dean-Stark trap). In some embodiments, the desiccant includes sodium sulfate. In some embodiments, the desiccant includes sodium sulfate. It may be thorium.

[0304] The first solvent may be an aromatic solvent (e.g., toluene, xylene, chlorobenzene, fluorobenzene, or trifluorotoluene), an ether (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, or 1,4-dioxane), a chlorinated solvent (e.g., dichloromethane or 1,2-dichloroethane), an ester (e.g., ethyl acetate, butyl acetate, or isobutyl acetate), an alcohol (e.g., methanol, ethanol, or isopropanol), or a combination thereof. In some embodiments, the first solvent includes toluene. In some embodiments, the first solvent may be toluene.

[0305] In some embodiments, C 1~4 The imine of the alkylalaninate has the formula: [ka] and wherein R can be phenyl, 2-chlorophenyl, 4-chlorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-phenylvinyl, 2-(4-methylphenyl)vinyl, 2-(4-hydroxy-3-methoxyphenyl)vinyl, 2-methylphenyl, 4-methylphenyl, or 4-methoxyphenyl. In some embodiments, R can be phenyl. In some embodiments, C 1~4 The imine of the alkylalaninate has the formula: [ka] may be the imine of isopropyl alaninato having the formula wherein R can be phenyl, 2-chlorophenyl, 4-chlorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-phenylvinyl, 2-(4-methylphenyl)vinyl, 2-(4-hydroxy-3-methoxyphenyl)vinyl, 2-methylphenyl, 4-methylphenyl, or 4-methoxyphenyl. In some embodiments, R can be phenyl. In some embodiments, the imine of isopropyl alaninato is isopropyl 2-(benzylideneamino)propanoate: [ka] It may be.

[0306] The imine of isopropyl alaninato can be isolated in a solution of the first solvent that can be used in the condensation reaction. In some embodiments, isopropyl 2-(benzylideneamino)propanoate is isolated as a solution in toluene and can be used directly in the subsequent step without purification and / or solvent removal.

[0307] Generally, the condensation reaction (i.e., step 1) can be carried out at any suitable temperature. For example, the condensation reaction mixture can be at a temperature of 0°C to 80°C. In some embodiments, the condensation reaction mixture can be at a temperature of 20°C to 30°C.

[0308] Step 2 includes three steps as described in steps 2a, 2b, and 2c.

[0309] Regarding step 2a, C 1~4 alkyl alaninate imine, electrophile, second base, second solvent, C 1~4 The alkyl 2-amino-2-methylhexanoate imines and reaction temperatures are described herein.

[0310] In some embodiments, C 1~4The imine of alkyl alaninate can be the imine of isopropyl alaninate. In some embodiments, the imine of isopropyl alaninate can be isopropyl 2-(benzylideneamino)propanoate. In some embodiments, the imine of isopropyl alaninate can be a solution of isopropyl 2-(benzylideneamino)propanoate in toluene.

[0311] In some embodiments, the electrophile can be n-butyl bromide, n-butyl iodide, n-butyl methanesulfonate, n-butyl 4-methylbenzenesulfonate, or n-butyl sulfate. In some embodiments, the electrophile can be n-butyl bromide.

[0312] The second base may be an alkali alkoxide (e.g., sodium isopropoxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, or potassium isopropoxide), an alkali hydroxide in the presence of a phase transfer catalyst (e.g., sodium hydroxide or potassium hydroxide in combination with tetra-n-butylammonium bromide or tetra-n-butylammonium hydroxide), an alkali amide (e.g., lithium diisopropylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, or lithium 2,2,6,6-tetramethylpiperidide), an alkali carbonate (e.g., sodium carbonate, potassium carbonate, or cesium carbonate), or sodium hydride. In some embodiments, the second base includes sodium isopropoxide. In some embodiments, the second base may be sodium isopropoxide.

[0313] The second solvent may be an aromatic solvent (e.g., toluene, xylene, chlorobenzene, or fluorobenzene), an ether (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, or 1,4-dioxane), a polar aprotic solvent (e.g., dimethyl sulfoxide, N-methyl-2-pyrrolidone, or sulfolane), an alcohol (e.g., isopropanol, tert-butanol, or 2-methylbutan-2-ol), a chlorinated solvent (e.g., dichloromethane or chlorobenzene), or a combination thereof. In some embodiments, the second solvent includes tetrahydrofuran and toluene. In some embodiments, the second solvent may be tetrahydrofuran and toluene.

[0314] In some embodiments, C 1~4 The imine of alkyl 2-amino-2-methylhexanoate has the formula: [ka] and wherein R can be phenyl, 2-chlorophenyl, 4-chlorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-phenylvinyl, 2-(4-methylphenyl)vinyl, 2-(4-hydroxy-3-methoxyphenyl)vinyl, 2-methylphenyl, 4-methylphenyl, or 4-methoxyphenyl. In some embodiments, R can be phenyl. In some embodiments, C 1~4 The imine of alkyl 2-amino-2-methylhexanoate has the formula: [ka] and the imine of isopropyl 2-amino-2-methylhexanoate having the formula: wherein R can be phenyl, 2-chlorophenyl, 4-chlorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-phenylvinyl, 2-(4-methylphenyl)vinyl, 2-(4-hydroxy-3-methoxyphenyl)vinyl, 2-methylphenyl, 4-methylphenyl, or 4-methoxyphenyl. In some embodiments, R can be phenyl. In some embodiments, the imine of isopropyl 2-amino-2-methylhexanoate is isopropyl 2-(benzylideneamino)-2-methylhexanoate: [ka] It may be.

[0315] Upon completion, the second reaction mixture can be used directly in a subsequent step without removing the second solvent. In some embodiments, upon completion of the alkylation reaction, the second reaction mixture comprising isopropyl 2-(benzylideneamino)-2-methylhexanoate, tetrahydrofuran, and toluene can be used directly in a subsequent step without removing the solvent. It is possible.

[0316] Generally, the alkylation reaction (i.e., step 2a) can be carried out at any suitable temperature, for example, a temperature between 0° C. and 80° C. In some embodiments, the reaction mixture of the alkylation reaction can be at a temperature between 40° C. and 50° C.

[0317] Regarding step 2b, C 1~4 imine of alkyl 2-amino-2-methylhexanoate, first acid, third solvent, C 1~4 The first salt of alkyl 2-amino-2-methylhexanoate and the reaction temperature are described herein.

[0318] In some embodiments, the imine can be the imine of isopropyl 2-amino-2-methylhexanoate. In some embodiments, the imine can be isopropyl 2-(benzylideneamino)-2-methylhexanoate. In some embodiments, the imine can be the reaction mixture of step 2a comprising isopropyl 2-(benzylideneamino)-2-methylhexanoate, tetrahydrofuran, and toluene.

[0319] The first acid may be a mineral acid (e.g., sulfuric acid, hydrochloric acid, or phosphoric acid) or an organic acid (e.g., methanesulfonic acid, fumaric acid, acetic acid, formic acid, or ascorbic acid). In some embodiments, the first acid includes sulfuric acid. In some embodiments, the first acid may be in an aqueous solution. In some embodiments, the first acid includes an aqueous solution of sulfuric acid. In some embodiments, the first acid may be an aqueous solution of sulfuric acid.

[0320] In some embodiments, C 1~4 The first salt of alkyl 2-amino-2-methylhexanoate can be a first salt of isopropyl 2-amino-2-methylhexanoate. In some embodiments, the first salt of isopropyl 2-amino-2-methylhexanoate can be its sulfate salt.

[0321] The third solvent may be an aromatic solvent (e.g., toluene, xylene, chlorobenzene, or fluorobenzene), an ether (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, or 1,4-dioxane), a polar aprotic solvent (e.g., dimethyl sulfoxide, N-methyl-2-pyrrolidone, or sulfolane), an alcohol (e.g., isopropanol, tert-butanol, or 2-methylbutan-2-ol), a chlorinated solvent (e.g., dichloromethane or chlorobenzene), or a combination thereof. In some embodiments, the third solvent includes tetrahydrofuran, toluene, and water. In these embodiments, the third reaction mixture may be a biphasic reaction mixture. In some embodiments, the third solvent may be tetrahydrofuran, toluene, and water.

[0322] In some embodiments, the first salt of isopropyl 2-amino-2-methylhexanoate is isolated in aqueous solution and can be used directly in a subsequent step without purification and / or water removal. In some embodiments, the sulfate salt of isopropyl 2-amino-2-methylhexanoate is isolated in aqueous solution and can be used directly in a subsequent step without purification and water removal.

[0323] Generally, the hydrolysis reaction (i.e., step 2b) can be carried out at any suitable temperature, for example, a temperature between 0° C. and 80° C. In some embodiments, the reaction mixture of the hydrolysis reaction can be at a temperature between 20° C. and 30° C.

[0324] Steps 2a and 2b can be carried out in a one-pot reaction in which the second reaction mixture upon completion can be treated directly with an aqueous solution of the first acid to form a third reaction mixture.

[0325] Regarding step 2c, C 1~4 a first salt of alkyl 2-amino-2-methylhexanoate; a third base; a fourth solvent; C 1~4The alkyl 2-amino-2-methylhexanoate and reaction temperature are described herein.

[0326] In some embodiments, C 1~4 The first salt of alkyl 2-amino-2-methylhexanoate can be a first salt of isopropyl 2-amino-2-methylhexanoate. In some embodiments, the first salt of isopropyl 2-amino-2-methylhexanoate can be its sulfate salt. In some embodiments, the first salt of isopropyl 2-amino-2-methylhexanoate can be an aqueous solution of its sulfate salt.

[0327] The third base can be an inorganic base (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, tribasic sodium phosphate, or tribasic potassium phosphate) or an organic base (e.g., sodium acetate, potassium acetate, sodium methoxide, sodium tert-butoxide, or potassium tert-butoxide). In some embodiments, the third base can be in an aqueous solution. In some embodiments, the third base includes an aqueous solution of sodium hydroxide. In some embodiments, the third base can be an aqueous solution of sodium hydroxide.

[0328] The fourth solvent may be an aromatic solvent (e.g., toluene, xylene, or trifluorotoluene), an ether (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, or 1,4-dioxane), a chlorinated solvent (e.g., dichloromethane or 1,2-dichloroethane), or a combination thereof. In some embodiments, the fourth solvent includes 2-methyltetrahydrofuran. In some embodiments, the neutralization reaction (i.e., step 2c) may be carried out by extraction. In some embodiments, the fourth solvent may be 2-methyltetrahydrofuran.

[0329] In some embodiments, C1~4 The alkyl 2-amino-2-methylhexanoate can be isopropyl 2-amino-2-methylhexanoate. In some embodiments, the isopropyl 2-amino-2-methylhexanoate can be isolated as a solution in a fourth solvent. In some embodiments, the isopropyl 2-amino-2-methylhexanoate is isolated as a solution in 2-methyltetrahydrofuran and can be used directly in a subsequent step without purification and / or solvent removal.

[0330] Generally, the neutralization reaction (i.e., step 2c) can be carried out at any suitable temperature, for example, a temperature between 0° C. and 40° C. In some embodiments, the reaction mixture of the neutralization reaction can be at a temperature between 20° C. and 30° C.

[0331] Regarding step 3, C 1~4 Alkyl 2-amino-2-methylhexanoate, second acid, fifth solvent, C 1~4 The second salt of alkyl 2-amino-2-methylhexanoate and the reaction temperature are described herein.

[0332] In some embodiments, C 1~4 The alkyl 2-amino-2-methylhexanoate may be isopropyl 2-amino-2-methylhexanoate. In some embodiments, the isopropyl 2-amino-2-methylhexanoate may be a solution in 2-methyltetrahydrofuran.

[0333] The second acid can be phosphoric acid, sulfuric acid, 4-nitrobenzoic acid, fumaric acid, succinic acid, or tartaric acid. In some embodiments, the second acid may be in an aqueous solution. In some embodiments, the second acid may include phosphoric acid. In some embodiments, the second acid may be in an aqueous solution. In some embodiments, the second acid may include an aqueous solution of phosphoric acid. In some embodiments, the second acid may be an aqueous solution of phosphoric acid.

[0334] The fifth solvent can be an ether (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, or 1,4-dioxane), a ketone (e.g., acetone or methyl isobutyl ketone), an alcohol (e.g., ethanol or isopropanol), an ester (e.g., ethyl acetate, butyl acetate, or isobutyl acetate), a hydrocarbon (e.g., n-heptane, hexane, cyclohexane, methylcyclohexane), water, or a combination thereof. In some embodiments, the fifth solvent includes 2-methyltetrahydrofuran and water. In some embodiments, the fifth solvent can be 2-methyltetrahydrofuran and water.

[0335] In some embodiments, C 1~4 The second salt of alkyl 2-amino-2-methylhexanoate can be a second salt of isopropyl 2-amino-2-methylhexanoate. In some embodiments, the second salt of isopropyl 2-amino-2-methylhexanoate can be its phosphate salt. In some embodiments, the phosphate salt of isopropyl 2-amino-2-methylhexanoate can be used directly without purification.

[0336] Generally, the salt-forming reaction (i.e., step 3) can be carried out at any suitable temperature, for example, a temperature between 0° C. and 40° C. In some embodiments, the reaction mixture of the salt-forming reaction can be at a temperature between 20° C. and 30° C.

[0337] Regarding step 4, C 1~4 a second salt of alkyl 2-amino-2-methylhexanoate, an enzyme, a fourth base, a sixth solvent, C 1~4 The alkyl (R)-2-amino-2-methylhexanoate or salt thereof and the reaction temperature are described herein.

[0338] In some embodiments, C 1~4The second salt of alkyl 2-amino-2-methylhexanoate can be a second salt of isopropyl 2-amino-2-methylhexanoate. In some embodiments, the second salt of isopropyl 2-amino-2-methylhexanoate can be its phosphate salt.

[0339] The enzyme in step 4) can be subtilisin A, a serine endopeptidase (e.g., Alcalase® or other preparations), or other proteases and hydrolases (e.g., protease from Aspergillus oryzae, aminolipase A from Aspergillus niger, or lipase from Candida lipolytica). In some embodiments, the enzyme includes subtilisin A, a serine endopeptidase. In some embodiments, the enzyme includes Alcalase®. In some embodiments, the enzyme can be subtilisin A, a serine endopeptidase. In some embodiments, the enzyme can be Alcalase®.

