Methods of making osivelotor

Abstract

The present disclosure relates to processes and intermediates that are useful for preparing Compound 1 having the formula Compound 1: or a salt thereof.

Description

PC073096A METHODS OF MAKING OSIVELOTOR FIELD

[0001] The present disclosure relates generally to the field of organic synthetic methodology for the preparation of compounds that modulate hemoglobin, such as osivelotor, and the synthetic intermediates prepared thereby. BACKGROUND

[0002] Sickle cell disease is a disorder of the red blood cells, found particularly among those of African and Mediterranean descent. The basis for sickle cell disease is found in sickle hemoglobin (HbS), which contains a point mutation relative to the prevalent peptide sequence of hemoglobin A (HbA).

[0003] Hemoglobin (Hb) transports oxygen molecules from the lungs to various tissues and organs throughout the body. Hemoglobin binds and releases oxygen through conformational changes. Sickle hemoglobin (HbS) contains a point mutation where glutamic acid is replaced with valine, making HbS susceptible to polymerization under hypoxic conditions to give the HbS containing red blood cells their characteristic sickle shape. The sickled cells are also more rigid than normal red blood cells, and their lack of flexibility can lead to blockage of blood vessels.

[0004] Compounds that modulate hemoglobin and are useful in treating disorders mediated by abnormal Hb (such as HbS) are disclosed in U.S. Patent No.10,683,285, the disclosure of which is hereby incorporated by reference in its entirety.

[0005] There remains a need for improved or alternate processes to prepare compounds thatSUMMARY

[0006] Provided herein are processes and intermediates useful for making Compound 1:,or a salt thereof.

[0007] In one aspect, the present disclosure provides a compound of Formula A:, or a salt thereof, wherein R1is H or Bz, and R2is H, F, Cl, Br, I, OTf, OTs, or OMs.

[0008] In some embodiments, R1is H. In some embodiments, R1is Bz.

[0009] In some embodiments, R2is Br. In some embodiments, R2is I.

[0010] In another aspect, the present disclosure provides a compound according to the formula of Compound 2:, or a salt thereof.

[0011] In another aspect, the present disclosure provides a crystalline Compound 2 Form 1 having the formula:, characterized by a powder X-Ray diffractogram comprising diffraction peaks 17.3 ± 0.2, 23.7 ±0.2, 24.1 ± 0.2, 25.2 ± 0.2, and 25.4 ± 0.2 °2 as determined on a diffractor using Cu-Kradiation.

[0012] In another aspect, the present disclosure provides a process for preparing Compound 1:comprising: (i) contacting 2-bromo-6-fluorobenzaldehyde with methanol or trimethylorthoacetate and toluenesulfonic acid monohydrate to form Compound 11 according to the formula:; (ii) contacting Compound 11 with Compound 5 according to the formula:and potassium tert-butoxide to form Compound 12 according to the formula:; (iii) contacting Compound 12 with Compound 8 according to the formula:and 2-chloro 1-methylpyiridinium toluenesulfonate to form Compound 2 according to the formula:; (iv) contacting Compound 2 with a copper catalyst, a ligand, and a base in a solvent to form a mixture (v) contacting the mixture after step (iv) with hydrochloric acid solution in a solvent to form Compound 1a HCl salt:(vi) contacting Compound 1a with sodium citrate in a solvent to form Compound 1. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG.1 shows the PXRD spectrum of crystalline Compound 2 Form 1. DETAILED DESCRIPTION

[0014] The present disclosure provides processes for preparing Compound 1, or a salt thereof, and useful intermediates for making Compound 1. The present disclosure may be understood more readily by reference to the following detailed description of the embodiments of the disclosure and the Examples included herein. It is to be understood that this disclosure is not limited to the specific synthetic methods of making that may vary. It is also to be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

[0015] E1. A compound of Formula A, or a salt thereof, as defined above.

[0016] E2. A compound of embodiment E1, or a salt thereof, wherein R1is Bz.

[0017] E3. A compound of any one of embodiments E1 to E2, wherein R2is Br or I.

[0018] E4. A compound according to the formula of Compound 2:, or a salt thereof.

[0019] E5. A crystalline Compound 2 Form 1 having the formula:, characterized by a powder X-ray diffractogram comprising diffraction peaks 17.3 ± 0.2, 23.7 ±0.2, 24.1 ± 0.2, 25.2 ± 0.2, and 25.4 ± 0.2 as determined on a diffractor using Cu-Kradiation.

[0020] E6. A crystalline Compound 2 Form 1 of embodiment E5, wherein the powder X-ray diffractogram further comprises diffraction peaks 7.2 ± 0.2, 17.1 ± 0.2, 19.4 ± 0.2, 20.4 ± 0.2,and 26.9 ± 0.2 °2 as determined on a diffractor using Cu-K radiation.

[0021] E7. A crystalline Compound 2 Form 1 of any one of embodiments E5 or E6, wherein the crystalline Compound 2 Form 1 is characterized by the powder X-ray diffractogram as substantially shown in FIG.1.

[0022] E8. A process for preparing Compound 1:comprising: (i) contacting Compound 2:with a catalyst in a solvent to form Compound 3:(ii) contacting Compound 3 with a base in a solvent to form a mixture; (iii) contacting the mixture after step (ii) with hydrochloric acid solution in a solvent to form Compound 1a HCl salt:; and (iv) contacting Compound 1a with sodium citrate in a solvent to form Compound 1.

[0023] E9. A process for preparing Compound 1:comprising: (i) contacting Compound 2:with a catalyst and a base in a solvent to form a mixture; (ii) contacting the mixture after step (i) with hydrochloric acid solution in a solvent to form Compound 1a HCl salt: ;(iii) contacting Compound 1a with sodium citrate in a solvent to form Compound 1.

[0024] E10. A process of any one of embodiments E8 to E9, wherein the catalyst comprises copper.

[0025] E11. A process of any one of embodiments E8 to E10, wherein the catalyst further comprises a ligand.

[0026] E12. A process of any one of embodiments E8 to E11, wherein the catalyst comprises copper iodide and 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl)picolinamide.

[0027] E13. A process of embodiment E12, wherein the ratio of copper iodide to 6-hydroxy- N-(4-hydroxy-2,6-dimethylphenyl)picolinamide is from about 1:5 to about 1:1.

[0028] E14. A process of any one of embodiments E8 to E13, further comprising: contacting a compound of Formula B:wherein:are hydrogen or C1-C6 alkyl; with a compound of Formula C:wherein R7is OH or Cl, to form Compound 2.

