Process for preparation of toll-like receptor modulator compounds

Abstract

The present disclosure provides a process for the preparation of (R)-2-((2-amino-7-fluoropyrido [3, 2-d] pyrimidin-4-yl) amino)-2-methylhex-1-ol or a salt thereof. The present disclosure also provides methods for preparing compounds of formulae III, IV, V, VI, VII, VIII, IX, and X. In addition, the present disclosure provides compounds of formulae III, IV, V, and XI.

Description

[0001] This application is a divisional application of patent application No. 202080057308.3, filed on June 25, 2020, entitled "Method for preparing Toll-like receptor modulator compounds".

[0002] Cross-reference to related applications

[0003] This application claims priority to U.S. Provisional Application No. 62 / 868,662, filed June 28, 2019, which is incorporated herein by reference in its entirety for all purposes. Background Technology

[0004] The Toll-like receptor (TLR) family plays a crucial role in pathogen recognition and innate immune activation. Toll-like receptor 8 (TLR-8) is primarily expressed by bone marrow immune cells, and its activation stimulates a broad immune response. TLR-8 agonists activate bone marrow dendritic cells, monocytes, monocyte-derived dendritic cells, and Kupffer cells, leading to the production of pro-inflammatory cytokines and chemokines such as interleukin-18 (IL-18), interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ). These agonists also promote the production of co-stimulatory molecules such as CD4+. 8+ Increased expression of cells, major histocompatibility complex molecules (MAIT, NK cells) and chemokine receptors.

[0005] In summary, the activation of these innate and adaptive immune responses induces immune responses and provides therapeutic benefits in a variety of conditions involving autoimmunity, inflammation, allergies, asthma, graft rejection, graft-versus-host disease (GvHD), infection, cancer, and immunodeficiency. For example, in 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 pro-inflammatory cytokines, which are expected to enhance HBV-specific T cell responses, activate intrahepatic NK cells, and drive antiviral immune remodeling. See, for example, Wille-Reece, U. et al., J Exp Med, Vol. 203, pp. 1249-1258, 2006; Peng, G. et al., Science, Vol. 309, pp. 1380-1384, 2005; Jo, J. et al., PLoS Pathogens, Vol. 10, pp. 11004210, 2014; and Watashi, K. et al., J Biol Chem, Vol. 288, pp. 31715-31727, 2013.

[0006] Given their potential to treat a variety of diseases, potent and selective modulators of TLR-8 receptors with reduced off-target potential are in particular demand. Toll-like receptor modulator compounds, such as diaminopyrido[3,2-d]pyrimidine compounds and methods for their preparation, are disclosed in WO 2016 / 141092. However, methods for preparing diaminopyrido[3,2-d]pyrimidine compounds remain needed. Summary of the Invention

[0007] In one embodiment, this disclosure provides a method for preparing compounds of formula I:

[0008]

[0009] A method using its salt or a salt thereof, the method comprising:

[0010] a) Forming a first reaction mixture comprising compounds of formula III:

[0011]

[0012] Or its salt, a compound having the formula PG-NHC(=NH)NH2 or its salt, a first base and a first solvent, to form a compound of formula II:

[0013]

[0014] or its salt; and

[0015] b) Forming a second reaction mixture comprising a compound of formula II or a salt thereof, a deprotecting agent, and a second solvent to provide a compound of formula I or a salt thereof.

[0016] Where R 1 R 2 and R 3 Each of the following is an independent element: hydrogen, F, Cl, CN, CF3, C 1-3 Alkyl or C 1-3 Alkoxy; R 4 It is hydrogen or methyl; R 5 It is C 3-6 Alkyl group; X is F, Cl, Br, I or OTs; and PG is an amino protecting group.

[0017] In another embodiment, this disclosure provides a method for preparing compounds of formula I:

[0018]

[0019] A method using its salt or a salt thereof, the method comprising:

[0020] a) Forming a first reaction mixture comprising compounds of formula III:

[0021]

[0022] Or its salt, a compound having the formula PG-NHC(=NH)NH2 or its salt, a first transition metal catalyst, a first base and a first solvent, to form a compound of formula II:

[0023]

[0024] or its salt; and

[0025] b) Forming a second reaction mixture comprising a compound of formula II or a salt thereof, a deprotecting agent, and a second solvent to provide a compound of formula I or a salt thereof.

[0026] Where R 1 R 2 and R 3 Each of the following is an independent element: hydrogen, F, Cl, CN, CF3, C 1-3 Alkyl or C 1-3 Alkoxy; R 4 It is hydrogen or methyl; R 5 It is C 3-6 Alkyl group; X is Cl, Br, I or OTs; and PG is an amino protecting group.

[0027] In another embodiment, this disclosure provides a compound for preparing formula Ib:

[0028]

[0029] A method using its salt or a salt thereof, the method comprising:

[0030] a4) Forming a seventh reaction mixture comprising compounds of formula VIIIb:

[0031]

[0032] Or its salts, oxaloyl chloride, N,N-dimethylformamide, 2-methyltetrahydrofuran, to form compounds of formula VIIb:

[0033]

[0034] or its salt;

[0035] a3) Forming a sixth reaction mixture comprising a compound of formula VIIb or a salt thereof, and a compound of formula VIb:

[0036]

[0037] An aqueous solution of potassium carbonate, 2-methyltetrahydrofuran, and water are used to form a compound of formula Vb:

[0038]

[0039] or its salt;

[0040] A fourth reaction mixture is formed, comprising a compound of formula Vb or a salt thereof, thionyl chloride, and 2-methyltetrahydrofuran to form a compound of formula IVb-1:

[0041]

[0042] or its salt;

[0043] A third reaction mixture is formed, comprising a compound of formula IVb-1 or a salt thereof, an aqueous solution of sodium hydroxide, tetra-n-butylammonium hydrogen sulfate, and 2-methyltetrahydrofuran, to form a compound of formula IIIb:

[0044]

[0045] or its salt;

[0046] A first reaction mixture is formed, the first reaction mixture comprising a compound of formula IIIb or a salt thereof, and a compound of formula IXa, wherein n is 0 to 1:

[0047]

[0048] Copper(II) acetate, tripotassium phosphate, cysteine, 2-methyltetrahydrofuran, and acetonitrile are used to form a compound of formula IIb:

[0049]

[0050] or its salt;

[0051] b) Forming a second reaction mixture comprising a compound of formula IIb or a salt thereof, trifluoroacetic acid, and dichloromethane to prepare a trifluoroacetic acid salt of a compound of formula Ib:

[0052] as well as

[0053] c) Forming a ninth reaction mixture comprising a trifluoroacetate of a compound of formula Ib, sodium hydroxide, ethanol, and water to provide a compound of formula Ib in a neutral form.

[0054] In some embodiments, this disclosure provides a method for preparing compounds of formula II:

[0055]

[0056] A method using its salt or a salt thereof, the method comprising:

[0057] a) Forming a first reaction mixture comprising compounds of formula V:

[0058]

[0059] The compound or its salt, a compound having the formula PG-NHC(=NH)NH2 or its salt, a first transition metal catalyst, a first base and a first solvent, to form a compound or its salt of formula II.

[0060] Where R 1 R 2 and R 3 They can be hydrogen, F, Cl, CN, CF3, and C, respectively. 1-3 Alkyl or C 1-3 Alkoxy; R 4 It can be hydrogen or methyl; R 5 It can be C 3-6 Alkyl group; X can be F, Cl, Br, I or OTs; and PG can be an amino protecting group.

[0061] In another embodiment, this disclosure provides a method for preparing compounds of formula I:

[0062]

[0063] A method using its salt or a salt thereof, the method comprising:

[0064] a) Forming a first reaction mixture comprising compounds of formula III:

[0065]

[0066] A compound having the formula H2NC(=NH)NH2 or a salt thereof, a first base, and a first solvent, to form a compound or a salt thereof of formula I.

[0067] Where R 1 R 2 and R 3 They can be hydrogen, F, Cl, CN, CF3, and C, respectively. 1-3 Alkyl or C 1-3 Alkoxy; R 4 It can be hydrogen or methyl; R 5 It can be C 3-6 Alkyl; and X can be F, Cl, Br, I or OTs.

[0068] In another embodiment, this disclosure provides a compound for preparing formula XVIII:

[0069]

[0070] A method using its salt or a salt thereof, the method comprising:

[0071] a) Forming a first reaction mixture comprising compounds of formula XV:

[0072]

[0073] Compounds of formula XVI-1:

[0074]

[0075] Or its salt, having the formula R 7 -NHC(=NH)NH2 compounds or their salts, first transition metals

[0076] A catalyst, a first base, and a first solvent are used to form a compound of formula XVIII or a salt thereof, wherein R 1 R 2 and R 3 Each of the following is an independent element: hydrogen, F, Cl, CN, CF3, C 1-3 Alkyl or C 1-3 Alkoxy; R 4 It is hydrogen or methyl; R 5 It is C 1-6 Alkyl; R 6 It is hydrogen, OH, or O-PG1; R 7 It is hydrogen or PG; X and X 1 Each is independently F, Cl, Br, I or OTs; PG is an amino protecting group; and PG1 is a hydroxyl protecting group.

[0077] In another embodiment, this disclosure provides a method for preparing compounds of formula I:

[0078]

[0079] A method using its salt or a salt thereof, the method comprising:

[0080] a) Forming a first reaction mixture comprising compounds of formula XI:

[0081]

[0082] Or its salts, or compounds of formula VI:

[0083]

[0084] Or its salt, a first base, and a first solvent, to form a compound of formula X:

[0085]

[0086] or its salt;

[0087] b) To form 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 form a compound of formula II:

[0088]

[0089] or its salt; and

[0090] b) Forming a third reaction mixture comprising a compound of formula II or a salt thereof, a deprotecting agent, and a third solvent to provide a compound of formula I or a salt thereof.

[0091] Where R 1 R 2 and R 3 Each of the following is an independent element: hydrogen, F, Cl, CN, CF3, C 1-3 Alkyl or C 1-3 Alkoxy; R 4 It is hydrogen or methyl; R 5 It is C 3-6 Alkyl group; and PG is an amino protecting group.

[0092] In another embodiment, this disclosure provides a compound for preparing formula Ib:

[0093]

[0094] A method using its salt or a salt thereof, the method comprising:

[0095] a) Forming a first reaction mixture comprising compounds of formula XIb:

[0096]

[0097] Or its salts, or compounds of formula VIb:

[0098]

[0099] N,N-diisopropylethylamine, 2-methyltetrahydrofuran, and isopropyl acetate are used to form a compound of formula Xb:

[0100]

[0101] or its salt;

[0102] 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 form a compound of formula IIb:

[0103]

[0104] or its salt; and

[0105] c) Forming a third reaction mixture comprising a compound of formula IIb or a salt thereof, trifluoroacetic acid, and dichloromethane to prepare a trifluoroacetic acid salt of a compound of formula Ib:

[0106] as well as

[0107] d) Forming a fourth reaction mixture comprising trifluoro[a] of a compound of formula Ib

[0108] Acetate, sodium hydroxide, ethanol, and water are used to provide a compound of formula Ib in a salt-free form. In another embodiment, this disclosure provides a compound of formula III:

[0109]

[0110] or its salt, wherein R 1 R 2 and R 3 Each of the following is an independent element: hydrogen, F, Cl, CN, CF3, C 1-3 Alkyl or C 1-3 Alkoxy; R 4 It is hydrogen or methyl; R 5 It is C 3-6 Alkyl; and X is F, Cl, Br, I or OTs.

[0111] In another embodiment, this disclosure provides a compound of formula III:

[0112]

[0113] or its salt, wherein R 1 R 2 and R 3 Each of the following is an independent element: hydrogen, F, Cl, CN, CF3, C 1-3 Alkyl or C 1-3 Alkoxy; R 4 It is hydrogen or methyl; R 5 It is C 3-6 Alkyl; and X is Cl, Br, I or OTs.

[0114] In another embodiment, this disclosure provides a compound of formula IV:

[0115]

[0116] or its salt, wherein R 1 R 2 and R 3 Each of the following is an independent element: hydrogen, F, Cl, CN, CF3, C 1-3 Alkyl or C 1-3 Alkoxy; R 4 It is hydrogen or methyl; R 5 It is C 3-6 Alkyl; X is F, Cl, Br, I or OTs; and AG 1 It is Cl, Br, OSO3H, OSO3 - OMs, OTs, or OTf.

[0117] In another embodiment, this disclosure provides a compound of formula IV:

[0118]

[0119] or its salt, wherein R 1 R 2 and R 3 Each of the following is an independent element: hydrogen, F, Cl, CN, CF3, C 1-3 Alkyl or C 1-3 Alkoxy; R 4 It is hydrogen or methyl; R 5 It is C 3-6 Alkyl; X is F, Cl, Br, I or OTs; and AG 1 It is Cl, Br, OMs, OTs, or OTf.

[0120] In another embodiment, this disclosure provides a compound of formula V:

[0121]

[0122] or its salt, wherein R 1 R 2 and R 3 Each of the following is an independent element: hydrogen, F, Cl, CN, CF3, C 1-3 Alkyl or C 1-3 Alkoxy; R 4 It is hydrogen or methyl; R 5 It is C 3-6Alkyl; and X is F, Cl, Br, I, or OTs, provided that the compound of formula V is not 3-bromo-N-(1-hydroxy-3-methylbut-2-yl)pyridineamide, 3-bromo-N-(1-hydroxy-3,3-dimethylbut-2-yl)pyridineamide, 3-bromo-N-(1-hydroxy-4-methylpent-2-yl)pyridineamide, 3-bromo-N-(1-hydroxy-4-methylpent-2-yl)pyridineamide, 3,6-dichloro -N-(1-hydroxy-3-methylbut-2-yl)pyridine amide, 3,6-dichloro-N-(1-hydroxy-4-methylpent-2-yl)pyridine amide, 3,4,5-trichloro-N-(1-hydroxy-3-methylbut-2-yl)pyridine amide, 3,6-dichloro-N-(1-hydroxy-4,4-dimethylpent-2-yl)pyridine amide or 3,4,5-trichloro-N-(1-hydroxy-4-methylpent-2-yl)pyridine amide.

[0123] In another embodiment, this disclosure provides a compound of formula V:

[0124]

[0125] or its salt, wherein R 1 R 2 and R 3 Each of the following is an independent element: hydrogen, F, Cl, CN, CF3, C 1-3 Alkyl or C 1-3 Alkoxy; R 4 It is hydrogen or methyl; R 5 It is C 3-6 Alkyl; and X is Cl, Br, I, or OTs, provided that the compound of formula V is not 3-bromo-N-(1-hydroxy-3-methylbut-2-yl)pyridineamide, 3-bromo-N-(1-hydroxy-3,3-dimethylbut-2-yl)pyridineamide, 3-bromo-N-(1-hydroxy-4-methylpent-2-yl)pyridineamide, 3-bromo-N-(1-hydroxy-4-methylpent-2-yl)pyridineamide, 3,6-dichloro- N-(1-hydroxy-3-methylbut-2-yl)pyridine amide, 3,6-dichloro-N-(1-hydroxy-4-methylpent-2-yl)pyridine amide, 3,4,5-trichloro-N-(1-hydroxy-3-methylbut-2-yl)pyridine amide, 3,6-dichloro-N-(1-hydroxy-4,4-dimethylpent-2-yl)pyridine amide or 3,4,5-trichloro-N-(1-hydroxy-4-methylpent-2-yl)pyridine amide.

[0126] In another embodiment, this disclosure provides a compound of formula XII:

[0127]

[0128] or its salt, wherein R1 R 2 and R 3 Each of the following is an independent element: hydrogen, F, Cl, CN, CF3, C 1-3 Alkyl or C 1-3 alkoxy groups; and R 6 and R 7 Each is independently hydrogen, C 1-4 Alkyl or C 3-6 cycloalkyl, or R 6 and R 7 Combining to form 3- to 6-membered N-linked heterocyclic alkyl groups, optionally having one or two additional heteroatoms selected from O and S, provided that R 1 R 2 and R 3 At least one of them is F, Cl, CN, CF3, C 1-3 Alkyl or C 1-3 Alkyl group. Attached Figure Description

[0129] Figure 1 The preparation of compound Ib by a transition metal-mediated coupling reaction of (R)-2-((2-((3,4-dimethylbenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhex-1-ol (IIb) with a protected guanidine compound is shown.

[0130] Figure 2 The preparation of a compound of formula Ib by two consecutive nucleophilic aromatic substitution reactions of 2,4-dichloro-7-fluoropyridinium[3,2-d]pyrimidine (XIb) provides (R)-2-((2-((3,4-dimethylbenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhex-1-ol (IIb), which is then deprotected to form (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhex-1-ol (Ib).

[0131] Figure 3A Compounds of formula VIb are shown to be prepared by a series of steps including condensation, alkylation / hydrolysis, salt formation, enzymatic resolution, BOC protection, reduction and deprotection / TsOH salt formation. Figure 3B Alternative methods for preparing (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate isopropyl ester are shown.

[0132] Figure 4 The preparation of compounds of formula VIb is shown via steps of cyclocondensation, nucleophilic addition, reduction, and hydrogenolysis / TsOH salt formation.

[0133] Figure 5A The preparation of compounds of formula VIIIb by halogen exchange, cyanidation and hydrolysis is shown. Figure 5B An alternative method for preparing 3-bromo-5-fluoro-2-iodopyridine is shown.

[0134] Figure 6 The preparation of compounds of formula VIIIb by amidation, bromination and hydrolysis is shown.

[0135] Figure 7A The preparation of compounds of formula XIb by cyanation, cyclization with carbon dioxide, and chlorination is shown. Figure 7B An alternative method is shown for preparing 7-fluoropyrido[3,2-d]pyrimidine-2,4-diol by a combination of oxidation and cyclization with triphosgene.

[0136] Figure 8 The preparation of compounds of formula IIIb from compounds of formula IIb by sulfonation, ion exchange and cyclization steps is shown.

[0137] Figure 9 Compounds of formula IIb are shown to be prepared from 3,5-difluoropyridinecarboxylic acid (VIIIb-1) by coupling (R)-2-(3-fluoro-5-fluoropyridin-2-yl)-4-butyl-4-methyl-4,5-dihydrooxazole (IIIb-1) with a protected guanidine compound.

[0138] Figure 10 Compounds of formula IIb are shown to be prepared by a transition metal-mediated coupling reaction of (R)-3-bromo-5-fluoro-N-(1-hydroxy-2-methylhex-2-yl)pyridine amide (Vb) with a protected guanidine compound.

[0139] Figure 11 Compounds of formula Ib were prepared by direct coupling reaction of (R)-2-(3-fluoro-5-fluoropyridin-2-yl)-4-butyl-4-methyl-4,5-dihydrooxazole (IIIb-1) with a guanidine salt.

[0140] Figure 12 Compounds of formula Ib are shown to be prepared by condensation reaction of 2-bromo-3,5-difluoropyridine, (R)-2-isocyano-2-methylhex-1-ol and guanidine salt.

[0141] Figure 13 The preparation of isopropyl 2-amino-2-methylhexanoate from hex-2-one via 2-amino-2-methylhexanonitrile is shown.

[0142] Figure 14 The preparation of compounds of formula VIb is shown via steps of nucleophilic addition, Bz protection, reduction and deprotection / TsOH salt formation.

[0143] Figure 15 The preparation of a compound of formula VIb is shown by reducing the salt of (R)-2-amino-2-methylhexanoic acid and forming a TsOH salt.

[0144] Figure 16 The preparation of (R)-2-amino-2-methylhexanoate salt from (2S,4R)-3-benzoyl-4-methyl-2-phenyloxazolidin-5-one via alkylation and hydrolysis steps is shown. Detailed Implementation

[0145] I. Overview

[0146] This disclosure provides methods for preparing compounds of formula I or salts thereof, specifically (R)-2-((2-amino-7-fluoropyridino[3,2-d]pyrimidin-4-yl)amino)-2-methylhexane-1-ol. This disclosure also provides methods for preparing compounds of formulas III, IV, V, VI, VII, VIII, IX, and X. Additionally, this disclosure provides compounds of formulas III, IV, V, and XI.

[0147] II. Definition

[0148] The abbreviations used in this article have their conventional meanings in the fields of chemistry and biology.

[0149] "alkyl" refers to an alkyl group having an indicated number of carbon atoms (i.e., C10, C20, C30, C40, C50, C6 ... 1-6 Alkyl groups refer to straight-chain or branched saturated aliphatic groups (one to six carbons). Alkyl groups can include any number of carbons, such as C60, C70, C6 ... 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, C 1-6Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, and hexyl.

[0150] "Alkoxy" refers to an alkyl group having an oxygen atom attached to the alkyl group at the junction: alkyl-O-. Alkoxy groups can have any suitable number of carbon atoms, such as C1-C6. Examples of alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexaoxy, etc.

[0151] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic, fused bicyclic, or bridged polycyclic cyclic assembly containing 3 to 12 carbon ring atoms or the indicated number of atoms. Cycloalkyl can include any number of carbons, such as C64. 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, norbornene, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. The cycloalkyl group may also 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 norbornediene. When the cycloalkyl group is a saturated monocyclic C3-C8 cycloalkyl group, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. When the cycloalkyl group is a saturated monocyclic C3-C8 cycloalkyl group... 3-6 When cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0152] "N-linked heterocyclic alkyl" or "nitrogen-linked heterocyclic alkyl" refers to a heterocyclic alkyl group linked through the N-position on a ring. For example, N-linked aziridinyl is aziridin-1-yl, N-linked nitrogen-heterocyclic butyl is nitrogen-butane-1-yl, N-linked pyrrolyl is pyrrolidine-1-yl, N-linked piperidinyl is piperidin-1-yl, N-linked pyrazolyl is pyrazolidine-1-yl or pyrazolidine-2-yl, N-linked imidazoalkyl can be imidazoidine-1-yl or imidazoidine-3-yl, N-linked piperazinyl is piperazin-1-yl or piperazin-4-yl, N-linked oxazolyl is oxazolidine-3-yl, N-linked isoxazolyl isoxazolidine-2-yl, N-linked thiazoalkyl is thiazoidine-3-yl, N-linked isothiazolyl is isothiazolidine-2-yl, and N-linked morpholinyl is 4-morpholinyl.

[0153] “OMs” refers to methanesulfonates; “OTs” refers to p-toluenesulfonates; and “OTf” refers to trifluoromethanesulfonates.

[0154] "Forming a reaction mixture" refers to a method of bringing at least two different substances into contact such that they are mixed together and can react, altering one of the initial reactants or forming a third different substance or product. 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 of one or more of the added reagents, which may be generated in the reaction mixture.

[0155] "Acid" refers to an acid that, according to the Bronsted-Lowry definition, can provide a proton (H+). + Compounds of which, according to the Lewis definition, are electron pair acceptors. Acids that can be used in this disclosure are... -Lowry acids include, but are not limited to, alkanes or carboxylic acids (formic acid, acetic acid, citric acid, lactic acid, oxalic acid, etc.), fluorinated carboxylic acids (trifluoroacetic acid), sulfonic acids, and inorganic acids as defined herein. Mineral acids are inorganic acids, such as hydrogen halides (hydrofluoric acid, hydrochloric acid, hydrobromic acid, etc.), halooxygenated acids (hypochlorous acid, perchloric acid, etc.), as well as sulfuric acid, nitric acid, phosphoric acid, chromic acid, and boric acid. Sulfonic acids include methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, etc.

[0156] "Lewis acid" refers to a compound or ionic substance that can accept electron pairs from a donor compound. Lewis acids that can be used in this disclosure include, but are not limited to, boron trifluoride diethyl ether, lithium chloride, zinc chloride, titanium tetrachloride, silicon tetrachloride, aluminum chloride, samarium(II) iodide, cerium(III) chloride, and lanthanum(III) chloride lithium chloride complexes.

[0157] "Base" refers to a functional group that deprotonates water to produce hydroxide ions. Bases that can be used in this disclosure include organic and inorganic bases. Exemplary organic bases include amines, carboxylates, basic alkoxides, metal amides, and alkyl or alkenyl metal compounds, as defined herein. Exemplary inorganic bases include basic bicarbonates, basic carbonates, basic triphosphates, basic diphosphates, basic hydroxides, and basic hydrides, as defined herein. Amines that can be used in this disclosure include tertiary amines, aromatic amine bases, and amidine compounds, as defined herein.

[0158] "Tertiary amine" refers to a compound having the formula N(R)3, wherein the R group can be alkyl, aryl, heteroalkyl, heteroaryl, etc., or two R groups together to form an N-linked heterocyclic alkyl group. 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, quinine ring, and 1,4-diazabicyclo[2.2.2]octane (DABCO).

[0159] "Aromatic amine base" refers to a 5- to 10-membered heteroaryl compound containing N or a tertiary amine having the formula N(R)3, wherein at least one R group is aryl or heteroaryl. Aromatic amine bases that can be used in this application include, but are not limited to, pyridine, dimethylpyridine (e.g., 2,6-dimethylpyridine, 3,5-dimethylpyridine, and 2,3-dimethylpyridine), trimethylpyridine (e.g., 2,3,4-trimethylpyridine, 2,3,5-trimethylpyridine, 2,3,6-trimethylpyridine, 2,4,5-trimethylpyridine, 2,4,6-trimethylpyridine, and 3,4,5-trimethylpyridine), 4-dimethylaminopyridine, imidazole, dimethylaniline, and diethylaniline.

[0160] In this article, "amidine compounds" refers to a class of chemical compounds including, but not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).

[0161] "Carboxylates" refer to a class of compounds consisting of alkali metal cations or phosphonium and carboxylate anions (RC(O)O). - A chemical compound composed of ) wherein the R group can be alkyl or aryl. Carboxylate salts that can be used in this 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 acetate (KOC(O)C(CH3)3), and tetrabutylphosphonium malonate.

[0162] "Alkaline bicarbonates" refer to a class of compounds consisting of alkali metal cations and bicarbonate anions (HCO3-).- Chemical compounds composed of [missing information]. Basic carbonates that can be used in this disclosure include lithium bicarbonate (LiHCO3), sodium bicarbonate (LiHCO3), potassium bicarbonate (KHCO3), and cesium bicarbonate (CsHCO3).

[0163] "Alkaline carbonates" refer to a class of carbonates composed of alkali metal cations and carbonate anions (CO3-). 2- Chemical compounds composed of [missing information]. Basic carbonates that can be used in this disclosure include lithium carbonate (Li₂CO₃), sodium carbonate (Na₂CO₃), potassium carbonate (K₂CO₃), and cesium carbonate (Cs₂CO₃).

[0164] "Alkaline phosphate trisal" refers to a class of compounds consisting of alkali metal cations and phosphate anions (PO4). 3- Chemical compounds composed of [missing information]. Basic triphosphates that can be used in this disclosure include trisodium phosphate (Na3PO4) and tripotassium phosphate (K3PO4).

[0165] "Alkaline dihydrogen phosphate" refers to a class of dihydrogen phosphates composed of an alkali metal cation and a hydrogen phosphate anion (HPO4). 2- Chemical compounds composed of [missing information]. Basic dihydrogen phosphates that can be used in this disclosure include disodium hydrogen phosphate (Na₂HPO₄) and dipotassium hydrogen phosphate (K₂HPO₄).

[0166] "Alkaline hydroxides" refer to a class of compounds consisting of alkali metal cations and hydroxide anions (OH-). - Chemical compounds composed of [missing information]. The alkaline hydroxides that can be used in this disclosure include lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), and cesium hydroxide (CsOH).

[0167] "Basic alkoxides" refer to a class of compounds consisting of alkali metal cations and alkoxide anions (RO). - A chemical compound composed of ) where R is C 1-4 Alkyl groups. Basic alkoxides that can be used in this disclosure include, but are not limited to, sodium isopropoxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, and potassium isopropoxide.

[0168] "Metalamide" refers to a class of coordination compounds consisting of a metal center having an amide ligand of the form -NR2, wherein R is an alkyl, cycloalkyl, or silyl group. Metalamides that can be used in this disclosure include, but are not limited to, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, 2,2,6,6-tetramethylpiperidine, 2,2,6,6-tetramethylpiperidinyl magnesium chloride, bis(2,2,6,6-tetramethylpiperidinyl)magnesium, and di-n-butyllithium(2,2,6,6-tetramethylpiperidinyl)magnesium.

[0169] "Alkyl and alkenyl metal compounds" refers to a class of chemical compounds consisting of a metal central bond and an alkyl or alkenyl group. Alkyl and alkenyl metal compounds that can be used in this disclosure include, but are not limited to, n-butyllithium, isopropyl magnesium chloride, tri-n-butyllithium magnesium, di-n-butyl magnesium, di-sec-butyl magnesium, and ethyl-n-butyl magnesium.

[0170] "Basic hydrides" refer to a class of compounds consisting of alkali metal cations and hydride anions (H+). - Chemical compounds composed of [missing information]. Basic hydrides that can be used in this disclosure include lithium hydride, sodium hydride, and potassium hydride.

[0171] A “protecting group” is a compound in which a functional group is made unresponsive to a specific set of reaction conditions but 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 compounds disclosed in “Protective Groups in Organic Synthesis”, 4th edition, TW Greene and PGM Watts, John Wiley & Sons, New York, 2006, which is incorporated herein by reference in its entirety.