[0340] The fourth base can be an inorganic base (e.g., tribasic sodium phosphate, tribasic potassium phosphate, dibasic sodium phosphate, dibasic potassium phosphate, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate) or an organic base (e.g., sodium acetate or potassium acetate). In some embodiments, the fourth base includes tribasic potassium phosphate. In some embodiments, the fourth base can be in an aqueous solution. In some embodiments, the fourth base includes an aqueous solution of tribasic potassium phosphate. In some embodiments, the fourth base can be an aqueous solution of potassium phosphate tribasic.

[0341] The sixth solvent can be a mixture of water and a water-miscible organic co-solvent (e.g., acetone, dimethyl sulfoxide, acetonitrile, or tert-butanol), a mixture of water and a water-immiscible organic co-solvent (e.g., methyl tert-butyl ether, ethyl acetate, or methyl isobutyl ketone). In some embodiments, the sixth solvent includes acetone and water. In some embodiments, the sixth solvent can be acetone and water.

[0342] In some embodiments, C 1~4 The alkyl (R)-2-amino-2-methylhexanoate can be isopropyl (R)-2-amino-2-methylhexanoate. The isopropyl (R)-2-amino-2-methylhexanoate can be isolated in a solution in a water-immiscible organic co-solvent that can be used in the sixth reaction mixture. In some embodiments, the isopropyl (R)-2-amino-2-methylhexanoate is isolated as a solution in methyl tert-butyl ether and can be used directly in a subsequent step without purification and / or solvent removal.

[0343] Generally, the enzymatic resolution reaction (i.e., step 4) can be carried out at any suitable temperature, for example, a temperature between 0° C. and 50° C. In some embodiments, the reaction mixture for the enzymatic resolution can be at a temperature between 30° C. and 40° C.

[0344] Regarding step 5, C 1~4 Alkyl (R)-2-amino-2-methylhexanoate or its salt, BOC-protected reagent, seventh solvent, C 1~4 The alkyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate and reaction temperature are described herein.

[0345] In some embodiments, C 1~4The alkyl (R)-2-amino-2-methylhexanoate can be isopropyl (R)-2-amino-2-methylhexanoate. In some embodiments, the isopropyl (R)-2-amino-2-methylhexanoate can be in solution in methyl tert-butyl ether.

[0346] In some embodiments, the BOC-protecting reagent may be di-tert-butyl dicarbonate, di-tert-butyl-iminodicarboxylate, or tert-butyl chloroformate. In some embodiments, the BOC-protecting reagent includes di-tert-butyl dicarbonate. In some embodiments, the BOC-protecting reagent may be di-tert-butyl dicarbonate.

[0347] The seventh solvent can be an ether (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, or 1,4-dioxane), a ketone (e.g., acetone or methyl isobutyl ketone), an ester (e.g., ethyl acetate, butyl acetate, or isobutyl acetate), an aromatic solvent (e.g., toluene or xylene), a chlorinated solvent (e.g., dichloromethane or 1,2-dichloroethane), water, or a combination thereof. In some embodiments, the seventh solvent includes methyl tert-butyl ether. In some embodiments, the seventh solvent can be methyl tert-butyl ether.

[0348] In some embodiments, C 1~4 The alkyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate may be isopropyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate. Isopropyl(R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate can be isolated in the seventh solvent. In some embodiments, isopropyl(R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate is isolated as a solution in methyl tert-butyl ether and can be used directly in a subsequent step without purification and / or removal of methyl tert-butyl ether.

[0349] Generally, the BOC protection reaction (i.e., step 5) can be carried out at any suitable temperature, for example, a temperature between 0° C. and 100° C. In some embodiments, the reaction mixture of the BOC protection reaction can be at a temperature between 20° C. and 30° C.

[0350] Regarding step 6, C 1~4 Isolation of alkyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate, reductant, promoter, eighth solvent, tert-butyl (R)-(1-hydroxy-2-methylhexan-2-yl)carbamate, and reaction temperatures are described herein.

[0351] In some embodiments, C 1~4 The alkyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate can be isopropyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate. In some embodiments, the isopropyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate can be a solution in methyl tert-butyl ether.

[0352] The reductant can be any suitable reducing agent capable of reducing an ester group (e.g., an isopropyl ester) to the corresponding —CHOH. For example, the reductant can be a borohydride reagent (e.g., lithium borohydride, potassium borohydride, lithium triethylborohydride, or sodium borohydride / iodine), an aluminum hydride reagent (e.g., lithium aluminum hydride or diisobutylaluminum hydride). In some embodiments, the reductant includes lithium borohydride. In some embodiments, the reductant includes a solution of lithium borohydride in tetrahydrofuran. In some embodiments, the reductant can be lithium borohydride. In some embodiments, the reductant can be a solution of lithium borohydride in tetrahydrofuran.

[0353] The promoter may be an alcohol (e.g., methanol, ethanol, n-propanol, isopropanol, or tert-butanol). In some embodiments, the promoter includes methanol. In some embodiments, the promoter may be methanol.

[0354] The eighth solvent can be an ether (such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, or 1,2-dimethoxyethane), an aromatic solvent (e.g., toluene or xylene), or a combination thereof. In some embodiments, the eighth solvent includes methyl tert-butyl ether and tetrahydrofuran. In some embodiments, the eighth solvent can be methyl tert-butyl ether and tetrahydrofuran.

[0355] The tert-butyl (R)-(1-hydroxy-2-methylhexan-2-yl)carbamate can be isolated in the eighth solvent. In some embodiments, the tert-butyl (R)-(1-hydroxy-2-methylhexan-2-yl)carbamate is isolated as a solution in methyl tert-butyl ether and can be used directly in a subsequent step without purification and / or removal of methyl tert-butyl ether.

[0356] Generally, the reduction reaction (i.e., step 6) can be carried out at any suitable temperature, for example, a temperature between 0° C. and 60° C. In some embodiments, the reaction mixture of the reduction reaction can be at a temperature between 20° C. and 30° C.

[0357] For Step 7, the tert-butyl (R)-(1-hydroxy-2-methylhexan-2-yl)carbamate, the third acid, the ninth solvent, the salt of (R)-2-amino-2-methylhexan-1-ol, and the reaction temperature are described herein.

[0358] In some embodiments, the tert-butyl (R)-(1-hydroxy-2-methylhexan-2-yl)carbamate can be a solution in methyl tert-butyl ether.

[0359] The third acid can be a sulfonic acid (e.g., p-toluenesulfonic acid, methanesulfonic acid, or benzenesulfonic acid), a mineral acid (e.g., hydrochloric acid or sulfuric acid), or an organic acid (e.g., trifluoroacetic acid). In some embodiments, the third acid includes p-toluenesulfonic acid. In some embodiments, the third acid can be p-toluenesulfonic acid.

[0360] The ninth solvent can be an alcohol (e.g., methanol, ethanol, n-propanol, isopropanol, or n-butanol), an ether (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, or 1,2 dimethoxyethane), an aromatic solvent (e.g., toluene or xylene), a chlorinated solvent (e.g., dichloromethane or 1,2-dichloroethane), a ketone solvent (e.g., acetone or methyl isobutyl ketone), an ester (e.g., ethyl acetate, butyl acetate, or isobutyl acetate), or a combination thereof. In some embodiments, the ninth solvent includes isopropanol. In some embodiments, the ninth solvent can be isopropanol.

[0361] In some embodiments, the salt of (R)-2-amino-2-methylhexan-1-ol has Formula VIb: [ka] The compound may be:

[0362] Generally, the BOC deprotection reaction (i.e., step 7) can be carried out at any suitable temperature, for example, a temperature between 0° C. and 100° C. In some embodiments, the reaction mixture of the BOC deprotection reaction can be at a temperature between 40° C. and 60° C.

[0363] 2. Preparation of salts of (R)-2-amino-2-methylhexan-1-ol, Route 2 In some embodiments, steps 3, 4, and 5 above can be replaced with steps 8 and 9 as shown in the scheme in Figure 3B to provide Boc-protected isopropyl (R)-2-amino-2-methylhexanoate.

[0364] In some embodiments, the present disclosure provides (R)-2-amino-2-methylhexan-1-ol: [ka] and a method for preparing a salt of This method is 1) C 1~4 Alkyl alaninate: [ka] or a salt thereof, an aldehyde, a first base, a drying agent, and a first solvent to form a first reaction mixture comprising: [ka] C 1~4 forming an imine of the alkyl alanina; 2a)C 1~4 forming a second mixture comprising the imine of the alkyl alaninato, an electrophile, a second base, and a second solvent to produce a compound of the formula: [ka] forming an imine of C1-4 alkyl 2-amino-2-methylhexanoate having the formula: 2b)C 1~4 forming a third reaction mixture comprising the imine of alkyl 2-amino-2-methylhexanoate, the first acid, and a third solvent to form C 1~4 Alkyl 2-amino-2-methylhexanoate: [ka] forming a salt of 2c)C 1~4 a salt of alkyl 2-amino-2-methylhexanoate and a third base; forming a fourth reaction mixture comprising: a fourth solvent; and water to obtain a neutral form of C 1~4 forming an alkyl 2-amino-2-methylhexanoate; 8) C 1~4 forming a fifth reaction mixture comprising alkyl 2-amino-2-methylhexanoate, a second acid, and a fifth solvent to produce C1~4 Alkyl (R)-2-amino-2-methylhexanoate: [ka] forming a first salt of 9) C 1~4 forming a sixth reaction mixture comprising the first salt of alkyl (R)-2-amino-2-methylhexanoate, the BOC-protected reagent, the fourth base, and a sixth solvent to form C 1~4 Alkyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate: [ka] and forming 6) C 1~4 forming an eighth reaction mixture comprising alkyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate, a reductant, a promoter, and an eighth solvent to produce tert-butyl (R)-(1-hydroxy-2-methylhexan-2-yl)carbamate: [ka] and forming 7) forming a ninth reaction mixture comprising tert-butyl (R)-(1-hydroxy-2-methylhexan-2-yl)carbamate, a third acid, and a ninth solvent to provide a salt of (R)-2-amino-2-methylhexan-1-ol; wherein R can be unsubstituted or substituted aryl, or unsubstituted or substituted aryl -CH=CH-.

[0365] In some embodiments, C in any one of the formulas or compounds of steps 1, 2a, 2b, 2c, 8-9, and 6 1~4Alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments, C in any one of the formulas or compounds of steps 1, 2a, 2b, 2c, 8-9, and 6 1~4 The alkyl may be isopropyl.

[0366] Steps 1, 2a, 2b, 3c, 6, and 7 are described above in the preparation of (R)-2-amino-2-methylhexan-1-ol, Route 1.

[0367] Regarding step 8, C 1~4 Alkyl 2-amino-2-methylhexanoate, second acid, fifth solvent, C 1~4 Alkyl (R)-2-amino-2-methylhexanoate first The salts and reaction temperatures are described herein.

[0368] In some embodiments, C 1~4 The alkyl 2-amino-2-methylhexanoate may be isopropyl 2-amino-2-methylhexanoate. In some embodiments, the isopropyl 2-amino-2-methylhexanoate may be a solution in 2-methyltetrahydrofuran.

[0369] The second acid may be an amino acid (e.g., N-acetyl-L-leucine, N-acetyl-L-aspartic acid, or N-acetyl-L-phenylalanine), tartaric acid or a derivative thereof (e.g., dibenzoyl-D-tartaric acid, di-p-toluoyl-D-tartaric acid, L-mandelic acid, or O-acetyl-D-mandelic acid). In some embodiments, the second acid includes N-acetyl-L-leucine. In some embodiments, the second acid may be N-acetyl-L-leucine.

[0370] The fifth solvent may be an ether (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, or 1,2 dimethoxyethane), a ketone (e.g., acetone or methyl isobutyl ketone), an alcohol (e.g., methanol, ethanol, n-propanol, or isopropanol), an ester (e.g., ethyl acetate, butyl acetate, or isobutyl acetate), a hydrocarbon solvent (e.g., hexane, n-heptane, cyclohexane, or methylcyclohexane), or a combination thereof. In some embodiments, the fifth solvent includes 2-methyltetrahydrofuran. In some embodiments, the fifth solvent may be 2-methyltetrahydrofuran.

[0371] In some embodiments, C 1~4 The first salt of alkyl(R)-2-amino-2-methylhexanoate can be a first salt of isopropyl(R)-2-amino-2-methylhexanoate. In some embodiments, C 1~4 The first salt of the alkyl (R)-2-amino-2-methylhexanoate has the formula: [ka] The compound may be an N-acetyl-L-leucine salt of In some embodiments, C 1~4 The first salt of the alkyl (R)-2-amino-2-methylhexanoate has the formula: [ka] The compound may be an N-acetyl-L-leucine salt of

[0372] The first salt of isopropyl (R)-2-amino-2-methylhexanoate can be used directly in the subsequent step 9 without purification. In some embodiments, the N-acetyl-L-leucine salt of isopropyl (R)-2-amino-2-methylhexanoate can be used directly in the subsequent step 9 without purification.

[0373] Generally, the salt formation and resolution reaction (i.e., step 8) can be carried out at any suitable temperature, e.g., 0 The reaction mixture for the salt formation and resolution reaction may be at a temperature of from 20°C to 50°C.

[0374] Regarding step 9, C 1~4 a first salt of alkyl(R)-2-amino-2-methylhexanoate, a BOC-protected reagent, a fourth base, a sixth solvent, C 1~4 The alkyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate and reaction temperature are described herein.

[0375] In some embodiments, C 1~4 The first salt of alkyl (R)-2-amino-2-methylhexanoate can be a first salt of isopropyl (R)-2-amino-2-methylhexanoate. In some embodiments, the first salt of isopropyl (R)-2-amino-2-methylhexanoate can be an N-acetyl-L-leucine salt.

[0376] In some embodiments, the BOC-protecting reagent may be di-tert-butyl dicarbonate, di-tert-butyl-iminodicarboxylate, or tert-butyl chloroformate. In some embodiments, the BOC-protecting reagent includes di-tert-butyl dicarbonate. In some embodiments, the BOC-protecting reagent may be di-tert-butyl dicarbonate.