[0029] E15. A process of any one of embodiments E8 to E13, further comprising: contacting a compound of Formula B:wherein:are hydrogen or C1-C6alkyl; with: (a) a Grignard reagent; (b) compound 4:(c) benzoyl chloride or benzoyl anhydride, to form Compound 2.

[0030] E16. A process of any one of embodiments E14 to E15, whereinand R6are each independently methyl.

[0031] E17. A process of any one of embodiments E14 to E16, wherein R4is methyl or phenyl.

[0032] E18. A process of embodiment E14, wherein R7is OH.

[0033] E19. A process of any one of embodiments E8 to E13, further comprising: contacting a compound of Formula L:wherein: R14and R15are each independently H or C1-C6 alkyl; or R14and R15, taken together with the oxygen atom to which they are attached to, form a 3- to 8- membered heterocycloalkyl, wherein the 3- to 8-membered heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 instances of C1-C6 alkyl; with a compound of Formula C:wherein R7is OH or Cl, to from Compound 2.

[0034] E20. A process of embodiment E19, wherein R14and R15are each independently C1-C6alkyl.

[0035] E21. A process of any one of embodiments E19 to E20, wherein the compound of Formula L is compound 14 according to the formula:or a salt thereof.

[0036] E22. A process of making Compound 1:comprising: (i) contacting a compound of Formula Ewherein R8and R9are each independently selected from F, Cl, Br, and I, with a compound of Formula F: wherein: R10is adamantylR11is C1-C6alkyl or aryl; and R12and R13are each independently hydrogen or C1-C6alkyl; to form a compound of Formula G:(ii) contacting a compound of Formula G with Compound 5:rm a compound of Formula H; (iii) contacting a compound of Formula H with a compound of Formula C:wherein R7is OH or Cl rm a compound of Formula J:; (iv) contacting a compound of Formula J with a catalyst in a solvent to form a mixture; (v) contacting the solution from step (iv) with a base in a solvent to form Compound 3:; (vi) contacting Compound 3 with hydrochloric acid solution in a solvent to form Compound 1a HCl salt:(vii) contacting Compound 1a with sodium citrate in a solvent to form Compound 1.

[0037] E23. A process of embodiment E22, wherein the catalyst of step (iv) comprises copper iodide and 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl)picolinamide.

[0038] E24. A process of embodiment E23, wherein the ratio of copper iodide to 6-hydroxy- N-(4-hydroxy-2,6-dimethylphenyl)picolinamide is from about 1:5 to about 1:1.

[0039] E25. A process of making Compound 1:comprising: (i) contacting a compound of Formula Ewherein R8and R9are each independently selected from F, Cl, Br, and I, with a reagent and an acid to form a compound of Formula K:wherein: R14and R15are each independently H or C1-C6 alkyl; or R14and R15, taken together with the oxygen atom to which they are attached to, form a 3- to 8- membered heterocycloalkyl, wherein the 3- to 8-membered heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 instances of C1-C6 alkyl; (ii) contacting a compound of Formula K with Compound 5:to form a compound of Formula L(iii) contacting a compound of Formula L with a compound of Formula C:wherein R7is OH or Cl to form a compound of Formula J:; wherein R8is selected from F, Cl, Br, and I (iv) contacting a compound of Formula J with a catalyst and a base in a solvent to form a mixture; (v) contacting the mixture after step (iv) with hydrochloric acid solution in a solvent to form Compound 1a HCl salt:(vi) contacting Compound 1a with sodium citrate in a solvent to form Compound 1.

[0040] E26. A process of embodiment E25, wherein the reagent of step (i) is selected from methanol, trimethylorthoacetate, and 2,2-dimethyl-1,3-propanediol.

[0041] E27. A process of any one of embodiments E25 to E26, wherein the reagent of step (i) is trimethylorthoacetate or methanol.

[0042] E28. A process of any one of embodiments E25 to E27, wherein the catalyst of step (iv) comprises copper.

[0043] E29. A process of making Compound 1:comprising: (i) contacting 2-bromo-6-fluorobenzaldehyde with methanol or trimethylorthoacetate, and toluenesulfonic acid monohydrate to form Compound 11 according to the formula:; (ii) contacting Compound 11 with Compound 5 according to the formula:and potassium tert-butoxide to form Compound 12 according to the formula:Compound 12 ;(iii) contacting Compound 12 with Compound 8 according to the formula:and 2-chloro 1-methylpyiridinium toluenesulfonate to form Compound 2 according to the formula:Compound 2 ; (iv) contacting Compound 2 with a copper catalyst, a ligand, and a base in a solvent to form a mixture; (v) contacting the mixture after step (iv) with hydrochloric acid solution in a solvent to form Compound 1a HCl salt:; and (vi) contacting Compound 1a with sodium citrate in a solvent to form Compound 1.

[0044] E30. A process of Embodiment E29, wherein the ligand is 6-hydroxy-N-(4-hydroxy- 2,6-dimethylphenyl)picolinamide. Definitions

[0045] The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on thescope of the present disclosure but is instead provided as a description of exemplary embodiments.

[0046] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0047] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In other embodiments, the term “about” includes the indicated value or parameter ± 5%. In certain other embodiments, the term “about” includes the indicated value or parameter ± 2.5%. In certain other embodiments, the term “about” includes the indicated value or parameter ± 2%. In some other embodiments, the term “about” includes the indicated value or parameter ± 1%. In some other embodiments, the term “about” includes the indicated value or parameter ± 0.5%. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0048] The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.

[0049] The prefix “Cu-v” indicates that the following group has from u to v carbon atoms. For example, “C1-6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.

[0050] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl) or 1 to 4 carbon atoms (i.e., C1-4alkyl). Examples of alkyl groups include, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2) and tert- butyl (i.e., -C(CH3)3); and “propyl” includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0051] “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C6-20 aryl), 6 to 12 carbon ring atoms (i.e., C6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C6-10 aryl). Examples of aryl groups include, e.g., phenyl, naphthyl,fluorenyl and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl regardless of the point of attachment. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl regardless of the point of attachment.

[0052] “Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp3carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl and the like. Further, the term cycloalkyl is intended to encompass any non-aromatic ring which may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule. Still further, cycloalkyl also includes “spirocycloalkyl” when there are two positions for substitution on the same carbon atom, for example spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

[0053] “Halogen” or “halo” refers to atoms occupying group VIIA of the periodic table, such as fluoro, chloro, bromo or iodo.