[0172] "Amino protecting group" refers to a protecting group used to protect an amino group. As used herein, and unless otherwise stated, "amino" means -NH2. Exemplary amino protecting groups include, but are not limited to, benzyloxycarbonyl (Cbz) groups, p-methoxybenzylcarbonyl (Moz or MeOZ) groups, tert-butoxycarbonyl (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), toluenesulfonyl(t) groups, Troc (trichloroethyl chloroformate) groups, and other sulfonamide (Nosyl & Nps) groups.

[0173] "Deprotecting agent" refers to one or more chemical substances or reagents that remove the protecting groups as defined above, thereby restoring the functional groups to their original state.

[0174] "Metal" refers to a metallic element in the periodic table, which may be neutral, or negatively or positively charged due to having more or fewer electrons in its valence shell than a neutral metallic element. Metals that can be used in this disclosure include alkali metals and transition metals. Alkali metals in this disclosure include alkali metal cations. Alkali metal cations that can be used in this disclosure include Li. + Na + K + and Cs +Transition metals that can be used in this 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 that can be used in this disclosure include transition metal cations, such as Cd. 2+ Co 2+ Co + Cr 2+ Cr + Cu + (i.e., Cu(I)), Cu 2+ (i.e., Cu(II)), Fe 2+ Fe + Mn 2+ Mn + Ni 2+ Ni + Pd 2+ (i.e., Pd(II)) and Zn 2+ .

[0175] A "catalyst" is a substance that increases the rate of a chemical reaction by lowering its activation energy, while remaining constant during the reaction. Catalysts can be classified as homogeneous or heterogeneous. A homogeneous catalyst is a catalyst in which the molecules are dispersed in the same phase as the reactant molecules. A heterogeneous catalyst is a catalyst in which the molecules are not in the same phase as the reactants; these reactants are typically gases or liquids adsorbed onto the surface of a solid catalyst. The catalysts used in this disclosure are both homogeneous and heterogeneous catalysts.

[0176] "Transition metal catalysts" refer to compounds composed of transition metals as defined above, which can be neutral or positively charged.

[0177] A "ligand" is a molecule (functional group) that bonds to a central metal atom to form a coordination complex. Bonding to a metal typically involves one or more electron pairs formally donating electrons to the ligand. The nature of the metal-ligand bond can range from covalent to ionic. Furthermore, the metal-ligand bond sequence can range from one to three. Typically, the ligand is considered an electron donor and the metal as an electron acceptor. Exemplary ligands in this disclosure are tertiary amines as defined above, polypyridyl ligands as defined herein, and amino acids as defined herein.

[0178] "Polypyridyl ligands" refer to a class of compounds containing at least two pyridine moieties linked by chemical bonds (e.g., 2,2'-bipyridine compounds) or as 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.

[0179] "Amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs that function in a manner similar to naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those subsequently modified, such as hydroxyproline, γ-carboxyglutamic acid, and O-phosphoserine.

[0180] A “phase transfer agent” or “phase transfer catalyst (PTC)” is a catalyst that facilitates the migration of reactants from one phase to another phase in which the reaction occurs. Phase transfer catalysis is a special form of heterogeneous catalysis. In the absence of a phase transfer catalyst, ionic reactants are typically soluble in the aqueous phase but insoluble in the organic phase. The catalyst acts similarly to a detergent that dissolves a salt into the organic phase. By using the PTC method, faster reactions can be achieved, higher conversions or yields can be obtained, fewer byproducts can be produced, the need for expensive or hazardous solvents that dissolve all reactants in one phase can be eliminated, the need for expensive feedstocks can be eliminated, and / or waste problems can be minimized. PTC is not limited to systems with both hydrophilic and hydrophobic reactants. PTC is sometimes used in liquid / solid and liquid / gas reactions. As the name suggests, it transports one or more of the reactants to a second phase containing both reactants. Phase transfer catalysts used for anionic reactants are typically quaternary ammonium salts, as defined herein.

[0181] "Quaternary ammonium salt" refers to a salt of a quaternary ammonium cation, as defined herein. A quaternary ammonium cation, also known as quaternary ammonium, is a cation with the formula NR4. + Positively charged compounds, wherein the R group can be alkyl, aryl, or a combination thereof. With ammonium ions (NH4+) + Unlike primary, secondary, or tertiary ammonium cations, quaternary ammonium cations are permanently charged, regardless of the pH of their solution.

[0182] "Activator" refers to a reagent capable of converting a less reactive functional group in a molecule into a more reactive functional group, which has an increased tendency to undergo the specified chemical reaction. In some embodiments, for example, the activator 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 activator 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). Other non-limiting examples of reactive functional groups include OSO3H and -OSO3 - .

[0183] "Chlorinating agents" are reagents that can add a chlorine group (-Cl) to a compound. Representative chlorinating agents include, but are not limited to, phosphorus oxychloride, thionyl chloride, oxalyl chloride, and thionyl chloride.

[0184] "Brominizing agent" refers to a reagent that can add a bromine group (-Br) to a compound. Representative brominating agents include, but are not limited to, bromine, N-bromosuccinimide, dibromotriphenylphosphine, tetrabutylammonium tribromide, trimethylphenylammonium tribromide, N-bromoacetamide, pyridinium tribromide, dibromodimethylhydantoin, tribromoisocyanuric acid, N-bromosaccharin, and 1,2-dibromo-1,1,2,2-tetrachloroethane.

[0185] "Sulfonating agent" refers to an agent that can add sulfonic acid groups -OSO3 to a compound. - The reagent. Representative sulfonating agents include, but are not limited to, sulfur trioxide, sulfur trioxide complexes (e.g., dioxane, pyridine, polyvinylpyridine, trimethylamine, triethylamine, dimethylaniline, oxothiazane, 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, tetramethylhexamethylenediamide, ethyl N,N'-dimethylcarbamate, formylmorpholine, N,N'-dimethylbenzamide, dimethylcyanamide, n-propylpiperidine, n-isopentylpiperidine, N-benzylpiperidine, trimethylphosphine oxide, tetrahydrofuran, diethyl sulfide, anthraquinone, benzoanthrone, benzonaphthone, or 2,6-dimethyl-γ-pyranone), chlorosulfonic acid, and sulfur dioxide.

[0186] "Accelerator" refers to a substance added to reactants (e.g., chlorinating agents as described above) to improve their performance in a chemical reaction (e.g., the formation of an acyl chloride of formula VII from an acid of formula VIII). The accelerator itself has little or no catalytic effect in the reaction.

[0187] “Cyclization agent” or “cyclization agents” means one or more reagents (when used in combination) that can promote cyclization reactions by reactions known in the art (e.g., the formation of 4,5-dihydrooxazole from compounds of formula V).

[0188] "Solvent" refers to a substance capable of dissolving a solute, such as a liquid. 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 protons that can be removed, such as by having hydroxyl or carboxyl groups. Protic solvents lack such groups. Representative polar protic solvents include alcohols (methanol, ethanol, propanol, isopropanol, etc.), acids (formic acid, acetic acid, etc.), 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 nonpolar solvents include alkanes (pentane, hexane, etc.), cycloalkanes (cyclopentane, cyclohexane, etc.), benzene, and toluene. Other solvents may be used in this disclosure.

[0189] Solvents can also be grouped 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 (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.).

[0190] “Salt” means an acid or base salt of a compound used in the methods of this disclosure. Salts that can be used in this disclosure include, but are not limited to, hemisulfates, sulfates, chlorides, bromides, carbonates, nitrates, and acetates. A hemisulfate is a compound in which only one of only two basic groups forms a salt with sulfuric acid. Carbonates include salts of bicarbonates (or biscarbonates). Exemplary examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, and quaternary ammonium (iodomethane, iodoethane, etc.) salts. It should be understood that pharmaceutically acceptable salts are non-toxic. Further information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0191] III. Methods for preparing compounds

[0192] This disclosure includes several methods for preparing compounds of formula I.

[0193] A. A method for preparing compounds of formula I from formula III

[0194] 1. Prepare Formula I from Formula III

[0195] In some embodiments, this disclosure provides a method for preparing compounds of formula I:

[0196]

[0197] A method using its salt or a salt thereof, the method comprising:

[0198] a) Forming a first reaction mixture comprising compounds of formula III:

[0199]

[0200] Or its salt, a compound having the formula PG-NHC(=NH)NH2 or its salt, a first base and a first solvent, to form a compound of formula II:

[0201]

[0202] or its salt; and

[0203] b) Forming a second reaction mixture comprising a compound of formula II or a salt thereof,

[0204] Deprotecting agent and second solvent to provide a compound of formula I or a salt thereof.

[0205] Where R 1 R 2 and R 3 They can be hydrogen, F, Cl, CN, CF3, and C, respectively. 1-3 Alkyl or C 1-3 Alkoxy; R 4 It can be hydrogen or methyl; R 5 It can be C 3-6 Alkyl group; X can be F, Cl, Br, I or OTs; and PG can be an amino protecting group.

[0206] In one embodiment, this disclosure provides a method for preparing compounds of formula I:

[0207]

[0208] A method using its salt or a salt thereof, the method comprising:

[0209] a) Forming a first reaction mixture comprising compounds of formula III:

[0210]

[0211] Or its salt, a compound having the formula PG-NHC(=NH)NH2 or its salt, a first transition metal catalyst, a first base and a first solvent, to form a compound of formula II:

[0212]

[0213] or its salt; and

[0214] b) Forming a second reaction mixture comprising a compound of formula II or a salt thereof,

[0215] Deprotecting agent and second solvent to provide a compound of formula I or a salt thereof.

[0216] Where R 1 R 2 and R 3 They can be hydrogen, F, Cl, CN, CF3, and C, respectively. 1-3 Alkyl or C 1-3 Alkoxy; R 4 It can be hydrogen or methyl; R 5 It can be C 3-6 Alkyl group; X can be F, Cl, Br, I or OTs; and PG can be an amino protecting group.

[0217] In one embodiment, this disclosure provides a method for preparing compounds of formula I:

[0218]

[0219] A method using its salt or a salt thereof, the method comprising:

[0220] a) Forming a first reaction mixture comprising compounds of formula III:

[0221]

[0222] Or its salt, a compound having the formula PG-NHC(=NH)NH2 or its salt, a first transition metal catalyst, a first base and a first solvent, to form a compound of formula II:

[0223]

[0224] or its salt; and

[0225] b) Forming a second reaction mixture comprising a compound of formula II or a salt thereof,

[0226] Deprotecting agent and second solvent to provide a compound of formula I or a salt thereof.

[0227] Where R 1 R 2 and R 3 They can be hydrogen, F, Cl, CN, CF3, and C, respectively. 1-3 Alkyl or C 1-3 Alkoxy; R 4 It can be hydrogen or methyl; R 5 It can be C 3-6 Alkyl group; X can be Cl, Br, I or OTs; and PG can be an amino protecting group.

[0228] Compounds having the formula PG-NHC(=NH)NH2 can be in any suitable form. In some embodiments, compounds having the formula PG-NHC(=NH)NH2 can be in a neutral form. In some embodiments, compounds having the formula PG-NHC(=NH)NH2 can be in salt form. In some embodiments, compounds having the formula PG-NHC(=NH)NH2 can be its hemisulfate, sulfate, chloride, bromide, carbonate, nitrate, or acetate. In some embodiments, compounds having the formula PG-NHC(=NH)NH2 can have the formula IX:

[0229]

[0230] Where n can be 0 to 1. In some embodiments, the compound of formula IX can be a hemisulfate (where n can be 1 / 2), a sulfate (where n can be 1), or a combination thereof. In some embodiments, the compound of formula IX can be a hemisulfate (where n can be 1 / 2).

[0231] PG can be an amino protecting group. Suitable amino protecting groups include, but are not limited to, benzyloxycarbonyl (Cbz) groups, p-methoxybenzylcarbonyl (Moz or MeOZ) groups, tert-butoxycarbonyl (BOC) groups, 2-trimethylsilaneethoxymethyl (SEM) groups, 9-fluorenylmethoxycarbonyl (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, toluenesulfonyl (Ts) groups, Troc (trichloroethyl chloroformate) groups, and other sulfonamide (Nosyl & Nps) groups. In some embodiments, PG can be 2,4-dimethoxybenzyl.

[0232] In some embodiments, the compound of formula IX may have formula IXa:

[0233]

[0234] Where n can be 0 to 1. In some embodiments, the compound of formula IXa can be a hemisulfate (where n can be 1 / 2), a sulfate (where n can be 1), or a combination thereof. In some embodiments, the compound of formula IXa can be a hemisulfate having formula IXb:

[0235]

[0236] 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, but are not limited to, Cd. 2+ Co 2+ Co + Cr 2+ Cr + Cu + (i.e., Cu(I)), Cu 2+ (i.e., Cu(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 comprises copper metal, copper oxide, copper (I) salt, copper (II) salt, or combinations thereof. In some embodiments, the first transition metal catalyst comprises a copper (I) salt. In some embodiments, the first transition metal catalyst comprises a copper (II) salt. In some embodiments, the first transition metal catalyst may be copper iodide (I), copper bromide (I), copper chloride (I), copper acetate (I), copper carbonate (I), copper nitrate (I), copper sulfate (I), copper phosphate (I), copper 3-methylsalicylate (I), copper thiophene-2-carboxylate (I), copper oxide (I), copper iodide (II), copper bromide (II), copper chloride (II), copper acetate (II), copper carbonate (II), copper nitrate (II), copper sulfate (II), copper pyrophosphate (II), copper phosphate (II), copper tartrate (II), copper oxide (II), or combinations 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 combinations thereof. In some embodiments, the first transition metal catalyst comprises copper(II) acetate. In some embodiments, the first transition metal catalyst may be copper(II) acetate.

[0237] The first base can be a basic carbonate, a basic bicarbonate, a basic triphosphate, a carboxylate, an amidine compound, or a combination thereof. Suitable basic carbonates include lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Suitable basic bicarbonates include lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate. Suitable basic triphosphates include trisodium phosphate and tripotassium phosphate. Suitable carboxylatees include, but are not limited to, lithium acetate, sodium acetate, potassium acetate, cesium acetate, potassium trimethylacetate, and tetrabutylphosphonium malonate. 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). In some embodiments, the first base may be lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, trisodium phosphate, tripotassium 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 combinations thereof. In some embodiments, the first base includes tripotassium phosphate. In some embodiments, the first base may be tripotassium phosphate.

[0238] The first solvent can be any suitable polar or nonpolar protic or aprotic solvent. In some embodiments, the first solvent can be acetonitrile, propionitrile, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentylmethyl ether, isopropanol, 2-methylbut-2-ol, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, toluene, trifluorotoluene, xylene, or combinations 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 can be 2-methyltetrahydrofuran and acetonitrile.

[0239] In some embodiments, the first reaction mixture further comprises a first ligand. In some embodiments, the first ligand may be an amino acid, a polypyridyl ligand, or a tertiary amine. Suitable amino acids include naturally occurring and synthetic amino acids, as well as amino acid analogs that function in a manner similar 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"-tert-bipyridine. 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 may be arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, α-(methyl) The first ligand comprises (amino) isobutyric acid, (4-methyl-1-piperazinyl)acetic acid, N-acetylcysteine, 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 combinations thereof. In some embodiments, the first ligand comprises cysteine, selenocysteine, N-acetylcysteine, or homocysteine. In some embodiments, the first ligand comprises cysteine. In some embodiments, the first ligand comprises L-cysteine. In some embodiments, the first ligand may be cysteine, selenocysteine, N-acetylcysteine, or homocysteine. In some embodiments, the first ligand may be cysteine. In some embodiments, the first ligand may be L-cysteine.

[0240] Typically, the first reaction (i.e., step a) can be carried out at ambient temperature to elevated temperatures. For example, the first reaction mixture can be carried out at a temperature of 30°C to 110°C or heated to reflux. In some embodiments, the first reaction mixture can be carried out at temperatures 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 carried out at a temperature of 55°C to the reflux temperature. In some embodiments, the first reaction mixture can be heated to reflux.

[0241] Once the first reaction is complete, the first transition metal catalyst can be removed from the reaction mixture using a second ligand (e.g., ethylenediaminetetraacetic acid (EDTA) or disodium EDTA). In some embodiments, the first transition metal catalyst can be removed from the first reaction mixture using a second ligand upon completion of the first reaction. In some embodiments, the second ligand comprises ethylenediaminetetraacetic acid or a salt thereof. In some embodiments, the first transition metal catalyst can be removed from the first reaction mixture using ethylenediaminetetraacetic acid or a salt thereof upon completion of the first reaction. In some embodiments, Cu(II) can be removed from the first reaction mixture using disodium ethylenediaminetetraacetic acid upon completion of the first reaction.

[0242] Compounds of Formula II can be deprotected by various methods known in the art to provide compounds of Formula I or salts thereof. When PG is 2,4-dimethoxybenzyl, compounds of Formula II can be deprotected by various methods, such as under acidic, reducing (hydrogenolysis) or oxidizing conditions, to provide compounds of Formula I or salts thereof.

[0243] In some embodiments, the deprotecting agent may be an acid. In some embodiments, the acid may be trifluoroacetic acid, trichloroacetic acid, acetic acid, formic acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof. In some embodiments, the acid includes trifluoroacetic acid. In some embodiments, the acid may be trifluoroacetic acid.

[0244] In some embodiments, the deprotecting agent may be a hydrogen source, and the second reaction mixture further comprises a second transition metal catalyst. In some embodiments, the hydrogen source may be ammonium formate, formic acid, hydrogen, or a combination thereof. In some embodiments, the hydrogen source comprises hydrogen. In some embodiments, the hydrogen source comprises ammonium formate. In some embodiments, the hydrogen source comprises formic acid. In some embodiments, the second transition metal catalyst may be carbon-supported palladium hydroxide, carbon-supported palladium, or platinum oxide. In some embodiments, the second transition metal catalyst comprises carbon-supported palladium hydroxide. In some embodiments, the second transition metal catalyst comprises carbon-supported palladium. In some embodiments, the second transition metal catalyst comprises platinum oxide. In some embodiments, the deprotecting agent may be hydrogen, and the second reaction mixture further comprises carbon-supported palladium hydroxide, carbon-supported palladium, or platinum oxide. In some embodiments, the deprotecting agent comprises ammonium formate, and the second reaction mixture further comprises carbon-supported palladium hydroxide, carbon-supported palladium, or platinum oxide. In some embodiments, the deprotecting agent comprises formic acid, and the second reaction mixture further comprises carbon-supported palladium hydroxide, carbon-supported palladium, or platinum oxide. In some embodiments, the deprotecting agent comprises formic acid, and the second solvent comprises formic acid.

[0245] In some embodiments, the hydrogen source may be hydrogen gas. In some embodiments, the hydrogen source may be ammonium formate. In some embodiments, the hydrogen source may be formic acid. In some embodiments, the second transition metal catalyst may be carbon-supported palladium hydroxide. In some embodiments, the second transition metal catalyst may be carbon-supported palladium. In some embodiments, the second transition metal catalyst may be platinum oxide. In some embodiments, the deprotecting agent may be ammonium formate, and the second reaction mixture further comprises carbon-supported palladium hydroxide, carbon-supported palladium, or platinum oxide. In some embodiments, the deprotecting agent may be formic acid, and the second reaction mixture further comprises carbon-supported palladium hydroxide, carbon-supported palladium, or platinum oxide. In some embodiments, the deprotecting agent may be formic acid, and the second solvent may be formic acid.

[0246] In some embodiments, the deprotectant may be boron tribromide, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, cerium ammonium nitrate, or a combination of trifluoromethanesulfonic acid and 1,3-dimethoxybenzene.

[0247] The second solvent can be any suitable polar or nonpolar protic or aprotic solvent. In some embodiments, the second solvent can 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 combinations thereof. In some embodiments, the second solvent includes formic acid. In some embodiments, the second solvent includes dichloromethane. In some embodiments, the second solvent can be formic acid. In some embodiments, the second solvent can be dichloromethane.

[0248] Typically, the second reaction (i.e., step b) can be carried out at any suitable temperature, for example, between -10°C and 80°C. In some embodiments, the second reaction mixture can be at temperatures between -10°C and 80°C, 0°C and 50°C, 10°C and 50°C, 20°C and 50°C, or 20°C and 40°C. In some embodiments, the second reaction mixture can be at temperatures between 20°C and 40°C. In some embodiments, the second reaction mixture can be at a temperature of about 30°C. In some embodiments, the second reaction mixture can be at a temperature of about 40°C. In some embodiments, the second solvent comprises dichloromethane, and the second reaction mixture can be heated to reflux. In some embodiments, the second solvent can be dichloromethane, and the second reaction mixture can be heated to reflux.

[0249] 2. Preparation of Formula III from Formula IV

[0250] In some implementations, the method further includes, prior to step a):

[0251] a1) Forming a third reaction mixture comprising compounds of formula IV:

[0252]

[0253] or its salt, a second base and a third solvent, to form a compound of formula III or its salt, wherein AG 1 It is Cl, Br, OSO3H, OSO3 - OMs, OTs, or OTf.

[0254] In some implementations, the method further includes, prior to step a):

[0255] a1) Forming a third reaction mixture comprising compounds of formula IV:

[0256]

[0257] or its salt, a second base and a third solvent, to form a compound of formula III or its salt, wherein AG 1 It is Cl, Br, OMs, OTs, or OTf.

[0258] The second base can be a tertiary amine, an aromatic amine base, a basic carbonate, a basic bicarbonate, a basic triphosphate, a basic 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, dimethylpyridine (e.g., 2,6-dimethylpyridine, 3,5-dimethylpyridine, and 2,3-dimethylpyridine), trimethylpyridine (e.g., 2,3,4-trimethylpyridine, 2,3,5-trimethylpyridine, 2,3,6-trimethylpyridine, 2,4,5-trimethylpyridine, 2,4,6-trimethylpyridine, and 3,4,5-trimethylpyridine), and 4-dimethylaminopyridine. Suitable basic carbonates include lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Suitable basic bicarbonates include lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate. Suitable basic triphosphates include trisodium phosphate and tripotassium phosphate. Suitable basic 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-dimethylpyridine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, tripotassium phosphate, sodium hydroxide, potassium hydroxide, or combinations thereof. The second base may be in an aqueous solution. In some embodiments, the second base comprises an aqueous solution of sodium hydroxide. In some embodiments, the second base may be an aqueous solution of sodium hydroxide.

[0259] The third solvent can be any suitable polar aprotic solvent or nonpolar solvent. In some embodiments, the third solvent can be tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, xylene, or combinations thereof. In some embodiments, the third solvent includes 2-methyltetrahydrofuran. In some embodiments, the third solvent can be 2-methyltetrahydrofuran.

[0260] 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 includes 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 bisulfate, 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 bisulfate. In some embodiments, the quaternary ammonium salt can be tetra-n-butylammonium bisulfate. In some embodiments, the phase transfer agent can be tetra-n-butylammonium bisulfate.

[0261] Typically, the third reaction (i.e., step a1) can be carried out at any suitable temperature. For example, the third reaction mixture can be carried out at a temperature from 0°C to 80°C. In some embodiments, the third reaction mixture can be carried out at a temperature from 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 carried out at a temperature from 15°C to 50°C. In some embodiments, the third reaction mixture can be carried out at a temperature of about 35°C.

[0262] In some embodiments, the compound of formula IV has the following formula:

[0263]

[0264] In some embodiments, the compound of formula IV has the following formula:

[0265]

[0266] Where Y + It is a metal ion M + or ammonium salt HA + Any suitable metal ion M can be used. + This includes, but is not limited to, lithium, sodium, potassium, calcium, or cesium. Any suitable ammonium salt (HA) can be used. + This includes, but is not limited to, trimethylammonium, triethylammonium, or dicyclohexammonium. In some embodiments, Y + It is sodium. In some implementations, Y + It is HNMe3 + In some embodiments, the compound of formula IV has the following formula:

[0267]

[0268] In some embodiments, the third solvent includes acetonitrile, propionitrile, butyronitrile, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, 2-methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, cyclopentylmethyl 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 may be 2-methyl-2-butanol.

[0269] In some embodiments, the third reaction mixture further includes additives. Suitable additives include, but are not limited to, thionyl chloride, oxalyl chloride, phosphorus oxychloride (V), phosphorus pentachloride (V), methanesulfonyl chloride, p-toluenesulfonic acid, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, water, acetic anhydride, 4-dimethylaminopyridine, or tetrabutylammonium salts (e.g., hydrogen sulfate, chloride, bromide, or iodide salts). In some embodiments, no additives are present.

[0270] 3. Preparation of Formula IV from Formula V

[0271] In some implementations, the method further includes, prior to step a1):

[0272] a2) Forming a fourth reaction mixture comprising compounds of formula V:

[0273]

[0274] Or its salt, a first activator, and a fourth solvent, to form a compound of formula IV:

[0275]

[0276] Or its salt.

[0277] In some implementation schemes, AG 1 It can be Cl; and the first activator can be the first chlorinating agent. The first chlorinating agent can be any suitable chlorinating agent capable of converting the -OH group of formula V into the corresponding -Cl group (i.e., AG). 1 It can be Cl from Formula IV. In some embodiments, the first chlorinating agent can 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 can be oxalyl chloride. In some embodiments, the first chlorinating agent is thionyl chloride.

[0278] In some implementation schemes, AG 1 It can be Br; and the first activator can be a brominating agent. The brominating agent can be any suitable brominating agent capable of converting the -OH group of formula V into the corresponding -Br group (i.e., AG). 1 It can be Br in Formula IV). In some embodiments, the brominating agent can be dibromotriphenylphosphine or tribromoisocyanuric acid.

[0279] In some implementation schemes, AG 1It can be OMs, OTs, or OTf; and the first activator can be methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride, p-toluenesulfonic acid, p-toluenesulfonic anhydride, or trifluoromethanesulfonic anhydride. In some embodiments, AG 1 It can be OMs; and the first activator can be methanesulfonyl chloride or methanesulfonic anhydride. In some embodiments, AG 1 It can be OMs; and the first activator includes methanesulfonyl chloride. In some embodiments, AG 1 It can be OTs; and the first activator includes p-toluenesulfonyl chloride. In some embodiments, AG 1 It can be OTf; and the first activator includes trifluoromethanesulfonic anhydride. In some embodiments, AG 1 It can be OTs; and the first activator can be p-toluenesulfonyl chloride. In some embodiments, AG 1 It can be OTf; and the first activator can be trifluoromethanesulfonic anhydride.

[0280] The fourth solvent can be any suitable polar aprotic solvent and / or nonpolar solvent. In some embodiments, the fourth solvent can be tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, xylene, or combinations thereof. In some embodiments, the fourth solvent includes 2-methyltetrahydrofuran. In some embodiments, the fourth solvent can be 2-methyltetrahydrofuran.

[0281] Typically, when the first activator can be the 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 carried out at a temperature of 0°C to 80°C. In some embodiments, the fourth reaction mixture can be carried out 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 carried out at a temperature of 15°C to 50°C. In some embodiments, the fourth reaction mixture can be carried out at a temperature of about 50°C.

[0282] In some implementations, the method further includes, prior to step a1):

[0283] a2) Forming a fourth reaction mixture comprising compounds of formula V:

[0284]

[0285] Or its salt, a first activator, and a fourth solvent, to form a compound of formula IV-2:

[0286] as well as

[0287] Compounds of formula IV-2 or their salts are treated with an ion-exchange reagent in a fourth solvent to form compounds of formula IV:

[0288]

[0289] or its salt, wherein AG 1 Is it OSO3H or OSO3? - .

[0290] In some implementation schemes, AG 1 It can be OSO3H or OSO3 - Furthermore, the first activator can be a sulfonating agent. The sulfonating agent can be one capable of converting the -OH group of formula V into the corresponding -OSO3H or OSO3. - Any suitable sulfonating agent. In some embodiments, the sulfonating agent may be sulfur trioxide, chlorosulfonic acid, sulfur dioxide, or a sulfur trioxide complex. In some embodiments, the sulfur trioxide complex can be sulfur trioxide complexed with dioxane, pyridine, polyvinylpyridine, trimethylamine, triethylamine, dimethylaniline, oxothiazepine, 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, tetramethylhexamethylenediamide, ethyl N,N'-dimethylcarbamate, formylmorpholine, N,N'-dimethylbenzamide, dimethylcyanamide, n-propylpiperidine, n-isopentylpiperidine, N-benzylpiperidine, trimethylphosphine oxide, tetrahydrofuran, diethyl sulfide, anthraquinone, benzoanthrone, benzonaphthone, or 2,6-dimethyl-γ-pyranone. In some embodiments, the sulfonating agent includes a sulfur trioxide trimethylamine complex. In some embodiments, the sulfonating agent may be a sulfur trioxide trimethylamine complex.

[0291] In some embodiments of the compound of formula IV-2, wherein Y + It is hydrogen, pyridinium, trimethylammonium, triethylammonium, methylpyridinium, quinolineon, tri-n-propylammonium, tri-n-butylammonium, morpholinium optionally substituted with methyl, ethyl, or n-butyl, pentamethylguanidineonium, N,N'-dimethylethylenediammonium, dimethylaminocyanide, or benzylpiperidinium. In some embodiments of formula IV-2, Y + It is trimethylammonium.