[0377] The sixth solvent may be an ether (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, or 1,2-dimethoxyethane), a ketone (e.g., acetone or methyl isobutyl ketone), an ester (e.g., ethyl acetate, butyl acetate, or isobutyl acetate), an aromatic solvent (e.g., toluene or xylene), a chlorinated solvent (e.g., dichloromethane or 1,2-dichloroethane), an alcohol (e.g., ethanol, n-butanol, or 2-propanol), water, or a combination thereof. In some embodiments, the sixth solvent includes water. In some embodiments, the sixth solvent may be water.

[0378] In some embodiments, C 1~4 The alkyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate can be isopropyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate. In some embodiments, the isopropyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate can be isolated in the fifth solvent. In some embodiments, the isopropyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate is isolated as a solution in methyl tert-butyl ether and can be used directly in a subsequent step without purification and / or removal of methyl tert-butyl ether.

[0379] Generally, the BOC protection reaction (i.e., step 9) can be carried out at any suitable temperature, for example, a temperature between 0° C. and 100° C. In some embodiments, the reaction mixture for the BOC protection reaction can be at a temperature between 20° C. and 30° C.

[0380] 3. Preparation of salts of (R)-2-amino-2-methylhexan-1-ol, Route 3 In some embodiments, the present disclosure provides (R)-2-amino-2-methylhexan-1-ol: [ka] and a method for preparing a salt of This method is 10) Forming a first reaction mixture comprising (R)-2-amino-2-phenylethan-1-ol or a salt thereof, a substrate, a dehydrating agent or additive, and a first solvent to produce (R)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one: [ka] and forming 11) forming a second reaction mixture comprising (R)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one, a Lewis acid, a nucleophile, and a second solvent to produce (3R,5R)-3-butyl-3-methyl-5-phenylmorpholin-2-one: [ka] and forming 12) Forming a third reaction mixture comprising (3R,5R)-3-butyl-3-methyl-5-phenylmorpholin-2-one, a reducing agent, and a third solvent to produce (R)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-methylhexan-1-ol: [ka] and forming 13) forming a fourth reaction mixture comprising (R)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-methylhexan-1-ol, a hydrogen source, a catalyst, an acid, and a fourth solvent to provide a salt of (R)-2-amino-2-methylhexan-1-ol.

[0381] In some embodiments, (R)-2-amino-2-methylhexan-1-ol can be prepared according to steps 10-13 as shown in the scheme in FIG.

[0382] For step 10, the substrate, dehydrating agent or additive, first solvent, and reaction temperature are described herein.

[0383] The substrate can be an alkyl pyruvate (e.g., methyl pyruvate or ethyl pyruvate), pyruvic acid, or 2,2-diethoxypropionic acid ethyl ester. In some embodiments, the substrate includes ethyl pyruvate. In some embodiments, the substrate can be ethyl pyruvate.

[0384] The dehydrating agent or additive may be an organic acid (e.g., para-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, or trichloroacetic acid), a metal halide (lithium chloride, magnesium chloride, or zinc chloride), magnesium sulfate, sodium sulfate, azeotropic removal of water (e.g., Dean-Stark trap), or 4 Å molecular sieves. In some embodiments, the dehydrating agent or additive includes 4 Å molecular sieves. In some embodiments, the dehydrating agent or additive may be 4 Å molecular sieves.

[0385] The first solvent may be an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, or methyl tert-butyl ether), an aromatic solvent (e.g., toluene, trifluorotoluene, benzene, or xylene), a hydrocarbon solvent (e.g., n-heptane, cyclohexane, or methylcyclohexane), an alcohol solvent (e.g., methanol, ethanol, 1-butanol, 2,2,2-trifluoroethanol, or hexafluoro-isopropanol), a chlorinated solvent (e.g., dichloromethane, 1,2-dichloroethane, or chloroform), or a mixture thereof. In some embodiments, the first solvent can be 2,2,2-trifluoroethanol, 2,2,2-trifluoroethanol, or a combination thereof. In some embodiments, the first solvent can be 2,2,2-trifluoroethanol.

[0386] Generally, the cyclocondensation reaction (i.e., step 10) can be carried out at any suitable temperature, for example, a temperature between 20° C. and 110° C. In some embodiments, the reaction mixture of the cyclocondensation reaction can be at a temperature between 20° C. and reflux temperature. In some embodiments, the reaction mixture of the cyclocondensation reaction can be heated to reflux.

[0387] For step 11, the Lewis acid, nucleophile, second solvent, and reaction temperature are described herein.

[0388] The Lewis acid may be boron trifluoride diethyl etherate, lithium chloride, zinc chloride, titanium tetrachloride, silicon tetrachloride, aluminum chloride, samarium (II) iodide, cerium (III) chloride, or lanthanum (III) chloride lithium chloride complex. In some embodiments, the Lewis acid includes boron trifluoride diethyl etherate. In some embodiments, the Lewis acid may be boron trifluoride diethyl etherate.

[0389] The nucleophile may be n-butyl magnesium chloride, n-butyl lithium, or n-butyl zinc bromide. In some embodiments, the nucleophile includes n-butyl magnesium chloride. In some embodiments, the nucleophile may be n-butyl magnesium chloride.

[0390] The second solvent may be an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, methyl tert-butyl ether, or diethyl ether), an aromatic solvent (e.g., toluene or trifluorotoluene), or a methyl ether (e.g., methyl tert-butyl ether). The second solvent may be a hexane, a hydrocarbon solvent (e.g., n-hexane, n-heptane, cyclohexane, or methylcyclohexane), a chlorinated solvent (e.g., dichloromethane or chlorobenzene), or a combination thereof. In some embodiments, the second solvent includes tetrahydrofuran. In some embodiments, the second solvent may be tetrahydrofuran.

[0391] Generally, the nucleophilic addition reaction (ie, step 11) can be carried out at any suitable temperature, for example, a temperature between -78°C and -40°C.

[0392] For step 12, the reducing agent, third solvent, and reaction temperature are described herein.

[0393] The reducing agent may be lithium borohydride, lithium aluminum hydride, aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, borane complex of tetrahydrofuran and dimethyl sulfide, lithium triethylborohydride, sodium borohydride aluminum chloride complex, lithium 9-boratabicyclo[3.3.1]nonane, diisobutylaluminum hydride, lithium tri-tert-butoxyaluminum hydride, or potassium borohydride. In some embodiments, the reducing agent includes lithium borohydride. In some embodiments, the reducing agent may be lithium borohydride.

[0394] The third solvent may be an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, methyl tert-butyl ether, or diethyl ether), an aromatic solvent (e.g., toluene, xylene, or trifluorotoluene), a hydrocarbon solvent (e.g., n-hexane, n-heptane, or cyclohexane), or a combination thereof. In some embodiments, the third solvent includes tetrahydrofuran. In some embodiments, the third solvent may be tetrahydrofuran.

[0395] The reduction reaction mixture (i.e., step 12) can further include an additive. The additive can be an alcohol (e.g., methanol, ethanol, n-butanol, isopropanol, or tert-butanol).

[0396] Generally, the reduction reaction (i.e., step 12) can be carried out at any suitable temperature, for example, a temperature between −40° C. and 50° C. In some embodiments, the reaction mixture of the reduction reaction can be at a temperature between 0° C. and 20° C.

[0397] For Step 13, the hydrogen source, catalyst, acid, fourth solvent, salt of (R)-2-amino-2-methylhexan-1-ol, and reaction temperature are described herein.

[0398] The hydrogen source may be hydrogen gas, formic acid, ammonium formate, cyclohexene, hydrazine, or sodium hypophosphite. In some embodiments, the hydrogen source includes hydrogen gas. In some embodiments, the hydrogen source may be hydrogen gas.

[0399] The catalyst may be palladium hydroxide on carbon, palladium on carbon, or platinum oxide. In some embodiments, the catalyst includes palladium hydroxide on carbon. In some embodiments, the catalyst may be palladium hydroxide on carbon.

[0400] The acid may be a sulfonic acid (e.g., p-toluenesulfonic acid, methanesulfonic acid, or benzenesulfonic acid), a mineral acid (e.g., hydrochloric acid or sulfuric acid), or an organic acid (e.g., trifluoroacetic acid). In some embodiments, the acid may be p-toluenesulfonic acid. In some embodiments, the acid may be p-toluenesulfonic acid.

[0401] The fourth solvent may be an alcohol solvent (e.g., methanol, ethanol, or isopropanol), an organic acid solvent (e.g., acetic acid or formic acid), an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, or tert-butyl methyl ether), a polar aprotic solvent (e.g., N-methyl-2-pyrrolidone, N,N-dimethylformamide, or N,N-dimethylacetamide), or a combination thereof. In some embodiments, the fourth solvent includes ethanol. In some embodiments, the fourth solvent may be ethanol.

[0402] In some embodiments, the salt of (R)-2-amino-2-methylhexan-1-ol has Formula VIb: [ka] The compound may be:

[0403] Generally, the hydrogenation reaction (i.e., step 13) can be carried out at any suitable temperature, for example, a temperature between 0° C. and 85° C. In some embodiments, the reaction mixture of the hydrogenation reaction can be at a temperature between 20° C. and reflux. In some embodiments, the reaction mixture of the hydrogenation reaction can be heated to reflux.

[0404] 4. Preparation of salts of (R)-2-amino-2-methylhexan-1-ol, Route 4 In some embodiments, the present disclosure provides (R)-2-amino-2-methylhexan-1-ol: [ka] and a method for preparing a salt of This method is 1) Formula: [ka] C 1~4 alkyl alaninate imines, forming a first reaction mixture comprising an electrophile, a first base, a first catalyst, and a first solvent to produce a compound of the formula: [ka] C 1~4 forming an imine of alkyl (R)-2-amino-2-methylhexanoate; 2a)C 1~4 forming a second reaction mixture comprising the imine of alkyl (R)-2-amino-2-methylhexanoate, the first acid, and the second solvent to produce (R)-2-amino-2-methylhexanoate: [ka] forming a crude first salt of 2b) triturating the crude first salt of (R)-2-amino-2-methylhexanoate in a second solvent to provide a first salt of (R)-2-amino-2-methylhexanoate; 3a) forming a third reaction mixture comprising a first salt of (R)-2-amino-2-methylhexanoate, benzyl chloride, a second base, a third solvent, and water to produce a compound of the formula: [ka] forming a salt of (R)-2-benzamido-2-methylhexanoate having the formula: 3b) forming a fourth reaction mixture comprising a salt of (R)-2-benzamido-2-methylhexanoate, a second acid, a fourth solvent, and water to form (R)-2-benzamido-2-methylhexanoate; 4a) forming a fifth reaction mixture comprising (R)-2-benzamido-2-methylhexanoate, a first reducing agent, and a fifth solvent to produce a compound of the formula: [ka] (R)-N-(1-hydroxy-2-methylhexan-2-yl)benzamide having the formula or a salt thereof; 4b) forming a sixth reaction mixture comprising (R)-N-(1-hydroxy-2-methylhexan-2-yl)benzamide or a salt thereof, a second reducing agent, a second catalyst, a third acid, and a sixth solvent to provide a salt of (R)-2-amino-2-methylhexan-1-ol; wherein R can be unsubstituted or substituted aryl, or unsubstituted or substituted aryl -CH=CH-.

[0405] In some embodiments, (R)-2-amino-2-methylhexan-1-ol can be prepared according to steps 1-4 as shown in the scheme in FIG.

[0406] In some embodiments, C in any one of the formulas or compounds of step 1 1~4 Alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments, C in any one of the formulas or compounds of Step 1 1~4 Alkyl includes isopropyl. In some embodiments, C in any one of the formulas or compounds of Step 1 1~4 In some embodiments, the C alkyl in any one of the formulas or compounds of Step 1 can be isopropyl. 1~4 Alkyl includes tert-butyl. In some embodiments, C in any one of the formulas or compounds of Step 1 1~4 The alkyl may be tert-butyl.

[0407] C in step 1 1~4 Imines of alkylalaninates can be prepared according to methods described herein, for example, in Section F, Section 1, and Example 8.

[0408] Regarding step 1, C 1~4 an imine of alkyl alaninate, an electrophile, a first base, a first catalyst, a first solvent, C1~4 The alkyl (R)-2-amino-2-methylhexanoate imine and reaction temperatures are described herein.

[0409] In some embodiments, C 1~4 The imine of the alkylalaninate has the formula: [ka] and wherein R can be phenyl, 2-chlorophenyl, 4-chlorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-phenylvinyl, 2-(4-methylphenyl)vinyl, 2-(4-hydroxy-3-methoxyphenyl)vinyl, 2-methylphenyl, 4-methylphenyl, or 4-methoxyphenyl. In some embodiments, R includes 4-chlorophenyl. In some embodiments, C 1~4 The imine of the alkylalaninate has the formula: [ka] and may be a tert-butyl imine having the formula: wherein R can be phenyl, 2-chlorophenyl, 4-chlorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-phenylvinyl, 2-(4-methylphenyl)vinyl, 2-(4-hydroxy-3-methoxyphenyl)vinyl, 2-methylphenyl, 4-methylphenyl, or 4-methoxyphenyl. In some embodiments, R can be 4-chlorophenyl. In some embodiments, the imine of tert-butyl alaninato is tert-butyl 2-((4-chlorobenzylidene)amino)proline. Panoate: [ka] It may be. In some embodiments, the imine of tert-butyl alaninato can be a solution of tert-butyl 2-((4-chlorobenzylidene)amino)propanoate in toluene.

[0410] In some embodiments, the electrophile can be n-butyl bromide, n-butyl iodide, n-butyl methanesulfonate, n-butyl 4-methylbenzenesulfonate, or n-butyl sulfate. In some embodiments, the electrophile includes n-butyl bromide. In some embodiments, the electrophile can be n-butyl bromide.