[0054] “Heteroaryl” refers to an aromatic group having a single ring, multiple rings or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C1-20heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8heteroaryl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. In certain instances, heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, e.g., acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl,furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1- oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl and triazinyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0055] “Heterocyclic ring” or “heterocyclyl” or “heterocycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. The term “heterocyclyl” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused-heterocyclyl groups and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged or spiro, and may comprise one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O-) moieties. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the attachment to the remainder of the molecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e., C2-20heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2-12heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-10heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2-8heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3-12heterocyclyl), 3 to 8 ring carbon atoms (i.e., C3-8heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C3-6heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen. Examples of heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl,octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl. The term “heterocyclyl” also includes “spiroheterocyclyl” when there are two positions for substitution on the same carbon atom. Examples of the spiro-heterocyclyl rings include, e.g., bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of the fused-heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.

[0056] The term “reagent” refers to a substance or compound that may be added to bring about a chemical reaction.

[0057] The terms “solvent” or “inert solvent” refer to a solvent inert under the conditions of the reaction being described in conjunction therewith.

[0058] In some embodiments, the solvent is an “organic solvent” or “inert organic solvent,” which includes, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine, and the like. Unless specified to the contrary, the solvents used in the reactions of the present disclosure are inert organic solvents, and the reactions are carried out under an inert gas, such as nitrogen.

[0059] The term “coupling reagent” or “coupling agent” refers to a compound that aids in bringing about a reaction to couple one compound to another compound.

[0060] The term “metalating reagent” refers to a compound of the generic formula X-M-Rn, where M is a metal, R is an alkyl or aryl, and X is a counterion, such as a halide or alkali metal which may or may not be present. Exemplary metalating reagents include, but are not limited to, isopropyl magnesium chloride, methyl magnesium chloride, n-butyl magnesium chloride, phenyl magnesium chloride, lithium dimethylcopper, lithium diethylcopper, and lithium di-n- butylcopper.

[0061] The term “reducing agent” or “reductant” refers to an element or compound that loses an electron to an oxidizing agent in a redox reaction. Reducing agents increase the electron density on carbon centers, either by bond formation between the carbon and a less electronegative atom, or by bond breaking between the carbon and a more electronegative atom.Reducing agents usually accomplish this change in electron density by the addition of hydrogen, or the substitution of hydrogen for an electronegative atom on the carbon center.

[0062] The term “deprotecting reagent” refers to a compound that aids in removal of a protecting group (such as a hydroxy protecting group or amine protecting group).

[0063] The term “leaving group” refers to an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons. The non-limiting examples of a leaving group include, halo, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, (4-bromo-benzene)sulfonyloxy, (4- nitro-benzene)sulfonyloxy, (2-nitro-benzene)-sulfonyloxy, (4-isopropyl-benzene)sulfonyloxy, (2,4,6-tri-isopropyl-benzene)-sulfonyloxy, (2,4,6-trimethyl-benzene)sulfonyloxy, (4-tertbutyl- benzene)sulfonyloxy, benzenesulfonyloxy, (4-methoxy-benzene)sulfonyloxy, and the like.

[0064] The term “hydroxy protecting group” refers to a chemical moiety which is added to, and later removed from, a hydroxy functionality to obtain chemoselectivity in a subsequent chemical reaction. Exemplary protecting groups, as well as the methods for deprotection, include, but are not limited to, acetyl (Ac) (removed by acid or base), benzoyl (Bz) (removed by acid or base), benzyl (Bn) (removed by hydrogenolysis), -methoxyethoxymethyl ether (MEM) (removed by acid), dimethoxytrityl or [bis-(4-methoxyphenyl)phenylmethyl] (DMT) (removed by weak acid), methoxymethyl ether (MOM) (removed by acid), methoxytrityl or [(4- methoxyphenyl)diphenylmethyl] (MMT) (removed by acid and hydrogenolysis), p- methoxybenzyl ether (PMB) (removed by acid, hydrogenolysis, or oxidation), methylthiomethyl ether (removed by acid), pivaloyl (Piv) (removed by acid, base or reductant agents), tetrahydropyranyl (THP) (removed by acid), tetrahydrofuran (THF) (removed by acid), trityl (triphenylmethyl, Tr) (removed by acid and hydrogenolysis), silyl ether (e.g., trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tri-iso-propylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers) (removed by acid or fluoride ion, such as NaF, TBAF (tetra-n- butylammonium fluoride, HF-Py, or HF-NEt3)), methyl ethers (removed by cleavage is by TMSI in dichloromethane or acetonitrile or chloroform, or BBr3 in DCM), and ethoxyethyl ethers (EE) (removed by 1N hydrochloric acid).

[0065] The term “amine protecting group” refers to a chemical moiety which is added to, and later removed from, an amine functionality to obtain chemoselectivity in a subsequent chemical reaction. Exemplary protecting groups, as well as the methods for deprotection, include, but are not limited to, 9-fluorenylmethoxycarbonyl (Fmoc) (removed by base), tert-butyloxycarbonyl (Boc) (removed by strong acid), carboxybenzyl (Cbz) (removed by hydrogenolysis), acetyl (Ac) (removed by base), benzyl (Bn) (removed by hydrogenolysis), benzoyl (Bz) (removed by base),carbamate (removed by acid and mild heating), p-methoxybenzyl (PMB) (removed by hydrogenolysis), 3,4-dimethoxybenzyl (DMPM) (removed by hydrogenolysis), p- methoxyphenyl (PMP) (removed by ammonium cerium(IV) nitrate (CAN)), tosyl (Ts) (removed by concentrated acid and strong reducing agents), and 2,2,2-trichloroethoxycarbonyl (Troc) (removed by Zn insertion in the presence of acetic acid).

[0066] Any formula or structure given herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to2H (deuterium, D),3H (tritium),11C,13C,14C,15N,18F,31P,32P,35S,36Cl and125I. Various isotopically labeled compounds of the present disclosure, for example, those into which radioactive isotopes such as3H and14C are incorporated, are provided herein. Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

[0067] The disclosure also includes “deuterated analogs” of compounds of Formula I in which from 1 to n hydrogens attached to a carbon atom is / are replaced by deuterium, in which n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound of Formula I when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci.5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0068] Deuterium labeled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and / or an improvement in therapeutic index. An18F labeled compound may be useful for PET or SPECT studies. Isotopically labeled compounds of this disclosure can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readilyavailable isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compound of Formula I.