[0292] In some embodiments, the ion exchange agent may be an ion exchange resin (e.g., ion exchange resin I, II, III, IV or V); IR-120, for example, H + Form, Na +Forms, IRA-67, IRA-402, IRA-410, 15; and For example, 50W x 4, 50W-XZ8, 1-X8); mineral acids (e.g., hydrochloric acid or hydrobromic acid); carboxylates (e.g., disodium sebate, sodium hexanoate, sodium 2-ethylhexanoate, calcium 2-ethylhexanoate, or potassium 2-ethylhexanoate); hydroxides or alkoxides (e.g., lithium tert-butoxide, sodium tert-pentoxide, potassium tert-pentoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, or cesium hydroxide); amines (e.g., dicyclohexylamine or N-methylcyclohexylamine); or others (e.g., sodium tetrafluoroborate, dipotassium hydrogen phosphate, calcium sulfate, or ferrocyanide). In some embodiments, the ion exchange reagent includes sodium 2-ethylhexanoate. In some embodiments, the ion exchange reagent may be sodium 2-ethylhexanoate.

[0293] In some embodiments, the compound of formula IV is in the form of an acid having the following formula:

[0294]

[0295] In some embodiments, the compound of formula IV is in the form of a salt having the following formula:

[0296]

[0297] Where Y + It is a metal ion M + or ammonium salt HA + Any suitable metal ion M can be used. + 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 dicyclohexammonium. In some embodiments, Y + It is sodium. In some embodiments, the compound of formula IV has the following formula:

[0298]

[0299] In some embodiments, the fourth solvent can be any suitable polar aprotic solvent and / or nonpolar solvent. In some embodiments, the fourth solvent can be acetonitrile, propionitrile, butyronitrile, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, 2-methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, cyclopentylmethyl ether, isopropyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, acetone, methyl isobutyl ketone, toluene, trifluorotoluene, xylene, benzonitrile, dichloromethane, 1,2-dichloroethane, chlorobenzene, or combinations thereof. In some embodiments, the fourth solvent includes acetonitrile, 2-methyltetrahydrofuran, or combinations thereof. In some embodiments, the fourth solvent includes acetonitrile and 2-methyltetrahydrofuran. In some embodiments, the fourth solvent can be acetonitrile, 2-methyltetrahydrofuran, or combinations thereof. In some embodiments, the fourth solvent can be acetonitrile and 2-methyltetrahydrofuran.

[0300] Typically, the sulfonation and ion exchange steps of the fourth reaction (i.e., step a2) can be carried out at any suitable temperature. For example, the sulfonation reaction mixture can be carried out at a temperature of 0°C to 100°C. In some embodiments, the sulfonation reaction mixture can be carried out at temperatures 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 carried out at a temperature of 60°C to 80°C. For example, the ion exchange reaction mixture can be carried out at a temperature of 0°C to 50°C. In some embodiments, the ion exchange reaction mixture can be carried out 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 carried out at a temperature of about 20°C.

[0301] 4. Prepare Formula III from Formula V

[0302] In some implementations, the method further includes, prior to step a):

[0303] a1-2) forms a fifth reaction mixture, which comprises compounds of formula V:

[0304]

[0305] Or its salt, one or more cyclizing agents and a fifth solvent, to form a compound of formula III or its salt.

[0306] The one or more cyclizing agents can be any suitable reagent capable of forming a 4,5-dihydrooxazole moiety from a compound of formula V via cyclization. The one or more cyclizing agents can be reagents 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 can be dehydrating agents used alone, such as methyl N-(triethylammonium sulfonyl)-carbamate (also known as Burgess reagent). The one or more cyclizing agents can be diethylaminosulfonium trifluoride (DAST) that 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, N-(triethylammonium sulfonyl)-methyl carbamate, or diethylaminosulfonium trifluoride.

[0307] The fifth solvent can be any suitable polar aprotic solvent and / or nonpolar solvent. In some embodiments, the fifth solvent can be tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, xylene, or combinations thereof. In some embodiments, the fifth solvent includes 2-methyltetrahydrofuran. In some embodiments, the fifth solvent can be 2-methyltetrahydrofuran.

[0308] 5. Formula V is prepared from Formula VII and Formula VI.

[0309] In some implementations, the method further includes, prior to step a2) or a1-2):

[0310] a3) Forming a sixth reaction mixture comprising compounds of formula VII:

[0311]

[0312] Or its salts, or compounds of formula VI:

[0313]

[0314] Or its salt, third base and sixth solvent, to form a compound of formula V or its salt.

[0315] The compounds of formula VI can be in any suitable form. In some embodiments, the compounds of formula VI can be in a neutral form. In some embodiments, the compounds of formula VI can be in salt form. In some embodiments, the compounds of formula VI can be their toluenesulfonate salts.

[0316] The third base can be a tertiary amine, an aromatic amine base, a basic carbonate, a basic bicarbonate, a basic triphosphate, a basic 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, dimethylpyridine (e.g., 2,6-dimethylpyridine, 3,5-dimethylpyridine, and 2,3-dimethylpyridine), trimethylpyridine (e.g., 2,3,4-trimethylpyridine, 2,3,5-trimethylpyridine, 2,3,6-trimethylpyridine, 2,4,5-trimethylpyridine, 2,4,6-trimethylpyridine, and 3,4,5-trimethylpyridine), and 4-dimethylaminopyridine. Suitable basic carbonates include lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Suitable basic bicarbonates include lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate. Suitable basic triphosphates include trisodium phosphate and tripotassium phosphate. Suitable basic 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-dimethylpyridine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, tripotassium phosphate, sodium hydroxide, potassium hydroxide, or combinations thereof. 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.

[0317] The sixth solvent can be any suitable polar aprotic solvent and / or nonpolar solvent. In some embodiments, the sixth solvent further comprises water. In those embodiments, the sixth reaction (i.e., step a3) can be a biphasic reaction. In some embodiments, the sixth solvent can be tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, xylene, water, or combinations thereof. In some embodiments, the sixth solvent comprises 2-methyltetrahydrofuran. In some embodiments, the sixth solvent comprises 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.

[0318] Typically, the sixth reaction (i.e., step a3) can be carried out at any suitable temperature. For example, the fourth reaction mixture can be carried out at a temperature of 0°C to 60°C. In some embodiments, the fourth reaction mixture can be carried out 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 carried out at a temperature of 20°C to 30°C. In some embodiments, the third reaction mixture can be carried out at a temperature of about 20°C.

[0319] 6. Prepare Formula VII from Formula VIII

[0320] In some implementations, the method further includes, prior to step a3):

[0321] a4) Forming a seventh reaction mixture comprising compounds of formula VIII:

[0322]

[0323] Or its salt, second chlorinating agent, accelerator and seventh solvent, to form a compound of formula VII or its salt.

[0324] 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 oxychloride, phosphorus pentachloride, or (chloromethylene)dimethylammonium 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 can be oxalyl chloride. In some embodiments, the second chlorinating agent can be thionyl chloride.

[0325] In some embodiments, the accelerator may be N,N-dimethylformamide, N,N-dimethylacetamide, or dichloromethylene-dimethylammonium chloride. In some embodiments, the accelerator includes N,N-dimethylformamide. In some embodiments, the accelerator may be N,N-dimethylformamide.

[0326] The seventh solvent can be any suitable polar aprotic solvent and / or nonpolar solvent. In some embodiments, the seventh solvent can be tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, xylene, or combinations thereof. In some embodiments, the seventh solvent includes 2-methyltetrahydrofuran. In some embodiments, the seventh solvent can be 2-methyltetrahydrofuran.

[0327] Typically, the seventh reaction (i.e., step a4) can be carried out at any suitable temperature. For example, the seventh reaction mixture can be carried out at a temperature from 0°C to 60°C. In some embodiments, the seventh reaction mixture can be carried out at a temperature from 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 carried out at a temperature from 20°C to 30°C. In some embodiments, the seventh reaction mixture can be carried out at a temperature of about 20°C.

[0328] 7. Prepare formula V from formulas VIII and VI

[0329] In some implementations, the method further includes, prior to step a2) or a1-2):

[0330] a3-1) forms an eighth reaction mixture comprising compounds of formula VIII:

[0331]

[0332] Or its salts, or compounds of formula VI:

[0333]

[0334] Or its salt, second activator, fourth base and eighth solvent, to form a compound of formula V or its salt.

[0335] The compounds of formula VI can be in any suitable form. In some embodiments, the compounds of formula VI can be in a neutral form. In some embodiments, the compounds of formula VI can be in salt form. In some embodiments, the compounds of formula VI can be their toluenesulfonate salts.

[0336] The second activator can be any peptide coupling agent capable of activating an acid group (e.g., an acid group of formula III) to react with an amine (e.g., a compound of formula VI) to form an amide bond (e.g., an amide group of formula V). Peptide coupling agents 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'-tetramethylurea hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), hydroxybenzotriazole (HOBt), and 1-hydroxy-7-azabenzotriazole (HOAt). In some implementations, the second activator may be isobutyl chloroformate or 1,1'-carbonyldiimidazole.

[0337] The fourth base can 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, dimethylpyridine (e.g., 2,6-dimethylpyridine, 3,5-dimethylpyridine, and 2,3-dimethylpyridine), trimethylpyridine (e.g., 2,3,4-trimethylpyridine, 2,3,5-trimethylpyridine, 2,3,6-trimethylpyridine, 2,4,5-trimethylpyridine, 2,4,6-trimethylpyridine, and 3,4,5-trimethylpyridine), and 4-dimethylaminopyridine. In some embodiments, the fourth base may be triethylamine, tri-n-butylamine, N,N-diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine, pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine, or combinations thereof. In some embodiments, the fourth base comprises N,N-diisopropylethylamine. In some embodiments, the fourth base may be N,N-diisopropylethylamine.

[0338] The eighth solvent can be any suitable polar aprotic solvent and / or nonpolar solvent. In some embodiments, the eighth solvent can be N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, acetonitrile, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, xylene, or combinations 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 can be N,N-dimethylformamide. In some embodiments, the eighth solvent can be 2-methyltetrahydrofuran. In some embodiments, the eighth solvent can be N,N-dimethylformamide and 2-methyltetrahydrofuran.

[0339] A compound of formula I in a neutral form 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 a salt of the compound of formula I, a fifth base, and a ninth solvent to provide a compound of formula I in a neutral form.

[0340] The fifth base can be a basic carbonate or a basic hydroxide. Suitable basic carbonates include sodium carbonate and potassium carbonate. Suitable basic 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 includes sodium hydroxide. In some embodiments, the fifth base can be in an aqueous solution. In some embodiments, the fifth base includes 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.

[0341] The ninth solvent can be any suitable alcohol solvent, ester solvent, and / or water. In some embodiments, the ninth solvent can 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 can be i) ethanol and water or ii) ethyl acetate and water. In some embodiments, the ninth solvent can be ethanol and water. In some embodiments, the ninth solvent can be ethyl acetate and water.

[0342] When the ninth solvent includes an ester solvent (e.g., ethyl acetate or isopropyl acetate), the partitioned reaction mixture may be further treated with an aqueous solution of sodium bicarbonate upon completion of the reaction.

[0343] Typically, the ninth reaction (i.e., step c) can be carried out at any suitable temperature. For example, the ninth reaction mixture can be carried out at a temperature from 0°C to 60°C. In some embodiments, the ninth reaction mixture can be carried out at a temperature from 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 carried out at a temperature from 20°C to 40°C. In some embodiments, the ninth reaction mixture can be carried out at a temperature of about 20°C. In some embodiments, the ninth reaction mixture can be carried out at a temperature of about 40°C.

[0344] 8. Prepare Formula II from Formula III

[0345] In some embodiments, this disclosure provides a method for preparing compounds of formula II:

[0346]

[0347] A method using its salt or a salt thereof, the method comprising:

[0348] a) Forming a first reaction mixture comprising compounds of formula III:

[0349]

[0350] Or its salt, a compound having the formula PG-NHC(=NH)NH2 or its salt, and a first solvent to form a compound of formula II:

[0351]

[0352] or its salt,

[0353] Where R 1 R 2 and R 3 They can be hydrogen, F, Cl, CN, CF3, and C, respectively. 1-3 Alkyl or C 1-3 Alkoxy; R 4 It can be hydrogen or methyl; R 5 It can be C 3-6 Alkyl group; X can be F; and PG can be an amino protecting group.

[0354] Compounds having the formula PG-NHC(=NH)NH2 can be in any suitable form. In some embodiments, compounds having the formula PG-NHC(=NH)NH2 can be in a neutral form. In some embodiments, compounds having the formula PG-NHC(=NH)NH2 can be in salt form. In some embodiments, compounds having the formula PG-NHC(=NH)NH2 can be its hemisulfate, sulfate, chloride, bromide, carbonate, nitrate, or acetate. In some embodiments, compounds having the formula PG-NHC(=NH)NH2 can have the formula IXc:

[0355]

[0356] In some embodiments, PG may be an amino protecting group. Suitable amino protecting groups include, but are not limited to, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, acetyl, trifluoroacetyl, 2,2,5,7,8-pentamethyl-trypanol-6-sulfonyl chloride, p-toluenesulfonyl, 4-methoxy-2,3,6-trimethylbenzenesulfonyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-chlorobenzyl. In some embodiments, PG may be 2,4-dimethoxybenzyl.

[0357] In some embodiments, the first reaction mixture further comprises a first base. The first base may be 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, or 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, or tetrabutylammonium hydroxide), an alkoxide (e.g., lithium phenolate), or a silanol (e.g., potassium trimethylsilanol, sodium trimethylsilanol, lithium silanol, or dimethylsilanol). Sodium phenylsilanol), phosphates (e.g., tripotassium phosphate, tricalcium phosphate, trimagnesium phosphate, trisodium phosphate, disodium hydrogen phosphate or dipotassium hydrogen 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-enpyridine, 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-pyrimidine[1,2-a]pyrimidine, 1,8-bis(dimethylamino)naphthalene or N,N,N'N'-tetramethyl-1,8-naphthyldiamine, amides (e.g., lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, diisopropyl Lithium amide, sodium diisopropylamide, or lithium dicyclohexylamide; alkyl metals (e.g., n-butyllithium, tert-butyllithium, methyllithium, phenyllithium, lithium naphthene, or sodium naphthene); alkoxides (e.g., magnesium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, sodium tert-pentoxide, or potassium tert-pentoxide); phosphines (e.g., tert-butylimino-tris(pyrrolidine)phosphene, 2-tert-butylimino-tris(pyrrolidine)phosphene, or 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphene); or combinations thereof. In some embodiments, the first base comprises cesium carbonate. In some embodiments, the first base may be cesium carbonate.

[0358] The first solvent can be any suitable polar or nonpolar proton or aprotic solvent. The first solvent can be a polar aprotic solvent (e.g., N,N'-dimethylformamide, N,N'-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, acetonitrile, propionitrile, butyronitrile, nitromethane, or nitrobenzene), an ether (tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, methyl tert-butyl ether, or cyclopentylmethyl ether), an alcohol (e.g., methanol, ethanol, n-butanol, 2-butanol, tert-butanol, 2-methylbut-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 butyl acetate), a chloride 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 comprises 2-methyltetrahydrofuran. In some implementations, the first solvent may be 2-methyltetrahydrofuran.

[0359] In some embodiments, the first reaction mixture further includes an additive. The additive may be 4-dimethylaminopyridine, 4-piperidinopyridine, 4-pyrrolidinepyridine, imidazole, N-methylimidazolidine, or 9-azajulonidine. In some embodiments, no additive is present.

[0360] Typically, the first reaction (i.e., step a) can be carried out at ambient temperature to elevated temperatures. For example, the first reaction mixture can be carried out at temperatures from 30°C to 150°C. In some embodiments, the first reaction mixture can be carried out at temperatures from 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 carried out at temperatures from 40°C to 80°C. In some embodiments, the first reaction mixture can be carried out at temperatures about 80°C.

[0361] In some implementations, the method further includes, prior to step a):

[0362] a1) Forming a third reaction mixture comprising compounds of formula IV:

[0363]

[0364] or its salt, a second base and a third solvent, to form a compound of formula III or its salt, wherein X is F; and AG 1 It is Cl.

[0365] The second base can 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-dimethylpyridine, or trimethylpyridine), or an inorganic base (e.g., sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, cesium carbonate, or potassium phosphate). The second base can be in an aqueous solution. In some embodiments, the second base comprises an aqueous solution of sodium hydroxide.

[0366] The third solvent can be any suitable polar aprotic solvent or nonpolar solvent. The third 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 (benzene, toluene, or xylene), water, or a combination thereof. In some embodiments, the third solvent comprises 2-methyltetrahydrofuran. In some embodiments, the third solvent comprises 2-methyltetrahydrofuran and water. In some embodiments, the third solvent can be 2-methyltetrahydrofuran. In some embodiments, the third solvent can be 2-methyltetrahydrofuran and water.

[0367] 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 may be an ammonium salt (e.g., tetra-n-butylammonium bisulfate, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, benzalkonium chloride, or dodecylethyldimethylammonium bromide). In some embodiments, the phase transfer agent comprises tetra-n-butylammonium bisulfate. In some embodiments, the phase transfer agent may be tetra-n-butylammonium bisulfate.

[0368] Typically, the third reaction (i.e., step a1) can be carried out at any suitable temperature. For example, the third reaction mixture can be carried out at a temperature of 20°C to 80°C. In some embodiments, the third reaction mixture can be carried out 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 carried out at a temperature of 20°C to 40°C.

[0369] In some implementations, the method further includes, prior to step a1):

[0370] a2) Forming a fourth reaction mixture comprising compounds of formula V:

[0371]

[0372] Or its salt, a first activator, and a fourth solvent, to form a compound of formula IV:

[0373]

[0374] or its salt, where X is F; and AG 1 It is Cl.

[0375] In some embodiments, the first activator may be a first chlorinating agent. The first chlorinating agent may be any suitable chlorinating agent capable of converting the -OH group of formula V into the corresponding -Cl group (i.e., AG). 1 It can be Cl from Formula IV. In some embodiments, the first chlorinating agent can be thionyl chloride, oxalyl chloride, phosphorus oxychloride (V), phosphorus pentachloride (V), methanesulfonyl chloride, p-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 can be oxalyl chloride. In some embodiments, the first chlorinating agent can be thionyl chloride.

[0376] The fourth solvent can be any suitable polar aprotic solvent and / or nonpolar solvent. The fourth 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), or a combination thereof. In some embodiments, the fourth solvent comprises 2-methyltetrahydrofuran. In some embodiments, the fourth solvent can be 2-methyltetrahydrofuran.

[0377] Typically, the fourth reaction (i.e., step a2) can be carried out at any suitable temperature. For example, the fourth reaction mixture can be carried out at a temperature from 0°C to 80°C. In some embodiments, the fourth reaction mixture can be carried out at a temperature from 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 carried out at a temperature from 50°C to 70°C.

[0378] In some implementations, the method further includes, prior to step a2) or a1-2):

[0379] a3) Forming a sixth reaction mixture comprising compounds of formula VII:

[0380]

[0381] Or its salts, or compounds of formula VI:

[0382]

[0383] or its salt, a third base and a sixth solvent, to form a compound of formula V or its salt, wherein X is F.

[0384] The compounds of formula VI can be in any suitable form. In some embodiments, the compounds of formula VI can be in a neutral form. In some embodiments, the compounds of formula VI can be in salt form. In some embodiments, the compounds of formula VI can be their toluenesulfonate salts.

[0385] The third base can 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-dimethylpyridine, or trimethylpyridine), or an inorganic base (e.g., sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, or tripotassium phosphate). In some embodiments, the third base can 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 can be potassium carbonate. In some embodiments, the third base can be an aqueous solution of potassium carbonate.

[0386] The sixth solvent can be any suitable polar aprotic solvent and / or nonpolar solvent. In some embodiments, the sixth solvent further comprises water. In some embodiments, the sixth reaction (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 comprises 2-methyltetrahydrofuran. In some embodiments, the sixth solvent comprises 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.

[0387] Typically, the sixth reaction (i.e., step a3) can be carried out at any suitable temperature. For example, the sixth reaction mixture can be carried out at a temperature from 0°C to 60°C. In some embodiments, the sixth reaction mixture can be carried out at a temperature from 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 carried out at a temperature from 20°C to 30°C. In some embodiments, the sixth reaction mixture can be carried out at a temperature of about 20°C.

[0388] In some implementations, the method further includes, prior to step a3):

[0389] a4) Forming a seventh reaction mixture comprising compounds of formula VIII:

[0390]

[0391] Or its salt, a second chlorinating agent, a accelerator and a seventh solvent, to form a compound of formula VII or a salt thereof, wherein X is F.

[0392] The second chlorinating agent can be any suitable chlorinating agent capable of converting the -C(O)OH group of formula VIII into the -C(O)Cl group of formula VII. In some embodiments, the second chlorinating agent can be oxalyl chloride, thionyl chloride, phosphorus oxychloride (V), phosphorus pentachloride (V), (chloromethylene)dimethylammonium 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.

[0393] In some embodiments, the accelerator may be N,N-dimethylformamide or dichloromethylene-dimethylammonium chloride. In some embodiments, the accelerator includes N,N-dimethylformamide. In some embodiments, the accelerator may be N,N-dimethylformamide.

[0394] The seventh solvent can be any suitable polar aprotic solvent and / or nonpolar solvent. In some embodiments, the seventh 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 seventh solvent includes 2-methyltetrahydrofuran. In some embodiments, the seventh solvent can be 2-methyltetrahydrofuran.

[0395] Typically, the seventh reaction (i.e., step a4) can be carried out at any suitable temperature. For example, the seventh reaction mixture can be carried out at a temperature from 0°C to 60°C. In some embodiments, the seventh reaction mixture can be carried out at a temperature from 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 carried out at a temperature from 20°C to 30°C. In some embodiments, the seventh reaction mixture can be carried out at a temperature of about 20°C.

[0396] Compounds of Formula II can be deprotected by various methods known in the art to provide compounds of Formula I or salts thereof. In some embodiments, when PG is 2,4-dimethoxybenzyl, compounds of Formula II can be deprotected by various methods, such as under acidic, reducing (hydrogenolysis) or oxidizing conditions, to provide compounds of Formula I or salts thereof, as described herein.

[0397] 9. Schemes for Formulas I, II, III, IV, V, VII, and VIII

[0398] In some embodiments of any of formulas I, II, III, IV, V, VII, and VIII, R 2 It can be Cl, F, CN, CF3, C 1-3 Alkyl or C 1-3 alkoxy groups; and R 1 and R 3 They can be hydrogen, F, Cl, CN, CF3, and C, respectively. 1-3 Alkyl or C 1-3 Alkyl group. C 1-3 The alkyl group can be methyl, ethyl, n-propyl, or isopropyl. C 1-3 The alkoxy group can be methoxy, ethoxy, n-propoxy, or isopropoxy. In some embodiments of any of formulas I, II, III, IV, V, VII, and VIII, R 2 It can be Cl, F, CN, CF3, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; and R 1 and R 3 Each of these can be hydrogen, F, Cl, CN, CF3, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy. In some embodiments of any of formulas I, II, III, IV, V, VII, and VIII, R 2 It can be Cl, F, CN, CF3, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; and R 1 and R 3 Each of them may be hydrogen. In some embodiments of any of formulas I, II, III, IV, V, VII, and VIII, R 2 It can be F, and R 1 and R 3 Each of them is hydrogen.

[0399] In some embodiments of any of Formulas I, II, III, IV, V, and VI, R 4 It can be hydrogen. In some embodiments of any of formulas I, II, III, IV, V, and VI, R 4 It can be methyl.

[0400] In some embodiments of any of Formulas I, II, III, IV, V, and VI, R 5 It can be C 3-6 Alkyl group. In some embodiments of any of formulas I, II, III, IV, V, and VI, R 5It can be n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or hexyl. In some embodiments of any of formulas I, II, III, IV, V, and VI, R 5 It can be n-butyl.

[0401] In some embodiments of any of Formulas I, II, III, IV, V, and VI, R 4 It can be methyl; and R 5 It can be C 3-6 Alkyl group. In some embodiments of any of formulas I, II, III, IV, V, and VI, R 4 It can be methyl; and R 5 It can be n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or hexyl. In some embodiments of any of formulas I, II, III, IV, V, and VI, R 4 It can be methyl; and R 5 It can be n-butyl.

[0402] In some embodiments of any of Formulas III, IV, V, VII, and VIII, X may be F, Br, I, or OTs. In some embodiments of any of Formulas III, IV, V, VII, and VIII, X may be Br. In some embodiments of any of Formulas III, IV, V, VII, and VIII, X may be F.

[0403] In some embodiments, the compound of formula Ia may have formula I:

[0404]

[0405] or its salt, wherein R 2 and R 5 As defined and described in this article.

[0406] In some embodiments, the compound of formula Ia may have formula Ib:

[0407]

[0408] Or its salt.

[0409] In some embodiments, the compound of formula II may have formula IIa:

[0410]

[0411] or its salt, wherein R 2 and R 5 As defined and described in this article.

[0412] In some embodiments, the compound of formula II may have formula IIb:

[0413]

[0414] Or its salt.

[0415] In some embodiments, compounds of formula III may have formula IIIa:

[0416]

[0417] or its salt, wherein R 2 and R 5 As defined and described in this article.

[0418] In some embodiments, the compound of formula III may have formula IIIa-1:

[0419]

[0420] or its salt, wherein R 2 and R 5 As defined and described in this article.

[0421] In some embodiments, compounds of formula III may have formula IIIb:

[0422]

[0423] Or its salt.

[0424] In some embodiments, the compound of formula III may have formula IIIb-1:

[0425]

[0426] Or its salt.

[0427] In some embodiments, the compound of formula IV may have formula IV-1:

[0428]

[0429] or its salt, wherein R 1 R 2 R 3 R 4 R 5 X is as defined and described in this document.

[0430] In some embodiments, the compound of formula IV-1 may have formula IVa-1:

[0431]

[0432] or its salt, wherein R 2 and R 5 As defined and described in this article.

[0433] In some embodiments, the compound of formula IV-2 may have formula IVa-1:

[0434]

[0435] or its salt, wherein R 2 and R 5 As defined and described in this article.

[0436] In some embodiments, the compound of formula IV-1 may have formula IVb-1:

[0437]

[0438] Or its salt.

[0439] In some embodiments, the compound of formula IV-2 may have formula IVb-1:

[0440]

[0441] Or its salt.

[0442] In some embodiments, compounds of formula Va may have formula V:

[0443]

[0444] or its salt, wherein R 2 and R 5 As defined and described in this article.

[0445] In some embodiments, compounds of formula Va-1 may have formula V:

[0446]

[0447] or its salt, wherein R 2 and R 5 As defined and described in this article.

[0448] In some embodiments, compounds of formula Vb may have formula V:

[0449]

[0450] Or its salt.

[0451] In some embodiments, the compound of formula Vb-1 may have formula V:

[0452]

[0453] Or its salt.

[0454] In some embodiments, compounds of formula VIa may have formula VI:

[0455]

[0456] or its salt, wherein R 5 As defined and described in this article.

[0457] In some embodiments, compounds of formula VIb may have formula VI:

[0458]

[0459] In some embodiments, the compound of formula VII may have formula VIIa:

[0460]

[0461] or its salt, wherein R 2 As defined and described in this article.

[0462] In some embodiments, the compound of formula VII may have formula VIIa-1:

[0463]

[0464] or its salt, wherein R 2 As defined and described in this article.

[0465] In some embodiments, the compound of formula VII may have formula VIIb:

[0466]

[0467] Or its salt.

[0468] In some embodiments, the compound of formula VII may have formula VIIb-1:

[0469]

[0470] Or its salt.

[0471] In some embodiments, compounds of formula VIII may have formula VIIIa:

[0472]

[0473] or its salt, wherein R 2 As defined and described in this article.

[0474] In some embodiments, compounds of formula VIII may have formula VIIIa-1:

[0475]

[0476] or its salt, wherein R 2 As defined and described in this article.

[0477] In some embodiments, compounds of formula VIII may have formula VIIIb:

[0478]

[0479] Or its salt.

[0480] In some embodiments, compounds of formula VIII may have formula VIIIb-1:

[0481]

[0482] Or its salt.

[0483] In some embodiments, this disclosure provides a compound for preparing formula Ib:

[0484]

[0485] A method using its salt or a salt thereof, the method comprising:

[0486] a4) Forming a seventh reaction mixture comprising compounds of formula VIIIb:

[0487]

[0488] Or its salts, oxaloyl chloride, N,N-dimethylformamide, 2-methyltetrahydrofuran, to form compounds of formula VIIb:

[0489]

[0490] or its salt;

[0491] A sixth reaction mixture is formed, comprising a compound of formula VIIb or a salt thereof, and a compound of formula VIb:

[0492]

[0493] An aqueous solution of potassium carbonate, 2-methyltetrahydrofuran, and water are used to form a compound of formula Vb:

[0494]

[0495] or its salt;

[0496] A fourth reaction mixture is formed, comprising a compound of formula Vb or a salt thereof, thionyl chloride, and 2-methyltetrahydrofuran to form a compound of formula IVb-1:

[0497]

[0498] or its salt;

[0499] A third reaction mixture is formed, comprising a compound of formula IVb-1 or a salt thereof, an aqueous solution of sodium hydroxide, tetra-n-butylammonium hydrogen sulfate, and 2-methyltetrahydrofuran, to form a compound of formula IIIb:

[0500]

[0501] or its salt;

[0502] A first reaction mixture is formed, the first reaction mixture comprising a compound of formula IIIb or a salt thereof, and a compound of formula IXa, wherein n is 0 to 1:

[0503]

[0504] Copper(II) acetate, tripotassium phosphate, cysteine, 2-methyltetrahydrofuran, and acetonitrile are used to form a compound of formula IIb:

[0505]

[0506] or its salt;

[0507] b) Forming a second reaction mixture comprising a compound of formula IIb or a salt thereof, trifluoroacetic acid, and dichloromethane to prepare a trifluoroacetic acid salt of a compound of formula Ib:

[0508] as well as

[0509] c) Forming a ninth reaction mixture comprising a trifluoroacetate of a compound of formula Ib, sodium hydroxide, ethanol, and water to provide a compound of formula Ib in a neutral form.