[0411] The first base can be a hydroxide (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, rubidium hydroxide, barium hydroxide, calcium hydroxide, or tetra-n-butylammonium hydroxide), an alkoxide (e.g., sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, potassium isopropoxide, or sodium tert-pentoxide), a carbonate (e.g., sodium carbonate, potassium carbonate, rubidium carbonate, magnesium carbonate, calcium carbonate, strontium carbonate, barium carbonate, or ammonium carbonate), a hydride (e.g., sodium hydride or potassium hydride), or a combination thereof. In some embodiments, the first base includes potassium hydroxide and potassium carbonate. In some embodiments, the first base can be potassium hydroxide and potassium carbonate.

[0412] In some embodiments, the first catalyst can be a chiral auxiliary. In some embodiments, the first catalyst can be N-benzylcinchonidinium chloride, N-benzylcinchonidinium bromide, N-[4-(trifluoromethyl)benzyl]cinchoninium bromide, N-(9-anthracenylmethyl)cinchoninium chloride, (11bS)-(+)-4,4-dibutyl-4,5-dihydro-2,6-bis(3,4,5-trifluorophenyl)-3H-dinaphtho[2,1-c:1′,2′-e]azepinium bromide, (11bS)-4,4-dibutyl-4,5-dihydro-2,6-bis[3,5-bis(trifluoromethyl)phenyl]-3H-dinaphtho[2,1-c:1′,2′-e]phosphepinium bromide, or O-allyl-N-(9-anthracenylmethyl)cinchonidinium bromide. In some embodiments, the first catalyst includes N-benzylcinchonium chloride (BCNC). In some embodiments, the first catalyst can be N-benzylcinchonium chloride (BCNC).

[0413] In some embodiments, the first solvent is an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, methyl tert-butyl ether, or cyclopentyl methyl ether), a chlorinated solvent (e.g., dichloromethane, 1,2-dichloroethane, or chlorobenzene), an aromatic solvent (e.g., toluene, xylene, anisole, or trifluorotoluene), water, or a combination thereof. In some embodiments, the first solvent includes toluene. In some embodiments, the first solvent can be toluene.

[0414] In some embodiments, C 1~4 The imine of alkyl-2-amino-2-methylhexanoate has the formula: [ka] and wherein R can be phenyl, 2-chlorophenyl, 4-chlorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-phenylvinyl, 2-(4-methylphenyl)vinyl, 2-(4-hydroxy-3-methoxyphenyl)vinyl, 2-methylphenyl, 4-methylphenyl, or 4-methoxyphenyl. In some embodiments, R can be 4-chlorophenyl. In some embodiments, C 1~4 The imine of alkyl (R)-2-amino-2-methylhexanoate has the formula: [ka] and the imine of tert-butyl (R)-2-amino-2-methylhexanoate having the formula: wherein R can be phenyl, 2-chlorophenyl, 4-chlorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-phenylvinyl, 2-(4-methylphenyl)vinyl, 2-(4-hydroxy-3-methoxyphenyl)vinyl, 2-methylphenyl, 4-methylphenyl, or 4-methoxyphenyl. In some embodiments, R can be 4-chlorophenyl. In some embodiments, the imine of tert-butyl (R)-2-amino-2-methylhexanoate is tert-butyl (R)-2-(chlorobenzylideneamino)-2-methylhexanoate: [ka] It may be.

[0415] In some embodiments, C 1~4 Alkyl(R)-2-amino-2-methylhexanoate The imine of the ester can be used directly in a subsequent step after removing the first solvent. In some embodiments, once the alkylation reaction is complete, tert-butyl (R)-2-(chlorobenzylideneamino)-2-methylhexanoate can be used directly in a subsequent step after removing the first solvent.

[0416] In some embodiments, the first reaction mixture upon completion can be used directly in a subsequent step without removing the first solvent. In some embodiments, once the alkylation reaction is complete, the second reaction mixture comprising tert-butyl (R)-2-(chlorobenzylideneamino)-2-methylhexanoate and toluene can be used directly in a subsequent step without removing the solvent.

[0417] Generally, the alkylation reaction (i.e., step 1) can be carried out at any suitable temperature, for example, a temperature between −10° C. and 40° C. In some embodiments, the reaction mixture of the alkylation reaction can be at a temperature between 0° C. and 30° C.

[0418] In some embodiments, step 2 comprises two steps as described in steps 2a and 2b.

[0419] In some embodiments, with respect to steps 2a and 2b, C 1~4 The imine of alkyl (R)-2-amino-2-methylhexanoate, the first acid, the second solvent, the first salt of (R)-2-amino-2-methylhexanoate, and the reaction temperature are described herein.

[0420] In some embodiments, the imine can be the imine of tert-butyl (R)-2-amino-2-methylhexanoate. In some embodiments, the imine can be the imine of tert-butyl (R)-2-(chlorobenzylideneamino)-2-methylhexanoate. In some embodiments, the imine can be the reaction mixture of Step 1 comprising tert-butyl (R)-2-(chlorobenzylideneamino)-2-methylhexanoate and toluene.

[0421] In some embodiments, the first acid may be a mineral acid (e.g., hydrochloric acid, phosphoric acid, sulfuric acid, chlorosulfuric acid, or oleum), an organic acid (e.g., methanesulfonic acid, fumaric acid, acetic acid, formic acid, or ascorbic acid), or a combination thereof. In some embodiments, the first acid includes hydrochloric acid. In some embodiments, the first acid may be hydrochloric acid. In some embodiments, the first acid may be in an aqueous solution. In some embodiments, the first acid includes an aqueous solution of hydrochloric acid. In some embodiments, the first acid may be an aqueous solution of hydrochloric acid.

[0422] In some embodiments, the first salt of (R)-2-amino-2-methylhexanoate can be its hydrochloride salt.

[0423] In some embodiments, the second solvent can be an aromatic solvent (toluene, xylene, or trifluorotoluene), an ether (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, or 1,4-dioxane), a chlorinated solvent (e.g., dichloromethane or 1,2-dichloroethane), an alcohol (e.g., ethanol, 2-propanol, 1-butanol, tert-butanol, 2-methylbutan-2-ol, or trifluoroethanol), a hydrocarbon solvent (e.g., n-heptane, hexane, cyclohexane, or methylcyclohexane), or a combination thereof. In some embodiments, the second solvent includes 2-propanol. In some embodiments, the second solvent can be 2-propanol. In some embodiments, the second solvent can be 2-propanol. The second solvent may be toluene and 2-propanol.

[0424] In some embodiments, the crude (R)-2-amino-2-methylhexanoate first salt may be triturated with a second solvent to provide the (R)-2-amino-2-methylhexanoate first salt. In some embodiments, the crude (R)-2-amino-2-methylhexanoate first salt may be triturated with toluene to provide the (R)-2-amino-2-methylhexanoate first salt. In some embodiments, the crude (R)-2-amino-2-methylhexanoate hydrochloride may be triturated with toluene to provide the (R)-2-amino-2-methylhexanoate hydrochloride. In some embodiments, the (R)-2-amino-2-methylhexanoate first salt can be used directly in a subsequent step without purification. In some embodiments, the (R)-2-amino-2-methylhexanoate hydrochloride can be used directly in a subsequent step without purification.

[0425] Generally, the hydrolysis reaction (i.e., step 2a) can be carried out at any suitable temperature, for example, a temperature between 20°C and 80°C. In some embodiments, the reaction mixture of the hydrolysis reaction can be at a temperature between 50°C and 70°C. Generally, the trituration (i.e., step 2b) can be carried out at any suitable temperature, for example, a temperature between 10°C and 40°C. In some embodiments, the trituration can be at room temperature.

[0426] In some embodiments, step 3 comprises two steps as described in steps 3a and 3b.

[0427] In some embodiments, with respect to step 3a, the first salt of (R)-2-amino-2-methylhexanoate, the second base, the third solvent, the salt of (R)-2-benzamido-2-methylhexanoate, and the reaction temperature are described herein.

[0428] In some embodiments, the first salt of (R)-2-amino-2-methylhexanoate is its hydrochloride salt.

[0429] In some embodiments, the second base can be a hydroxide (e.g., lithium hydroxide, sodium hydroxide, cesium hydroxide, or tetra-n-butylammonium hydroxide), an alkoxide (e.g., sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, or sodium tert-pentoxide), a carbonate (e.g., sodium carbonate or potassium carbonate), a hydride (e.g., sodium hydride or potassium hydride), an amine (e.g., triethylamine, tri-n-butylamine, N,N'-diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine, pyridine, 2,6-lutidine, collidine, or 4-dimethylaminopyridine), or a combination thereof. In some embodiments, the second base can be in an aqueous solution. In some embodiments, the second base includes an aqueous solution of sodium hydroxide. In some embodiments, the second base can be an aqueous solution of sodium hydroxide.

[0430] In some embodiments, the third solvent may be an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, methyl tert-butyl ether, or cyclopentyl methyl ether), a chlorinated solvent (e.g., dichloromethane, 1,2-dichloroethane, or chlorobenzene), an aromatic solvent (e.g., toluene, xylene, anisole, or trifluorotoluene), water, or a combination thereof. In some embodiments, the third solvent includes water. In some embodiments, the third solvent may be water.

[0431] In some embodiments, the salt of (R)-2-benzamido-2-methylhexanoate can be its sodium salt. In some embodiments, the sodium salt of (R)-2-benzamido-2-methylhexanoate can be used directly without purification.

[0432] Generally, the protection reaction (i.e., step 3a) can be carried out at any suitable temperature, for example, a temperature between −10° C. and 50° C. In some embodiments, the reaction mixture for the protection reaction can be at a temperature between 0° C. and 30° C.

[0433] In some embodiments, for step 3b, the salt of (R)-2-benzamido-2-methylhexanoate, the second acid, the fourth solvent, and the reaction temperature are described herein.

[0434] In some embodiments, the salt of (R)-2-benzamido-2-methylhexanoate is the sodium salt thereof.

[0435] In some embodiments, the second acid may be a mineral acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, or sulfuric acid), an organic acid (e.g., trichloroacetic acid or formic acid), or a combination thereof. In some embodiments, the second acid may be in an aqueous solution. In some embodiments, the second acid includes an aqueous solution of hydrochloric acid. In some embodiments, the second acid may be an aqueous solution of hydrochloric acid.

[0436] In some embodiments, the fourth solvent can be an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, methyl tert-butyl ether, or cyclopentyl methyl ether), a chlorinated solvent (e.g., dichloromethane, 1,2-dichloroethane, or chlorobenzene), an aromatic solvent (toluene, xylene, anisole, or trifluorotoluene), an alcohol (e.g., 2-propanol, 2-butanol, tert-butanol, 2-methylbutan-2-ol, 2,2,2-trifluoroethanol, or hexafluoro-2-propanol), a ketone (methyl isobutyl ketone or methyl ethyl ketone), an ester (e.g., isopropyl acetate or n-butyl acetate), water, or a combination thereof. In some embodiments, the fourth solvent includes water. In some embodiments, the fourth solvent can be water.

[0437] Generally, the acidification reaction (i.e., step 3b) can be carried out at any suitable temperature, for example, a temperature between −10° C. and 50° C. In some embodiments, the reaction mixture of the acidification reaction can be at a temperature between 0° C. and 30° C.

[0438] In some embodiments, step 4 comprises two steps as described in steps 4a and 4b.

[0439] In some embodiments, for step 4a, the first reducing agent, the fifth solvent, and the reaction temperature are described herein.

[0440] In some embodiments, the first reducing agent can be any suitable reducing agent capable of reducing an ester group (e.g., an isopropyl ester) to the corresponding -CHOH. In some embodiments, the first reducing agent can be diborane, borane tetrahydrofuran complex, borane dimethyl sulfide complex, borane decyl methyl sulfide complex, borane dimethylamine complex, borane ammonia complex, borane pyridine complex, borane trimethylamine complex, The first reducing agent may be borane N,N-diethylaniline complex, borane morpholine complex, borane methyl 6-morpholinohexyl sulfide complex, borane diphenylphosphine complex, sodium borohydride / boron trifluoride, lithium aluminum hydride, aluminum hydride, or diisobutylaluminum hydride. In some embodiments, the first reducing agent includes borane tetrahydrofuran complex. In some embodiments, the first reducing agent may be borane tetrahydrofuran complex.

[0441] In some embodiments, the fifth solvent can be an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, methyl tert-butyl ether, or diethyl ether), an aromatic solvent (e.g., toluene, xylene, or trifluorotoluene), a hydrocarbon solvent (e.g., n-hexane, n-heptane, or cyclohexane), or a combination thereof. In some embodiments, the fifth solvent includes tetrahydrofuran. In some embodiments, the fifth solvent can be tetrahydrofuran.

[0442] Generally, the reduction reaction (i.e., step 4a) can be carried out at any suitable temperature, for example, a temperature between −40° C. and 80° C. In some embodiments, the reaction mixture of the reduction reaction can be at a temperature between 25° C. and 65° C.

[0443] In some embodiments, for step 4b, the second reducing agent, the second catalyst, the third acid, the sixth solvent, the salt of (R)-2-amino-2-methylhexan-1-ol, and the reaction temperature are described herein.

[0444] In some embodiments, the second reducing agent may be hydrogen gas, formic acid, ammonium formate, cyclohexene, hydrazine, sodium hypophosphite, or a combination thereof. In some embodiments, the second reducing agent includes hydrogen gas. In some embodiments, the second reducing agent may be hydrogen gas.

[0445] In some embodiments, the second catalyst may be a palladium catalyst. In some embodiments, the second catalyst may be palladium hydroxide on carbon, palladium on carbon, platinum on carbon, or platinum oxide. In some embodiments, the second catalyst includes palladium hydroxide on carbon. In some embodiments, the second catalyst may be palladium hydroxide on carbon.

[0446] In some embodiments, the third acid can be a sulfonic acid (e.g., para-toluenesulfonic acid, methanesulfonic acid, or benzenesulfonic acid), a mineral acid (e.g., hydrochloric acid or sulfuric acid), or an organic acid (e.g., trifluoroacetic acid). In some embodiments, the third acid includes para-toluenesulfonic acid. In some embodiments, the third acid can be para-toluenesulfonic acid.