[0069] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.

[0070] In many cases, the compounds of this disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0071] Base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N- alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. Acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.

[0072] In some cases, the “salt” of a given compound is a pharmaceutically acceptable salt. The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts may be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine,diethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0073] Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.

[0074] Provided are also pharmaceutically acceptable salts, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use. Intermediates

[0075] In one aspect, the present disclosure provides a compound of Formula A:, or a salt thereof, wherein R1is H or Bz, and R2is H, F, Cl, Br, I, OTf, OTs, or OMs.

[0076] In some embodiments, R1is H. In some embodiments, R1is Bz.

[0077] In some embodiments, R2is Br. In some embodiments, R2is I.

[0078] In another aspect, the present disclosure provides a compound according to the formula of Compound 2:, or a salt thereof.

[0079] In another aspect, the present disclosure provides a crystalline Compound 2 Form 1 having the formula:, characterized by a powder X-Ray diffractogram comprising diffraction peaks 17.3 ± 0.2, 23.7 ±0.2, 24.1 ± 0.2, 25.2 ± 0.2, and 25.4 ± 0.2 °2 as determined on a diffractor using Cu-Kradiation.

[0080] In some embodiments, the crystalline Compound 2 Form 1 characterized by the powder X-ray diffractogram further comprises diffraction peaks 7.2 ± 0.2, 17.1 ± 0.2, 19.4 ± 0.2, 20.4 ±0.2, and 26.9 ± 0.2 °2 as determined on a diffractor using Cu-K radiation.

[0081] In some embodiments, the crystalline Compound 2 Form 1 characterized by powder X- Ray diffractogram further comprises diffraction one or more peaks 8.4 ± 0.2, 8.9 ± 0.2, 16.6 ± 0.2, 16.8 ± 0.2, 18.3 ± 0.2, 20.2 ± 0.2, 21.0 ± 0.2, 21.8 ± 0.2, 23.5 ± 0.2, 24.6 ± 0.2, 25.8 ± 0.2,26.0 ± 0.2, 28.1 ± 0.2, 29.7 ± 0.2, and 30.1 ± 0.2 °2 , as determined on a diffractor using Cu-Kradiation.

[0082] In some embodiments, the crystalline Compound 2 From 1 is characterized by the powder X-ray diffractogram as substantially shown in FIG.1.Processes

[0083] Provided herein are processes for preparing Compound 1 or a salt thereof, and useful intermediates, or a salt thereof, .

[0084] The present processes may be performed using methods disclosed herein and routine modifications thereof which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein, e.g. compounds having structures described by one or more of Formula I, or other formulas or compounds disclosed herein, may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g. from Sigma Aldrich or other chemical suppliers.

[0085] Typical embodiments of compounds in accordance with the present disclosure may be synthesized using the general reaction schemes described below. It will be apparent given the description herein that the general schemes may be altered by substitution of the starting materials with other materials having similar structures to result in products that are correspondingly different. Descriptions of syntheses follow to provide numerous examples of how the starting materials may vary to provide corresponding products. Given a desired product for which the substituent groups are defined, the necessary starting materials generally may be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using published methods. For synthesizing compounds which are embodiments of the present disclosure, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group. The identity of the final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein.

[0086] The compounds of this disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0087] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. Forexample, numerous protecting groups are described in T. W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references cited therein.

[0088] Furthermore, the compounds of this disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.

[0089] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5thEdition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0090] In each of the exemplary schemes it may be advantageous to separate reaction products from one another and / or from starting materials. The desired products of each step or series of steps is separated and / or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium, and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.

[0091] Another class of separation methods involves treatment of a mixture with a reagent selected to bind to or render otherwise separable a desired product, unreacted starting material,reaction by product, or the like. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like. Alternatively, the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid / liquid ion extraction reagents (LIX), or the like.

[0092] Selection of appropriate methods of separation depends on the nature of the materials involved. For example, boiling point, and molecular weight in distillation and sublimation, presence or absence of polar functional groups in chromatography, stability of materials in acidic and basic media in multiphase extraction, and the like. One skilled in the art will apply techniques most likely to achieve the desired separation.

[0093] A single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113, 3) 283-302). Racemic mixtures of chiral compounds of the disclosure can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions.

[0094] In another aspect, the present disclosure provides a process for preparing Compound 1:comprising: (i) contacting Compound 2:with a catalyst in a solvent to form Compound 3:(ii) contacting Compound 3 with a base in a solvent to form a mixture; (iii) contacting the mixture after step (ii) with hydrochloric acid solution in a solvent to form Compound 1a HCl salt:; and (iv) contacting Compound 1a with sodium citrate in a solvent to form Compound 1.

[0095] In another aspect, the present disclosure provides a process for preparing Compound 1:comprising: (i) contacting Compound 2:with a catalyst in a solvent to form Compound 3:(ii) contacting Compound 3 with a base in a solvent to form a mixture; (iii) contacting the mixture after step (ii) with hydrochloric acid solution in a solvent to form Compound 1a HCl salt:(iv) contacting Compound 1a with sodium citrate in a solvent to form Compound 1.

[0096] In another aspect, the present disclosure provides a process of making Compound 1:comprising: (i) contacting Compound 2:with a catalyst and a base in a solvent to form a mixture; (ii) contacting the mixture after step (i) with hydrochloric acid solution in a solvent to form Compound 1a HCl salt:; and (iii) contacting Compound 1a with sodium citrate in a solvent to form Compound 1.

[0097] In some embodiments, the catalyst of step (i) comprises copper.

[0098] In some embodiments, the catalyst of step (i) further comprises a ligand.

[0099] In some embodiments, the catalyst of step (i) comprises copper iodide and 6-hydroxy- N-(4-hydroxy-2,6-dimethylphenyl)picolinamide.

[0100] In some embodiments, the ratio of copper iodide to 6-hydroxy-N-(4-hydroxy-2,6- dimethylphenyl)picolinamide is from about 1:5 to about 1:1.

[0101] In some embodiments, the ratio of copper iodide to 6-hydroxy-N-(4-hydroxy-2,6- dimethylphenyl)picolinamide is from about 1:5 to about 1:1. In some embodiments, the ratio of copper iodide to 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl)picolinamide is about 1:5, about 1:4, about 1:3, about 1:2, or about 1:1.

[0102] In some embodiments, the solvent of step (i) comprises water.

[0103] In some embodiments, the solvent of step (i) further comprises an alcohol.