[0510] In some embodiments, the compound of formula IXa may have formula IXb:

[0511]

[0512] In some embodiments, this disclosure provides a compound for preparing formula Ib:

[0513]

[0514] A method using its salt or a salt thereof, the method comprising:

[0515] a4) Forming a seventh reaction mixture comprising compounds of formula VIIIb-1:

[0516]

[0517] Or its salts, oxaloyl chloride, N,N-dimethylformamide, 2-methyltetrahydrofuran, to form compounds of formula VIIb-1:

[0518]

[0519] or its salt;

[0520] A sixth reaction mixture is formed, comprising a compound of formula VIIb-1 or a salt thereof, and a compound of formula VIb:

[0521]

[0522] An aqueous solution of potassium carbonate, 2-methyltetrahydrofuran, and water are used to form a compound of formula Vb-1:

[0523]

[0524] or its salt;

[0525] A fourth reaction mixture is formed, comprising a compound of formula Vb-1 or a salt thereof, thionyl chloride, and 2-methyltetrahydrofuran, to form a compound of formula IVb-2:

[0526]

[0527] or its salt;

[0528] A third reaction mixture is formed, comprising a compound of formula IVb-2 or a salt thereof, an aqueous solution of sodium hydroxide, tetra-n-butylammonium hydrogen sulfate, and 2-methyltetrahydrofuran, to form a compound of formula IIIb-1:

[0529]

[0530] or its salt;

[0531] A first reaction mixture is formed, comprising a compound of formula IIIb-1 or a salt thereof, and a compound of formula IXc:

[0532]

[0533] Cesium carbonate and 2-methyltetrahydrofuran, to form a compound of formula IIb:

[0534]

[0535] or its salt;

[0536] b) Forming a second reaction mixture comprising a compound of formula IIb or a salt thereof, trifluoroacetic acid, and dichloromethane to prepare a trifluoroacetic acid salt of a compound of formula Ib:

[0537]

[0538] c) Forming a ninth reaction mixture comprising a trifluoroacetate of a compound of formula Ib, sodium hydroxide, ethanol, and water to provide a compound of formula Ib in a neutral form.

[0539] In some embodiments, compounds of formula Vb or Vb-1, or salts thereof, may be isolated in a solution comprising 2-methyltetrahydrofuran and used in step a2) without purification and / or removal of the 2-methyltetrahydrofuran. In some embodiments, compounds of formula IVb-1 or IVb-2, or salts thereof, may be isolated in a solution comprising 2-methyltetrahydrofuran and used in step a1) without purification and / or removal of the 2-methyltetrahydrofuran. In some embodiments, compounds of formula IIIb or IIIb-1, or salts thereof, may be isolated in a solution comprising 2-methyltetrahydrofuran and used in step a) without purification and / or removal of the 2-methyltetrahydrofuran. In some embodiments, compounds of formula Vb or Vb-1, or salts thereof, compounds of formula IVb-1 or IVb-2, or salts thereof, and compounds of formula IIIb or IIIb-1, or salts thereof, may each be isolated in a solution comprising 2-methyltetrahydrofuran and used in the following steps without purification and / or removal of the 2-methyltetrahydrofuran. In some embodiments, compounds of formula Vb or Vb-1, or salts thereof, may be separated in a solution comprising 2-methyltetrahydrofuran and used in step a2) without removing the 2-methyltetrahydrofuran. In some embodiments, compounds of formula IVb-1 or IVb-2, or salts thereof, may be separated in a solution comprising 2-methyltetrahydrofuran and used in step a1) without removing the 2-methyltetrahydrofuran. In some embodiments, compounds of formula IIIb or IIIb-1, or salts thereof, may be separated in a solution comprising 2-methyltetrahydrofuran and used in step a) without removing the 2-methyltetrahydrofuran. In some embodiments, compounds of formula Vb or Vb-1, or salts thereof, compounds of formula IVb-1 or IVb-2, or salts thereof, and compounds of formula IIIb or IIIb-1, or salts thereof, may each be separated in a solution comprising 2-methyltetrahydrofuran and used in the following steps without removing the 2-methyltetrahydrofuran.

[0540] In some embodiments, a compound of formula Vb or a salt thereof may be isolated in a solution comprising 2-methyltetrahydrofuran and used in step a2) without purification and / or removal of the 2-methyltetrahydrofuran. In some embodiments, a compound of formula IVb-1 or a salt thereof may be isolated in a solution comprising 2-methyltetrahydrofuran and used in step a1) without purification and / or removal of the 2-methyltetrahydrofuran. In some embodiments, a compound of formula IIIb or a salt thereof may be isolated in a solution comprising 2-methyltetrahydrofuran and used in step a) without purification and / or removal of the 2-methyltetrahydrofuran. In some embodiments, a compound of formula Vb or a salt thereof, a compound of formula IVb-1 or a salt thereof, and a compound of formula IIIb or a salt thereof may each be isolated in a solution comprising 2-methyltetrahydrofuran and used in the following steps without purification and / or removal of the 2-methyltetrahydrofuran. In some embodiments, a compound of formula Vb or a salt thereof may be separated in a solution comprising 2-methyltetrahydrofuran and used in step a2) without removing the 2-methyltetrahydrofuran. In some embodiments, a compound of formula IVb-1 or a salt thereof may be separated in a solution comprising 2-methyltetrahydrofuran and used in step a1) without removing the 2-methyltetrahydrofuran. In some embodiments, a compound of formula IIIb or a salt thereof may be separated in a solution comprising 2-methyltetrahydrofuran and used in step a) without removing the 2-methyltetrahydrofuran. In some embodiments, a compound of formula Vb or a salt thereof, a compound of formula IVb-1 or a salt thereof, and a compound of formula IIIb or a salt thereof may each be separated in a solution comprising 2-methyltetrahydrofuran and used in the following steps without removing the 2-methyltetrahydrofuran.

[0541] In some embodiments, compounds of formula VIIb or VIIb-1, or salts thereof, may be formed in situ and used in step a3) without purification and / or removal of 2-methyltetrahydrofuran.

[0542] In some embodiments, a compound of formula VIIb or a salt thereof may be formed in situ and used in step a3) without purification and / or removal of 2-methyltetrahydrofuran.

[0543] In some embodiments, compounds of formula VIIb or VIIb-1 or their salts, compounds of formula Vb or Vb-1 or their salts, compounds of formula IVb-1 or IVb-2 or their salts, and compounds of formula IIIb or IIIb-1 or their salts may each be separated in a solution comprising 2-methyltetrahydrofuran and used in the following steps without purification and / or removal of 2-methyltetrahydrofuran.

[0544] 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 may each be separated in a solution comprising 2-methyltetrahydrofuran and used in the following steps without purifying and / or removing the 2-methyltetrahydrofuran.

[0545] B. Method for preparing compounds of formula I from formula V

[0546] In some embodiments, this disclosure provides a method for preparing compounds of formula II:

[0547]

[0548] A method using its salt or a salt thereof, the method comprising:

[0549] a) Forming a first reaction mixture comprising compounds of formula V:

[0550]

[0551] 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, wherein R 1 R 2 and R 3 They can be hydrogen, F, Cl, CN, CF3, and C, respectively. 1-3 Alkyl or C 1-3 Alkoxy; R4 It can be hydrogen or methyl; R 5 It can be C 3-6 Alkyl group; X can be F, Cl, Br, I or OTs; and PG can be an amino protecting group.

[0552] Compounds having the formula PG-NHC(=NH)NH2 can be in any suitable form. In some embodiments, compounds having the formula PG-NHC(=NH)NH2 can be in a neutral form. In some embodiments, compounds having the formula PG-NHC(=NH)NH2 can be in salt form. In some embodiments, compounds having the formula PG-NHC(=NH)NH2 can be its hemisulfate, sulfate, chloride, bromide, carbonate, nitrate, or acetate. In some embodiments, compounds having the formula PG-NHC(=NH)NH2 can have the formula IX:

[0553]

[0554] Where n can be 0 to 1. In some embodiments, the compound of formula IX can be a hemisulfate (where n can be 1 / 2), a sulfate (where n can be 1), or a combination thereof. In some embodiments, the compound of formula IX can be a hemisulfate (where n can be 1 / 2).

[0555] In some embodiments, PG may be an amino protecting group. Suitable amino protecting groups include, but are not limited to, benzyloxycarbonyl (Cbz) groups, p-methoxybenzylcarbonyl (Moz or MeOZ) groups, tert-butoxycarbonyl (BOC) groups, 2-trimethylsilaneethoxymethyl (SEM) groups, 9-fluorenylmethoxycarbonyl (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, toluenesulfonyl (Ts) groups, Troc (trichloroethyl chloroformate) groups, and other sulfonamide (Nosyl & Nps) groups. In some embodiments, PG may be 2,4-dimethoxybenzyl.

[0556] In some embodiments, the compound of formula IX may have formula IXa:

[0557]

[0558] Where n can be 0 to 1. In some embodiments, the compound of formula IXa can be a hemisulfate (where n can be 1 / 2), a sulfate (where n can be 1), or a combination thereof. In some embodiments, the compound of formula IXa can be a hemisulfate having formula IXb:

[0559]

[0560] In some embodiments, X may be Br. In some embodiments, the compound of formula V may be a compound of formula Vb.

[0561] In some embodiments, the first transition metal catalyst may be a compound comprising 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, but are not limited to, Cd. 2+ Co 2+ Co + Cr 2+ Cr + Cu + (i.e., Cu(I)), Cu 2+ (i.e., Cu(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 comprises copper metal, copper oxide, copper (I) salt, copper (II) salt, or combinations thereof. In some embodiments, the first transition metal catalyst comprises a copper (I) salt. In some embodiments, the first transition metal catalyst may be a copper (I) salt. In some embodiments, the first transition metal catalyst comprises a copper (II) salt. In some embodiments, the first transition metal catalyst may be a copper (II) salt. In some embodiments, the first transition metal catalyst may be copper iodide (I), copper bromide (I), copper chloride (I), copper acetate (I), copper carbonate (I), copper nitrate (I), copper sulfate (I), copper phosphate (I), copper 3-methylsalicylic acid copper (I), thiophene-2-carboxylic acid copper (I), copper oxide (I), copper iodide (II), copper bromide (II), copper chloride (II), copper acetate (II), copper carbonate (II), copper nitrate (II), copper sulfate (II), copper pyrophosphate (II), copper phosphate (II), copper tartrate (II), copper oxide (II), or combinations 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 comprises copper(II) iodide. In some embodiments, the first transition metal catalyst may be copper(II) iodide.

[0562] The first base can be a basic carbonate, a basic bicarbonate, a basic triphosphate, a carboxylate, an amidine compound, or a combination thereof. Suitable basic carbonates include lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Suitable basic bicarbonates include lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate. Suitable basic triphosphates include trisodium phosphate and tripotassium phosphate. Suitable carboxylatees include, but are not limited to, lithium acetate, sodium acetate, potassium acetate, cesium acetate, potassium trimethylacetate, and tetrabutylphosphonium malonate. 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). In some embodiments, the first base may be lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, trisodium phosphate, tripotassium 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 combinations thereof. In some embodiments, the first base includes tripotassium phosphate. In some embodiments, the first base may be tripotassium phosphate.

[0563] The first solvent can be any suitable polar or nonpolar protic or aprotic solvent. In some embodiments, the first solvent can be acetonitrile, propionitrile, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentylmethyl ether, isopropanol, 2-methylbut-2-ol, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, toluene, trifluorotoluene, xylene, or combinations thereof. In some embodiments, the first solvent includes acetonitrile. In some embodiments, the first solvent can be acetonitrile.

[0564] In some embodiments, the first reaction mixture further comprises a first ligand. In some embodiments, the first ligand may be an amino acid, a polypyridyl ligand, or a tertiary amine. Suitable amino acids include naturally occurring and synthetic amino acids, as well as amino acid analogs that function in a manner similar 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"-tert-bipyridine. Suitable tertiary amines include, but are not limited to, triethylamine, tri-n-butylamine, N,N-di-di-bipyridine, etc. Isopropylethylamine, N-methylpyrrolidine, N-methylmorpholine, 1,4-diazabicyclo[2.2.2]-octane, and N,N,N',N'-tetramethylethylenediamine. In some embodiments, the first ligand may be arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, 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-acetylcysteine, 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'-di Carboxylic acids, N,N,N',N'-tetramethylethylenediamine, or combinations thereof. In some embodiments, the first ligand comprises 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 comprises 2,2'-bipyridine. In some embodiments, the first ligand may be 2,2'-bipyridine.

[0565] In some embodiments, the first reaction mixture further comprises a dehydrating agent or additive. In some embodiments, the dehydrating agent or additive may be... screen, screen, A sieve or silica gel. In some implementations, the dehydrating agent or additive may be... screen.

[0566] Typically, the first reaction (i.e., step a) can be carried out at ambient temperature to elevated temperatures. For example, the first reaction mixture can be carried out at a temperature of 30°C to 110°C or heated to reflux. In some embodiments, the first reaction mixture can be carried out at temperatures 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 carried out at a temperature of 50°C to the reflux temperature. In some embodiments, the first reaction mixture can be heated to reflux.

[0567] Once the first reaction is complete, the first transition metal catalyst can be removed from the reaction mixture using a second ligand (e.g., ethylenediaminetetraacetic acid (EDTA) or disodium EDTA). In some embodiments, the first transition metal catalyst can be removed from the first reaction mixture using a second ligand upon completion of the first reaction. In some embodiments, the second ligand comprises ethylenediaminetetraacetic acid or a salt thereof. In some embodiments, the first transition metal catalyst can be removed from the first reaction mixture using ethylenediaminetetraacetic acid or a salt thereof upon completion of the first reaction. In some embodiments, Cu(I) can be removed from the first reaction mixture using disodium ethylenediaminetetraacetic acid upon completion of the first reaction.

[0568] Compounds of Formula II can be deprotected by various methods known in the art to provide compounds of Formula I or salts thereof. When PG is 2,4-dimethoxybenzyl, compounds of Formula II can be deprotected by various methods, such as under acidic, reducing (hydrogenolysis) or oxidizing conditions, to provide compounds of Formula I or salts thereof, as described in Section 1 of Section A.

[0569] C. A method for preparing compounds of formula I from formula III via unprotected guanidine.

[0570] In some embodiments, this disclosure provides a method for preparing compounds of formula I:

[0571]

[0572] A method using its salt or a salt thereof, the method comprising:

[0573] a) Forming a first reaction mixture comprising compounds of formula III:

[0574]

[0575] A compound having the formula H2NC(=NH)NH2 or a salt thereof, a first base, and a first solvent are used to form a compound of formula I or a salt thereof, wherein R 1 R 2 and R 3 They can be hydrogen, F, Cl, CN, CF3, and C, respectively. 1-3 Alkyl or C 1-3 Alkoxy; R 4 It can be hydrogen or methyl; R 5 It can be C 3-6 Alkyl; and X can be F, Cl, Br, I or OTs.

[0576] In some implementations, X can be F.

[0577] Compounds having the formula H₂NC(=NH)NH₂ can be in any suitable form. In some embodiments, compounds having the formula H₂NC(=NH)NH₂ can be in a neutral form. In some embodiments, compounds having the formula H₂NC(=NH)NH₂ can be in salt form. In some embodiments, compounds having the formula H₂NC(=NH)NH₂ can be its hemisulfate, sulfate, chloride, bromide, carbonate, nitrate, or acetate. In some embodiments, compounds having the formula H₂NC(=NH)NH₂ can have formula XIV:

[0578]

[0579] Where n can be 0 to 1. In some embodiments, the compound of formula XIV can be a hemisulfate (where n can be 1 / 2), a sulfate (where n can be 1), or a combination thereof. In some embodiments, the compound of formula XIV can be a hemisulfate (where n can be 1 / 2).

[0580] In some embodiments, the first base may be absent or present. When present, the first base may be a carbonate (e.g., cesium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, magnesium carbonate, calcium carbonate, strontium carbonate, barium carbonate, or 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, or tetrabutylammonium hydroxide), lithium phenolate, or a silanol (e.g., potassium trimethylsilanol, sodium trimethylsilanol, lithium silanol, or sodium dimethylphenylsilanol). Phosphates (e.g., tripotassium phosphate, tricalcium phosphate, trimagnesium phosphate, trisodium phosphate, disodium hydrogen phosphate, or dipotassium hydrogen 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-pyrimidin[1,2-a]pyrimidin, 1,8-bis(dimethylamino)naphthalene or N,N,N'N'-tetramethyl-1,8-naphthyldiamine, 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., n-butyllithium, tert-butyllithium, methyllithium, phenyllithium, lithium naphthene, or sodium naphthene), alkoxides (e.g., magnesium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, sodium tert-pentoxide, or potassium tert-pentoxide), phosphines (e.g., tert-butylimino-tris(pyrrolidine)phosphene, 2-tert-butylimino-tris(pyrrolidine)phosphene, or 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphene), or combinations thereof. In some embodiments, the first base may be lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, trisodium phosphate, tripotassium 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 combinations thereof. In some embodiments, the first base is present and includes cesium carbonate. In some embodiments, the first base may be cesium carbonate.

[0581] The first solvent can be any suitable polar or nonpolar proton or aprotic solvent. The first solvent can be a polar aprotic solvent (e.g., N,N'-dimethylformamide, N,N'-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, acetonitrile, propionitrile, butyronitrile, nitromethane, or nitrobenzene), an ether (tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, methyl tert-butyl ether, or cyclopentylmethyl ether), an alcohol (e.g., methanol, ethanol, n-butanol, 2-butanol, tert-butanol, 2-methylbut-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 butyl acetate), a chloride 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 may be acetonitrile, propionitrile, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, isopropanol, 2-methylbut-2-ol, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, toluene, trifluorotoluene, xylene, or combinations thereof. In some embodiments, the first solvent includes N,N'-dimethylacetamide. In some embodiments, the first solvent may be N,N'-dimethylacetamide.

[0582] In some embodiments, the first reaction mixture further includes an additive. The additive may be 4-dimethylaminopyridine, 4-piperidinopyridine, 4-pyrrolidinepyridine, imidazole, N-methylimidazolidine, or 9-azajulonidine. In some embodiments, no additive is present.

[0583] Typically, the first reaction (i.e., step a) can be carried out at ambient temperature to elevated temperatures. For example, the first reaction mixture can be carried out at temperatures from 20°C to 150°C. In some embodiments, the first reaction mixture can be carried out at temperatures from 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 carried out at temperatures from 60°C to 80°C. In some embodiments, the first reaction mixture can be carried out at temperatures about 80°C.

[0584] Compounds of Formula III can be prepared according to any of the methods described herein. Embodiments of Formulas I, III, IV, V, VII, and VIII are as described in Section 9 of Section A.

[0585] In some embodiments, this disclosure provides a compound for preparing formula Ib:

[0586]

[0587] A method using its salt or a salt thereof, the method comprising:

[0588] a) Forming a first reaction mixture comprising compounds of formula IIIb-1:

[0589]

[0590] Or its salts, or compounds of formula XIVa:

[0591]

[0592] Cesium carbonate and N,N'-dimethylacetamide, to form a compound of formula Ib or a salt thereof.

[0593] D. A method for preparing compounds of formula I via guanidine salts.

[0594] In some embodiments, this disclosure provides a compound for preparing formula XVIII:

[0595]

[0596] A method using its salt or a salt thereof, the method comprising:

[0597] a) Forming a first reaction mixture comprising compounds of formula XV:

[0598]

[0599] Compounds of formula XVI-1:

[0600]

[0601] Or its salt, having the formula R 7 A compound of formula XVIII or a salt thereof, a first transition metal catalyst, a first base, and a first solvent, wherein...

[0602] R 1 R 2 and R 3 Each of the following is an independent element: hydrogen, F, Cl, CN, CF3, C 1-3 Alkyl or C 1-3 Alkoxy;

[0603] R 4 It is hydrogen or methyl;

[0604] R 5 It is C 1-6 alkyl;

[0605] R6 It is hydrogen, OH or O-PG 1 ;

[0606] R 7 It is hydrogen or PG;

[0607] X and X 1 Each can be independently F, Cl, Br, I, or OTs;

[0608] PG is an amino protecting group; and

[0609] PG1 is a hydroxyl protecting group.

[0610] In some implementation schemes, R 6 It can be hydrogen. In some implementations, R 6 It can be OH.

[0611] In some embodiments, compounds of formula XVIII may have formula I:

[0612]

[0613] or its salt, wherein R 5 It is C 3-6 alkyl.

[0614] In some embodiments, compounds of formula XVI have formula XVIa:

[0615]

[0616] In some implementation schemes, PG 1 It can be a hydroxyl protecting group. Suitable hydroxyl protecting groups include, but are not limited to, 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, triacetyl, or trifluoroacetyl), aryl groups (e.g., phenyl, 4-methoxyphenyl, or 4-bromophenyl), alkyl or heterocyclic alkyl groups (e.g., allyl, tert-butyl, or tetrahydropyranyl), and arylalkyl groups (e.g., benzyl, p-methoxybenzyl, or 2,4-dimethoxybenzyl). In some embodiments, PG 1 It can be 2,4-dimethoxybenzyl.

[0617] In some implementation schemes, R 7 It can be hydrogen. In some implementations, formula R 7-NHC(=NH)NH2 can be of the formula H2NC(=NH)NH2. Compounds having the formula H2NC(=NH)NH2 can be in any suitable form. In some embodiments, compounds having the formula H2NC(=NH)NH2 can be in a neutral form. In some embodiments, compounds having the formula H2NC(=NH)NH2 can be in salt form. In some embodiments, compounds having the formula H2NC(=NH)NH2 can be its hemisulfate, sulfate, chloride, bromide, carbonate, nitrate, or acetate. In some embodiments, compounds having the formula H2NC(=NH)NH2 can have the formula XIV:

[0618]

[0619] Where n can be 0 to 1. In some embodiments, the compound of formula XIV can be a hemisulfate (where n can be 1 / 2), a sulfate (where n can be 1), or a combination thereof. In some embodiments, the compound of formula XIV can be a hemisulfate (where n can be 1 / 2).

[0620] In some implementation schemes, R 7 It can be PG. In some implementations, formula R 7 -NHC(=NH)NH2 can be of the formula PG-NHC(=NH)NH2. Compounds having the formula PG-NHC(=NH)NH2 can be in any suitable form. In some embodiments, compounds having the formula PG-NHC(=NH)NH2 can be in a neutral form. In some embodiments, compounds having the formula PG-NHC(=NH)NH2 can be in salt form. In some embodiments, compounds having the formula PG-NHC(=NH)NH2 can be its hemisulfate, sulfate, chloride, bromide, carbonate, nitrate, or acetate. In some embodiments, compounds having the formula PG-NHC(=NH)NH2 can have the formula IX:

[0621]

[0622] Where n can be 0 to 1. In some embodiments, the compound of formula IX can be a hemisulfate (where n can be 1 / 2), a sulfate (where n can be 1), or a combination thereof. In some embodiments, the compound of formula IX can be a hemisulfate (where n can be 1 / 2).

[0623] In some embodiments, PG may be an amino protecting group. Suitable amino protecting groups include, but are not limited to, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, acetyl, trifluoroacetyl, 2,2,5,7,8-pentamethyl-trypanol-6-sulfonyl chloride, p-toluenesulfonyl, 4-methoxy-2,3,6-trimethylbenzenesulfonyl, 4-methoxybenzyl, 2-chlorobenzyl, or 2,4-dimethoxybenzyl. In some embodiments, PG may be 2,4-dimethoxybenzyl.

[0624] In some embodiments, the compound of formula IX may have formula IXa:

[0625]

[0626] Where n can be 0 to 1. In some embodiments, the compound of formula IXa can be a hemisulfate (where n can be 1 / 2), a sulfate (where n can be 1), or a combination thereof. In some embodiments, the compound of formula IXa can be a hemisulfate having formula IXb:

[0627]

[0628] 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, but are not limited to, Cd. 2+ Co 2+ Co + Cr 2+ Cr + Cu + (i.e., Cu(I)), Cu 2+ (i.e., Cu(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 a Pd catalyst. In some embodiments, the first transition metal catalyst may 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 may be a Pd(II) catalyst. In some embodiments, the Pd(II) catalyst may be palladium(II) acetate, palladium(II) pivalate, palladium(II) propionate, palladium(II) trifluoroacetate, palladium(II) bromide, palladium(II) chloride, or tris(dibenzylacetone)dipalladium(O).Palladium dichloride (II), (2-dicyclohexylphosphino-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium methanesulfonate (II), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium methanesulfonate (II), [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium methanesulfonate (II), (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium methanesulfonate (II), (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium methanesulfonate Palladium sulfonate (II), [(di(1-adamantyl)-butylphosphine)-2-(2'-amino-1,1'-biphenyl)palladium methanesulfonate (II), [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium methanesulfonate (II), [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium methanesulfonate (II), [(1,3,5,7-tetramethyl-6-phenyl-2,4,6-trioxa-6-phosphoadamantane)-2-(2'-amino-1,1'- Palladium (II) methanesulfonate [(2-{bis[3,5-bis(trifluoromethyl)phenyl]phosphine}-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methanesulfonate (II), (2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate (II), [(2-di-tert-butylphospho-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2-aminobiphenyl)]methanesulfonate (II), [2-(di-1-adamantylphospho] Palladium(II) methanesulfonate [2',4',6'-triisopropyl-3,6-dimethoxybiphenyl][2-(2'-amino-1,1'-biphenyl)], [(di-tert-butylneoptiophorephosphine)-2-(2-aminobiphenyl)]methanesulfonate, methanesulfonyl(2-(di-tert-butylphosphine)-1,1'-binaphthyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), methanesulfonyl(di-tert-butyl)methylphosphine(2'-amino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonyl-2-dicyclohexylphosphine-2-(N,N-dimethylamino)biphenyl(2'-amino-1,1'-biphenyl-2-yl)palladium(II), or combinations thereof. In some embodiments, the first transition metal catalyst comprises palladium(II) acetate. In some embodiments, the first transition metal catalyst may be palladium(II) acetate.

[0629] In some embodiments, the first base can be any suitable inorganic or organic base. In some embodiments, the first base can be 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 tetrabutylammonium hydroxide), a silanol (e.g., potassium trimethylsilanol, sodium trimethylsilanol, lithium silanol, or sodium dimethylphenylsilanol), a phosphate (e.g., tripotassium phosphate, tricalcium phosphate, trimagnesium phosphate, trisodium phosphate, disodium hydrogen phosphate, or dipotassium hydrogen phosphate), a carboxylate (e.g., sodium acetate, potassium acetate, trimethylacetate, or potassium propionate), an alkoxide (e.g., sodium tert-butoxide, potassium tert-butoxide, or sodium tert-pentoxide), or an amine (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-pyrimidine[1,2-a]pyrimidine, 1,8-bis(dimethylamino)naphthalene or N,N,N'N'-tetramethyl-1,8-naphthyldiamine, amides (e.g., lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, sodium diisopropylamide, lithium dicyclohexylamide) or combinations thereof. In some embodiments, the first base may be cesium carbonate, lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, strontium carbonate, barium carbonate, or ammonium carbonate, or combinations thereof. In some embodiments, the first base may be lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, or combinations thereof. In some embodiments, the first base includes cesium carbonate. In some embodiments, the first base may be cesium carbonate.

[0630] In some implementations, the first solvent can be any suitable polar or nonpolar protic or aprotic solvent. In some embodiments, the first solvent may be a polar aprotic solvent (e.g., N,N'-dimethylformamide, N,N'-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, acetonitrile, propionitrile, butyronitrile, nitromethane, or nitrobenzene), an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, methyl tert-butyl ether, or cyclopentylmethyl ether), an alcohol (e.g., 2-propanol, 2-butanol, tert-butanol, 2-methylbut-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 butyl acetate), a chloride 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.

[0631] In some embodiments, the first reaction mixture further comprises a first ligand. In some embodiments, the first ligand may be 1,3-bis(dicyclohexylphosphino)propane, 1,2-bis(dimethylphosphino)ethane, bis(diphenylphosphino)methane, di(1-adamantyl)-n-butylphosphine, 2-(dicyclohexylphosphino)biphenyl, triphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine, di-tert-butyl-(methyl)phosphine, di-tert-butyl(phenyl)phosphine, tricyclohexylphosphine, triisopropylphosphine, n-butyldadamantylphosphine, 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl, 4 5-Bis(diphenylphosphino)-9,9-dimethyloxanthracene, 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-tert-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-biphenyl)di-tert-butylphosphine, 2-(di-tert-butylphosphino)biphenyl, (2-biphenyl)dicyclohexylphosphine, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2',4',6 The first ligand comprises '-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',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 their tetrafluoroborates. In some embodiments, the first ligand comprises 1,3-bis(dicyclohexylphosphino)propane. In some embodiments, the first ligand may be 1,3-bis(dicyclohexylphosphino)propane.