[0447] In some embodiments, the sixth solvent can be an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, methyl tert-butyl ether, or cyclopentyl methyl ether), a chlorinated solvent (e.g., dichloromethane, 1,2-dichloroethane, or chlorobenzene), an aromatic solvent (toluene, xylene, anisole, or trifluorotoluene), an alcohol (e.g., ethanol, 2-propanol, 2-butanol, tert-butanol, 2-methylbutan-2-ol, 2,2,2-trifluoroethanol, or hexafluoro-2-propanol), a ketone (e.g., methyl isobutyl ketone or methyl ethyl ketone), an ester (e.g., isopropyl acetate or n-butyl acetate), or a combination thereof. In some embodiments, the sixth solvent includes ethanol. In some embodiments, the sixth solvent may be ethanol.

[0448] In some embodiments, the salt of (R)-2-amino-2-methylhexan-1-ol has Formula VIb: [ka] The compound may be:

[0449] Generally, the Bz deprotection reaction (i.e., step 4b) can be carried out at any suitable temperature, for example, a temperature between 0° C. and 85° C. In some embodiments, the reaction mixture of the Bz deprotection reaction can be at a temperature between 20° C. and 80° C.

[0450] Alternatively, in some embodiments, the Bz deprotection reaction of step 4b can be achieved using lead tetraacetate or sodium periodate with bromine.

[0451] 5. Preparation of salts of (R)-2-amino-2-methylhexan-1-ol, Route 5 In some embodiments, the present disclosure provides (R)-2-amino-2-methylhexan-1-ol: [ka] and a method for preparing a salt of This method is 1) (R)-2-amino-2-methylhexanoate: [ka] The first salt, forming a first reaction mixture comprising a reducing agent and a first solvent to form a compound of the formula: [ka] forming (R)-2-amino-2-methylhexan-1-ol having the formula: 2) forming a second reaction mixture comprising (R)-2-amino-2-methylhexan-1-ol, an acid, and a second solvent to provide a salt of (R)-2-amino-2-methylhexan-1-ol.

[0452] In some embodiments, (R)-2-amino-2-methylhexan-1-ol can be prepared according to steps 1 and 2 as shown in the scheme in FIG.

[0453] In some embodiments, for Step 1, the first salt of (R)-2-amino-2-methylhexanoate, the reducing agent, the first solvent, and the reaction temperature are described herein.

[0454] In some embodiments, the first salt of (R)-2-amino-2-methylhexanoate is its hydrochloride salt.

[0455] In some embodiments, the reducing agent can be any suitable reducing agent capable of reducing an ester group (e.g., an isopropyl ester) to the corresponding —CHOH. In some embodiments, the reducing agent can be diborane, borane dimethyl sulfide complex, borane decyl methyl sulfide complex, borane dimethylamine complex, borane ammonia complex, borane pyridine complex, borane trimethylamine complex, borane N,N-diethylaniline complex, borane morpholine complex, borane methyl 6-morpholinohexyl sulfide complex, sodium borohydride / boron trifluoride, diisobutylaluminum hydride, or lithium aluminum hydride. In some embodiments, the reducing agent includes lithium aluminum hydride. In some embodiments, the reducing agent can be lithium aluminum hydride.

[0456] In some embodiments, the first solvent may be an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, methyl tert-butyl ether, or diethyl ether), an aromatic solvent (e.g., toluene, xylene, or trifluorotoluene), a hydrocarbon solvent (e.g., n-hexane, n-heptane, or cyclohexane), or a combination thereof. In some embodiments, the first solvent includes tetrahydrofuran. In some embodiments, the first solvent may be tetrahydrofuran.

[0457] Generally, the reduction reaction (i.e., step 1) can be carried out at any suitable temperature, for example, a temperature between 0° C. and 40° C. In some embodiments, the reaction mixture of the reduction reaction can be at a temperature between 10° C. and 20° C.

[0458] In some embodiments, for Step 2, the acid, second solvent, salt of (R)-2-amino-2-methylhexan-1-ol, and reaction temperature are described herein.

[0459] In some embodiments, the acid can be a sulfonic acid (e.g., para-toluenesulfonic acid, methanesulfonic acid, or benzenesulfonic acid), a mineral acid (e.g., hydrochloric acid or sulfuric acid), an organic acid (e.g., trifluoroacetic acid), or a combination thereof. In some embodiments, the acid includes para-toluenesulfonic acid. In some embodiments, the acid can be para-toluenesulfonic acid.

[0460] In some embodiments, the second solvent can be an alcohol (methanol, ethanol, n-propanol, or n-butanol), an ether (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, or 1,2-dimethoxyethane), an aromatic solvent (e.g., toluene, xylene, fluorobenzene, or trifluorotoluene), a chlorinated solvent (e.g., dichloromethane or 1,2-dichloroethane), a ketone (e.g., acetone or methyl isobutyl ketone), an ester (e.g., ethyl acetate, butyl acetate, or isobutyl acetate), or a combination thereof. In some embodiments, the second solvent includes ethanol. In some embodiments, the second solvent can be ethanol.

[0461] In some embodiments, the salt of (R)-2-amino-2-methylhexan-1-ol has Formula VIb: [ka] The compound may be:

[0462] Generally, the acidification reaction (i.e., step 2) can be carried out at any suitable temperature, for example, a temperature between 0° C. and 100° C. In some embodiments, the reaction mixture of the acidification reaction can be at a temperature between 15° C. and 30° C.

[0463] 6. Preparation of salts of (R)-2-amino-2-methylhexan-1-ol, Route 6 In some embodiments, the present disclosure provides (R)-2-amino-2-methylhexan-1-ol: [ka] and a method for preparing a salt of This method is 1) Formula: [ka] (2S,4R)-3-benzoyl-4-methyl-2-phenyloxazolidin-5-one having the formula or a salt thereof, an electrophile, a base, and a first solvent to form a first reaction mixture comprising: [ka] (2S,4R)-3-benzoyl-4-butyl-4-methyl-2-phenyloxazolidin-5-one having the formula or a salt thereof; 2) forming a second reaction mixture comprising (2S,4R)-3-benzoyl-4-butyl-4-methyl-2-phenyloxazolidin-5-one or a salt thereof, an acid, and optionally a second solvent to form a salt of (R)-2-amino-2-methylhexan-1-ol.

[0464] In some embodiments, (R)-2-amino-2-methylhexan-1-ol can be prepared according to steps 1 and 2 as shown in the scheme in FIG.

[0465] In some embodiments, for Step 1, the electrophile, base, first solvent, and reaction temperature are described herein.

[0466] In some embodiments, the electrophile can be n-butyl bromide, n-butyl iodide, n-butyl methanesulfonate, n-butyl 4-methylbenzenesulfonate, or n-butyl sulfate. In some embodiments, the electrophile includes n-butyl iodide. In some embodiments, the electrophile can be n-butyl iodide.

[0467] In some embodiments, the base can be lithium diisopropylamide, lithium diethylamide, lithium dicyclohexylamide, lithium dimethylamide, lithium 2,2,6,6-tetramethylpiperidide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, or sodium hydride. In some embodiments, the base includes lithium bis(trimethylsilyl)amide. In some embodiments, the base can be lithium bis(trimethylsilyl)amide.

[0468] In some embodiments, the first solvent can be an aromatic solvent (e.g., toluene, xylene, chlorobenzene, fluorobenzene, or trifluorotoluene), an ether (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, or 1,4-dioxane), a chlorinated solvent (e.g., dichloromethane or chlorobenzene), or a combination thereof. In some embodiments, the first solvent includes tetrahydrofuran. In some embodiments, the first solvent can be tetrahydrofuran.

[0469] Generally, the alkylation reaction (i.e., step 1) can be carried out at any suitable temperature, for example, a temperature between −100° C. and 0° C. In some embodiments, the reaction mixture of the alkylation reaction can be at a temperature between −78° C. and −50° C.

[0470] In some embodiments, the alkylation reaction of step 1 may also include an additive. Suitable additives include, but are not limited to, hexamethylphosphoramide, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, and 1,3-dimethyl-2-imidazolidinone.

[0471] In some embodiments, for Step 2, the acid, second solvent, salt of (R)-2-amino-2-methylhexan-1-ol, and reaction temperature are described herein.

[0472] In some embodiments, the acid can be a mineral acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid), a sulfonic acid (e.g., para-toluenesulfonic acid, methanesulfonic acid, or benzenesulfonic acid), an organic acid (e.g., trifluoroacetic acid). In some embodiments, the acid includes hydrochloric acid. In some embodiments, the acid includes an aqueous solution of hydrochloric acid. In some embodiments, the acid can be hydrochloric acid. In some embodiments, the acid can be an aqueous solution of hydrochloric acid.

[0473] In some embodiments, the second solvent is absent. In some embodiments, the second solvent, if present, is an alcohol (e.g., methanol, ethanol, or 2-propanol), an ether (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, or 1,2-dimethoxyethane), an aromatic solvent (toluene, xylene, fluorobenzene, or trifluorotoluene), a chlorinated solvent (e.g., dichloromethane or 1,2-dichloroethane), an ester (e.g., ethyl acetate, butyl acetate, or isobutyl acetate), water, or a combination thereof. In some embodiments, the second solvent includes water. In some embodiments, the second solvent may be water.

[0474] In some embodiments, the salt of (R)-2-amino-2-methylhexan-1-ol has Formula VIb: [ka] The compound may be:

[0475] In some embodiments, the salt of (R)-2-amino-2-methylhexan-1-ol has the formula: [ka] The compound may be:

[0476] Generally, the hydrolysis reaction (i.e., step 2) can be carried out at any suitable temperature, for example, a temperature between 0° C. and 120° C. In some embodiments, the reaction mixture of the hydrolysis reaction can be at a temperature between 60° C. and 100° C.

[0477] 7. Preparation of Compounds of Formula VIIIb, Route 1 In some embodiments, the present disclosure provides a compound of formula IIIb: [ka] or a salt thereof, the method comprising: 14) Forming a first reaction mixture comprising 2,3-dibromo-5-fluoropyridine or a salt thereof, a first iodination reagent, an additive, and a first solvent to produce 3-bromo-5-fluoro-2-iodopyridine: [ka] or forming a salt thereof, or 17) forming a second reaction mixture comprising 2,3-dibromo-5-fluoropyridine or a salt thereof, a second iodination reagent, a catalyst, a first ligand, and a second solvent to form 3-bromo-5-fluoro-2-iodopyridine or a salt thereof; 15) 3-Bromo-5-fluoro-2-iodopyridine or a salt thereof and a cyanating reagent forming a third reaction mixture comprising a second ligand and a third solvent to produce 3-bromo-5-fluoropicolinonitrile: [ka] or a salt thereof; 16) forming a fourth reaction mixture comprising 3-bromo-5-fluoropicolinonitrile or a salt thereof, an acid, and a fourth solvent to provide a compound of Formula VIIIb or a salt thereof; or forming a fifth reaction mixture comprising 3-bromo-5-fluoropicolinonitrile or a salt thereof, an enzyme, and a fifth solvent to provide a compound of Formula VIIIb or a salt thereof.

[0478] In some embodiments, compounds of Formula VIIIb can be prepared according to steps 14-16 as shown in the scheme of Figure 5A. In some embodiments, compounds of Formula VIIIb can be prepared according to step 17 as shown in the scheme of Figure 5B and according to steps 15-16 as shown in the scheme of Figure 5A.

[0479] For step 14, the first iodination reagent, additive, first solvent, and reaction temperature are described herein.

[0480] The first iodination reagent may be sodium iodide, lithium iodide, potassium iodide, cesium iodide, zinc iodide, magnesium iodide, copper(I) iodide, hydroiodic acid, trimethylsilyl iodide, or iodine. In some embodiments, the first iodination reagent includes sodium iodide. In some embodiments, the first iodination reagent may be sodium iodide.

[0481] The additive may be water, trimethylsilyl chloride, an ammonium salt (e.g., tetra-n-butylammonium iodide), 2,6-di-tert-butylpyridine, 2,6-di-tert-butyl-4-methylphenol, trimethylsilyl trifluoromethanesulfonate, an organic acid (e.g., acetic acid, formic acid, trichloroacetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or methanesulfonic acid), a mineral acid (e.g., hydrochloric acid or sulfuric acid), a dehydrating agent (e.g., bis(trimethylsilyl)acetamide, acetyl chloride, or triethyl orthoformate), or a combination thereof. In some embodiments, the additive includes trimethylsilyl chloride and water. In some embodiments, the additive may be trimethylsilyl chloride and water.

[0482] The first solvent may be an ester (e.g., ethyl acetate, butyl acetate, isopropyl acetate, or isobutyl acetate), an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, or methyl tert-butyl ether), a polar aprotic solvent (e.g., acetonitrile, propionitrile, benzonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, or sulfolane), an aromatic solvent (e.g., toluene, trifluorotoluene, benzene, or xylene), an organic acid solvent (e.g., acetic acid or formic acid), or a combination thereof. In some embodiments, the first solvent includes acetonitrile. In some embodiments, the first solvent may be acetonitrile.

[0483] Generally, the halogen exchange reaction (i.e., step 14) can be carried out at any suitable temperature, for example, a temperature between 20° C. and 110° C. In some embodiments, the reaction mixture of the halogen exchange reaction can be at a temperature between 20° C. and reflux. In some embodiments, the reaction mixture of the halogen exchange reaction can be heated to reflux.

[0484] In some embodiments, the halogen exchange reaction of step 14 can be replaced with a halogen exchange reaction of step 17. For step 17, the second iodination reagent, catalyst, first ligand, second solvent, and reaction temperature are described herein.

[0485] The second iodination reagent may be sodium iodide, lithium iodide, potassium iodide, cesium iodide, zinc iodide, or magnesium iodide. In some embodiments, the second iodination reagent includes sodium iodide. In some embodiments, the second iodination reagent may be sodium iodide.

[0486] The catalyst may be copper(I) iodide, copper(II) iodide, copper(I) bromide, or copper(II) bromide. In some embodiments, the catalyst includes copper(I) iodide. In some embodiments, the catalyst may be copper(I) iodide.

[0487] The first ligand can be trans-N,N'-dimethylcyclohexane-1,2-diamine (DMCHDA), N,N,N',N'-tetramethylethylenediamine, or N,N'-dimethylethylenediamine. In some embodiments, the first ligand includes trans-N,N'-dimethylcyclohexane-1,2-diamine. In some embodiments, the first ligand can be trans-N,N'-dimethylcyclohexane-1,2-diamine.