[0104] In some embodiments, the alcohol is selected from methanol, ethanol, propanol, and butanol.

[0105] In some embodiments, the solvent of step (i) comprises a mixture of water and ethanol.

[0106] In some embodiments, step (i) further comprises potassium phosphate.

[0107] In some embodiments, the base of step (ii) is an inorganic base.

[0108] In some embodiments, the base of step (ii) is a metal hydroxide. In some embodiments, the base of step (ii) is lithium hydroxide.

[0109] In some embodiments, the base of step (ii) is a potassium phosphate. In some embodiments, the base of step (ii) is potassium phosphate tribasic monohydrate.

[0110] In some embodiments, the solvent of step (ii) is an alcohol. In some embodiments, the solvent of step (ii) is methanol.

[0111] In some embodiments, the solvent of step (ii) is a mixture of solvents. In some embodiments, the solvent of step (ii) is a mixture of alcohols. In some embodiments, the solvent of step (ii) comprises methanol. In some embodiments, the solvent of step (ii) is a mixture of solvents comprising methanol. In some embodiments, the solvent of step (ii) is a mixture of methanol and ethanol.

[0112] In some embodiments, the solvent of step (iii) comprises an alcohol. In some embodiments, the solvent of step (iii) comprises isopropanol.

[0113] In some embodiments, the solvent of step (iii) is a mixture of an ether and an alcohol. In some embodiments, the solvent is a mixture of tetrahydrofuran and isopropanol.

[0114] In some embodiments, the solvent of step (iv) comprises ethyl acetate and methyl tert- butyl ether.

[0115] In some embodiments of the process of making Compound 1, the process further comprises: contacting a compound of Formula B:wherein: R3is adamantylR4is C1-C6alkyl or aryl; and R5and R6are each independently hydrogen or C1-C6alkyl; with a compound of Formula C:wherein R7is OH or Cl,to form Compound 2.

[0116] In some embodiments, the process further comprises: contacting a compound of Formula B:wherein: R3 is adamantylR4is C1-C6alkyl or aryl; and R5and R6are each independently hydrogen or C1-C6alkyl; with: (a) a Grignard reagent; (b) compound 4:Compound 4 benzoyl chloride or benzoyl anhydride, to form Compound 2.

[0117] In some embodiments,

[0118] In some embodiments, R5and R6are each independently methyl.

[0119] In some embodiments, R4is methyl or phenyl.

[0120] In some embodiments, R7is OH.

[0121] In some embodiments, further comprising T3P.

[0122] In some embodiments, the Grignard reagent is cyclohexyl magnesium chloride.

[0123] In some embodiments, the process further comprises: contacting a compound of Formula L:wherein: R14and R15are each independently H or C1-C6 alkyl; or R14and R15, taken together with the oxygen atom to which they are attached to, form a 3- to 8- membered heterocycloalkyl, wherein the 3- to 8-membered heterocycloalkyl is unsubstituted to substituted with 1, 2, or 3 instances of C1-C6 alkyl; with a compound of Formula C:wherein R7is OH or Cl, to from Compound 2.

[0124] In some embodiments, R14and R15are each independently C1-C6 alkyl.

[0125] In some embodiments, the compound of Formula L is compound 14 according to the formula:or a salt thereof.

[0126] In another aspect, the present disclosure provides a process of making Compound I:comprising: (i) contacting a compound of Formula EFormula E wherein R8and R9are each independently selected from F, Cl, Br, and I, with a compound of Formula F: Formula F wherein: R10is adamantylR11is C1-C6 alkyl or aryl; and R12and R13are each independently hydrogen or C1-C6 alkyl; to form a compound of Formula G:Formula G (ii) contacting a compound of Formula G with Compound 5:to form a compound of Formula HFormula H (iii) contacting a compound of Formula H with a compound of Formula C:wherein R7is OH or Cl to form a compound of Formula J:; wherein R8is selected from F, Cl, Br, and I (iv) contacting a compound of Formula J with a catalyst in a solvent to form a mixture; (v) contacting the solution from step (iv) with a base in a solvent to form Compound 3:; (vi) contacting Compound 3 with hydrochloric acid solution in a solvent to form Compound 1a HCl salt:(vii) contacting Compound 1a with sodium citrate in a solvent to form Compound 1.

[0127] In some embodiments, R8is Br.

[0128] In some embodiments, R9is F.

[0129] In some embodiments, R12and R13are each independently methyl.

[0130] In some embodiments, R11is methyl or phenyl.

[0131] In some embodiments, R7is OH or Cl.

[0132] In some embodiments, step (iii) further comprises T3P.

[0133] In some embodiments, the catalyst of step (iv) comprises copper.

[0134] In some embodiments, the catalyst of step (iv) further comprises a ligand.

[0135] In some embodiments, the catalyst of step (iv) comprises copper iodide and 6-hydroxy- N-(4-hydroxy-2,6-dimethylphenyl)picolinamide.

[0136] In some embodiments, the ratio of copper iodide to 6-hydroxy-N-(4-hydroxy-2,6- dimethylphenyl)picolinamide is from about 1:5 to about 1:1. In some embodiments, the ratio of copper iodide to 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl)picolinamide is about 1:5, about 1:4, about 1:3, about 1:2, or about 1:1.

[0137] In some embodiments, the solvent of step (iv) comprises water.

[0138] In some embodiments, the solvent of step (iv) further comprises an alcohol.

[0139] In some embodiments, the alcohol is selected from methanol, ethanol, propanol, and butanol.

[0140] In some embodiments, the solvent of step (iv) comprises a mixture of water and ethanol.

[0141] In some embodiments, step (iv) further comprises potassium phosphate.

[0142] In some embodiments, the base of step (v) is an inorganic base.

[0143] In some embodiments, the base of step (v) is a metal hydroxide. In some embodiments, the base of step (v) is lithium hydroxide.

[0144] In some embodiments, the base of step (v) is a potassium phosphate. In some embodiments, the base of step (v) is potassium phosphate tribasic monohydrate.

[0145] In some embodiments, the solvent from step (v) comprises an alcohol. In some embodiments, the solvent of step (v) comprises methanol.

[0146] In some embodiments, the solvent of step (v) is a mixture of solvents. In some embodiments, the solvent of step (v) is a mixture of alcohols. In some embodiments, the solvent of step (v) is a mixture of solvents comprising methanol. In some embodiments, the solvent of step (v) comprises methanol. In some embodiments, the solvent of step (v) is a mixture of methanol and ethanol.