[0632] Typically, the first reaction (i.e., step a) can be carried out at ambient temperature to elevated temperatures. For example, the first reaction mixture can be carried out at a temperature of 50°C to 120°C. In some embodiments, the first reaction mixture can be carried out at temperatures 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 carried out at a temperature of 70°C to 110°C. In some embodiments, the first reaction mixture can be carried out at about 90°C.

[0633] In some implementations, once the first reaction is complete, the first transition metal catalyst can be removed from the reaction mixture by silica gel filtration.

[0634] In some embodiments, the compound of formula Ia may have formula I:

[0635]

[0636] or its salt, wherein R 2 and R 5 As defined and described in this article.

[0637] In some embodiments, the compound of formula Ia may have formula Ib:

[0638]

[0639] Or its salt.

[0640] In some embodiments, compounds of formula XV may have formula XVa:

[0641]

[0642] or its salt, wherein R 2 X is as defined and described in this document.

[0643] In some embodiments, compounds of formula XV may have formula XVb:

[0644]

[0645] Or its salt.

[0646] In some embodiments, compounds of formula XVI-1 or XVI-2 may have formula XVIa.

[0647]

[0648] or its salt, wherein R 4 and R 5 As defined and described in this article.

[0649] In some embodiments, compounds of formula XVI-1 or XVI-2 may have formula XVIb.

[0650]

[0651] or its salt, wherein R 5 As defined and described in this article.

[0652] In some embodiments, compounds of formula XVI-1 or XVI-2 may have formula XVIc.

[0653]

[0654] Or its salt.

[0655] In some embodiments, this disclosure provides a compound for preparing formula Ib:

[0656]

[0657] A method using its salt or a salt thereof, the method comprising:

[0658] a) Forming a first reaction mixture comprising compounds of formula XVb:

[0659]

[0660] Or its salts, or compounds of formula XIVc:

[0661]

[0662] Or its salts, or compounds of formula XIVa:

[0663]

[0664] Palladium(II) acetate, cesium carbonate, 1,3-bis(dicyclohexylphosphino)propane, and toluene, to form a compound of formula Ib or a salt thereof.

[0665] E. Method for preparing compounds of formula I from formula XI

[0666] In another embodiment, this disclosure provides a method for preparing compounds of formula I:

[0667]

[0668] A method using its salt or a salt thereof, the method comprising:

[0669] a) Forming a first reaction mixture comprising compounds of formula XI:

[0670]

[0671] Or its salts, or compounds of formula VI:

[0672]

[0673] Or its salt, a first base, and a first solvent, to form a compound of formula X:

[0674]

[0675] or its salt;

[0676] b) To form 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 form a compound of formula II:

[0677]

[0678] or its salt; and

[0679] c) Forming a third reaction mixture comprising a compound of formula II or a salt thereof.

[0680] Deprotecting agent and third solvent to provide a compound of formula I or a salt thereof.

[0681] Where R 1 R 2 and R 3 They can be hydrogen, F, Cl, CN, CF3, and C, respectively. 1-3 Alkyl or C 1-3 Alkoxy; R 4 It can be hydrogen or methyl; R 5 It can be C 3-6 Alkyl groups; and PG can be an amino protecting group.

[0682] The compounds of formula VI can be in any suitable form. In some embodiments, the compounds of formula VI can be in a neutral form. In some embodiments, the compounds of formula VI can be in salt form. In some embodiments, the compounds of formula VI can be their toluenesulfonate salts.

[0683] The first base can be a tertiary amine, an aromatic amine base, an amidine compound, a basic carbonate, a basic bicarbonate, a basic triphosphate, a basic diphosphate, 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, quinine ring, and 1,4-diazabicyclo[2.2.2]-octane. Suitable aromatic amine bases include, but are not limited to, pyridine, dimethylpyridine (e.g., 2,6-dimethylpyridine, 3,5-dimethylpyridine, and 2,3-dimethylpyridine), trimethylpyridine (e.g., 2,3,4-trimethylpyridine, 2,3,5-trimethylpyridine, 2,3,6-trimethylpyridine, 2,4,5-trimethylpyridine, 2,4,6-trimethylpyridine, and 3,4,5-trimethylpyridine), 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 basic carbonates include lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Suitable basic bicarbonates include lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate. Suitable basic triphosphates include trisodium phosphate and tripotassium phosphate. Suitable basic diphosphates include disodium hydrogen phosphate and dipotassium hydrogen phosphate. In some embodiments, the first 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-dimethylpyridine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine, imidazole, 1,8-bis(dimethylamino)naphthalene, sodium bicarbonate, sodium carbonate, trisodium phosphate, disodium hydrogen phosphate, potassium bicarbonate, potassium carbonate, tripotassium phosphate, dipotassium hydrogen phosphate, cesium carbonate, or combinations thereof. In some embodiments, the first base comprises N,N-diisopropylethylamine. In some embodiments, the first base may be N,N-diisopropylethylamine.

[0684] The first solvent can be any suitable polar aprotic solvent and / or nonpolar solvent. In some embodiments, the first solvent can 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 combinations thereof. In some embodiments, the first solvent includes isopropyl acetate and 2-methyltetrahydrofuran. In some embodiments, the first solvent can be isopropyl acetate and 2-methyltetrahydrofuran.

[0685] 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 salt form. In some embodiments, the PG-NH2 compound can be its hemisulfate, sulfate, chloride, bromide, carbonate, nitrate, or acetate.

[0686] PG can be an amino protecting group. Suitable amino protecting groups include, but are not limited to, benzyloxycarbonyl (Cbz) groups, p-methoxybenzylcarbonyl (Moz or MeOZ) groups, tert-butoxycarbonyl (BOC) groups, 2-trimethylsilaneethoxymethyl (SEM) groups, 9-fluorenylmethoxycarbonyl (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, toluenesulfonyl (Ts) groups, Troc (trichloroethyl chloroformate) groups, and other sulfonamide (Nosyl & Nps) groups. In some embodiments, PG can be 2,4-dimethoxybenzyl.

[0687] In some implementations, the compound of PG-NH2 may be 2,4-dimethoxybenzylamine.

[0688] The second base can be a tertiary amine, an aromatic amine base, an amidine compound, a basic carbonate, a basic bicarbonate, a basic triphosphate, a basic diphosphate, 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, quinine ring, and 1,4-diazabicyclo[2.2.2]-octane. Suitable aromatic amine bases include, but are not limited to, pyridine, dimethylpyridine (e.g., 2,6-dimethylpyridine, 3,5-dimethylpyridine, and 2,3-dimethylpyridine), trimethylpyridine (e.g., 2,3,4-trimethylpyridine, 2,3,5-trimethylpyridine, 2,3,6-trimethylpyridine, 2,4,5-trimethylpyridine, 2,4,6-trimethylpyridine, and 3,4,5-trimethylpyridine), 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 basic carbonates include lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Suitable basic bicarbonates include lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate. Suitable basic triphosphates include trisodium phosphate and tripotassium phosphate. Suitable basic diphosphates include disodium hydrogen phosphate and dipotassium hydrogen 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-dimethylpyridine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine, imidazole, 1,8-bis(dimethylamino)naphthalene, sodium bicarbonate, sodium carbonate, trisodium phosphate, disodium hydrogen phosphate, potassium bicarbonate, potassium carbonate, tripotassium phosphate, dipotassium hydrogen phosphate, cesium carbonate, or combinations thereof. In some embodiments, the second base includes potassium carbonate. In some embodiments, the second base may be potassium carbonate.

[0689] The second solvent can be any suitable polar aprotic solvent and / or nonpolar solvent. In some embodiments, the second solvent can 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 combinations thereof. In some embodiments, the second solvent includes isopropyl acetate and 2-methyltetrahydrofuran. In some embodiments, the second solvent can be isopropyl acetate and 2-methyltetrahydrofuran.

[0690] Typically, the first reaction (i.e., step a) can be carried out at ambient temperature to elevated temperatures. For example, the first reaction mixture can be carried out at temperatures from 20°C to 100°C or heated to reflux. In some embodiments, the first reaction mixture can be carried out at temperatures from 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 carried out at temperatures from 50°C to reflux temperature. In some embodiments, the first reaction mixture can be carried out at temperatures of about 80°C. In some embodiments, the first reaction mixture can be heated to reflux.

[0691] Typically, the second reaction (i.e., step b) can be carried out at ambient temperature to elevated temperatures. For example, the second reaction mixture can be carried out at temperatures from 20°C to 100°C or heated to reflux. In some embodiments, the second reaction mixture can be carried out at temperatures from 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 carried out at temperatures from 50°C to reflux temperature. In some embodiments, the second reaction mixture can be carried out at temperatures of about 70°C. In some embodiments, the second reaction mixture can be heated to reflux.

[0692] Compounds of Formula II or their salts can be deprotected by various methods known in the art to provide compounds of Formula I or their salts. When PG is 2,4-dimethoxybenzyl, compounds of Formula II can be deprotected by various methods, such as under acidic, reducing (hydrogenolysis) or oxidizing conditions, to provide compounds of Formula I or their salts.

[0693] In some embodiments, the deprotecting agent may be an acid. In some embodiments, the acid may be trifluoroacetic acid, trichloroacetic acid, acetic acid, formic acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof. In some embodiments, the acid includes trifluoroacetic acid. In some embodiments, the acid may be trifluoroacetic acid.

[0694] In some embodiments, the deprotecting agent may be a hydrogen source, and the third reaction mixture further comprises a transition metal catalyst. In some embodiments, the hydrogen source may be ammonium formate, formic acid, hydrogen, or a combination thereof. In some embodiments, the hydrogen source comprises hydrogen. In some embodiments, the hydrogen source comprises ammonium formate. In some embodiments, the hydrogen source comprises formic acid. In some embodiments, the transition metal catalyst may be carbon-supported palladium hydroxide, carbon-supported palladium, or platinum oxide. In some embodiments, the transition metal catalyst comprises carbon-supported palladium hydroxide. In some embodiments, the transition metal catalyst comprises carbon-supported palladium. In some embodiments, the transition metal catalyst comprises platinum oxide. In some embodiments, the deprotecting agent may be hydrogen, and the third reaction mixture further comprises carbon-supported palladium hydroxide, carbon-supported palladium, or platinum oxide. In some embodiments, the deprotecting agent comprises ammonium formate, and the third reaction mixture further comprises carbon-supported palladium hydroxide, carbon-supported palladium, or platinum oxide. In some embodiments, the deprotecting agent comprises formic acid, and the third reaction mixture further comprises carbon-supported palladium hydroxide, carbon-supported palladium, or platinum oxide.

[0695] In some embodiments, the hydrogen source may be ammonium formate. In some embodiments, the hydrogen source may be formic acid. In some embodiments, the transition metal catalyst may be carbon-supported palladium hydroxide. In some embodiments, the transition metal catalyst may be carbon-supported palladium. In some embodiments, the transition metal catalyst may be platinum oxide. In some embodiments, the deprotecting agent may be ammonium formate, and the third reaction mixture further comprises carbon-supported palladium hydroxide, carbon-supported palladium, or platinum oxide. In some embodiments, the deprotecting agent may be formic acid, and the third reaction mixture further comprises carbon-supported palladium hydroxide, carbon-supported palladium, or platinum oxide.

[0696] In some embodiments, the deprotectant may be boron tribromide, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, cerium ammonium nitrate, or a combination of trifluoromethanesulfonic acid and 1,3-dimethoxybenzene.

[0697] The third solvent can be any suitable polar or nonpolar protic or aprotic solvent. In some embodiments, the third solvent can 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 combinations thereof. In some embodiments, the third solvent includes formic acid. In some embodiments, the deprotecting agent can be formic acid, and the third solvent can be formic acid. In some embodiments, the third solvent includes dichloromethane. In some embodiments, the third solvent can be dichloromethane.

[0698] Typically, the third reaction (i.e., step c) can be carried out at any suitable temperature, for example, between -10°C and 80°C. In some embodiments, the third reaction mixture can be at temperatures between -10°C and 80°C, 0°C and 50°C, 10°C and 50°C, 20°C and 50°C, or 20°C and 40°C. In some embodiments, the third reaction mixture can be at temperatures between 20°C and 40°C. In some embodiments, the third reaction mixture can be at a temperature of about 30°C. In some embodiments, the third reaction mixture can be at a temperature of about 40°C. In some embodiments, the third solvent can be dichloromethane, and the third reaction mixture can be heated to reflux.

[0699] In some embodiments, the method further includes c) forming a fourth reaction mixture comprising a salt of a compound of formula I, a third base, and a fourth solvent to provide a compound of formula I in a neutral form.

[0700] The third base can be a basic carbonate or a basic hydroxide. Suitable basic carbonates include sodium carbonate and potassium carbonate. Suitable basic 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 includes sodium hydroxide. 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.

[0701] The fourth solvent can be any suitable alcohol solvent, ester solvent, and / or water. In some embodiments, the fourth solvent can 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 can be i) ethanol and water or ii) ethyl acetate and water. In some embodiments, the fourth solvent can be ethanol and water. In some embodiments, the fourth solvent can be ethyl acetate and water.

[0702] When the fourth solvent includes an ester solvent (e.g., ethyl acetate or isopropyl acetate), the partitioned reaction mixture may be further treated with an aqueous solution of sodium bicarbonate upon completion of the reaction.

[0703] Typically, the fourth reaction (i.e., step d) can be carried out at any suitable temperature. For example, the fourth reaction mixture can be carried out at a temperature of 0°C to 60°C. In some embodiments, the fourth reaction mixture can be carried out 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 carried out at a temperature of 20°C to 40°C. In some embodiments, the fourth reaction mixture can be carried out at a temperature of about 20°C. In some embodiments, the fourth reaction mixture can be carried out at a temperature of about 40°C.

[0704] In some implementations of any of formulas I, II, X, and XI, R 2 It can be Cl, F, CN, CF3, C 1-3 Alkyl or C 1-3 alkoxy groups; and R 1 and R 3 They can be hydrogen, F, Cl, CN, CF3, and C, respectively. 1-3 Alkyl or C 1-3 Alkyl group. C 1-3 The alkyl group can be methyl, ethyl, n-propyl, or isopropyl. C 1-3 The alkoxy group can be methoxy, ethoxy, n-propoxy, or isopropoxy. In some embodiments of any of formulas I, II, X, and XI, R 2 It can be Cl, F, CN, CF3, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; and R 1 and R 3 Each of these can be hydrogen, F, Cl, CN, CF3, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy. In some embodiments of any of formulas I, II, X, and XI, R 2 It can be Cl, F, CN, CF3, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; and R 1 and R 3 Each of them can be hydrogen. In some embodiments of any of formulas I, II, X, and XI, R 2 It can be F, and R 1 and R 3 Each of them is hydrogen.

[0705] In some embodiments of any of Formulas I, II, VI, and X, R 4 It can be hydrogen. In some embodiments of any of formulas I, II, VI, and X, R 4 It can be methyl.

[0706] In some embodiments of any of Formulas I, II, VI, and X, R 5 It can be C 3-6 Alkyl group. In some embodiments, R 5 It can be n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or hexyl. In some embodiments of any of formulas I, II, VI, and X, R 5 It can be n-butyl.

[0707] In some embodiments of any of Formulas I, II, VI, and X, R 4 It can be methyl; and R 5 It can be C 3-6 Alkyl group. In some embodiments of any of formulas I, II, VI, and X, R 4 It can be methyl; and R 5 It can be n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or hexyl. In some embodiments of any of formulas I, II, VI, and X, R 4 It can be methyl; and R 5 It can be n-butyl.

[0708] In some embodiments, the compound of formula Ia may have formula I:

[0709]

[0710] or its salt, wherein R 2 and R 5 As defined and described in this article.

[0711] In some embodiments, the compound of formula Ia may have formula Ib:

[0712]

[0713] Or its salt.

[0714] In some embodiments, the compound of formula XI may have formula XIa:

[0715]

[0716] or its salt, wherein R 2 As defined and described in this article.

[0717] In some embodiments, the compound of formula XI may have formula Xb:

[0718]

[0719] Or its salt.

[0720] In some embodiments, compounds of formula VIa may have formula VI:

[0721]

[0722] Where R 5 As defined and described in this article.

[0723] In some embodiments, compounds of formula VIb may have formula VI:

[0724]

[0725] In some embodiments, compounds of formula X may have formula IXa:

[0726]

[0727] or its salt, wherein R 2 and R 5 As defined and described in this article.

[0728] In some embodiments, compounds of formula X may have formula IXb:

[0729]

[0730] Or its salt.

[0731] In some embodiments, this disclosure provides a compound for preparing formula Ib:

[0732]

[0733] A method using its salt or a salt thereof, the method comprising:

[0734] a) Forming a first reaction mixture comprising compounds of formula XIb:

[0735]

[0736] Or its salts, or compounds of formula VIb:

[0737]

[0738] N,N-diisopropylethylamine, 2-methyltetrahydrofuran, and isopropyl acetate are used to form a compound of formula Xb:

[0739]

[0740] or its salt;

[0741] 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 form a compound of formula IIb:

[0742]

[0743] or its salt; and

[0744] c) Forming a third reaction mixture comprising a compound of formula IIb or a salt thereof, trifluoroacetic acid, and dichloromethane to prepare a trifluoroacetic acid salt of a compound of formula Ib:

[0745] as well as

[0746] d) Forming a fourth reaction mixture comprising a trifluoroacetate of a compound of formula Ib, sodium hydroxide, ethanol, and water to provide a compound of formula Ib in a salt-free form.

[0747] In some embodiments, the compound of formula Xb or a salt thereof may be separated in a solution comprising 2-methyltetrahydrofuran and isopropyl acetate, and used in step b) without purification and / or removal of 2-methyltetrahydrofuran and isopropyl acetate. In some embodiments, the compound of formula Xb or a salt thereof may be separated in a solution comprising 2-methyltetrahydrofuran and isopropyl acetate, and used in step b) without removal of 2-methyltetrahydrofuran and isopropyl acetate. In some embodiments, the compound of formula Xb or a salt thereof may be separated in solid form by precipitation upon addition of n-heptane to a solution comprising 2-methyltetrahydrofuran and isopropyl acetate. In some embodiments, the compound of formula Xb or a salt thereof may be separated in solid form by precipitation upon addition of n-heptane to a solution comprising 2-methyltetrahydrofuran and isopropyl acetate, and used in step b) without purification.

[0748] F. Methods for preparing intermediates

[0749] The intermediates used in the methods disclosed herein can be prepared by a variety of methods.

[0750] 1. Preparation of salts of (R)-2-amino-2-methylhexane-1-ol, via route 1

[0751] In some embodiments, this disclosure provides a method for preparing salts of (R)-2-amino-2-methylhexane-1-ol:

[0752]

[0753] The method includes:

[0754] 1) Forming a first reaction mixture comprising alanine C having the following formula 1-4 Alkyl esters:

[0755]

[0756] Or its salt, aldehyde, first base, drying agent and first solvent, to form alanine C having the following formula 1-4 Imines of alkyl esters:

[0757]

[0758] 2a) Forming a second mixture comprising alanine C 1-4 Imines and hydroxyl groups of alkyl esters

[0759] Electrochemical reagent, second base, and second solvent to form 2-amino-2-methylhexane having the following formula

[0760] Acid C 1-4 Imines of alkyl esters:

[0761]

[0762] 2b) Forming a third reaction mixture comprising 2-amino-2-methylhexanoic acid C 1-4 An imine of an alkyl ester, a primary acid, and a third solvent are used to form 2-amino-2-methylhexanoic acid C. 1-4 First salt of alkyl esters:

[0763]

[0764] 2c) Forming a fourth reaction mixture comprising 2-amino-2-methylhexanoic acid C 1-4 The first salt, third base, fourth solvent, and water of the alkyl ester are used to form 2-amino-2-methylhexanoic acid C in a neutral form. 1-4 Alkyl esters;

[0765] 3) Forming a fifth reaction mixture comprising 2-amino-2-methylhexanoic acid C 1-4 Alkyl ester, second acid, and fifth solvent to form 2-amino-2-methylhexanoic acid C 1-4 The second salt of alkyl esters;

[0766] 4) Forming a sixth reaction mixture comprising 2-amino-2-methylhexanoic acid C 1-4 The second salt of the alkyl ester, the enzyme, the fourth base, and the sixth solvent to provide (R)-2-amino-2-methylhexanoic acid C 1-4 Alkyl esters:

[0767]

[0768] or its salt;

[0769] 5) Forming a seventh reaction mixture, the seventh reaction mixture comprising C 1-4 Alkyl(R)-2-amino

[0770] 2-Methylhexanoate or its salt, BOC protecting agent and seventh solvent to form (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoic acid C 1-4 Alkyl esters:

[0771]

[0772] 6) Forming an eighth reaction mixture comprising (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoic acid C 1-4 Alkyl ester, reducing agent, accelerator, and eighth solvent to form tert-butyl(R)-(1-hydroxy-2-methylhexyl-2-yl)carbamate:

[0773] as well as

[0774] 7) Forming a ninth reaction mixture comprising tert-butyl(R)-(1-hydroxy-2-methylhex-2-yl)carbamate, a third acid, and a ninth solvent to provide a salt of (R)-2-amino-2-methylhex-1-ol.

[0775] R can be an unsubstituted or substituted aryl group or an unsubstituted or substituted aryl group -CH=CH-.

[0776] In some embodiments, the salt of (R)-2-amino-2-methylhexane-1-ol can be determined according to, for example... Figure 3A The preparation is carried out according to steps 1 to 7 of the scheme.

[0777] In some embodiments, in any of the formulas or compounds in steps 1, 2a, 2b, 2c and 3 to 6, C 1-4 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments, in any of the formulas or compounds in steps 1, 2a, 2b, 2c, and 3 to 6, C 1-4 Alkyl groups can be isopropyl groups.

[0778] Regarding step 1, this article describes alanine C 1-4 Alkyl esters or their salts, aldehydes, primary bases, desiccants, primary solvents, alanine C 1-4 Imines of alkyl esters and reaction temperature.

[0779] In some implementations, alanine C 1-4Alkyl esters can be L-alanine C 1-4 Alkyl esters, D-alanine C 1-4 Alkyl esters or mixtures thereof. In some embodiments, alanine C 1-4 The alkyl ester can be alanine methyl ester, alanine ethyl ester, alanine n-propyl ester, alanine isopropyl ester, alanine n-butyl ester, alanine sec-butyl ester, or alanine tert-butyl ester. In some embodiments, alanine C... 1-4 The alkyl ester can be isopropyl alanine. In some embodiments, alanine C... 1-4 The alkyl ester can be L-alanine isopropyl ester. L-alanine isopropyl ester can be in any suitable form, such as a neutral form or a salt form. In some embodiments, L-alanine isopropyl ester can be its HCl salt.

[0780] The aldehyde can be any suitable aldehyde capable of forming an imine with an amine. For example, the 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-methyloxyphenyl)prop-2-enal, 2-methylbenzaldehyde, 4-methylbenzaldehyde, or 4-methoxybenzaldehyde. In some embodiments, the aldehyde can be benzaldehyde.

[0781] 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, trisodium phosphate, or tripotassium phosphate). In some embodiments, the first base includes trimethylamine. In some embodiments, the first base can be trimethylamine.

[0782] The desiccant can be any suitable reagent or method capable of removing water formed by condensation. For example, the desiccant can be sodium sulfate, magnesium sulfate, trialkyl orthoformate (e.g., trimethyl orthoformate), molecular sieves, or azeotropic water removal (e.g., using a Dean-Stark water separator). In some embodiments, the desiccant includes sodium sulfate. In some embodiments, the desiccant may be sodium sulfate.

[0783] 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.

[0784] In some implementations, alanine C 1-4 The imines of alkyl esters have the following formula:

[0785]

[0786] Wherein R can be phenyl, 2-chlorophenyl, 4-chlorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-phenylvinyl, 2-(4-methylphenyl)vinyl, 2-(4-hydroxy-3-methyloxyphenyl)vinyl, 2-methylphenyl, 4-methylphenyl, or 4-methoxyphenyl. In some embodiments, R can be phenyl. In some embodiments, alanine C 1-4 The imine of an alkyl ester can be an imine of an isopropyl alanine ester having the following formula:

[0787]

[0788] Wherein R can be phenyl, 2-chlorophenyl, 4-chlorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-phenylvinyl, 2-(4-methylphenyl)vinyl, 2-(4-hydroxy-3-methyloxyphenyl)vinyl, 2-methylphenyl, 4-methylphenyl, or 4-methoxyphenyl. In some embodiments, R can be phenyl. In some embodiments, the imine of isopropyl alanine can be isopropyl 2-(benzylamino)propionate.

[0789]

[0790] The imine of isopropyl isoalanine can be separated in a solution of a first solvent that can be used in the condensation reaction. In some embodiments, isopropyl 2-(benzylamino)propionate can be separated as a solution in toluene and used directly in the following steps without purification and / or removal of the solvent.

[0791] Typically, the condensation reaction (i.e., step 1) can be carried out at any suitable temperature. For example, the condensation reaction mixture can be carried out at a temperature from 0°C to 80°C. In some embodiments, the condensation reaction mixture can be carried out at a temperature from 20°C to 30°C.

[0792] Step 2 comprises three steps, as described in steps 2a, 2b and 2c.

[0793] Regarding step 2a, this article describes alanine C 1-4 Imines of alkyl esters, electrophilic reagents, second bases, second solvents, 2-amino-2-methylhexanoic acid C 1-4 Imines of alkyl esters and reaction temperature.

[0794] In some implementations, alanine C 1-4The imine of the alkyl ester can be the imine of isopropyl alanine ester. In some embodiments, the imine of isopropyl alanine ester can be isopropyl 2-(benzylamino)propionate. In some embodiments, the imine of isopropyl alanine ester can be a solution of isopropyl 2-(benzylamino)propionate in toluene.

[0795] In some embodiments, the electrophilic agent may be n-butyl bromide, n-butyl iodide, n-butyl methanesulfonate, n-butyl 4-methylbenzenesulfonate, or n-butyl sulfate. In some embodiments, the electrophilic agent may be n-butyl bromide.

[0796] The second base can be a basic alkoxide (e.g., sodium isopropoxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, or potassium isopropoxide), a basic hydroxide in the presence of a phase-transfer catalyst (e.g., sodium hydroxide or potassium hydroxide combined with tetrabutylammonium bromide or tetrabutylammonium hydroxide), a basic amide (e.g., lithium diisopropylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, or lithium 2,2,6,6-tetramethylpiperidine), a basic carbonate (e.g., sodium carbonate, potassium carbonate, or cesium carbonate), or sodium hydride. In some embodiments, the second base comprises sodium isopropoxide. In some embodiments, the second base may be sodium isopropoxide.

[0797] The second solvent can 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-methylbut-2-ol), a chlorinated solvent (e.g., dichloromethane or chlorobenzene), or a combination thereof. In some embodiments, the second solvent comprises tetrahydrofuran and toluene. In some embodiments, the second solvent can be tetrahydrofuran and toluene.

[0798] In some embodiments, 2-amino-2-methylhexanoic acid C 1-4 The imines of alkyl esters have the following formula:

[0799]

[0800] Wherein R can be phenyl, 2-chlorophenyl, 4-chlorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-phenylvinyl, 2-(4-methylphenyl)vinyl, 2-(4-hydroxy-3-methyloxyphenyl)vinyl, 2-methylphenyl, 4-methylphenyl, or 4-methoxyphenyl. In some embodiments, R can be phenyl. In some embodiments, 2-amino-2-methylhexanoic acid C 1-4 The imine of an alkyl ester can be an imine of isopropyl 2-amino-2-methylhexanoate having the following formula:

[0801]

[0802] Wherein R can be phenyl, 2-chlorophenyl, 4-chlorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-phenylvinyl, 2-(4-methylphenyl)vinyl, 2-(4-hydroxy-3-methyloxyphenyl)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 can be isopropyl 2-(benzylamino)-2-methylhexanoate.

[0803]

[0804] Upon completion, the second reaction mixture may be used directly in the following steps without removing the second solvent. In some embodiments, upon completion of the alkylation reaction, the second reaction mixture comprising isopropyl 2-(benzylamino)-2-methylhexanoate, tetrahydrofuran, and toluene may be used directly in the following steps without removing the solvent.

[0805] Typically, the alkylation reaction (i.e., step 2a) can be carried out at any suitable temperature, for example, between 0°C and 80°C. In some embodiments, the reaction mixture for the alkylation reaction can be carried out at a temperature between 40°C and 50°C.

[0806] Regarding step 2b, this article describes 2-amino-2-methylhexanoic acid C 1-4 Imine of alkyl ester, primary acid, third solvent, 2-amino-2-methylhexanoic acid C 1-4 The first salt of the alkyl ester and the reaction temperature.

[0807] In some embodiments, the imine may be an imine of isopropyl 2-amino-2-methylhexanoate. In some embodiments, the imine may be isopropyl 2-(benzylideneamino)-2-methylhexanoate. In some embodiments, the imine may be a reaction mixture from step 2a comprising isopropyl 2-(benzylideneamino)-2-methylhexanoate, tetrahydrofuran, and toluene.