[0488] The second solvent may be an ether (e.g., 1,4-dioxane or cyclopentyl methyl ether), an alcohol solvent (e.g., n-butanol, 1-hexanol, 2-methylbutan-2-ol, or isopropanol), a polar aprotic solvent (e.g., benzonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, or sulfolane), an aromatic solvent (e.g., toluene, trifluorotoluene, benzene, or xylene), or a combination thereof. In some embodiments, the second solvent includes n-butanol. In some embodiments, the second solvent may be n-butanol.

[0489] Generally, the halogen exchange reaction (i.e., step 17) can be carried out at any suitable temperature, for example, a temperature between 50° C. and 150° C. In some embodiments, the reaction mixture of the hydrolysis reaction can be at a temperature between 80° C. and reflux temperature.

[0490] For step 15, the cyanating reagent, second ligand, third solvent, and reaction temperature are described herein.

[0491] The cyanation reagent may be copper(I) cyanide, sodium cyanide, potassium cyanide, or trimethylsilyl cyanide. In some embodiments, the cyanation reagent includes copper(I) cyanide. In some embodiments, the cyanation reagent may be copper(I) cyanide.

[0492] The second ligand may be absent or present. When present, the second ligand may be selected from the group consisting of 1,10-phenanthroline, 3,4,7,8-tetramethyl-1,10-phenanthroline, 4,7-dichloro-1,10-phenanthroline, 4,7-dimethoxy-1,10-phenanthroline, trans-1,2-diaminocyclohexane, It may be N,N'-dimethyl-1,2-cyclohexanediamine, 4-dimethylaminopyridine, 8-hydroxyquinoline, tetramethylethylenediamine, 1-proline, 1-butylimidazole, or 2-isobutylcyclohexanone. In some embodiments, the second ligand may be absent.

[0493] The third solvent may be an ester (e.g., butyl acetate, isopropyl acetate, or isobutyl acetate), an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, or cyclopentyl methyl ether), an alcohol solvent (e.g., n-butanol, 2-methylbutan-2-ol, or isopropanol), a polar aprotic solvent (e.g., acetonitrile, propionitrile, benzonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, or sulfolane), an aromatic solvent (e.g., toluene, benzene, xylene, or trifluorotoluene), a chlorinated solvent (dichloromethane, 1,2-dichloroethane, chlorobenzene, or chloroform), or a combination thereof. In some embodiments, the third solvent includes acetonitrile. In some embodiments, the third solvent may be acetonitrile.

[0494] Generally, the cyanation reaction (i.e., step 15) can be carried out at any suitable temperature, for example, a temperature between 20° C. and 120° C. In some embodiments, the reaction mixture of the cyanation reaction can be at a temperature between 20° C. and reflux. In some embodiments, the reaction mixture of the cyanation reaction can be heated to reflux.

[0495] For step 16, the acid, fourth solvent, enzyme, and fifth solvent, and reaction temperature are described herein.

[0496] The acid may be sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, chloric acid, perchloric acid, nitric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, or phthalic acid. In some embodiments, the acid includes sulfuric acid. In some embodiments, the acid may be sulfuric acid.

[0497] The fourth solvent may be water, an alcohol (e.g., methanol, ethanol, n-propanol, or isopropanol), or a combination thereof. In some embodiments, the fourth solvent includes water. In some embodiments, the fourth solvent may be water.

[0498] The acid hydrolysis reaction in step 16 can be replaced with an enzymatic hydrolysis reaction. In some embodiments, the enzyme includes a nitrilase enzyme. The enzymatic hydrolysis reaction can be carried out in an aqueous buffer with and without the addition of an organic co-solvent. In some embodiments, the fifth solvent includes an aqueous buffer. In some embodiments, the fifth solvent includes an aqueous buffer and an organic co-solvent. The organic co-solvent can be an alcohol (e.g., methanol, ethanol, n-propanol, or isopropanol).

[0499] In some embodiments, the enzyme can be a nitrilase enzyme. In some embodiments, the fifth solvent can be an aqueous buffer solution. In some embodiments, the fifth solvent can be an aqueous buffer solution and an organic co-solvent. The organic co-solvent can be an alcohol (e.g., methanol, ethanol, n-propanol, or isopropanol).

[0500] Generally, the hydrolysis reaction (i.e., step 16) can be carried out at any suitable temperature, for example, a temperature between 20° C. and 120° C. In some embodiments, the reaction mixture of the hydrolysis reaction The temperature may be between 20°C and 100°C.

[0501] 8. Preparation of Compounds of Formula VIIIb, Route 2 In some embodiments, the present disclosure provides a compound of formula IIIb: [ka] or a salt thereof, the method comprising: 18a) forming a first reaction mixture comprising 5-fluoropicolinic acid or a salt thereof, an activator, a promoter, and a first solvent to activate the —C(O)OH group of 5-fluoropicolinic acid, thereby forming an activated form of 5-fluoropicolinic acid or a salt thereof; 18b) Active 5-fluoropicolinic acid or a salt thereof and R 6 R 7 forming a second reaction mixture comprising an amine of NH, a first base, and a second solvent to form a compound of formula XIII: [ka] or a salt thereof; and 19) forming a third reaction mixture comprising a compound of formula XIII or a salt thereof, a brominating agent, a second base, an additive, and a third solvent to produce a compound of formula XIIb: [ka] or a salt thereof; and 20) forming a fourth reaction mixture comprising the compound of Formula XIIb or a salt thereof, an acid, and a fourth solvent to provide a compound of Formula VIIIb or a salt thereof; In the formula, R 6 and R 7 are each independently hydrogen, C 1~4 Alkyl or C 3~6 cycloalkyl or R 6 and R 7 may be combined to form a 3-6 membered N-linked heterocycloalkyl, optionally having 1-2 additional heteroatoms selected from O and S.

[0502] In some embodiments, the compound of Formula VIIIb or a salt thereof can be prepared according to steps 18-20 as shown in the scheme of FIG.

[0503] Step 18 includes steps 18a and 18b.

[0504] For step 18a, the activator, promoter, first solvent, activated 5-fluoropicolinic acid, and reaction temperature are described herein. For step 18b, R 6 R 7 The NH amine, the first base, the second solvent, the compound of formula XIII, and the reaction temperatures are described herein.

[0505] The activating agent may be a chlorinating agent. In some embodiments, the chlorinating agent may be oxalyl chloride, thionyl chloride, phosphorus(V) oxychloride, phosphorus(V) pentachloride, or (chloromethylene)dimethyliminium chloride. In some embodiments, the activating (or chlorinating) agent includes oxalyl chloride. In some embodiments, the activated form of 5-fluoropicolinic acid may be 5-fluoropicolinoyl chloride.

[0506] The activating agent can be any peptide coupling reagent that can activate an acid group (e.g., the acid group of 5-fluoropicolinic acid) and thereby react with an amine (e.g., the amine of step 18b) to form an amide bond (e.g., the amide group of Formula XIII). In some embodiments, the activating agent can be 1,1'-carbonyldiimidazole or isobutyl chloroformate. In some embodiments, the activated form of 5-fluoropicolinic acid can be (5-fluoropyridin-2-yl)(1H-imidazol-1-yl)methanone or 5-fluoropicoline (isobutylcarbon) anhydride.

[0507] The promoter may be N,N-dimethylformamide, N,N-dimethylacetamide, or dichloromethylene-dimethyliminium chloride. In some embodiments, the promoter includes N,N-dimethylformamide. In some embodiments, the promoter may be N,N-dimethylformamide.

[0508] R 6 R 7 The amine of NH can be a primary amine (e.g., ethylamine, isopropylamine, tert-butylamine, or cyclohexylamine) or a secondary amine (e.g., diethylamine or morpholine). In some embodiments, R 6 R 7 The amine of NH may be tert-butylamine.

[0509] The first base may be absent or present. When a base is present, the base may be a tertiary amine (e.g., triethylamine, N,N-diisopropylethylamine, N-methylpyrrolidine, or N-methylmorpholine), an aromatic amine base (e.g., pyridine), or an inorganic base (e.g., sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, cesium carbonate, or tribasic potassium phosphate). In some embodiments, the first base may not be present.

[0510] The first and second solvents may be an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, or 1,4-dioxane), a chlorinated solvent (e.g., dichloromethane, chloroform, or 1,2-dichloroethane), an aromatic solvent (e.g., benzene, toluene, or xylene), or a combination thereof. In some embodiments, the first solvent includes 2-methyltetrahydrofuran. In some embodiments, the second solvent includes 2-methyltetrahydrofuran. The second reaction mixture (i.e., step 18b) may further include water and have a biphasic reaction. In some embodiments, the first solvent may be 2-methyltetrahydrofuran. In some embodiments, the second solvent may be 2-methyltetrahydrofuran. The second reaction mixture (i.e., step 18b) may further include water and have a biphasic reaction.

[0511] R 6 R 7 For amines of NH or compounds of formula XIII, R 6 and R 7 is as defined and explained herein.

[0512] In some embodiments, R 6 is hydrogen or C 1~4 It may be alkyl. 1~4 Alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments, R 6 may be hydrogen or ethyl. In some embodiments, R 6 may be hydrogen. In some embodiments, R 6 may be ethyl.

[0513] In some embodiments, R 7 is C 1~4 Alkyl or C 3~6 It may be cycloalkyl. 1~4Alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. 3~6 Cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 7 may be ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, or cyclohexyl. 7 may be ethyl, isopropyl, tert-butyl, or cyclohexyl. In some embodiments, R 7 may be tert-butyl.

[0514] In some embodiments, R 6 may be hydrogen, and R 7 is C 1~4 Alkyl, or C 3~6 In some embodiments, R 6 may be hydrogen, and R 7 may be ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, or cyclohexyl. 6 may be hydrogen, and R 7 may be ethyl, isopropyl, tert-butyl, or cyclohexyl. In some embodiments, R 6 may be hydrogen, and R 7 may be tert-butyl. In some embodiments, R 6 may be ethyl, R 7 is C 1~4 In some embodiments, R 6 and R 7 may each be ethyl.

[0515] In some embodiments, R 6 and R 7 may be combined to form an N-linked morpholinyl.

[0516] In some embodiments, the compound of formula XIII has the formula: [ka] N-(tert-butyl)-5-fluoropicolinamide having the formula or a salt thereof.

[0517] In some embodiments, N-(tert-butyl)-5-fluoropicolinamide is isolated as a solution in methylcyclohexane and can be used directly in a subsequent step without purification and / or removal of methylcyclohexane. In some embodiments, N-(tert-butyl)-5-fluoropicolinamide is isolated as a solution in 1,4-dioxane and can be used directly in a subsequent step without purification and / or removal of 1,4-dioxane. In some embodiments, N-(tert-butyl)-5-fluoropicolinamide is isolated as a solution in methylcyclopentyl ether and can be used directly in a subsequent step without purification and / or removal of methylcyclopentyl ether.

[0518] Generally, the reactions of steps 18a and 18b can be carried out at any suitable temperature, for example, a temperature between 5° C. and 60° C. In some embodiments, the reaction mixtures of both steps 18a and 18b can be at a temperature between 15° C. and 30° C.

[0519] Step 19 comprises steps 19a and 19b, where step 19a comprises a metallation step and step 19b comprises a bromination step.

[0520] For Step 19, the brominating agent, second base, additive, third solvent, compound of Formula XIIb, and reaction temperature are described herein.

[0521] In some embodiments, the compound of Formula XIII can be N-(tert-butyl)-5-fluoropicolinamide or a salt thereof. In some embodiments, N-(tert-butyl)-5-fluoropicolinamide or a salt thereof can be a solution thereof in methylcyclohexane. In some embodiments, N-(tert-butyl)-5-fluoropicolinamide or a salt thereof can be a solution thereof in 1,4-dioxane. In some embodiments, N-(tert-butyl)-5-fluoropicolinamide or a salt thereof can be a solution thereof in methylcyclopentyl ether.

[0522] The brominating agent may be bromine, N-bromosuccinimide, triphenylphosphine dibromide, tetrabutylammonium tribromide, trimethylphenylammonium tribromide, N-bromoacetamide, pyridinium tribromide, dibromodimethylhydantoin, tribromoisocyanuric acid, N-bromosaccharin, or 1,2-dibromo-1,1,2,2-tetrachloroethane. In some embodiments, the brominating agent includes bromine. In some embodiments, the brominating agent may be bromine.

[0523] The second base may be a metal amide base (e.g., lithium diisopropylamide, 2,2,6,6-tetramethylpiperidinyl magnesium chloride, lithium 2,2,6,6-tetramethylpiperidide, bis(2,2,6,6-tetramethylpiperidinyl)magnesium, or di-n-butyllithium (2,2,6,6-tetramethylpiperidinyl)magnesate), alkyl and alkenyl metals (n-butyllithium, isopropyl magnesium chloride, tri-n-butyllithium magnesate, di-n-butylmagnesium, ethyl n-butylmagnesium, or di-sec-butylmagnesium). In some embodiments, the base includes n-butylmagnesium. In some embodiments, the base may be n-butylmagnesium.

[0524] The additive may be absent or present. If present, the additive may be lithium chloride, lanthanum(III) chloride, N,N'-dimethylpropylene urea, N,N,N',N'-tetramethylethylenediamine, or hexamethylphosphoramide. In some embodiments, the additive may be absent.

[0525] The third solvent may be an ether (tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, methylcyclopentyl ether, or 1,4-dioxane), a non-polar solvent (e.g., cyclohexane, methylcyclohexane, or n-heptane), an aromatic solvent (e.g., benzene, toluene, or xylene), a chlorinated solvent (e.g., dichloromethane, 1,2-dichloroethane, or chlorobenzene), or a combination thereof. In some embodiments, the third solvent includes methylcyclohexane. In some embodiments, the third solvent may be methylcyclohexane.

[0526] For compounds of formula XIIb, R 6 and R 7 is defined and described herein (see also Section IV, Compounds of Formula XII). In some embodiments, R 6 may be hydrogen, and R 7 may be ethyl, isopropyl, tert-butyl, or cyclohexyl. In some embodiments, R 6 may be hydrogen, and R 7 tert In some embodiments, R 6 may be ethyl, R 7 is C 1~4 In some embodiments, R 6 and R 7 and R may each be ethyl. 6 and R 7 may be combined to form an N-linked morpholinyl.