[0147] In some embodiments, the solvent of step (vi) comprises an alcohol. In some embodiments, the solvent of step (vi) comprises isopropanol.

[0148] In some embodiments, the solvent of step (vi) is a mixture of an ether and an alcohol. In some embodiments, the solvent is a mixture of tetrahydrofuran and isopropanol.

[0149] In some embodiments, the solvent of step (vii) comprises ethyl acetate and methyl tert- butyl ether.

[0150] In some embodiments, Compound 1 is synthesized according to Scheme 1:

[0151] In another aspect, the present disclosure provides a process of making Compound I:comprising: (i) contacting a compound of Formula EFormula E wherein R8and R9are each independently selected from F, Cl, Br, and I, with a reagent and an acid to form a compound of Formula K:wherein: R14and R15are each independently H or C1-C6 alkyl; or R14and R15, taken together with the oxygen atom to which they are attached to, form a 3- to 8- membered heterocycloalkyl, wherein the 3- to 8-membered heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 instances of C1-C6 alkyl; (ii) contacting a compound of Formula K with Compound 5:to form a compound of Formula L(iii) contacting a compound of Formula L with a compound of Formula C:wherein R7is OH or Cl to form a compound of Formula J:; wherein R8is selected from F, Cl, Br, and I (iv) contacting a compound of Formula J with a catalyst and a base in a solvent to form a mixture; (v) contacting the mixture after step (iv) with hydrochloric acid solution in a solvent to form Compound 1a HCl salt:(vi) contacting Compound 1a with sodium citrate in a solvent to form Compound 1.

[0152] In some embodiments, the reagent of step (i) is selected from methanol, trimethylorthoacetate, and 2,2-dimethyl-1,3-propanediol.

[0153] In some embodiments, the reagent of step (i) is trimethylorthoacetate or methanol.

[0154] In some embodiments, the acid of step (i) is toluenesulfonic acid monohydrate.

[0155] In some embodiments, R8is Br. In some embodiments, R9is F.

[0156] In some embodiments, R12and R13are each independently methyl.

[0157] In some embodiments, R14and R15are each independently methyl.

[0158] In some embodiments, R11is methyl or phenyl.

[0159] In some embodiments, R7is OH or Cl.

[0160] In some embodiments, step (iii) further comprises T3P or chloro-1-methylpyridinium p- toluenesulfonate.

[0161] In some embodiments, the catalyst of step (iv) comprises copper.

[0162] In some embodiments, the catalyst of step (iv) further comprises ligand.

[0163] In some embodiments, the catalyst of step (iv) comprises copper iodide and 6-hydroxy- N-(4-hydroxy-2,6-dimethylphenyl)picolinamide.

[0164] In some embodiments, the ratio of copper iodide to 6-hydroxy-N-(4-hydroxy-2,6- dimethylphenyl)picolinamide is from about 1:5 to about 1:1.

[0165] In some embodiments, the solvent of step (iv) comprises water.

[0166] In some embodiments, the solvent of step (iv) further comprises an alcohol. In some embodiments, the alcohol is selected from methanol, ethanol, propanol, and butanol.

[0167] In some embodiments, the solvent of step (iv) comprises a mixture of water and ethanol.

[0168] In some embodiments, step (iv) further comprises potassium phosphate.

[0169] In some embodiments, the base of step (iv) is an inorganic base.

[0170] In some embodiments, the base of step (iv) is a metal hydroxide.

[0171] In some embodiments, the metal hydroxide is lithium hydroxide.

[0172] In some embodiments, the base of step (iv) is potassium phosphate tribasic monohydrate.

[0173] In some embodiments, the solvent of step (v) comprises an alcohol.

[0174] In some embodiments, the solvent of step (v) comprises isopropanol.

[0175] In some embodiments, the solvent of step (v) is a mixture of an ether and an alcohol.

[0176] In some embodiments, the solvent of step (v) is a mixture of tetrahydrofuran and isopropanol.

[0177] In some embodiments, the solvent of step (vi) comprises ethyl acetate and methyl tert- butyl ether.

[0178] In some embodiments, Compound 1 is synthesized according to Scheme 2:

[0179] In another aspect, the present disclosure provides a process of making Compound I:comprising: (i) contacting 2-bromo-6-fluorobenzaldehyde with methanol or trimethylorthoacetate and toluenesulfonic acid monohydrate to form Compound 11 according to the formula:; (ii) contacting Compound 11 with Compound 5 according to the formula:and potassium tert-butoxide to form Compound 12 according to the formula:Compound 12 ;(iii) contacting Compound 12 with Compound 8 according to the formula:and 2-chloro 1-methylpyiridinium toluenesulfonate to form Compound 2 according to the formula:; (iv) contacting Compound 2 with a copper catalyst, a ligand, and a base in a solvent to form a mixture; (v) contacting the mixture after step (iv) with hydrochloric acid solution in a solvent to form Compound 1a HCl salt:(vi) contacting Compound 1a with sodium citrate in a solvent to form Compound 1.

[0180] In some embodiments, the ligand is 6-hydroxy-N-(4-hydroxy-2,6- dimethylphenyl)picolinamide.

[0181] In some embodiments, the copper catalyst is copper iodide.

[0182] In some embodiments, the base in step (iv) is potassium phosphate. EXAMPLES

[0183] The following examples are given for the purpose of illustrating various embodiments of the disclosure and are not meant to limit the present disclosure in any fashion. The present examples, along with the methods described herein are presently representative of some embodiments, are exemplary, and are not intended as limitations on the scope of the disclosure. Changes therein and other uses which are encompassed within the spirit of the disclosure as defined by the scope of the claims will occur to those skilled in the art.