[0808] The first acid can 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 can be in an aqueous solution. In some embodiments, the first acid includes an aqueous solution of sulfuric acid. In some embodiments, the first acid can be an aqueous solution of sulfuric acid.

[0809] In some embodiments, 2-amino-2-methylhexanoic acid C 1-4The first salt of the alkyl ester can be the first salt of isopropyl 2-amino-2-methylhexanoate. In some embodiments, the first salt of isopropyl 2-amino-2-methylhexanoate can be its sulfate.

[0810] The third solvent can 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-methylbut-2-ol), a chlorinating solvent (e.g., dichloromethane or chlorobenzene), water, or a combination thereof. In some embodiments, the third solvent comprises tetrahydrofuran, toluene, and water. In those embodiments, the third reaction mixture can be a biphase reaction mixture. In some embodiments, the third solvent can be tetrahydrofuran, toluene, and water.

[0811] In some embodiments, the first salt of isopropyl 2-amino-2-methylhexanoate can be separated in an aqueous solution and used directly in the following steps without purification and / or removal of water. In some embodiments, the sulfate of isopropyl 2-amino-2-methylhexanoate can be separated in an aqueous solution and used directly in the following steps without purification and removal of water.

[0812] Typically, the hydrolysis reaction (i.e., step 2b) can be carried out at any suitable temperature, such as between 0°C and 80°C. In some embodiments, the reaction mixture for the hydrolysis reaction can be carried out at a temperature between 20°C and 30°C.

[0813] Steps 2a and 2b can be carried out in a single-reactor reaction, wherein upon completion the second reaction mixture can be directly treated with an aqueous solution of the first acid to form the third reaction mixture.

[0814] Regarding step 2c, this article describes 2-amino-2-methylhexanoic acid C 1-4 The first salt, third base, fourth solvent, and 2-amino-2-methylhexanoic acid C of alkyl esters 1-4 Alkyl esters and reaction temperature.

[0815] In some embodiments, 2-amino-2-methylhexanoic acid C 1-4 The first salt of the alkyl ester can be the first salt of isopropyl 2-amino-2-methylhexanoate. In some embodiments, the first salt of isopropyl 2-amino-2-methylhexanoate can be its sulfate. In some embodiments, the first salt of isopropyl 2-amino-2-methylhexanoate can be an aqueous solution of its sulfate.

[0816] The third base can be an inorganic base (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, trisodium phosphate, or tripotassium 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 comprises an aqueous solution of sodium hydroxide. In some embodiments, the third base can be an aqueous solution of sodium hydroxide.

[0817] 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 comprises 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.

[0818] In some embodiments, 2-amino-2-methylhexanoic acid C 1-4 The alkyl ester may be isopropyl 2-amino-2-methylhexanoate. In some embodiments, isopropyl 2-amino-2-methylhexanoate may be used as a solution in a fourth solvent for separation. In some embodiments, isopropyl 2-amino-2-methylhexanoate may be used as a solution in 2-methyltetrahydrofuran and directly in the following steps without purification and / or solvent removal.

[0819] Typically, the neutralization reaction (i.e., step 2c) can be carried out at any suitable temperature, such as between 0°C and 40°C. In some embodiments, the reaction mixture for the neutralization reaction can be carried out at a temperature between 20°C and 30°C.

[0820] Regarding step 3, this article describes 2-amino-2-methylhexanoic acid C 1-4 Alkyl ester, second acid, fifth solvent, 2-amino-2-methylhexanoic acid C 1-4 The second salt of the alkyl ester and the reaction temperature.

[0821] In some embodiments, 2-amino-2-methylhexanoic acid C 1-4 The alkyl ester can be isopropyl 2-amino-2-methylhexanoate. In some embodiments, isopropyl 2-amino-2-methylhexanoate can be a solution of it in 2-methyltetrahydrofuran.

[0822] 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 includes phosphoric acid. In some embodiments, the second acid can be in an aqueous solution. In some embodiments, the second acid includes an aqueous solution of phosphoric acid. In some embodiments, the second acid can be an aqueous solution of phosphoric acid.

[0823] The fifth solvent may 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 comprises 2-methyltetrahydrofuran and water. In some embodiments, the fifth solvent may be 2-methyltetrahydrofuran and water.

[0824] In some embodiments, 2-amino-2-methylhexanoic acid C 1-4 The second salt of the alkyl ester can be the second salt of isopropyl 2-amino-2-methylhexanoate. In some embodiments, the second salt of isopropyl 2-amino-2-methylhexanoate can be its phosphate. In some embodiments, the phosphate of isopropyl 2-amino-2-methylhexanoate can be used directly without purification.

[0825] Typically, the salt formation reaction (i.e., step 3) can be carried out at any suitable temperature, such as between 0°C and 40°C. In some embodiments, the reaction mixture for the salt formation reaction can be carried out at a temperature between 20°C and 30°C.

[0826] Regarding step 4, this article describes 2-amino-2-methylhexanoic acid C 1-4 The second salt of alkyl esters, enzyme, fourth base, sixth solvent, (R)-2-amino-2-methylhexanoic acid C 1-4 Alkyl esters or their salts and reaction temperature.

[0827] In some embodiments, 2-amino-2-methylhexanoic acid C 1-4 The second salt of the alkyl ester can be the second salt of isopropyl 2-amino-2-methylhexanoate. In some embodiments, the second salt of isopropyl 2-amino-2-methylhexanoate can be its phosphate.

[0828] The enzyme in step 4) can be a serine intrapeptidase, subtilisin A (e.g., Or other formulations thereof) or other proteases and hydrolases (e.g., proteases from Aspergillus oryzae, Amano lipase A from Aspergillus niger, or lipases from Candida lipolytica). In some embodiments, the enzyme comprises a serine endopeptidase, subtilisin A. In some embodiments, the enzyme comprises In some embodiments, the enzyme may be a serine intrapeptidase, subtilisin A. In some embodiments, the enzyme may be...

[0829] The fourth base can be an inorganic base (e.g., trisodium phosphate, tripotassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen 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 tripotassium phosphate. In some embodiments, the fourth base can be in an aqueous solution. In some embodiments, the fourth base includes an aqueous solution of tripotassium phosphate. In some embodiments, the fourth base can be an aqueous solution of tripotassium phosphate.

[0830] The sixth solvent may be a mixture of water and a water-miscible organic cosolvent (e.g., acetone, dimethyl sulfoxide, acetonitrile, or tert-butanol), or a mixture of water and a water-immiscible organic cosolvent (e.g., methyl tert-butyl ether, ethyl acetate, or methyl isobutyl ketone). In some embodiments, the sixth solvent comprises acetone and water. In some embodiments, the sixth solvent may be acetone and water.

[0831] In some implementations, (R)-2-amino-2-methylhexanoic acid C 1-4 The alkyl ester may be isopropyl (R)-2-amino-2-methylhexanoate. Isopropyl (R)-2-amino-2-methylhexanoate can be separated in a solution of an organic co-solvent immiscible with water, which can be used in the sixth reaction mixture. In some embodiments, isopropyl (R)-2-amino-2-methylhexanoate can be separated as a solution in methyl tert-butyl ether and used directly in the following steps without purification and / or solvent removal.

[0832] Typically, the enzymatic resolution reaction (i.e., step 4) can be carried out at any suitable temperature, such as between 0°C and 50°C. In some embodiments, the reaction mixture for the enzymatic resolution reaction can be carried out at a temperature between 30°C and 40°C.

[0833] Regarding step 5, this article describes (R)-2-amino-2-methylhexanoic acid C 1-4 Alkyl esters or their salts, BOC protecting agents, seventh solvent, (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoic acid C 1-4Alkyl esters and reaction temperature.

[0834] In some implementations, (R)-2-amino-2-methylhexanoic acid C 1-4 The alkyl ester can be isopropyl (R)-2-amino-2-methylhexanoate. In some embodiments, isopropyl (R)-2-amino-2-methylhexanoate can be a solution thereof in methyl tert-butyl ether.

[0835] In some embodiments, the BOC protecting agent may be di-tert-butyl dicarbonate, di-tert-butyl imine dicarboxylate, or tert-butyl chloroformate. In some embodiments, the BOC protecting agent includes di-tert-butyl dicarbonate. In some embodiments, the BOC protecting agent may be di-tert-butyl dicarbonate.

[0836] 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 may be methyl tert-butyl ether.

[0837] In some embodiments, (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoic acid C 1-4 The alkyl ester can be isopropyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate. Isopropyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate can be separated in a seventh solvent. In some embodiments, isopropyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate can be separated as a solution in methyl tert-butyl ether and used directly in the following steps without purification and / or removal of the methyl tert-butyl ether.

[0838] Typically, the BOC protection reaction (i.e., step 5) can be carried out at any suitable temperature, such as between 0°C and 100°C. In some embodiments, the reaction mixture for the BOC protection reaction can be carried out at a temperature between 20°C and 30°C.

[0839] Regarding step 6, this article describes (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoic acid C 1-4 Alkyl ester, reducing agent, accelerator, eighth solvent, separation of (R)-(1-hydroxy-2-methylhex-2-yl)carbamate tert-butyl ester and reaction temperature.

[0840] In some embodiments, (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoic acid C1-4 The alkyl ester can be isopropyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate. In some embodiments, isopropyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate can be a solution thereof in methyl tert-butyl ether.

[0841] The reducing agent can be any suitable reducing agent capable of reducing ester groups (e.g., isopropyl ester) to the corresponding -CH2OH. For example, the reducing agent can be a borohydride reagent (e.g., lithium borohydride, potassium borohydride, triethyllithium borohydride, or sodium / iodine borohydride) or an aluminum hydride reagent (e.g., lithium aluminum hydride or diisobutylaluminum hydride). In some embodiments, the reducing agent includes lithium borohydride. In some embodiments, the reducing agent includes a solution of lithium borohydride in tetrahydrofuran. In some embodiments, the reducing agent can be lithium borohydride. In some embodiments, the reducing agent can be a solution of lithium borohydride in tetrahydrofuran.

[0842] The accelerator can be an alcohol (e.g., methanol, ethanol, n-propanol, isopropanol, or tert-butanol). In some embodiments, the accelerator includes methanol. In some embodiments, the accelerator may be methanol.

[0843] The eighth solvent may be an ether (diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, or 1,2-dimethoxyethane, etc.), an aromatic solvent (e.g., toluene or xylene), or a combination thereof. In some embodiments, the eighth solvent comprises methyl tert-butyl ether and tetrahydrofuran.

[0844] (R)-(1-hydroxy-2-methylhexyl-2-yl)carbamate tert-butyl ester can be separated in an eighth solvent. In some embodiments, (R)-(1-hydroxy-2-methylhexyl-2-yl)carbamate tert-butyl ester can be separated as a solution in methyl tert-butyl ether and used directly in the following steps without purification and / or removal of methyl tert-butyl ether.

[0845] Typically, the reduction reaction (i.e., step 6) can be carried out at any suitable temperature, such as between 0°C and 60°C. In some embodiments, the reaction mixture for the reduction reaction can be carried out at a temperature between 20°C and 30°C.

[0846] Regarding step 7, this article describes (R)-(1-hydroxy-2-methylhex-2-yl)carbamate tert-butyl ester, the third acid, the ninth solvent, the salt of (R)-2-amino-2-methylhex-1-ol, and the reaction temperature.

[0847] In some embodiments, (R)-(1-hydroxy-2-methylhex-2-yl)carbamate tert-butyl ester can be a solution thereof in methyl tert-butyl ether.

[0848] 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.

[0849] The ninth solvent may 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 may be isopropanol.

[0850] In some embodiments, the salt of (R)-2-amino-2-methylhexane-1-ol can be a compound of formula VIb:

[0851]

[0852] Typically, the BOC deprotection reaction (i.e., step 7) can be carried out at any suitable temperature, such as between 0°C and 100°C. In some embodiments, the reaction mixture for the BOC deprotection reaction can be carried out at a temperature between 40°C and 60°C.

[0853] 2. Preparation of salts of (R)-2-amino-2-methylhexane-1-ol, via route 2

[0854] In some implementations, steps 3, 4, and 5 above can be replaced by steps 8 and 9, such as... Figure 3B The scheme shown is to provide Boc protection for isopropyl (R)-2-amino-2-methylhexanoate.

[0855] In some embodiments, this disclosure provides a method for preparing salts of (R)-2-amino-2-methylhexane-1-ol:

[0856]

[0857] The method includes:

[0858] 1) Forming a first reaction mixture comprising alanine C 1-4 Alkyl esters:

[0859]

[0860] Or its salt, aldehyde, first base, drying agent and first solvent, to form alanine C having the following formula 1-4 Imines of alkyl esters:

[0861]

[0862] 2a) Forming a second mixture comprising alanine C 1-4 Imines and hydroxyl groups of alkyl esters

[0863] Electrochemical reagent, second base, and second solvent to form 2-amino-2-methylhexane having the following formula

[0864] Acid C 1-4 Imines of alkyl esters:

[0865]

[0866] 2b) Forming a third reaction mixture comprising 2-amino-2-methylhexanoic acid C 1-4 An imine of an alkyl ester, a primary acid, and a third solvent are used to form 2-amino-2-methylhexanoic acid C. 1-4 Salts of alkyl esters:

[0867]

[0868] 2c) Forming a fourth reaction mixture comprising 2-amino-2-methylhexanoic acid C 1-4 An alkyl ester salt, a third base, a fourth solvent, and water are used to form 2-amino-2-methylhexanoic acid C in a neutral form. 1-4 Alkyl esters;

[0869] 8) Forming a fifth reaction mixture comprising 2-amino-2-methylhexanoic acid C 1-4 Alkyl ester, second acid, and fifth solvent to form (R)-2-amino-2-methylhexanoic acid C 1-4 First salt of alkyl esters:

[0870]

[0871] 9) Forming a sixth reaction mixture comprising (R)-2-amino-2-methylhexanoic acid C 1-4 The first salt of the alkyl ester, the BOC protecting agent, the fourth base, and the sixth solvent are used to form (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoic acid C. 1-4 Alkyl esters:

[0872]

[0873] 6) Forming an eighth reaction mixture comprising (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoic acid C 1-4 Alkyl ester, reducing agent, accelerator, and eighth solvent to form tert-butyl(R)-(1-hydroxy-2-methylhexyl-2-yl)carbamate:

[0874]

[0875] 7) Forming a ninth reaction mixture comprising tert-butyl(R)-(1-hydroxy-2-methylhex-2-yl)carbamate, a third acid, and a ninth solvent to provide a salt of (R)-2-amino-2-methylhex-1-ol.

[0876] R can be an unsubstituted or substituted aryl group or an unsubstituted or substituted aryl group -CH=CH-.

[0877] In some embodiments, in any of the formulas or compounds in steps 1, 2a, 2b, 2c, 8 to 9, and 6, C 1-4 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments, in any of the formulas or compounds in steps 1, 2a, 2b, 2c, 8 to 9, and 6, C 1-4 Alkyl groups can be isopropyl groups.

[0878] Steps 1, 2a, 2b, 3c, 6 and 7 are described above in the preparation of the salt of (R)-2-amino-2-methylhex-1-ol (routes 1).

[0879] Regarding step 8, this article describes 2-amino-2-methylhexanoic acid C 1-4 Alkyl ester, second acid, fifth solvent, (R)-2-amino-2-methylhexanoic acid C 1-4 The first salt of the alkyl ester and the reaction temperature.

[0880] In some embodiments, 2-amino-2-methylhexanoic acid C 1-4 The alkyl ester can be isopropyl 2-amino-2-methylhexanoate. In some embodiments, isopropyl 2-amino-2-methylhexanoate can be a solution of it in 2-methyltetrahydrofuran.

[0881] The second acid can 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., bibenzoyl-D-tartaric acid, ditolyl-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 can be N-acetyl-L-leucine.

[0882] 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 comprises 2-methyltetrahydrofuran.

[0883] In some implementations, (R)-2-amino-2-methylhexanoic acid C 1-4 The first salt of the alkyl ester can be the first salt of isopropyl (R)-2-amino-2-methylhexanoate. In some embodiments, (R)-2-amino-2-methylhexanoate C 1-4 The first salt of an alkyl ester can be an N-acetyl-L-leucine salt of the following formula:

[0884]

[0885] In some implementations, (R)-2-amino-2-methylhexanoic acid C 1-4 The first salt of an alkyl ester can be an N-acetyl-L-leucine salt of the following formula:

[0886]

[0887] The first salt of isopropyl (R)-2-amino-2-methylhexanoate can be used directly in 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 step 9 without purification.

[0888] Typically, the salt formation and resolution reaction (i.e., step 8) can be carried out at any suitable temperature, such as between 0°C and 80°C. In some embodiments, the reaction mixture for the salt formation and resolution reaction can be carried out at a temperature between 20°C and 50°C.

[0889] Regarding step 9, this article describes (R)-2-amino-2-methylhexanoic acid C1-4 First salt of alkyl ester, BOC-protecting reagent, fourth base, sixth solvent, (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoic acid C 1-4 Alkyl esters and reaction temperature.

[0890] In some implementations, (R)-2-amino-2-methylhexanoic acid C 1-4 The first salt of the alkyl ester can be the 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.

[0891] In some embodiments, the BOC protecting agent may be di-tert-butyl dicarbonate, di-tert-butyl imine dicarboxylate, or tert-butyl chloroformate. In some embodiments, the BOC protecting agent includes di-tert-butyl dicarbonate. In some embodiments, the BOC protecting agent may be di-tert-butyl dicarbonate.

[0892] 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.

[0893] In some embodiments, (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoic acid C 1-4 The alkyl ester can be isopropyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate. In some embodiments, isopropyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate can be separated in a fifth solvent. In some embodiments, isopropyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate can be separated as a solution in methyl tert-butyl ether and used directly in the following steps without purification and / or removal of methyl tert-butyl ether.

[0894] Typically, the BOC protection reaction (i.e., step 9) can be carried out at any suitable temperature, such as between 0°C and 100°C. In some embodiments, the reaction mixture for the BOC protection reaction can be carried out at a temperature between 20°C and 30°C.

[0895] 3. Preparation of salts of (R)-2-amino-2-methylhexane-1-ol, via route 3

[0896] In some embodiments, this disclosure provides a method for preparing salts of (R)-2-amino-2-methylhexane-1-ol:

[0897]

[0898] The method includes:

[0899] 10) Forming a first reaction mixture comprising (R)-2-amino-2-phenylethyl-1-ol or a salt thereof, a substrate, a dehydrating agent or additive, and a first solvent to form (R)-3-methyl

[0900] 5-phenyl-5,6-dihydro-2H-1,4-oxazine-2-one:

[0901]

[0902] 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

[0903] Formation of (3R,5R)-3-butyl-3-methyl-5-phenylmorpholin-2-one:

[0904]

[0905] 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 form (R)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-methylhexane-1-ol:

[0906] as well as

[0907] 13) Forming a fourth reaction mixture comprising (R)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-methylhex-1-ol, a hydrogen source, a catalyst, an acid, and a fourth solvent to provide a salt of (R)-2-amino-2-methylhex-1-ol.

[0908] In some embodiments, the salt of (R)-2-amino-2-methylhexane-1-ol can be determined according to, for example... Figure 4 The preparation is carried out in steps 10 to 13 as shown in the scheme.

[0909] Regarding step 10, this article describes the substrate, dehydrating agent or additive, first solvent, and reaction temperature.

[0910] The substrate may be an alkyl pyruvate (e.g., methyl pyruvate or ethyl pyruvate), pyruvate, or ethyl 2,2-diethoxypropionate. In some embodiments, the substrate includes ethyl pyruvate. In some embodiments, the substrate may be ethyl pyruvate.

[0911] Dehydrating agents or additives can be organic acids (e.g., p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, or trichloroacetic acid), metal halides (lithium chloride, magnesium chloride, or zinc chloride), magnesium sulfate, sodium sulfate, azeotropic water removal (e.g., Dean-Stark water separators), or... Molecular sieves. In some embodiments, the dehydrating agent or additive includes... Molecular sieves. In some implementations, the dehydrating agent or additive may be... Molecular sieve.

[0912] The first solvent can be an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentylmethyl 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 hexafluoroisopropanol), a chlorinated solvent (e.g., dichloromethane, 1,2-dichloroethane, or chloroform), or a combination thereof. In some embodiments, the first solvent comprises 2,2,2-trifluoroethanol. In some embodiments, the first solvent can be 2,2,2-trifluoroethanol.

[0913] Typically, the cyclization reaction (i.e., step 10) can be carried out at any suitable temperature, for example, between 20°C and 110°C. In some embodiments, the reaction mixture for the cyclization reaction can be at a temperature between 20°C and reflux temperature. In some embodiments, the reaction mixture for the cyclization reaction can be heated to reflux.

[0914] Regarding step 11, this article describes the Lewis acid, nucleophile, second solvent, and reaction temperature.

[0915] Lewis acids can be boron trifluoride diethyl ether, lithium chloride, zinc chloride, titanium tetrachloride, silicon tetrachloride, aluminum chloride, samarium(II) iodide, cerium(III) chloride, or lanthanum(III) chloride lithium chloride complexes. In some embodiments, the Lewis acid comprises boron trifluoride diethyl ether. In some embodiments, the Lewis acid can be boron trifluoride diethyl ether.

[0916] The nucleophile may be n-butylmagnesium chloride, n-butyllithium, or n-butylzinc bromide. In some embodiments, the nucleophile includes n-butylmagnesium chloride.

[0917] The second solvent can be an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentylmethyl ether, methyl tert-butyl ether, or diethyl ether), an aromatic solvent (e.g., toluene or trifluorotoluene), a hydrocarbon solvent (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 comprises tetrahydrofuran. In some embodiments, the second solvent may be tetrahydrofuran.

[0918] Typically, the nucleophilic addition reaction (i.e., step 11) can be carried out at any suitable temperature, such as between -78°C and -40°C.

[0919] Regarding step 12, this article describes the reducing agent, the third solvent, and the reaction temperature.

[0920] The reducing agent may be lithium borohydride, lithium aluminum hydride, aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, a borane complex of tetrahydrofuran and dimethyl sulfide, triethyllithium borohydride, sodium borohydride aluminum chloride complex, 9-boronadicyclo[3.3.1]nonane, diisobutylaluminum hydride, 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.

[0921] The third solvent can be an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentylmethyl 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 can be tetrahydrofuran.

[0922] The reduction reaction mixture (i.e., step 12) may further include an additive. The additive may be an alcohol (e.g., methanol, ethanol, n-butanol, isopropanol, or tert-butanol).

[0923] Typically, the reduction reaction (i.e., step 12) can be carried out at any suitable temperature, such as between -40°C and 50°C. In some embodiments, the reaction mixture for the reduction reaction can be carried out at a temperature between 0°C and 20°C.

[0924] Regarding step 13, this paper describes the hydrogen source, catalyst, acid, fourth solvent, salt of (R)-2-amino-2-methylhex-1-ol, and reaction temperature.

[0925] The hydrogen source can be hydrogen gas, formic acid, ammonium formate, cyclohexene, hydrazine, or sodium hypophosphite. In some embodiments, the hydrogen source includes hydrogen gas.

[0926] The catalyst can be carbon-supported palladium hydroxide, carbon-supported palladium, or platinum oxide. In some embodiments, the catalyst includes carbon-supported palladium hydroxide.

[0927] The 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 acid includes p-toluenesulfonic acid. In some embodiments, the acid can be p-toluenesulfonic acid.

[0928] 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, cyclopentylmethyl ether, or tert-butylmethyl 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.

[0929] In some embodiments, the salt of (R)-2-amino-2-methylhexane-1-ol can be a compound of formula VIb:

[0930]

[0931] Typically, the hydrogenation reaction (i.e., step 13) can be carried out at any suitable temperature, such as between 0°C and 85°C. In some embodiments, the reaction mixture for the hydrogenation reaction can be carried out at a temperature between 20°C and reflux temperature. In some embodiments, the reaction mixture for the hydrogenation reaction can be heated to reflux.

[0932] 4. Preparation of salts of (R)-2-amino-2-methylhexane-1-ol, via route 4

[0933] In some embodiments, this disclosure provides a method for preparing salts of (R)-2-amino-2-methylhexane-1-ol:

[0934]

[0935] The method includes:

[0936] 1) Forming a first reaction mixture comprising alanine C having the following formula 1-4 Imines of alkyl esters:

[0937]

[0938] An electrophilic reagent, a first base, a first catalyst, and a first solvent are used to form (R)-2-amino-2-methylhexanoic acid C having the following formula.1-4 Imines of alkyl esters:

[0939]

[0940] 2a) Forming a second reaction mixture comprising (R)-2-amino-2-methylhexane

[0941] Acid C 1-4 An imine of an alkyl ester, a first acid, and a second solvent to form (R)-2-amino-2-methyl

[0942] Crude first salt of hexanoic acid:

[0943]

[0944] 2b) Grind the crude first salt of (R)-2-amino-2-methylhexanoate in the second solvent to provide the first salt of (R)-2-amino-2-methylhexanoate;

[0945] 3a) Forming a third reaction mixture comprising (R)-2-amino-2-methylhexane

[0946] The first salt of the ester, benzyl chloride, the second base, the third solvent, and water are used to form a salt of (R)-2-benzamido-2-methylhexanoic acid having the following formula:

[0947]

[0948] 3b) Forming a fourth reaction mixture comprising a salt of (R)-2-benzamido-2-methylhexanoic acid, a second acid, a fourth solvent, and water to form (R)-2-benzamido-2-methylhexanoic acid;

[0949] 4a) Forming a fifth reaction mixture comprising (R)-2-benzamido-2-methylhexanoic acid, a first reducing agent, and a fifth solvent to form (R)-N-(1-hydroxy-2-methylhex-2-yl)benzamide having the following formula:

[0950]

[0951] or its salt;

[0952] 4b) Forming a sixth reaction mixture comprising (R)-N-(1-hydroxy-2-methylhex-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-methylhex-1-ol.

[0953] R can be an unsubstituted or substituted aryl group or an unsubstituted or substituted aryl group -CH=CH-.

[0954] In some embodiments, the salt of (R)-2-amino-2-methylhexane-1-ol can be determined according to, for example... Figure 14 The preparation is carried out according to steps 1 to 4 of the scheme.

[0955] In some embodiments, in any of the formulas or compounds in step 1, C 1-4 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments, in any of the formulas or compounds in step 1, C 1-4 Alkyl groups include isopropyl groups. In some embodiments, in any of the formulas or compounds in step 1, C... 1-4 The alkyl group may be isopropyl. In some embodiments, in any of the formulas or compounds in step 1, C 1-4 Alkyl groups include tert-butyl groups. In some embodiments, in any of the formulas or compounds in step 1, C... 1-4 The alkyl group can be tert-butyl.

[0956] alanine C in step 1 1-4 Imines of alkyl esters can be prepared according to the methods described herein, for example in Section 1 of Section F and Example 8.

[0957] Regarding step 1, this article describes alanine C 1-4 Imine of alkyl ester, electrophilic reagent, first base, first catalyst, first solvent, (R)-2-amino-2-methylhexanoic acid C 1-4 Imines of alkyl esters and reaction temperature.

[0958] In some implementations, alanine C 1-4 The imines of alkyl esters have the following formula:

[0959]

[0960] Wherein R can be phenyl, 2-chlorophenyl, 4-chlorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-phenylvinyl, 2-(4-methylphenyl)vinyl, 2-(4-hydroxy-3-methyloxyphenyl)vinyl, 2-methylphenyl, 4-methylphenyl, or 4-methoxyphenyl. In some embodiments, R includes 4-chlorophenyl. In some embodiments, alanine C 1-4 The imine of an alkyl ester can be the imine of alanine tert-butyl ester having the following formula:

[0961]

[0962] Wherein R can be phenyl, 2-chlorophenyl, 4-chlorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-phenylvinyl, 2-(4-methylphenyl)vinyl, 2-(4-hydroxy-3-methyloxyphenyl)vinyl, 2-methylphenyl, 4-methylphenyl, or 4-methoxyphenyl. In some embodiments, R can be 4-chlorophenyl. In some embodiments, the imine of alanine tert-butyl ester can be 2-((4-chlorobenzyl)amino)tert-butyl propionate.

[0963]

[0964] In some embodiments, the imine of alanine tert-butyl ester can be a solution of 2-((4-chlorobenzyl)amino)propionate tert-butyl ester in toluene.

[0965] In some embodiments, the electrophilic agent may be n-butyl bromide, n-butyl iodide, n-butyl methanesulfonate, n-butyl 4-methylbenzenesulfonate, or n-butyl sulfate. In some embodiments, the electrophilic agent includes n-butyl bromide. In some embodiments, the electrophilic agent may be n-butyl bromide.

[0966] The first base can be a hydroxide (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, rubidium hydroxide, barium hydroxide, calcium hydroxide, or tetrabutylammonium hydroxide), an alkoxide (e.g., sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, potassium isopropoxide, or sodium tert-amyloxide), 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 comprises potassium hydroxide and potassium carbonate. In some embodiments, the first base can be potassium hydroxide and potassium carbonate.