[0527] In some embodiments, the compound of Formula XIIb has Formula XIIc: [ka] or a salt thereof.

[0528] Generally, the metallation step (i.e., step 19a) in the bromination reaction (i.e., step 19) can be carried out at any suitable temperature, for example, from room temperature to reflux. In some embodiments, the reaction mixture of the metallation step in the bromination reaction can be at a temperature of 30°C to 80°C. Generally, the bromination step (i.e., step 19b) in the bromination reaction (i.e., step 19) can be carried out at any suitable temperature, for example, from -40°C to 0°C. In some embodiments, the reaction mixture of the bromination step in the bromination reaction can be at a temperature of -40°C to -15°C.

[0529] For step 20, the acid, fourth solvent, and reaction temperature are described herein.

[0530] The acid may be sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, chloric acid, perchloric acid, nitric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, or phthalic acid. In some embodiments, the acid includes sulfuric acid. In some embodiments, the acid may be sulfuric acid.

[0531] The fourth solvent may be water. In some embodiments, the solvent includes water.

[0532] Generally, the hydrolysis reaction (i.e., step 20) can be carried out at any suitable temperature, for example, a temperature between 20° C. and 100° C. In some embodiments, the reaction mixture of the hydrolysis reaction can be at a temperature between 50° C. and 100° C.

[0533] 9. Preparation of Compounds of Formula XIb, Route 1 In some embodiments, the present disclosure provides a compound of formula XIb: [ka] or a salt thereof, the method comprising: 21) Forming a first reaction mixture comprising 2-bromo-5-fluoropyridin-3-amine or a salt thereof, a cyanide source, a catalyst, and a first solvent to produce 3-amino-5-fluoropicolinonitrile: [ka] or a salt thereof; 22) forming a second reaction mixture comprising 3-amino-5-fluoropicolinonitrile or a salt thereof, carbon dioxide, a first base, and a second solvent to produce 7-fluoropyrido[3,2-d]pyrimidine-2,4-diol: [ka] or a salt thereof; 23) forming a third reaction mixture comprising 7-fluoropyrido[3,2-d]pyrimidine-2,4-diol, a chlorinating agent, a second base, and a third solvent to form a compound of formula XIb or a salt thereof.

[0534] In some embodiments, compounds of formula XIb can be prepared according to steps 21-23 as shown in the scheme in Figure 7A.

[0535] For step 21, the cyanide source, catalyst, first solvent, and reaction temperature are described herein.

[0536] The cyanide source may be zinc cyanide, potassium ferricyanide, copper(I) cyanide, potassium cyanide, sodium cyanide, trimethylsilyl cyanide, acetone cyanohydrin, hexamethylenetetramine, or ethyl cyanoacetate. In some embodiments, the cyanide source includes zinc cyanide. In some embodiments, the cyanide source may be zinc cyanide.

[0537] The catalyst may be a palladium catalyst with or without a tertiary phosphine ligand (e.g., tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), palladium(II) acetate, palladium(II) chloride, bis(triphenylphosphine)palladium(II) dichloride; bis(acetonitrile)palladium(II) dichloride, (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride, palladium(π-cinnamyl)chloride dimer, or (2-disilazane). cyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate), copper(I) catalysts (e.g., copper(I) cyanide, copper(I) iodide, copper(I) bromide, or copper(I) chloride) with or without diamine or amino acid ligands, or nickel(II) catalysts (e.g., (N,N,N'N'-tetramethylethylenediamine)NiCl(o-tolyl) or trans-chloro-(2-napthyl)-bis(trifluoromethyl)phenyl)propanol). In some embodiments, the catalyst may be tetrakis(triphenylphosphine)palladium(0). In some embodiments, the catalyst may be tetrakis(triphenylphosphine)palladium(0).

[0538] The first solvent is a polar aprotic solvent (e.g., N,N-dimethylformamide, N- The first solvent may be an ether (e.g., 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, or 1,2-dimethoxyethane), an alcohol (e.g., methanol, ethanol, 1-butanol, or 2-propanol), an aromatic solvent (e.g., toluene, xylene, or anisole), or a combination thereof. The first solvent may further include water. In some embodiments, the first solvent includes N,N-dimethylformamide. In some embodiments, the first solvent may be N,N-dimethylformamide.

[0539] Generally, the cyanation reaction (i.e., step 21) can be carried out at any suitable temperature, for example, a temperature between 40° C. and 140° C. In some embodiments, the reaction mixture of the cyanation reaction can be at a temperature between 80° C. and 110° C.

[0540] For step 22, the first base, second solvent, and reaction temperature are described herein.

[0541] The first base may be 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), tetramethylguanidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), or tert-butylimino-tri(pyrrolidino)phosphorene. In some embodiments, the first base includes 1,8-diazabicyclo[5.4.0]undec-7-ene. In some embodiments, the first base may be 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0542] The second solvent may be a polar aprotic solvent (e.g., N,N-dimethylformamide, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, dimethyl sulfoxide, or sulfolane), an aromatic amine base (e.g., pyridine, 2,6-lutidine, or collidine), an ether (e.g., 1,4-dioxane or cyclopentyl methyl ether), a chlorinated solvent (e.g., 1,2-dichloroethane or chlorobenzene), an aromatic solvent (e.g., toluene, xylene, trifluorotoluene, etc.), or a combination thereof. In some embodiments, the second solvent includes N,N-dimethylformamide. In some embodiments, the second solvent may be N,N-dimethylformamide.

[0543] Generally, the cyclization reaction (i.e., step 22) can be carried out at any suitable temperature, for example, a temperature between 40° C. and 150° C. In some embodiments, the reaction mixture of the cyclization reaction can be at a temperature between 40° C. and 60° C.

[0544] For step 23, the chlorinating agent, second base, third solvent, and reaction temperature are described herein.

[0545] The chlorinating agent may be phosphorus oxychloride, phosphorus(V) chloride, or triphenylphosphine dichloride. In some embodiments, the chlorinating agent includes phosphorus oxychloride. In some embodiments, the chlorinating agent may be phosphorus oxychloride.

[0546] The second base may be absent or present. When present, the second base may be a tertiary amine (e.g., triethylamine, tri-n-butylamine, N,N-diisopropylethylamine, dimethylaniline, or diethylaniline) or an aromatic amine base (e.g., pyridine, 2,6-lutidine, or collidine). In some embodiments, the second base includes N,N-diisopropylethylamine. In some embodiments, the second base can be N,N diisopropylethylamine.

[0547] A third solvent may be absent, and the chlorination reaction may be carried out in neat phosphorus oxychloride. When a third solvent is present, the third solvent may be an aromatic solvent (e.g., toluene or xylene), an aromatic amine solvent (e.g., diethylaniline), a chlorinated solvent (e.g., chlorobenzene), or a combination thereof. In some embodiments, the third solvent includes toluene. In some embodiments, the third solvent may be toluene.

[0548] Generally, the chlorination reaction (i.e., step 23) can be carried out at any suitable temperature, for example, a temperature between 50° C. and 140° C. In some embodiments, the reaction mixture of the chlorination reaction can be at a temperature between 80° C. and 120° C.

[0549] 10. Preparation of Compounds of Formula XIb, Route 2 In some embodiments, step 22 above can be replaced by steps 24 and 25, as shown in the scheme of Figure 7B.

[0550] In some embodiments, the present disclosure provides a compound of formula XIb: [ka] or a salt thereof, the method comprising: 21) Forming a first reaction mixture comprising 2-bromo-5-fluoropyridin-3-amine or a salt thereof, a cyanide source, a catalyst, and a first solvent to produce 3-amino-5-fluoropicolinonitrile: [ka] or a salt thereof; 24) Forming a second reaction mixture comprising 3-amino-5-fluoropicolinonitrile or a salt thereof, an oxidizing agent, a first base, and a second solvent to produce 3-amino-5-fluoropicolinamide: [ka] or a salt thereof; 25) forming a third reaction mixture comprising 3-amino-5-fluoropicolinamide or a salt thereof, a cyclization reagent, and a third solvent to produce 7-fluoropyrido[3,2-d]pyrimidine-2,4-diol: [ka] or a salt thereof; 23) forming a fourth reaction mixture comprising 7-fluoropyrido[3,2-d]pyrimidine-2,4-diol or a salt thereof, a chlorinating agent, a second base, and a fourth solvent to form a compound of formula XIb or a salt thereof.

[0551] Steps 21 and 23 are described above in the preparation of compounds of formula XIb, Route 1.

[0552] For step 24, the oxidizing agent, first base, second solvent, and reaction temperature are described herein.

[0553] The oxidizing agent may be hydrogen peroxide, hydrogen peroxide urea adduct, lithium peroxide, benzoyl peroxide, or tert-butyl peroxide. In some embodiments, the oxidizing agent includes hydrogen peroxide. In some embodiments, the oxidizing agent may be in an aqueous solution. In some embodiments, the oxidizing agent may be an aqueous solution of hydrogen peroxide. In some embodiments, the oxidizing agent may be hydrogen peroxide.

[0554] The first base can be an alkali carbonate (e.g., sodium carbonate, potassium carbonate, or cesium carbonate) or an alkali hydroxide (e.g., sodium hydroxide, potassium hydroxide, or ammonium hydroxide). In some embodiments, the first base includes potassium carbonate. In some embodiments, the first base can be potassium carbonate.

[0555] The second solvent can be a polar aprotic solvent (e.g., N-methyl-2-pyrrolidone, N,N-dimethylacetamide, or dimethyl sulfoxide), an alcohol (e.g., methanol, ethanol, or tert-butanol), 1,4-dioxane, water, or a combination thereof. In some embodiments, the second solvent includes dimethyl sulfoxide. In some embodiments, the second solvent can be dimethyl sulfoxide.

[0556] Generally, the oxidation reaction (i.e., step 24) can be carried out at any suitable temperature, for example, a temperature between 20° C. and 120° C. In some embodiments, the reaction mixture of the oxidation reaction can be at a temperature between 20° C. and 40° C.

[0557] The oxidation reaction in step 24 can be replaced with a hydrolysis reaction using a mineral acid. In some embodiments, 3-amino-5-fluoropicolinonitrile or a salt thereof can be subjected to hydrolysis with a mineral acid, such as sulfuric acid, to form 3-amino-5-fluoropicolinamide or a salt thereof.

[0558] For step 25, the cyclization reagent, third solvent, and reaction temperature are described herein.

[0559] The cyclization reagent may be triphosgene, 1,1'-carbonyldiimidazole, phosgene, diphosgene, diphenyl carbonate, or sodium cyanate. In some embodiments, the cyclization reagent includes triphosgene. In some embodiments, the cyclization The reagent may be triphosgene.

[0560] The third solvent may be an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, or 1,4-dioxane), an aromatic solvent (e.g., toluene or xylene), a polar aprotic solvent (e.g., acetonitrile, propionitrile, or n-butylnitrile), an organic acid (e.g., acetic acid or chloroacetic acid), or a combination thereof. In some embodiments, the third solvent includes 1,4-dioxane. In some embodiments, the third solvent may be 1,4-dioxane.

[0561] Generally, the cyclization reaction of step 25 can be carried out at any suitable temperature, for example, a temperature between 20° C. and 150° C. In some embodiments, the reaction mixture of the cyclization reaction can be at a temperature between 90° C. and 110° C.

[0562] 11. Preparation of Formula IXa In some embodiments, the present disclosure provides a compound of formula IXa: [ka] and a method for preparing a compound of formula (I): The method includes forming a guanylation reaction mixture including a guanylation reagent, (2,4-dimethoxyphenyl)methanamine, a base, an additive, and a solvent to form a compound of formula IXb, where n can be 0 to 1.

[0563] The guanylation reagents were thiourea, 1H-pyrazole-1-carboxamidine hydrochloride, cyanamide, N,N-di-tert-butyloxycarbonyl-1H-pyrazole-1-carboxamidine, N,N-di-tert-butyloxycarbonyl-thiourea, SC 1~6 In some embodiments, the guanylating reagent may be an alkylisothiourea (e.g., S-methylisothiourea, S-ethylisothiourea, S-butylisothiourea, S-tert-butylisothiourea, or S-hexylisothiourea), or a salt thereof. 1~6In some embodiments, the guanylating reagent includes S-methylisothiourea. In some embodiments, the guanylating reagent includes S-methylisothiourea hemisulfate. In some embodiments, the guanylating reagent includes SC 1~6 In some embodiments, the guanylating reagent may be S-methylisothiourea. In some embodiments, the guanylating reagent may be S-methylisothiourea hemisulfate.

[0564] The base may be absent or present. If a base is present, the base may be a tertiary amine (e.g., triethylamine, tri-n-butylamine, or N,N-diisopropylethylamine). In some embodiments, the base may not be present.

[0565] The additive may be absent or present. If present, the additive may be a Lewis acid (e.g., tris-dimethylamino-aluminum dimer or scandium triflate). In some embodiments, the additive may be absent.

[0566] The solvent is an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1 The solvent may be N-methyl-2-pyrrolidone. In some embodiments, the solvent may be N-methyl-2-pyrrolidone. In some embodiments, the solvent may be N-methyl-2-pyrrolidone.

[0567] In some embodiments, the compound of formula IXa has formula IXb: [ka] It may be.

[0568] In some embodiments, the present disclosure provides a compound of formula IXb: [ka] and a method for preparing a compound of formula (I): The method includes forming a guanylation reaction mixture including S-methylisothiourea hemisulfate, (2,4-dimethoxyphenyl)methanamine, and N-methyl-2-pyrrolidone to form a compound of formula IXb.

[0569] Generally, the guanylation reaction can be carried out at any suitable temperature, for example, a temperature between 20° C. and 130° C. In some embodiments, the reaction mixture of the guanylation reaction can be at a temperature between 50° C. and 110° C.