[0184] Table 1 summarizes the abbreviations used in the present disclosure. Table 1 – Abbreviations AcCl acetyl chloride AcOH acetic acid Aq aqueous Bn benzyl Boc tert-butoxycarbonyl Boc2O di-tert-butyl dicarbonate Br broad Bz benzoyl tBu tert-butyl tBuOH tert-butanolTable 1 – Abbreviations tBuOK potassium tert-butoxide °C degrees Celsius CDCl3 deutero-chloroform CDI 1,1’-carboyldiimidazole chemical shift d doublet dd doublet of doublets ddd doublet of doublet of doublets dt doublet of triplets DCE 1,2-dichloroethane DCM dichloromethane DIAD diisopropyl azodicarboxylate DIPEA N-ethyldiisopropylamine or N,N-diisopropylethylamine DMA N,N-dimethylacetamide DMAC dimethylacetamide DME 1,2-dimethoxyethane DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DMSO-d6deuterodimethylsulfoxide DPPP 1,3-bis(diphenylphosphino)propane EDC N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide EDC.HCl N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride ESI electrospray ionization Et2O diethyl ether EtOAc ethyl acetate EtOH ethanol Et3N triethylamine g gram 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium HATU 3-oxid hexafluorophosphate HPLC high pressure liquid chromatographyTable 1 – Abbreviations HOBt 1-hydroxybenzotriazole hydrate hr hour(s) IPA isopropyl alcohol iPrOAc isopropyl acetate L liter LCMS liquid chromatography mass spectrometry m multiplet M molar m-CPBA 3-chloroperbenzoic acid MeCN acetonitrile MeMgBr methylmagnesium bromide MeOH_d4deuterated methanol MeOH methanol 2-MeTHF 2-methyl tetrahydrofuran mg milligram MHz mega Hertz min(s) minute(s) mL milliliter mmol millimole mol mole MS (m / z) mass spectrum peak MsCl mesyl chloride MTBE tert-butyl methyl ether NiCl2glyme nickel (II) chloride ethylene glycol dimethyl ether complex NMR nuclear magnetic resonance OTf trifluoromethanesulfonate OTs toluenesulfonate Oms methanesulfonate PMB para-methoxybenzyl PMD-NH2para-methoxybenzylamine pH power of hydrogen ppm parts per millionTable 1 – Abbreviations PXRD powder X-ray diffraction q quartet rt room temperature s singlet t triplet T3P propylphosphonic anhydride TBAF tert-butyl ammonium fluoride TBDMSCl tert-butyldimethylsilyl chloride TFA trifluoroacetic acid THF tetrahydrofuran TMSCl trimethylsilyl chloride TMSCN trimethylsilyl cyanide TMSCHN2 (diazomethyl)trimethylsilane TsCl p-toluenesulfonyl chloride Ts2O p-toluenesulfonic anhydride μL microliter μmol micromole Example 1 – Synthesis of Compound 1 according to Scheme 3Step 1 – Synthesis of 1-(2-bromo-6-fluorophenyl)-N-(2-phenylpropan-2-yl)methanimine (Compound 6)

[0185] To a 250 mL vessel was charged 2-bromo-6-fluoro-benzaldehyde (188 mmol, 38.1 g) followed by methyl tert-butyl ether (150 mL, 111 g) and cumylamine (186 mmol, 26.7 mL, 25.2 g). The reaction mixture was then heated at 60-75 °C to achieve reflux. After 20-30 minutes of reaction time, methyl tert-butyl ether was removed by distillation to provide the desired product 1-(2-bromo-6-fluorophenyl)-N-(2-phenylpropan-2-yl)methanimine (compound 6) as an oil (186 mmol, 59.6 g).

[0186] 1H NMR (400 MHz, DMSO-d6) ppm: 1.60 (s, 6 H), 7.20 - 7.29 (m, 1 H), 7.31 - 7.48 (m, 6 H), 7.55 (d, J=7.80 Hz, 1 H), 8.34 (s, 1 H).

[0187] 13C NMR (100 MHz, DMSO-d6) ppm 29.7, 64.3, 116.4 (d, J= 22 Hz), 123.7 (d, J= 4.4 Hz),125.4 (d, J= 14 Hz), 126.3, 126.8, 128.5, 129.3 (m), 132.4-132.5 (m), 122.5, 147.8, 153.0-153.1 (m), 159.2, 161.8. Step 2 – Synthesis of (S,E)-1-(2-bromo-6-(morpholin-3-ylmethoxy)phenyl)-N-(2-

[0188] To a 1L reactor was charged potassium tert-butoxide (1 mol / L) in tetrahydrofuran (205 mmol, 205 mL, 185 g, 1.20 equiv.) and the resulting mixture was cooled to 0 to -5 °C. (R)- morpholin-3-ylmethanol (compound 5, 176 mmol, 20.6 g, 1.03 equiv.) and tetrahydrofuran (40 mL, 2 vol) were then added to the reaction mixture at 0 °C. After about 30 minutes, Compound 6 (186 mmol, 59.6 g, 1.09 equiv.) in tetrahydrofuran (40 mL, 2 vol) was added at 0 °C. The resulting reaction mixture was then heated to 45 °C over 3 h, and stirred overnight at 45 °C. Thereaction mixture was then cooled to -5 °C and used without further manipulation in Step 4 below. Step 3 –

[0189] To a 1-liter vessel under nitrogen at ambient conditions and agitation at 250 rpm was charged dimethylacetamide (350 mL, 7 mL / g), followed by pyridine-2-carboxamide oxime (4.12 g, 28.6 mmol, 0.09 equiv.), tetrabutylammonium iodide (29.4 g, 79.4 mmol, 0.250 equiv.), and NiCl2-glyme complex (5.50 g, 23.8 mmol, 0.0750 equiv.) to provide a green solution. After 20 minutes, zinc dust (41.6 g, 634 mmol, 2.00 equiv.), and trifluoroacetic acid (2.46 mL, 31.8 mmol, 0.1 equiv.) were added at 25 ± 5 °C. The resulting reaction mixture was then heated to 50-53 °C, followed by addition of 2-chloronicotinic acid (50.0 g, 318 mmol, 1.00 equiv.) and 2- bromoethylbenzoate (75.6 mL, 109 g, 476 mmol, 1.50 equiv.) in portions (at least 5 portions) every 20-30 min to ensure the temperature of the reaction mixture temperature does not exceed 55 °C. Upon completion of addition, the resulting reaction mixture was heated at 53 °C for 12 hours. The reaction mixture was then cooled to 35 °C and quenched with the addition of glycine (318 mmol, 24.4 g, 1.00 equiv.) and water (200 mL, 200 g) which was an exothermic process. The resulting mixture was then charged with potassium hydroxide (11.5 Mol / L) in water (82.8 mL, 120.4 g, 3.00 equiv.) at 30-45 °C and held for 45 min. The mixture was then filtered to remove zinc salts, and the filtrate was washed with water (200 mL, 200 g). The combined filtrate was then heated to 40-43 °C, followed by addition of citric acid (91.4 g, 1.50 equiv.) until the pH of the filtrate solution is around 4. The resulting mixture was then heated to 35-45 °C and held for 30 min, followed by addition of water (400 mL, 400 g). The resulting mixture was heated at ~40-43 °C for 1 h, followed by cooling to 20 °C over 1 hour timespan, and left sitting at 20 °C for 4 h, during which time the desired product precipitated from the solution. The resulting solids were isolated by filtration, washed with water (200 mL), and dried under vacuum over night with a nitrogen. The resulting residue was purified further by recrystallization in a solvent mixture of 2-propanol and water to provide the desired 2-(2- (benzoyloxy)ethyl)nicotinic acid (compound 8) as an off-white crystalline solid in an isolated yield of 78% yield (66.7.0 g) with a measured melting point of 145-146 °C.