[0967] In some embodiments, the first catalyst may be a chiral auxiliary agent. In some embodiments, the first catalyst may be N-benzyloctinopeptide chloride, N-benzyloctinopeptide bromide, N-[4-(trifluoromethyl)benzyl]octinopeptide bromide, N-(9-anthraylmethyl)octinopeptide chloride, (11bS)-(+)-4,4-dibutyl-4,5-dihydro-2,6-bis(3,4,5-trifluorophenyl)-3H-dinaphthalo[2,1-c:1′,2′-e]azapyridine bromide, (11bS)-4,4-dibutyl-4,5-dihydro-2,6-bis[3,5-bis(trifluoromethyl)phenyl]-3H-dinaphthalo[2,1-c:1′,2′-e]phosphine bromide, or O-allyl-N-(9-anthraylmethyl)octinopeptide bromide. In some embodiments, the first catalyst comprises N-benzyloctoctin chloride (BCNC).

[0968] In some embodiments, the first solvent may be an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, methyl tert-butyl ether, or cyclopentylmethyl 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 may be toluene.

[0969] In some implementations, (R)-2-amino-2-methylhexanoic acid C 1-4 The imines of alkyl esters have the following formula:

[0970]

[0971] Wherein R can be phenyl, 2-chlorophenyl, 4-chlorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-phenylvinyl, 2-(4-methylphenyl)vinyl, 2-(4-hydroxy-3-methyloxyphenyl)vinyl, 2-methylphenyl, 4-methylphenyl, or 4-methoxyphenyl. In some embodiments, R can be 4-chlorophenyl. In some embodiments, (R)-2-amino-2-methylhexanoic acid C 1-4 The imine of an alkyl ester can be tert-butyl (R)-2-amino-2-methylhexanoate having the following formula:

[0972]

[0973] Wherein R can be phenyl, 2-chlorophenyl, 4-chlorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-phenylvinyl, 2-(4-methylphenyl)vinyl, 2-(4-hydroxy-3-methyloxyphenyl)vinyl, 2-methylphenyl, 4-methylphenyl, or 4-methoxyphenyl. In some embodiments, R can be 4-chlorophenyl. In some embodiments, the imine of (R)-2-amino-2-methylhexanoate tert-butyl ester can be (R)-2-(chlorobenzylamino)-2-methylhexanoate tert-butyl ester.

[0974]

[0975] In some implementations, (R)-2-amino-2-methylhexanoic acid C 1-4 The imine of the alkyl ester can be used directly in the following steps after the removal of the first solvent. In some embodiments, (R)-2-(chlorobenzylamino)-2-methylhexanoate tert-butyl ester can be used directly in the following steps after the removal of the first solvent upon completion of the alkylation reaction.

[0976] In some embodiments, upon completion, the first reaction mixture may be used directly in the following steps without removing the first solvent. In some embodiments, upon completion of the alkylation reaction, the second reaction mixture comprising (R)-2-(chlorobenzylamino)-2-methylhexanoate tert-butyl ester and toluene may be used directly in the following steps without removing the solvent.

[0977] Typically, the alkylation reaction (i.e., step 1) can be carried out at any suitable temperature, for example, between -10°C and 40°C. In some embodiments, the reaction mixture for the alkylation reaction can be carried out at a temperature between 0°C and 30°C.

[0978] In some implementations, step 2 includes two steps, as described in steps 2a and 2b.

[0979] In some embodiments, with respect to steps 2a and 2b, this document describes (R)-2-amino-2-methylhexanoic acid C 1-4 The imine of the alkyl ester, the first acid, the second solvent, the first salt of (R)-2-amino-2-methylhexanoate, and the reaction temperature.

[0980] In some embodiments, the imine may be an imine of (R)-2-amino-2-methylhexanoate tert-butyl ester. In some embodiments, the imine may be (R)-2-(chlorobenzylamino)-2-methylhexanoate tert-butyl ester. In some embodiments, the imine may be a reaction mixture from step 1 comprising (R)-2-(chlorobenzylamino)-2-methylhexanoate tert-butyl ester and toluene.

[0981] In some embodiments, the first acid may be a mineral acid (e.g., hydrochloric acid, phosphoric acid, sulfuric acid, chlorosulfonic acid, or fuming sulfuric acid), 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.

[0982] In some embodiments, the first salt of (R)-2-amino-2-methylhexanoate may be its hydrochloride salt.

[0983] In some embodiments, the second solvent may 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-methylbut-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 may be 2-propanol. In some embodiments, the second solvent includes toluene and 2-propanol. In some embodiments, the second solvent may be toluene and 2-propanol.

[0984] In some embodiments, the crude first salt of (R)-2-amino-2-methylhexanoate is ground with a second solvent to provide the first salt of (R)-2-amino-2-methylhexanoate. In some embodiments, the crude first salt of (R)-2-amino-2-methylhexanoate is ground with toluene to provide the first salt of (R)-2-amino-2-methylhexanoate. In some embodiments, the crude hydrochloride of (R)-2-amino-2-methylhexanoate is ground with toluene to provide the hydrochloride of (R)-2-amino-2-methylhexanoate. In some embodiments, the first salt of (R)-2-amino-2-methylhexanoate can be used directly in the following steps without purification. In some embodiments, the hydrochloride of (R)-2-amino-2-methylhexanoate can be used directly in the following steps without purification.

[0985] Typically, the hydrolysis reaction (i.e., step 2a) can be carried out at any suitable temperature, for example, between 20°C and 80°C. In some embodiments, the reaction mixture for the hydrolysis reaction can be carried out at a temperature between 50°C and 70°C. Typically, the grinding (i.e., step 2b) can be carried out at any suitable temperature, for example, between 10°C and 40°C. In some embodiments, the grinding can be carried out at room temperature.

[0986] In some implementations, step 3 includes two steps, as described in steps 3a and 3b.

[0987] In some embodiments, regarding step 3a, the first salt, second base, third solvent, salt of (R)-2-amino-2-methylhexanoate, and reaction temperature are described herein.

[0988] In some embodiments, the first salt of (R)-2-amino-2-methylhexanoate is its hydrochloride salt.

[0989] In some embodiments, the second base may be a hydroxide (e.g., lithium hydroxide, sodium hydroxide, cesium hydroxide, or tetrabutylammonium 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-dimethylpyridine, trimethylpyridine, or 4-dimethylaminopyridine), or a combination thereof. In some embodiments, the second base may be in an aqueous solution. In some embodiments, the second base comprises an aqueous solution of sodium hydroxide. In some embodiments, the second base may be an aqueous solution of sodium hydroxide.

[0990] 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 cyclopentylmethyl 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.

[0991] In some embodiments, the salt of (R)-2-benzamido-2-methylhexanoic acid may be its sodium salt. In some embodiments, the sodium salt of (R)-2-benzamido-2-methylhexanoic acid may be used directly without purification.

[0992] Typically, the protection reaction (i.e., step 3a) can be carried out at any suitable temperature, for example, between -10°C and 50°C. In some embodiments, the reaction mixture for the protection reaction can be carried out at a temperature between 0°C and 30°C.

[0993] In some embodiments, regarding step 3b, the salt of (R)-2-benzamido-2-methylhexanoic acid, the second acid, the fourth solvent, and the reaction temperature are described herein.

[0994] In some embodiments, the salt of (R)-2-benzamido-2-methylhexanoic acid is its sodium salt.

[0995] In some embodiments, the second acid may be a mineral acid (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 comprises an aqueous solution of hydrochloric acid. In some embodiments, the second acid may be an aqueous solution of hydrochloric acid.

[0996] In some embodiments, the fourth solvent may be an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, methyl tert-butyl ether, or cyclopentylmethyl 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-methylbut-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 may be water.

[0997] Typically, the acidification reaction (i.e., step 3b) can be carried out at any suitable temperature, for example, between -10°C and 50°C. In some embodiments, the reaction mixture for the acidification reaction can be carried out at a temperature between 0°C and 30°C.

[0998] In some implementations, step 4 includes two steps, as described in steps 4a and 4b.

[0999] In some implementations, regarding step 4a, this document describes the first reducing agent, the fifth solvent, and the reaction temperature.

[1000] In some embodiments, the first reducing agent can be any suitable reducing agent capable of reducing ester groups (e.g., isopropyl ester) to the corresponding -CH2OH. In some embodiments, the first reducing agent can be diborane, boran tetrahydrofuran complex, boran dimethyl sulfide complex, boran dodecyl methyl sulfide complex, boran dimethylamine complex, boran ammonia complex, boran pyridine complex, boran trimethylamine complex, boran N,N-diethylaniline complex, boran morpholine complex, boran methyl 6-morpholine hexyl sulfide complex, boran diphenylphosphine complex, sodium borohydride / boron trifluoride, lithium aluminum hydride, aluminum hydride, or diisobutylaluminum hydride. In some embodiments, the first reducing agent includes a boran tetrahydrofuran complex. In some embodiments, the first reducing agent can be a boran tetrahydrofuran complex.

[1001] In some embodiments, the fifth solvent may be an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentylmethyl 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 may be tetrahydrofuran.

[1002] Typically, the reduction reaction (i.e., step 4a) can be carried out at any suitable temperature, for example, between -40°C and 80°C. In some embodiments, the reaction mixture for the reduction reaction can be carried out at a temperature between 25°C and 65°C.

[1003] In some embodiments, regarding step 4b, this document describes the second reducing agent, the second catalyst, the third acid, the sixth solvent, the salt of (R)-2-amino-2-methylhex-1-ol, and the reaction temperature.

[1004] In some embodiments, the second reducing agent may be hydrogen, formic acid, ammonium formate, cyclohexene, hydrazine, sodium hypophosphite, or combinations thereof. In some embodiments, the second reducing agent includes hydrogen. In some embodiments, the second reducing agent may be hydrogen.

[1005] In some embodiments, the second catalyst may be a palladium catalyst. In some embodiments, the second catalyst may be carbon-supported palladium hydroxide, carbon-supported palladium, carbon-supported platinum, or platinum oxide. In some embodiments, the second catalyst includes carbon-supported palladium hydroxide. In some embodiments, the second catalyst may be carbon-supported palladium hydroxide.

[1006] In some embodiments, 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.

[1007] In some embodiments, the sixth solvent may be an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, methyl tert-butyl ether, or cyclopentylmethyl 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-methylbut-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.

[1008] In some embodiments, the salt of (R)-2-amino-2-methylhexane-1-ol can be a compound of formula VIb:

[1009]

[1010] Typically, the Bz deprotection reaction (i.e., step 4b) can be carried out at any suitable temperature, for example, between 0°C and 85°C. In some embodiments, the reaction mixture for the Bz deprotection reaction can be carried out at a temperature between 20°C and 80°C.

[1011] Alternatively, in some embodiments, the Bz deprotection reaction in step 4b can be achieved with lead tetraacetate or sodium periodate and bromine.

[1012] 5. Preparation of salts of (R)-2-amino-2-methylhexane-1-ol, via route 5.

[1013] In some embodiments, this disclosure provides a method for preparing salts of (R)-2-amino-2-methylhexane-1-ol:

[1014]

[1015] The method includes:

[1016] 1) Forming a first reaction mixture comprising a first salt of (R)-2-amino-2-methylhexanoate:

[1017]

[1018] A reducing agent and a first solvent are used to form (R)-2-amino-2-methylhexane-1-ol having the following formula:

[1019]

[1020] 2) Forming a second reaction mixture comprising (R)-2-amino-2-methylhexane

[1021] -1-ol, acid, and a second solvent to provide a salt of (R)-2-amino-2-methylhexane-1-ol.

[1022] In some embodiments, the salt of (R)-2-amino-2-methylhexane-1-ol can be determined according to, for example... Figure 15 The preparation is carried out according to steps 1 and 2 of the scheme.

[1023] In some embodiments, regarding step 1, this document describes the first salt, reducing agent, first solvent, and reaction temperature of (R)-2-amino-2-methylhexanoate.

[1024] In some embodiments, the first salt of (R)-2-amino-2-methylhexanoate is its hydrochloride salt.

[1025] In some embodiments, the reducing agent can be any suitable reducing agent capable of reducing ester groups (e.g., isopropyl ester) to the corresponding -CH2OH. In some embodiments, the reducing agent can be diborane, boronane dimethyl sulfide complex, boronane dodecyl methyl sulfide complex, boronane dimethylamine complex, boronane ammonia complex, boronane pyridine complex, boronane trimethylamine complex, boronane N,N-diethylaniline complex, boronane morpholine complex, boronane methyl 6-morpholine hexyl 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.

[1026] In some embodiments, the first solvent may be an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentylmethyl 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 comprises tetrahydrofuran. In some embodiments, the first solvent may be tetrahydrofuran.

[1027] Typically, the reduction reaction (i.e., step 1) can be carried out at any suitable temperature, such as between 0°C and 40°C. In some embodiments, the reaction mixture for the reduction reaction can be carried out at a temperature between 10°C and 20°C.

[1028] In some embodiments, regarding step 2, this document describes the acid, the second solvent, the salt of (R)-2-amino-2-methylhexane-1-ol, and the reaction temperature.

[1029] In some embodiments, 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), an organic acid (e.g., trifluoroacetic acid), or a combination thereof. In some embodiments, the acid includes p-toluenesulfonic acid. In some embodiments, the acid may be p-toluenesulfonic acid.

[1030] In some embodiments, the second solvent may 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 may be ethanol.

[1031] In some embodiments, the salt of (R)-2-amino-2-methylhexane-1-ol can be a compound of formula VIb:

[1032]

[1033] Typically, the acidification reaction (i.e., step 2) can be carried out at any suitable temperature, such as between 0°C and 100°C. In some embodiments, the reaction mixture for the acidification reaction can be carried out at a temperature between 15°C and 30°C.

[1034] 6. Preparation of salts of (R)-2-amino-2-methylhexane-1-ol, via route 6

[1035] In some embodiments, this disclosure provides a method for preparing salts of (R)-2-amino-2-methylhexane-1-ol:

[1036]

[1037] The method includes:

[1038] 1) Forming a first reaction mixture comprising (2,4R)-3-benzoyl-4-methyl-2-phenyloxazolidin-5-one having the following formula:

[1039]

[1040] Or its salt, electrophilic reagent, base and first solvent, to form (2S,4R)-3-benzoyl-4-butyl-4-methyl-2-phenyloxazolidin-5-one having the following formula:

[1041]

[1042] or its salt; and

[1043] 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 an optional second solvent to form a salt of (R)-2-amino-2-methylhex-1-ol.

[1044] In some embodiments, the salt of (R)-2-amino-2-methylhexane-1-ol can be determined according to, for example... Figure 16 The preparation is carried out according to steps 1 and 2 of the scheme.

[1045] In some implementations, regarding step 1, this document describes the electrophilic reagent, the base, the first solvent, and the reaction temperature.

[1046] In some embodiments, the electrophilic agent may be n-butyl bromide, n-butyl iodide, n-butyl methanesulfonate, n-butyl 4-methylbenzenesulfonate, or n-butyl sulfate. In some embodiments, the electrophilic agent includes n-butyl iodide. In some embodiments, the electrophilic agent may be n-butyl iodide.

[1047] In some embodiments, the base may be lithium diisopropylamide, lithium diethylamide, lithium dicyclohexylamide, lithium dimethylamide, lithium 2,2,6,6-tetramethylpiperidine, 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 may be lithium bis(trimethylsilyl)amide.

[1048] In some embodiments, 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 chlorobenzene), or a combination thereof. In some embodiments, the first solvent comprises tetrahydrofuran. In some embodiments, the first solvent may be tetrahydrofuran.

[1049] Typically, the alkylation reaction (i.e., step 1) can be carried out at any suitable temperature, such as between -100°C and 0°C. In some embodiments, the reaction mixture for the alkylation reaction can be carried out at a temperature between -78°C and -50°C.

[1050] In some embodiments, the alkylation reaction in step 1 may also include additives. 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-imidazolone.

[1051] In some embodiments, regarding step 2, this document describes the acid, the second solvent, the salt of (R)-2-amino-2-methylhexane-1-ol, and the reaction temperature.

[1052] In some embodiments, the acid may be a mineral acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid), a sulfonic acid (e.g., p-toluenesulfonic acid, methanesulfonic acid, or benzenesulfonic acid), or 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 may be hydrochloric acid. In some embodiments, the acid may be an aqueous solution of hydrochloric acid.

[1053] In some embodiments, a second solvent is not present. In some embodiments, when present, the second solvent may be 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.

[1054] In some embodiments, the salt of (R)-2-amino-2-methylhexane-1-ol can be a compound of formula VIb:

[1055]

[1056] In some embodiments, the salt of (R)-2-amino-2-methylhexane-1-ol can be a compound of the following formula:

[1057]

[1058] Typically, the hydrolysis reaction (i.e., step 2) can be carried out at any suitable temperature, such as between 0°C and 120°C. In some embodiments, the reaction mixture for the hydrolysis reaction can be carried out at a temperature between 60°C and 100°C.

[1059] 7. Preparation of compounds of formula VIIIb, via route 1

[1060] In some embodiments, this disclosure provides a compound for the preparation of formula VIIIb:

[1061]

[1062] A method using its salt or a salt thereof, the method comprising:

[1063] 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 form 3-bromo-5-fluoro-2-iodopyridine:

[1064]

[1065] or its salt, or

[1066] 17) Forming a second reaction mixture comprising 2,3-dibromo-5-fluoropyridine or a salt thereof, a second iodination agent, a catalyst, a first ligand and a second solvent to form 3-bromo-5-fluoro-2-iodopyridine or a salt thereof;

[1067] 15) To form a third reaction mixture comprising 3-bromo-5-fluoro-2-iodopyridine or a salt thereof, a cyaniding agent, a second ligand, and a third solvent to form 3-bromo-5-fluoropyridine nitrile:

[1068]

[1069] or its salt; and

[1070] 16) Forming a fourth reaction mixture comprising 3-bromo-5-fluoropiperidine nitrile or a salt thereof, an acid, and a fourth solvent to provide a compound of formula VIIIb or a salt thereof, or

[1071] A fifth reaction mixture is formed, comprising 3-bromo-5-fluoropyridine nitrile or a salt thereof, an enzyme, and a fifth solvent to provide a compound of formula VIIIb or a salt thereof.

[1072] In some embodiments, the compound of formula VIIIb can be determined according to, for example... Figure 5A The preparation is carried out according to steps 14 to 16 of the scheme shown. In some embodiments, the compound of formula VIIIb can be prepared according to... Figure 5B The scheme shows steps 17 and as follows Figure 5A The preparation is carried out in steps 15 to 16 as shown in the scheme.

[1073] Regarding step 14, this article describes the first iodination reagent, the additive, the first solvent, and the reaction temperature.

[1074] The first iodizing agent may be sodium iodide, lithium iodide, potassium iodide, cesium iodide, zinc iodide, magnesium iodide, copper iodide (I), hydroiodic acid, trimethylsilyl iodide, or iodine. In some embodiments, the first iodizing agent includes sodium iodide. In some embodiments, the first iodizing agent may be sodium iodide.

[1075] The additive may be water, trimethylsilyl chloride, ammonium salts (e.g., tetra-n-butylammonium iodide), 2,6-di-tert-butylpyridine, 2,6-di-tert-butyl-4-methylphenol, trimethylsilyl trifluoromethanesulfonate, organic acids (e.g., acetic acid, formic acid, trichloroacetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or methanesulfonic acid), mineral acids (e.g., hydrochloric acid or sulfuric acid), dehydrating agents (e.g., bis(trimethylsilyl)acetamide, acetyl chloride, or triethyl orthoformate), or combinations thereof. In some embodiments, the additive comprises trimethylsilyl chloride and water. In some embodiments, the additive may be trimethylsilyl chloride and water.

[1076] The first solvent can be an ester (e.g., ethyl acetate, butyl acetate, isopropyl acetate, or isobutyl acetate), an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentylmethyl 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.

[1077] Typically, the halogen exchange reaction (i.e., step 14) can be carried out at any suitable temperature, for example, between 20°C and 110°C. In some embodiments, the reaction mixture for the halogen exchange reaction can be carried out at a temperature between 20°C and reflux temperature. In some embodiments, the reaction mixture for the halogen exchange reaction can be heated to reflux.

[1078] In some embodiments, the halogen exchange reaction in step 14 can be replaced by the halogen exchange reaction in step 17. Regarding step 17, the second iodide reagent, catalyst, first ligand, second solvent, and reaction temperature are described herein.

[1079] The second iodizing agent may be sodium iodide, lithium iodide, potassium iodide, cesium iodide, zinc iodide, or magnesium iodide. In some embodiments, the second iodizing agent includes sodium iodide. In some embodiments, the second iodizing agent may be sodium iodide.

[1080] The catalyst may be copper iodide (I), copper iodide (II), copper bromide (I), or copper bromide (II). In some embodiments, the catalyst includes copper iodide (I). In some embodiments, the catalyst may be copper iodide (I).

[1081] The first ligand may be trans-N,N'-dimethylcyclohexane-1,2-diamine (DMCHDA), N,N,N',N'-tetramethylethylenediamine, or N,N'-dimethylethylenediamine. In some embodiments, the first ligand comprises trans-N,N'-dimethylcyclohexane-1,2-diamine. In some embodiments, the first ligand may be trans-N,N'-dimethylcyclohexane-1,2-diamine.

[1082] The second solvent can be an ether (e.g., 1,4-dioxane or cyclopentylmethyl ether), an alcohol solvent (e.g., n-butanol, 1-hexanol, 2-methylbut-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.

[1083] Typically, the halogen exchange reaction (i.e., step 17) can be carried out at any suitable temperature, such as between 50°C and 150°C. In some embodiments, the reaction mixture for the hydrolysis reaction can be carried out at temperatures from 80°C to the reflux temperature.

[1084] Regarding step 15, this article describes the cyaniding reagent, the second ligand, the third solvent, and the reaction temperature.

[1085] The cyaniding agent may be copper cyanide (I), sodium cyanide, potassium cyanide, or trimethylsilyl cyanide. In some embodiments, the cyaniding agent includes copper cyanide (I).

[1086] The second ligand may be absent or present. When present, the second ligand may be 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, N,N'-dimethyl-1,2-cyclohexanediamine, 4-dimethylaminopyridine, 8-hydroxyquinoline, tetramethylethylenediamine, L-proline, 1-butylimidazolium, or 2-isobutylcyclohexanone. In some embodiments, the second ligand may be absent.

[1087] The third solvent can be an ester (e.g., butyl acetate, isopropyl acetate, or isobutyl acetate), an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, or cyclopentylmethyl ether), an alcohol solvent (e.g., n-butanol, 2-methylbut-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.

[1088] Typically, the cyanidation reaction (i.e., step 15) can be carried out at any suitable temperature, for example, between 20°C and 120°C. In some embodiments, the reaction mixture for the cyanidation reaction can be carried out at a temperature between 20°C and reflux temperature. In some embodiments, the reaction mixture for the cyanidation reaction can be heated to reflux.

[1089] Regarding step 16, this article describes the acid, the fourth solvent, the enzyme, and the fifth solvent, as well as the reaction temperature.

[1090] The acid can 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 can be sulfuric acid.

[1091] 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.

[1092] The acid hydrolysis reaction in step 16 can be replaced by an enzymatic hydrolysis reaction. In some embodiments, the enzymatic hydrolysis includes nitrile hydrolases. The enzymatic hydrolysis reaction can be carried out in an aqueous buffer solution with or without an organic co-solvent. In some embodiments, the fifth solvent includes an aqueous buffer solution. In some embodiments, the fifth solvent includes 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).

[1093] In some embodiments, the enzymatic catalyst may be a nitrile hydrolase. In some embodiments, the fifth solvent may be an aqueous buffer solution. In some embodiments, the fifth solvent may be an aqueous buffer solution and an organic co-solvent. The organic co-solvent may be an alcohol (e.g., methanol, ethanol, n-propanol, or isopropanol).

[1094] Typically, the hydrolysis reaction (i.e., step 16) can be carried out at any suitable temperature, for example, between 20°C and 120°C. In some embodiments, the reaction mixture for the hydrolysis reaction can be carried out at a temperature between 20°C and 100°C.

[1095] 8. Preparation of compounds of formula VIIIb, via route 2

[1096] In some embodiments, this disclosure provides a compound for the preparation of formula VIIIb:

[1097]

[1098] A method using its salt or a salt thereof, the method comprising:

[1099] 18a) Forming a first reaction mixture comprising 5-fluoropyridinecarboxylic acid or a salt thereof, an activator, a promoter and a first solvent to activate the -C(O)OH group of 5-fluoropyridinecarboxylic acid, thereby forming the activated form of 5-fluoropyridinecarboxylic acid or a salt thereof;

[1100] 18b) Forming a second reaction mixture comprising the activated form of 5-fluoropyridinecarboxylic acid or a salt thereof, R 6 R 7 An amine of NH, a first base, and a second solvent, to form a compound of formula XIII:

[1101]

[1102] or its salt;

[1103] 19) To form 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 form a compound of formula XIIb:

[1104]

[1105] or its salt; and

[1106] 20) Forming a fourth reaction mixture comprising a 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, wherein R 6 and R 7 Each is independently hydrogen, C 1-4 Alkyl or C 3-6 cycloalkyl, or R 6 and R 7 Combining to form 3- to 6-membered N-linked heterocyclic alkyl groups, optionally having one or two additional heteroatoms selected from O and S.

[1107] In some embodiments, the compound of formula VIIIb or a salt thereof may be used according to, for example Figure 6 The preparation is carried out in steps 18 to 20 as shown in the scheme.

[1108] Step 18 includes steps 18a and 18b.

[1109] Regarding step 18a, this document describes the activator, accelerator, first solvent, activated form of 5-fluoropyridinecarboxylic acid, and reaction temperature. Regarding step 18b, this document describes R... 6 R 7 The amine of NH, the first base, the second solvent, the compound of formula XIII, and the reaction temperature.

[1110] The activator may be a chlorinating agent. In some embodiments, the chlorinating agent may be oxalyl chloride, thionyl chloride, phosphorus oxychloride (V), phosphorus pentachloride (V), or (chloromethylene)dimethylammonium chloride. In some embodiments, the activating (or chlorinating) agent includes oxalyl chloride. In some embodiments, the activated form of 5-fluoropyridinecarboxylic acid may be 5-fluoropyridine chloride.

[1111] The activator can be any peptide coupling agent capable of activating an acid group (e.g., the acid group of 5-fluoropyridinecarboxylic acid) to react with an amine (e.g., the amine in step 18b) to form an amide bond (e.g., the amide group of formula XIII). In some embodiments, the activator can be 1,1'-carbonyldiimidazole or isobutyl chloroformate. In some embodiments, the activated form of 5-fluoropyridinecarboxylic acid can be (5-fluoropyridin-2-yl)(1H-imidazol-1-yl) methyl ketone or 5-fluoropyridine (isobutyl carbonate) anhydride.

[1112] The accelerator may be N,N-dimethylformamide, N,N-dimethylacetamide, or dichloromethylene-dimethylammonium chloride. In some embodiments, the accelerator includes N,N-dimethylformamide. In some embodiments, the accelerator may be N,N-dimethylformamide.

[1113] R 6 R 7 The amine in 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 can be tert-butylamine.

[1114] The presence or absence of a first base is permissible. When a base is present, it can 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 tripotassium phosphate). In some embodiments, the first base may be absent.

[1115] The first and second solvents can be ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, or 1,4-dioxane), chlorinated solvents (e.g., dichloromethane, chloroform, or 1,2-dichloroethane), aromatic solvents (e.g., benzene, toluene, or xylene), or combinations thereof. In some embodiments, the first solvent comprises 2-methyltetrahydrofuran. In some embodiments, the second solvent comprises 2-methyltetrahydrofuran. The second reaction mixture (i.e., step 18b) may further comprise water to have a biphase reaction. In some embodiments, the first solvent can be 2-methyltetrahydrofuran. In some embodiments, the second solvent can be 2-methyltetrahydrofuran. The second reaction mixture (i.e., step 18b) may further comprise water to have a biphase reaction.

[1116] Regarding R 6 R 7 NH amines or compounds of formula XIII, R 6 and R 7 As defined and described in this article.

[1117] In some implementation schemes, R 6 It can be hydrogen or C 1-4 Alkyl group. C 1-4 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments, R 6 It can be hydrogen or ethyl. In some embodiments, R 6 It can be hydrogen. In some implementations, R 6 It can be ethyl.

[1118] In some implementation schemes, R 7 It can be C 1-4 Alkyl or C 3-6 Cycloalkyl. C 1-4 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. C 3-6 The cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 7 It can be ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, or cyclohexyl. In some embodiments, R 7 It can be ethyl, isopropyl, tert-butyl, or cyclohexyl. In some embodiments, R 7 It can be tert-butyl.

[1119] In some implementation schemes, R 6 It can be hydrogen; and R 7 It can be C 1-4 Alkyl or C 3-6 Cycloalkyl. In some embodiments, R 6It can be hydrogen; and R 7 It can be ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, or cyclohexyl. In some embodiments, R 6 It can be hydrogen; and R 7 It can be ethyl, isopropyl, tert-butyl, or cyclohexyl. In some embodiments, R 6 It can be hydrogen and R 7 It can be tert-butyl. In some implementations, R 6 It can be ethyl; and R 7 It can be C 1-4 Alkyl group. In some embodiments, R 6 and R 7 Each can be an ethyl group.

[1120] In some implementation schemes, R 6 and R 7 They can be combined to form N-linked morpholino groups.