[0570] 12. C via 2-amino-2-methylhexanenitrile 1~4 Preparation of alkyl 2-amino-2-methylhexanoates In some embodiments, the present disclosure provides 1~4 Alkyl 2-amino-2-methylhexanoate: [ka] or a salt thereof, the method comprising: 1) Formula: [ka] Hexan-2-one having the formula forming a first reaction mixture comprising a cyanide, optionally a first acid, a drying agent, optionally an additive, and a first solvent to produce a compound having the formula: [ka] 2-amino-2-methylhexanenitrile having or a salt thereof; 2a) 2-amino-2-methylhexanenitrile or a salt thereof and C 1~4 forming a second reaction mixture comprising an alkyl alcohol, a second acid, and water to produce C 1~4 forming a salt of alkyl 2-amino-2-methylhexanoate; 2b)C 1~4 forming a third reaction mixture comprising a salt of alkyl 2-amino-2-methylhexanoate, a base, and a second solvent to produce the neutral form of C 1~4 forming an alkyl 2-amino-2-methylhexanoate.

[0571] In some embodiments, C 1~4 Alkyl 2-amino-2-methylhexanoates have the formula: [ka] The compound may be isopropyl 2-amino-2-methylhexanoate, having the formula:

[0572] In some embodiments, isopropyl 2-amino-2-methylhexanoate can be prepared according to the steps shown in the scheme of FIG.

[0573] In some embodiments, C 1~4 C in alkyl 2-amino-2-methylhexanoate or its salt 1~4 The alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. 1~4 C in alkyl 2-amino-2-methylhexanoate or its salt 1~4 The alkyl may be isopropyl.

[0574] In some embodiments, for step 1, the cyanide, first acid, drying agent, additive, first solvent, and reaction temperature are described herein.

[0575] In some embodiments, the cyanide can be hydrogen cyanide, sodium cyanide, potassium cyanide, ammonium cyanide, trimethylsilyl cyanide, tert-butyldimethylsilyl cyanide, potassium hexacyanoferrate(III), potassium hexacyanoferrate(II), sodium ferrocyanide, acetone cyanohydrin, triphenylacetonitrile, ethyl cyanoformate, diethyl cyanophosphate, acetyl cyanide, or a combination thereof. In some embodiments, the cyanide includes sodium cyanide. In some embodiments, the cyanide can be sodium cyanide.

[0576] In some embodiments, the first acid is absent. In some embodiments, the first reaction mixture further comprises a first acid. The first acid may be ammonium chloride, para-toluenesulfonic acid, oxalic acid, formic acid, acetic acid, guanidine hydrochloride, cyanuric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or a combination thereof. In some embodiments, the acid includes ammonium chloride. In some embodiments, the acid may be ammonium chloride.

[0577] In some embodiments, the desiccant may be magnesium sulfate, sodium sulfate, trialkyl orthoformate (e.g., trimethyl orthoformate), azeotropic removal of water (e.g., Dean-Stark trap), or molecular sieves. In some embodiments, the desiccant includes magnesium sulfate.

[0578] In some embodiments, no additive is present. In some embodiments, the first reaction mixture further comprises an additive. In some embodiments, the additive may be a Lewis acid such as scandium(III) triflate, boron trifluoride etherate, zinc iodide, lithium chlorite, trimethylsilyl trifluoromethanesulfonate, bismuth chloride, magnesium bromide, ruthenium(III) chloride, or a combination thereof.

[0579] In some embodiments, the first solvent may be an alcohol (e.g., methanol, ethanol, 2-propanol, 1-butanol, tert-butanol, 2-methylbutan-2-ol, or trifluoroethanol), a hydrocarbon solvent (e.g., n-heptane, hexane, cyclohexane, or methylcyclohexane), a polar aprotic solvent (e.g., acetonitrile, propionitrile, or butyronitrile), an organic acid (e.g., acetic acid, formic acid, or trifluoroacetic acid), a chlorinated solvent (e.g., dichloromethane or chlorobenzene), an aromatic solvent (e.g., toluene, xylene, nitrobenzene, trifluorotoluene, or fluorobenzene), water, or a combination thereof. In some embodiments, the first solvent includes methanol. In some embodiments, the first solvent may be methanol.

[0580] Generally, the first reaction (i.e., step 1) can be carried out at any suitable temperature. For example, the first reaction mixture can be at a temperature of 0°C to 70°C. In some embodiments, the first reaction mixture can be at a temperature of 0°C to 40°C.

[0581] In some embodiments, step 2 comprises two steps as described in steps 2a and 2b.

[0582] In some embodiments, with respect to step 2a, 1~4 Alkyl alcohol, secondary acid, C 1~4 The salt of alkyl 2-amino-2-methylhexanoate and the reaction temperature are described herein.

[0583] In some embodiments, C 1~4 The alkyl alcohol may be methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, or tert-butanol. 1~4 Alkyl alcohols include methanol. In some embodiments, C 1~4 The alkyl alcohol may be methanol.

[0584] In some embodiments, the second acid may be a mineral acid (e.g., sulfuric acid, hydrochloric acid, phosphoric acid, chlorosulfuric acid, oleum, fluorosulfuric acid, or fluoroantimonic acid), an organic acid (e.g., methanesulfonic acid or triflic acid), or a combination thereof. In some embodiments, the second acid includes sulfuric acid. In some embodiments, the second acid may be sulfuric acid.

[0585] In some embodiments, C 1~4 The salt of alkyl 2-amino-2-methylhexanoate may be a sulfate, hydrochloride, phosphate, chlorosulfate, oleum, fluorosulfate, fluoroantimonate, methanesulfonate, or triflate. 1~4 The salt of alkyl 2-amino-2-methylhexanoate may be a sulfate salt. 1~4 The salt of alkyl 2-amino-2-methylhexanoate may be isopropyl 2-amino-2-methylhexanoate sulfate.

[0586] Generally, the second reaction (i.e., step 2a) can be carried out at any suitable temperature. For example, the second reaction mixture can be at a temperature of 50°C to 150°C. In some embodiments, the second reaction mixture can be at a temperature of 70°C to 100°C.

[0587] In some embodiments, for step 2b, the base, second solvent, and reaction temperature are described herein.

[0588] In some embodiments, the base can be an inorganic base (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, tribasic sodium phosphate, or tribasic potassium phosphate), an organic base (e.g., sodium acetate, potassium acetate, sodium methoxide, sodium tert-butoxide, or potassium tert-butoxide), or a combination thereof. In some embodiments, the base includes sodium hydroxide. In some embodiments, the base can be sodium hydroxide. In some embodiments, the base can be in an aqueous solution. In some embodiments, the base includes an aqueous solution of sodium hydroxide. In some embodiments, the base can be an aqueous solution of sodium hydroxide.

[0589] In some embodiments, the second solvent can be an aromatic solvent (e.g., toluene, xylene, or trifluorotoluene), an ether (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, or 1,4-dioxane), a chlorinated solvent (e.g., dichloromethane or 1,2-dichloroethane), or a combination thereof. In some embodiments, the second solvent includes 2-methyltetrahydrofuran. In some embodiments, the second solvent can be 2-methyltetrahydrofuran.

[0590] Generally, the third reaction (i.e., step 2b) can be carried out at any suitable temperature. For example, the third reaction mixture can be at a temperature of 0°C to 40°C. In some embodiments, the third reaction mixture can be at a temperature of 20°C to 30°C.

[0591] IV.Compound In another embodiment, the present disclosure provides a compound of formula III: [ka] or a salt thereof, wherein R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl or C 1~3 may be alkoxy, and R 4 may be hydrogen or methyl, R 5 is C 3~6 It may be alkyl, and X may be F, Cl, Br, I, or OTs.

[0592] In another embodiment, the present disclosure provides a compound of formula III: [ka] or a salt thereof, wherein R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl or C 1~3 may be alkoxy, and R 4 may be hydrogen or methyl, R 5 is C 3~6 It may be alkyl, and X may be Cl, Br, I, or OTs.

[0593] In some embodiments, R 2 are Cl, F, CN, CF3, C 1~3 Alkyl or C 1~3 may be alkoxy, and R 1 and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl or C 1~3 It may be alkoxy. 1~3 Alkyl may be methyl, ethyl, n-propyl, or isopropyl. 1~3 Alkoxy can be methoxy, ethoxy, n-propoxy, or isopropoxy. In some embodiments, R 2may be Cl, F, CN, CF, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; R 1 and R 3 may each independently be hydrogen, F, Cl, CN, CF, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy. 2 may be Cl, F, CN, CF, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; R 1 and R 3 and R may each be hydrogen. 2 may be F, and R 1 and R 3 may each be hydrogen.

[0594] In some embodiments, R 4 may be hydrogen. In some embodiments, R 4 may be methyl.

[0595] In some embodiments, R 5 is C 3~6 In some embodiments, R 5 may be n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or hexyl. 5 may be n-butyl.

[0596] In some embodiments, R 4 may be methyl, R 5 is C 3~6 In some embodiments, R 4 may be methyl, R 5 may be n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or hexyl.4 may be methyl, R 5 may be n-butyl.

[0597] In some embodiments, X can be F, Br, I, or OTs. In embodiments, X can be Br, I, or OTs. In some embodiments, X can be Br. In some embodiments, X can be F.

[0598] In some embodiments, the compound of Formula III has Formula IIIa: [ka] or a salt thereof, and R 2 and R 5 is as defined and explained herein.

[0599] In some embodiments, the compound of Formula III has the formula IIIa-1: [ka] or a salt thereof, and R 2 and R 5 is as defined and explained herein.

[0600] In some embodiments, the compound of Formula III has Formula IIIb: [ka] or a salt thereof.

[0601] In some embodiments, the compound of formula III has formula IIIb-1: [ka] or a salt thereof.

[0602] In another embodiment, the present disclosure provides a compound of formula IV: [ka] or a salt thereof, wherein R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl, or C 1~3 may be alkoxy, and R 4 may be hydrogen or methyl, R 5 is C 3~6 alkyl, X may be F, Cl, Br, I, or OTs, AG 1 are Cl, Br, OSO3H, OSO3 - , OMs, OTs, or OTf.

[0603] In another embodiment, the present disclosure provides a compound of formula IV: [ka] or a salt thereof, wherein R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl, or C 1~3 may be alkoxy, and R 4 may be hydrogen or methyl, R 5 is C 3~6 alkyl, X may be Cl, Br, I, or OTs, AG 1 may be Cl, Br, OMs, OTs, or OTf.

[0604] In some embodiments, R 2 are Cl, F, CN, CF3, C 1~3 Alkyl, or C 1~3 may be alkoxy, and R 1 and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl, or C 1~3 It may be alkoxy. 1~3Alkyl may be methyl, ethyl, n-propyl, or isopropyl. 1~3 Alkoxy can be methoxy, ethoxy, n-propoxy, or isopropoxy. In some embodiments, R 2 may be Cl, F, CN, CF, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; R 1 and R 3 may each independently be hydrogen, F, Cl, CN, CF, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy. 2 may be Cl, F, CN, CF, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; R 1 and R 3 and R may each be hydrogen. 2 may be F, and R 1 and R 3 may each be hydrogen.

[0605] In some embodiments, R 4 may be hydrogen. In some embodiments, R 4 may be methyl.

[0606] In some embodiments, R 5 is C 3~6 In some embodiments, R 5 may be n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or hexyl. 5 may be n-butyl.

[0607] In some embodiments, R 4 may be methyl, R 5 is C 3~6 In some embodiments, R4 may be methyl, R 5 may be n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or hexyl. 4 may be methyl, R 5 may be n-butyl.

[0608] In some embodiments, X can be F, Br, I, or OTs. In some embodiments, X can be Br, I, or OTs. In some embodiments, X can be Br. In some embodiments, X can be F.

[0609] In some embodiments, the AG 1 may be Cl. In some embodiments, AG 1 may be Br. In some embodiments, AG 1 may be OMs, OTs, or OTfs. In some embodiments, AG 1 is OSO3H or OSO3 - It may be.

[0610] In some embodiments, the compound of formula IV has formula IV-1: [ka] or a salt thereof, and R 1 , R 2 , R 3 , R 4 , R 5 , and X are as defined and explained herein.

[0611] In some embodiments, the compound of formula IV-1 has formula IVa-1: [ka] or a salt thereof, and R 2 and R 5 is as defined and explained herein.

[0612] In some embodiments, the compound of formula IV-1 has formula IVa-2: [ka] or a salt thereof, and R 2 and R 5 is as defined and explained herein.

[0613] In some embodiments, the compound of formula IV-1 has formula IVb-1: [ka] or a salt thereof.

[0614] In some embodiments, the compound of formula IV-1 has formula IVb-2: [ka] or a salt thereof.

[0615] In another embodiment, the present disclosure provides a compound of formula V: [ka] or a salt thereof, wherein R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF3, C 1~3 Alkyl, or C 1~3 may be alkoxy, and R 4...

Claims

1. Formula II: 【Chemistry 361】 or a salt thereof, comprising the steps of: a) Formula V: 【Chemical 362】 and a compound of the formula PG-NHC(=NH)NH ２ or a salt thereof, a first transition metal catalyst, a first base, and a first solvent to form the compound of formula II or a salt thereof; During the ceremony, R １ , R ２ , and R ３ are each independently hydrogen, F, Cl, CN, or CF ３ , C １～３ Alkyl, or C １～３ is an alkoxy; R ４ is hydrogen or methyl, R ５ is C ３～６ is alkyl, X is F, Cl, Br, I, or OTs; The method wherein PG is an amino protecting group.

2. The method of claim 1, wherein PG is 2,4-dimethoxybenzyl.

3. Formula V: 【Chemical 371】 or a salt thereof, wherein R １ , R ２ , and R ３ are each independently hydrogen, F, Cl, CN, or CF ３ , C １～３ Alkyl, or C １～３ is an alkoxy; R ４ is hydrogen or methyl, R ５ is C ３～６ is alkyl, X is F, Cl, Br, I, or OTs; However, the compound of formula V is 3-bromo-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide, 3-bromo-N-(1-hydroxy-3,3-dimethylbutan-2-yl)picolinamide, 3-bromo-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide, 3-bromo-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide, 3,6-dichloro-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide, 3,6-dichloro-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide, 3,4,5-trichloro-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide, 3,6-dichloro-N-(1-hydroxy-4,4-dimethylpentan-2-yl)picolinamide, 3,4,5-trichloro-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide, 【Chemistry 3】 is not a compound or a salt thereof.

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