[1121] In some embodiments, the compound of formula XIII can be N-(tert-butyl)-5-fluoropyridine carboxamide having the following formula:

[1122]

[1123] Or its salt.

[1124] In some embodiments, N-(tert-butyl)-5-fluoropyridine carboxamide can be separated as a solution in methylcyclohexane and used directly in the following steps without purification and / or removal of methylcyclohexane. In some embodiments, N-(tert-butyl)-5-fluoropyridine carboxamide can be separated as a solution in 1,4-dioxane and used directly in the following steps without purification and / or removal of 1,4-dioxane. In some embodiments, N-(tert-butyl)-5-fluoropyridine carboxamide can be separated as a solution in methylcyclopentyl ether and used directly in the following steps without purification and / or removal of methylcyclopentyl ether.

[1125] Typically, the reactions in steps 18a and 18b can be carried out at any suitable temperature, such as between 5°C and 60°C. In some embodiments, the reaction mixture of both steps 18a and 18b can be carried out at a temperature between 15°C and 30°C.

[1126] Step 19 includes steps 19a and 19b. Step 19a includes a metallization step, and step 19b includes a bromination step.

[1127] Regarding step 19, this article describes the brominating agent, the second base, the additive, the third solvent, the compound of formula XIIb, and the reaction temperature.

[1128] In some embodiments, the compound of formula XIII can be N-(tert-butyl)-5-fluoropyridine carboxamide or a salt thereof. In some embodiments, N-(tert-butyl)-5-fluoropyridine carboxamide or a salt thereof can be a solution thereof in methylcyclohexane. In some embodiments, N-(tert-butyl)-5-fluoropyridine carboxamide or a salt thereof can be a solution thereof in 1,4-dioxane. In some embodiments, N-(tert-butyl)-5-fluoropyridine carboxamide or a salt thereof can be a solution thereof in methylcyclopentyl ether.

[1129] The brominating agent may be bromine, N-bromosuccinimide, dibromotriphenylphosphine, 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.

[1130] The second base can be a metal amide base (e.g., lithium diisopropylamide, magnesium 2,2,6,6-tetramethylpiperidine chloride, lithium 2,2,6,6-tetramethylpiperidine, bis(2,2,6,6-tetramethylpiperidinyl)magnesium, or di-n-butyllithium(2,2,6,6-tetramethylpiperidinyl)magnesium), alkyl and alkenyl metals (n-butyllithium, isopropyl magnesium chloride, tri-n-butyllithium magnesium, di-n-butylmagnesium, ethyl-n-butylmagnesium, or di-sec-butylmagnesium). In some embodiments, the base includes di-n-butylmagnesium. In some embodiments, the base may be di-n-butylmagnesium.

[1131] Additives may or may not be present. When additives are present, they may be lithium chloride, lanthanum(III) chloride, N,N'-dimethylacrylurea, N,N,N',N'-tetramethylethylenediamine, or hexamethylphosphoramide. In some embodiments, additives may not be present.

[1132] The third solvent can be an ether (tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, methylcyclopentyl ether, or 1,4-dioxane), a nonpolar 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.

[1133] Regarding compounds of formula XIIb, R 6 and R 7 As defined and described herein (see also Section IV, compounds of formula XII). In some embodiments, R 6It can be hydrogen; and R 7 It can be ethyl, isopropyl, tert-butyl, or cyclohexyl. In some embodiments, R 6 It can be hydrogen and R 7 It can be tert-butyl. In some implementations, R 6 It can be ethyl; and R 7 It can be C 1-4 Alkyl group. In some embodiments, R 6 and R 7 Each can be ethyl. In some embodiments, R 6 and R 7 They can be combined to form N-linked morpholino groups.

[1134] In some embodiments, compounds of formula XIIb may have formula XIIc:

[1135]

[1136] Or its salt.

[1137] Typically, the metallization step (i.e., step 19a) in the bromination reaction (i.e., step 19) can be carried out at any suitable temperature, such as between room temperature and reflux temperature. In some embodiments, the reaction mixture for the metallization step in the bromination reaction can be carried out at a temperature between 30°C and 80°C. Typically, the bromination step (i.e., step 19b) in the bromination reaction (i.e., step 19) can be carried out at any suitable temperature, such as between -40°C and 0°C. In some embodiments, the reaction mixture for the bromination step in the bromination reaction can be carried out at a temperature between -40°C and -15°C.

[1138] Regarding step 20, this article describes the acid, the fourth solvent, and the reaction temperature.

[1139] The acid can 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 can be sulfuric acid.

[1140] The fourth solvent can be water. In some embodiments, the solvent includes water.

[1141] Typically, the hydrolysis reaction (i.e., step 20) can be carried out at any suitable temperature, for example, between 20°C and 100°C. In some embodiments, the reaction mixture for the hydrolysis reaction can be carried out at a temperature between 50°C and 100°C.

[1142] 9. Preparation of compounds of formula XIb, via route 1

[1143] In some embodiments, this disclosure provides a compound for preparing formula XIb:

[1144]

[1145] A method using its salt or a salt thereof, the method comprising:

[1146] 21) Forming a first reaction mixture comprising 2-bromo-5-fluoropyridine-3-amine or a salt thereof, a cyanide source, a catalyst, and a first solvent to form 3-amino-5-fluoropyridine nitrile:

[1147]

[1148] or its salt;

[1149] 22) A second reaction mixture is formed comprising 3-amino-5-fluoropyridine nitrile or a salt thereof, carbon dioxide, a first base, and a second solvent to form 7-fluoropyridine[3,2-d].

[1150] Pyrimidine-2,4-diol:

[1151]

[1152] or its salt; and

[1153] 23) A third reaction mixture is formed, comprising 7-fluoropyrido[3,2-d]

[1154] 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.

[1155] In some embodiments, the compound of formula XIb can be determined according to, for example... Figure 7A The preparation is carried out in steps 21 to 23 as shown in the scheme.

[1156] Regarding step 21, this paper describes the cyanide source, catalyst, first solvent, and reaction temperature.

[1157] The cyanide source may be zinc cyanide, potassium ferrocyanide, copper cyanide (I), 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.

[1158] The catalyst can be a palladium catalyst with or without a tertiary phosphine ligand (e.g., tetra(triphenylphosphine)palladium(0), tris(dibenzylacetone)palladium(0), palladium acetate(II), palladium chloride(II), bis(triphenylphosphine)palladium(II) dichloride; bis(acetonitrile)palladium(II), (1,1'-bis(diphenylphosphine)ferrocene)palladium(II), palladium(π-cinnamyl)chloride dimer or (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)][2-(2'-amino-1,1'-biphenyl)][2-(2'-amino-1,1'-biphenyl)][2-(2'-amino-1,1'-biphenyl)][2-(2'-amino-1,1'-biphenyl)][2' ... The catalyst may be tetra(triphenylphosphine)palladium(II)methanesulfonate, a copper(I) catalyst with or without a diamine or amino acid ligand (e.g., copper cyanide(I), copper iodide(I), copper bromide(I), or copper chloride(I)) or a nickel(II) catalyst (e.g., (N,N,N'N'-tetramethylethylenediamine)NiCl(o-tolyl) or trans-chloro-(2-naphthyl)-bis(triphenylphosphine)nickel(II)). In some embodiments, the catalyst comprises tetra(triphenylphosphine)palladium(O). In some embodiments, the catalyst may be tetra(triphenylphosphine)palladium(O).

[1159] The first solvent may be a polar aprotic solvent (e.g., N,N-dimethylformamide, N-methyl-2-pyrrolidone, or N,N-dimethylacetamide), 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 comprise water. In some embodiments, the first solvent comprises N,N-dimethylformamide. In some embodiments, the first solvent may be N,N'-dimethylformamide.

[1160] Typically, the cyanidation reaction (i.e., step 21) can be carried out at any suitable temperature, for example, between 40°C and 140°C. In some embodiments, the reaction mixture for the cyanidation reaction can be carried out at a temperature between 80°C and 110°C.

[1161] Regarding step 22, this article describes the first base, the second solvent, and the reaction temperature.

[1162] 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-tris(pyrrolidine)phosphene. In some embodiments, the first base comprises 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.

[1163] The second solvent can 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-dimethylpyridine, or trimethylpyridine), an ether (e.g., 1,4-dioxane or cyclopentylmethyl ether), a chlorinated solvent (e.g., 1,2-dichloroethane or chlorobenzene), an aromatic solvent (e.g., toluene, xylene, or trifluorotoluene), or a combination thereof. In some embodiments, the second solvent comprises N,N-dimethylformamide. In some embodiments, the second solvent can be N,N'-dimethylformamide.

[1164] Typically, the cyclization reaction (i.e., step 22) can be carried out at any suitable temperature, for example, between 40°C and 150°C. In some embodiments, the reaction mixture for the cyclization reaction can be carried out at a temperature between 40°C and 60°C.

[1165] Regarding step 23, this article describes the chlorinating agent, the second base, the third solvent, and the reaction temperature.

[1166] The chlorinating agent can be phosphorus oxychloride, phosphorus chloride (V), or triphenylphosphine dichloride. In some embodiments, the chlorinating agent includes phosphorus oxychloride. In some embodiments, the chlorinating agent can be phosphorus oxychloride.

[1167] A second base may or may not be 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-dimethylpyridine, or trimethylpyridine). In some embodiments, the second base comprises N,N-diisopropylethylamine. In some embodiments, the second base may be N,N-diisopropylethylamine.

[1168] A third solvent may be absent, and the chlorination reaction can be carried out in pure phosphorus oxychloride. When a third solvent is present, it may be an aromatic solvent (e.g., toluene or xylene), an aromatic amine solvent (e.g., diethylaniline), a chlorinating 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.

[1169] Typically, the chlorination reaction (i.e., step 23) can be carried out at any suitable temperature, for example, between 50°C and 140°C. In some embodiments, the reaction mixture for the chlorination reaction can be carried out at a temperature between 80°C and 120°C.

[1170] 10. Preparation of compounds of formula XIb, via route 2

[1171] In some implementations, step 22 above can be replaced by steps 24 and 25, such as... Figure 7B The scheme is shown.

[1172] In some embodiments, this disclosure provides a compound for preparing formula XIb:

[1173]

[1174] A method using its salt or a salt thereof, the method comprising:

[1175] 21) Forming a first reaction mixture comprising 2-bromo-5-fluoropyridine-3-amine or a salt thereof, a cyanide source, a catalyst, and a first solvent to form 3-amino-5-fluoropyridine nitrile:

[1177]

[1178] or its salt;

[1179] 24) To form a second reaction mixture comprising 3-amino-5-fluoropyridine nitrile or a salt thereof, an oxidizing agent, a first base, and a second solvent to form 3-amino-5-fluoropyridine methyl ether.

[1180] Amide:

[1181]

[1182] or its salt;

[1183] 25) A third reaction mixture comprising 3-amino-5-fluoropyridinecarboxamide or a salt thereof, a cyclizing agent, and a third solvent is formed to form 7-fluoropyrido[3,2-d]pyrimidine-2,4-diol:

[1184]

[1185] or its salt; and

[1186] 23) A fourth reaction mixture is formed, comprising 7-fluoropyrido[3,2-d]

[1187] 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.

[1188] Steps 21 and 23 are described above in the preparation of compounds of formula XIb (Routine 1). Regarding step 24, the oxidant, the first base, the second solvent, and the reaction temperature are described herein.

[1189] The oxidant can be hydrogen peroxide, hydrogen peroxide-urea adduct, lithium peroxide, benzoyl peroxide, or tert-butyl peroxide. In some embodiments, the oxidant includes hydrogen peroxide. In some embodiments, the oxidant can be in an aqueous solution. In some embodiments, the oxidant can be an aqueous solution of hydrogen peroxide. In some embodiments, the oxidant can be hydrogen peroxide.

[1190] The first base may be a basic carbonate (e.g., sodium carbonate, potassium carbonate, or cesium carbonate); or a basic 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 may be potassium carbonate.

[1191] 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.

[1192] Typically, the oxidation reaction (i.e., step 24) can be carried out at any suitable temperature, for example, between 20°C and 120°C. In some embodiments, the reaction mixture for the oxidation reaction can be carried out at a temperature between 20°C and 40°C.

[1193] The oxidation reaction in step 24 can be replaced by a hydrolysis reaction using a mineral acid. In some embodiments, 3-amino-5-fluoropyridine nitrile or a salt thereof can be hydrolyzed by a mineral acid such as sulfuric acid to form 3-amino-5-fluoropyridine carboxamide or a salt thereof.

[1194] Regarding step 25, this article describes the cyclizing agent, the third solvent, and the reaction temperature.

[1195] The cyclizing agent can be triphosgene, 1,1'-carbonyldiimidazole, phosgene, diphosgene, diphenyl carbonate, or sodium cyanate. In some embodiments, the cyclizing agent includes triphosgene. In some embodiments, the cyclizing agent can be triphosgene.

[1196] 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-butyl nitrile); an organic acid (e.g., acetic acid or chloroacetic acid); or a combination thereof. In some embodiments, the third solvent comprises 1,4-dioxane. In some embodiments, the third solvent may be 1,4-dioxane.

[1197] Typically, the cyclization reaction in step 25 can be carried out at any suitable temperature, for example, between 20°C and 150°C. In some embodiments, the reaction mixture for the cyclization reaction can be carried out at a temperature between 90°C and 110°C.

[1198] 11. Preparation of Formula IXa

[1199] In some embodiments, this disclosure provides a method for preparing compounds of formula IXa:

[1200]

[1201] The method includes forming a guanylate reaction mixture comprising a guanylate oxidizing agent, (2,4-dimethoxyphenyl)methylamine, a base, an additive, and a solvent to form a compound of formula IXb, wherein n can be 0 to 1.

[1202] The guanylate oxidizing agent can be thiourea, 1H-pyrazole-1-formamidin hydrochloride, aminocyanide, N,N-di-tert-butoxycarbonyl-1H-pyrazole-1-formamidin, N,N-di-tert-butoxycarbonyl-thiourea, SC 1-6 Alkyl isothioureas (e.g., S-methyl isothiourea, S-ethyl isothiourea, S-butyl isothiourea, S-tert-butyl-isothiourea, or S-hexyl isothiourea) or salts thereof. In some embodiments, the guanylate oxidizing agent includes SC. 1-6 Alkyl isothiourea. In some embodiments, the guanylate oxidizing agent comprises S-methyl isothiourea. In some embodiments, the guanylate oxidizing agent comprises S-methyl isothiourea hemisulfate. In some embodiments, the guanylate oxidizing agent may be SC... 1-6 Alkyl isothiourea. In some embodiments, the guanylate oxidizing agent may be S-methyl isothiourea. In some embodiments, the guanylate oxidizing agent may be S-methyl isothiourea hemisulfate.

[1203] A base may or may not be present. When a base is present, the base may be a tertiary amine (e.g., triethylamine, tri-n-butylamine, or N,N-diisopropylethylamine). In some embodiments, a base may not be present.

[1204] Additives may or may not be present. When additives are present, they may be Lewis acids (e.g., tri-dimethylamino-aluminum dimer or scandium trifluoromethanesulfonate). In some embodiments, additives may not be present.

[1205] The solvent can be an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, or cyclopentylmethyl ether), an alcohol (e.g., methanol, ethanol, n-butanol, 2-methylbut-2-ol, or isopropanol), water, a polar aprotic solvent (N-methyl-2-pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or sulfolane), a chlorinated solvent (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, or chloroform), or a combination thereof. In some embodiments, the solvent includes N-methyl-2-pyrrolidone. In some embodiments, the solvent may be N-methyl-2-pyrrolidone.

[1206] In some embodiments, the compound of formula IXa may have formula IXb:

[1207]

[1208] In some embodiments, this disclosure provides a method for preparing compounds of formula IXb:

[1209]

[1210] The method includes forming a guanylate reaction mixture comprising S-methylisothiourea hemisulfate, (2,4-dimethoxyphenyl)methylamine, and N-methyl-2-pyrrolidone to form a compound of formula IXb.

[1211] Typically, guanylate oxidase reactions can be carried out at any suitable temperature, such as between 20°C and 130°C. In some embodiments, the reaction mixture for the guanylate oxidase reaction can be carried out at a temperature between 50°C and 110°C.

[1212] 12. Preparation of 2-amino-2-methylhexanoic acid C from 2-amino-2-methylhexanonitrile 1-4 Alkyl esters

[1213] In some embodiments, this disclosure provides a method for preparing 2-amino-2-methylhexanoic acid C 1-4 Alkyl esters:

[1214]

[1215] A method using its salt or a salt thereof, the method comprising:

[1216] 1) Forming a first reaction mixture comprising a hexano-2-one having the following formula:

[1217]

[1218] Cyanide, optionally a first acid, a desiccant, optionally an additive, and a first solvent, to form 2-amino-2-methylhexanenitrile having the following formula:

[1219]

[1220] or its salt;

[1221] 2a) Forming a second reaction mixture comprising 2-amino-2-methylhexanonitrile or a salt thereof, C 1-4 Alkyl alcohol, secondary acid, and water to form 2-amino-2-methylhexanoic acid C 1-4 Salts of alkyl esters; and

[1222] 2b) Forming a third reaction mixture comprising 2-amino-2-methylhexanoic acid C 1-4 The salt, base, and second solvent of the alkyl ester form 2-amino-2-methylhexanoic acid C in a neutral form. 1-4 Alkyl esters.

[1223] In some embodiments, 2-amino-2-methylhexanoic acid C 1-4 Alkyl esters can be isopropyl 2-amino-2-methylhexanoate having the following formula:

[1224]

[1225] In some implementation schemes, it can be based on, for example Figure 13 The steps shown in the scheme are used to prepare isopropyl 2-amino-2-methylhexanoate.

[1226] In some embodiments, 2-amino-2-methylhexanoic acid C 1-4 C in alkyl esters or their salts 1-4 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments, 2-amino-2-methylhexanoic acid C 1-4 C in alkyl esters or their salts 1-4 Alkyl groups can be isopropyl groups.

[1227] In some implementations, regarding step 1, this document describes cyanide, a first acid, a desiccant, an additive, a first solvent, and a reaction temperature.

[1228] In some embodiments, the cyanide may 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 combinations thereof. In some embodiments, the cyanide includes sodium cyanide. In some embodiments, the cyanide may be sodium cyanide.

[1229] 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, p-toluenesulfonic acid, oxalic acid, formic acid, acetic acid, guanidine hydrochloride, cyanuric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof. In some embodiments, the acid comprises ammonium chloride. In some embodiments, the acid may be ammonium chloride.

[1230] In some embodiments, the desiccant may be magnesium sulfate, sodium sulfate, trialkyl orthoformate (e.g., trimethyl orthoformate), azeotropic water removal (e.g., Dean-Stark water separator), or molecular sieve. In some embodiments, the desiccant includes magnesium sulfate.

[1231] In some embodiments, no additives are present. In some embodiments, the first reaction mixture further includes additives. In some embodiments, the additives may be Lewis acids, including scandium(III) trifluoromethanesulfonate, boron trifluoride ether, zinc iodide, lithium chlorite, trimethylsilyl trifluoromethanesulfonate, bismuth chloride, magnesium bromide, ruthenium(III) chloride, or combinations thereof.

[1232] In some embodiments, the first solvent may be an alcohol (e.g., methanol, ethanol, 2-propanol, 1-butanol, tert-butanol, 2-methylbut-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.

[1233] Typically, the first reaction (i.e., step 1) can be carried out at any suitable temperature. For example, the first reaction mixture can be carried out at a temperature from 0°C to 70°C. In some embodiments, the first reaction mixture can be carried out at a temperature from 0°C to 40°C.

[1234] In some implementations, step 2 includes two steps, as described in steps 2a and 2b.

[1235] In some implementations, regarding step 2a, this document describes C 1-4 Alkyl alcohols, secondary acids, 2-amino-2-methylhexanoic acid C 1-4 Alkyl ester salts and reaction temperatures.

[1236] In some implementation schemes, C 1-4 The alkyl alcohol can be methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, or tert-butanol. In some embodiments, C 1-4 Alkyl alcohols include methanol. In some embodiments, C 1-4 Alkyl alcohols can be methanol.

[1237] In some embodiments, the second acid may be a mineral acid (e.g., sulfuric acid, hydrochloric acid, phosphoric acid, chlorosulfonic acid, fuming sulfuric acid, fluorosulfonic acid, or fluoroantimonyic acid), an organic acid (e.g., methanesulfonic acid or trifluoromethanesulfonic acid), or a combination thereof. In some embodiments, the second acid includes sulfuric acid. In some embodiments, the second acid may be sulfuric acid.

[1238] In some embodiments, 2-amino-2-methylhexanoic acid C 1-4 The salts of alkyl esters can be sulfates, hydrochlorides, phosphates, chlorosulfonates, fuming sulfates, fluorosulfonates, fluoroantimonates, methanesulfonates, or trifluoromethanesulfonates. In some embodiments, 2-amino-2-methylhexanoic acid C 1-4 The salt of the alkyl ester can be a sulfate. In some embodiments, 2-amino-2-methylhexanoic acid C 1-4 The salt of alkyl esters can be isopropyl 2-amino-2-methylhexanoate sulfate.

[1239] Typically, the second reaction (i.e., step 2a) can be carried out at any suitable temperature. For example, the second reaction mixture can be carried out at a temperature of 50°C to 150°C. In some embodiments, the second reaction mixture can be carried out at a temperature of 70°C to 100°C.

[1240] In some implementations, regarding step 2b, the base, the second solvent, and the reaction temperature are described herein.

[1241] In some embodiments, the base may be an inorganic base (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, trisodium phosphate, or tripotassium 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 may be sodium hydroxide. In some embodiments, the base may be in an aqueous solution. In some embodiments, the base includes an aqueous solution of sodium hydroxide. In some embodiments, the base may be an aqueous solution of sodium hydroxide.

[1242] In some embodiments, the second 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 second solvent comprises 2-methyltetrahydrofuran. In some embodiments, the second solvent may be 2-methyltetrahydrofuran.

[1243] Typically, the third reaction (i.e., step 2b) can be carried out at any suitable temperature. For example, the third reaction mixture can be carried out at a temperature of 0°C to 40°C. In some embodiments, the third reaction mixture can be carried out at a temperature of 20°C to 30°C.

[1244] IV. Compounds

[1245] In another embodiment, this disclosure provides a compound of formula III:

[1246]

[1247] or its salt, wherein R 1 R 2 and R 3 They can be hydrogen, F, Cl, CN, CF3, and C, respectively. 1-3 Alkyl or C 1-3 Alkoxy; R 4 It can be hydrogen or methyl; R 5 It can be C 3-6 Alkyl; and X can be F, Cl, Br, I or OTs.

[1248] In another embodiment, this disclosure provides a compound of formula III:

[1249]

[1250] or its salt, wherein R 1 R 2 and R 3 They can be hydrogen, F, Cl, CN, CF3, and C, respectively. 1-3 Alkyl or C 1-3 Alkoxy; R 4 It can be hydrogen or methyl; R 5 It can be C 3-6 Alkyl; and X can be Cl, Br, I or OTs.

[1251] In some implementation schemes, R 2 It can be Cl, F, CN, CF3, C 1-3 Alkyl or C 1-3alkoxy groups; and R 1 and R 3 They can be hydrogen, F, Cl, CN, CF3, and C, respectively. 1-3 Alkyl or C 1-3 Alkyl group. C 1-3 The alkyl group can be methyl, ethyl, propyl, or isopropyl. C 1-3 The alkoxy group can be methoxy, ethoxy, n-propoxy, or isopropoxy. In some embodiments, R 2 It can be Cl, F, CN, CF3, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; and R 1 and R 3 Each of these can be independently hydrogen, F, Cl, CN, CF3, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy. In some embodiments, R 2 It can be Cl, F, CN, CF3, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; and R 1 and R 3 Each of them can be hydrogen. In some implementations, R 2 It can be F, and R 1 and R 3 Each of them is hydrogen.

[1252] In some implementation schemes, R 4 It can be hydrogen. In some implementations, R 4 It can be methyl.

[1253] In some implementation schemes, R 5 It can be C 3-6 Alkyl group. In some embodiments, R 5 It can be n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or hexyl. In some embodiments, R 5 It can be n-butyl.

[1254] In some implementation schemes, R 4 It can be methyl; and R 5 It can be C 3-6 Alkyl group. In some embodiments, R 4 It can be methyl; and R 5 It can be n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or hexyl. In some embodiment...

Claims

1. A method for preparing a compound of formula I: or a salt thereof, the method comprising: a) forming a first reaction mixture comprising a compound of formula XI: or a salt thereof, a compound of formula VI: or a salt thereof, a first base, and a first solvent to form a compound of formula X: or its salts; b) forming a second reaction mixture, the second reaction mixture comprising the 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 form a compound of formula II: or its salts; as well as c) forming a third reaction mixture, the 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 R 1 , R 2 and R 3 are independently hydrogen, F, Cl, CN, CF3, C 1-3 Alkyl or C 1-3 Alkoxy; R 4 is hydrogen or methyl; R 5 It is C 3-6 Alkyl; and PG is an amino protecting group.

2. The method according to claim 1, wherein the compound of formula VI is a tosylate salt thereof.

3. The method according to claim 1 or 2, wherein the first base is 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-trimethylpyridine, 4-dimethylaminopyridine, imidazole, 1,8-bis(dimethylamino)naphthalene, sodium bicarbonate, sodium carbonate, trisodium phosphate, disodium hydrogen phosphate, potassium bicarbonate, potassium carbonate, tripotassium phosphate, dipotassium hydrogen phosphate, cesium carbonate or a combination thereof. The method of claim 1 , wherein the first base comprises N,N-diisopropylethylamine.

5. The method of claim 1, wherein the first solvent is 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. The method of claim 1 , wherein the first solvent comprises isopropyl acetate and 2-methyltetrahydrofuran.

7. The method according to claim 1, wherein the PG-NH2 compound is 2,4-dimethoxybenzylamine.

8. The method of claim 1, wherein the second base is 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-trimethylpyridine, 4-dimethylaminopyridine, imidazole, 1,8-bis(dimethylamino)naphthalene, sodium bicarbonate, sodium carbonate, trisodium phosphate, disodium hydrogen phosphate, potassium bicarbonate, potassium carbonate, tripotassium phosphate, dipotassium hydrogen phosphate, cesium carbonate, or a combination thereof.

9. The method of claim 1, wherein the second base comprises potassium carbonate.

10. The method of claim 1, wherein the second solvent is 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.

11. The method of claim 1, wherein the second solvent comprises isopropyl acetate and 2-methyltetrahydrofuran.

12. The method of claim 1, wherein the deprotecting agent is an acid.

13. The method of claim 12, wherein the acid is trifluoroacetic acid, trichloroacetic acid, acetic acid, formic acid, hydrochloric acid, sulfuric acid, phosphoric acid, or a combination thereof.

14. The method of claim 12 or 13, wherein the acid comprises trifluoroacetic acid.

15. The method of claim 1, wherein the deprotecting agent is a hydrogen source and the second reaction mixture further comprises a transition metal catalyst.

16. The method of claim 15, wherein the hydrogen source is ammonium formate, formic acid, hydrogen gas, or a combination thereof.

17. The method according to claim 15 or 16, wherein the transition metal catalyst is palladium hydroxide on carbon, palladium on carbon or platinum oxide.

18. The method of claim 1, wherein the deprotecting agent is boron tribromide, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, cerium ammonium nitrate, or a combination of trifluoromethanesulfonic acid and 1,3-dimethoxybenzene.

19. The method of claim 1, wherein the third solvent is 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.

20. The method of claim 1, wherein the third solvent comprises dichloromethane.

21. The method according to claim 1, further comprising: 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 compound of formula I in neutral form.

22. The method of claim 21, wherein the third base is sodium hydroxide or potassium hydroxide.

23. The method of claim 21 or 22, wherein the third base comprises sodium hydroxide.

24. The method of claim 21, wherein the fourth solvent is methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, water, or a combination thereof.

25. The method of claim 21, wherein the fourth solvent comprises i) ethanol and water or ii) ethyl acetate and water.

26. The method of claim 1, wherein the compound of formula I has formula Ia: or a salt thereof.

27. The method of claim 1, wherein the compound of formula I has formula Ib: or a salt thereof.

28. A method for preparing a compound of formula Ib: or a salt thereof, the method comprising: a) forming a first reaction mixture, said first reaction mixture comprising a compound of formula XIb: or a salt thereof, a compound of formula VIb: N,N-diisopropylethylamine, 2-methyltetrahydrofuran and isopropyl acetate to form a compound of formula Xb: or its salts; b) forming a second reaction mixture, the second reaction mixture comprising the compound of formula Xb or a salt thereof, 2,4-dimethoxybenzylamine, potassium carbonate, 2-methyltetrahydrofuran and isopropyl acetate to form a compound of formula IIb: or its salts; as well as c) forming a third reaction mixture, the third reaction mixture comprising the compound of formula IIb or a salt thereof, trifluoroacetic acid and dichloromethane to prepare a trifluoroacetate salt of the compound of formula Ib: as well as 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.

29. The process according to claim 28, wherein the compound of formula Xb or a salt thereof is isolated in a solution comprising 2-methyltetrahydrofuran and isopropyl acetate, and used in the following step b) without removing the 2-methyltetrahydrofuran and the isopropyl acetate.

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