[0190] 1H NMR (400 MHz, DMSO-d6) ppm 3.61 (t, J=6.63 Hz, 2 H), 4.69 (t, J=6.63 Hz, 2 H), 7.41 (dd, J=7.81, 4.68 Hz, 1 H), 7.50 (t, J=7.80 Hz, 2 H), 7.59 - 7.69 (m, 1 H), 7.85 - 7.90 (m, 2 H), 8.21 (dd, J=8.00, 1.76 Hz, 1 H), 8.68 (dd, J=4.68, 1.56 Hz, 1 H), 13.39 (s, 1 H). Step 4 – Synthesis of (S)-2-(3-(3-((3-bromo-2-formylphenoxy)methyl)morpholine-4- carbonyl)pyridin-2-yl)ethyl benzoate (Compound 2)

[0191] In a 1 L vessel was charged T3P (50%) in ethyl acetate, (427 mmol, 254 mL, 272 g, 2.50 equiv.) and triethylamine (1020 mmol, 143 mL, 104 g, 6.00 equiv.), and the resulting T3P solution was cooled to 0 °C, followed by addition of compound 8 (171 mmol, 46.3 g, 1.00 equiv.) to obtain a yellow-orange reaction mixture, which was held at 0 to -5 °C for at least 1 h.

[0192] To the reaction mixture from step 2 above, which contains compound 7, was charged the orange solution containing T3P-activated compound 8 at -5 °C, and the resulting mixture was cooled to -10 °C. After 20 minutes, the reaction mixture was warmed to 10 °C over 1 hour, and held at 10 °C. After 2 hours, the reaction mixture was warmed to 22 °C, quenched with water (200 mL, 200 g) and ethyl acetate (200 mL, 180 g). The aqueous phase was then separated and discarded. To the organic layer was then added citric acid (171 mmol, 19.9 mL, 32.8 g, 1.00 equiv.) and water (200 mL), and the resulting mixture was agitated for 30 minutes followed by settling for 30 minutes. The aqueous layer was then separated and discarded. The organic layer was then concentrated in vacuo down to a volume of ~75 mL, followed by addition of anhydrous ethanol (200 mL) and re-concentrated to ~100 mL. The resulting mixture was then charged with additional anhydrous ethanol (240 mL, 190 g), water (80.0 mL) and acetic acid (~3 mL), and then heated to 55 °C and held for 4 h. The mixture was then cooled to room temperature to allow crystals to form. After about 12 hours, the crystals were isolated by filtration, washed with ethanol, dried with suction for 3 hours, and transferred to a vacuum oven at 50 °C and held overnight. The desired product (S)-2-(3-(3-((3-bromo-2-formylphenoxy)methyl)morpholine-4- carbonyl)pyridin-2-yl)ethyl benzoate (Compound 2) was isolated in 80% yield (137 mmol, 75.8 g, 0.802 equiv.) with a measured melting point of 140-141 °C.

[0193] 1H NMR (400 MHz, DMSO-d6) ppm 2.90-5.02 (m, 13H), 7.00-8.10 (m, 10 H), 8.52- 8.68 (m, 1 H), 10-10.44(m, 1H).

[0194] 13C NMR (100 MHz, DMSO-d6) ppm 25.6, 26.0, 34.2, 43.2, 43.8, 47.5, 48.1, 53.5, 62.5, 63.6, 66.2, 66.6, 67.5, 113.5, 114.2, 122.0, 122.2, 122.9, 123.5, 124.0, 127.1, 129.1, 129.5, 130.2, 131.9, 133.7, 135.1, 135.9, 150.0, 150.1, 160.8, 161.8, 166.2, 168.3, 190.2. Step 5 – Synthesis of (S)-2-(3-(3-((2-formyl-3-hydroxyphenoxy)methyl)morpholine-4- carbonyl)pyridin-2-yl)ethyl benzoate (Compound 3)

[0195] In a 1 L vessel was charged compound 2 (60.0 g, 102.6 mmol), copper iodide (1.02 mmol, 0.200 g, 0.0100 equiv.), 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl)picolinamide (ligand, 4.10 mmol, 1.06 g, 0.0400 equiv.), anhydrous ethanol (180.0 mL, 142 g), and water (60.00 mL, 60.00 g), and the resulting mixture was stirred at 500 rpm. Potassium phosphate tribasic monohydrate (206 mmol, 49.8 g, 2.00 equiv.) was then added and the resulting mixture was heated to 50 °C. After 2.5 hours, the reaction mixture was cooled to room temperature, charged with water (360 mL) and neutralized with hydrochloric acid. To the resulting mixture was then added ethyl acetate (600 mL) and agitated for about 20 minutes. The aqueous layer was discarded, and the organic layer was concentrated in vacuo to provide the desired product (S)-2-(3-(3-((2-formyl-3-hydroxyphenoxy)methyl)morpholine-4-carbonyl)pyridin-2-yl)ethyl benzoate (compound 3) as a crude residue which was used in the next step without further purification. Step 6 – Synthesis of (S)-2-hydroxy-6-((4-(2-(2-hydroxyethyl)nicotinoyl)morpholin-3- yl)methoxy)benzaldehyde hydrochloride (Compound 1a)

[0196] To the crude compound 3 from step 5 above was added methanol (600 mL) and the resulting mixture was cooled to 0 °C. Lithium hydroxide (206 mmol, 8.62 g, 2.00 equiv.) was added at 0 °C and the resulting homogeneous solution was held for 3 hours. Hydrochloric acid in water (37%, 390 mmol, 32.00 mL, 19.02 g, 3.80 equiv.) was then added to adjust the pH of the mixture to about 4, followed by addition of propanol (120 mL), and the resulting mixture was concentrated. To the resulting crude residue was then added THF (150 mL, 133 g) and 2- propanol (150 mL, 118 g), and the resulting mixture was heated to 30-35 °C. To this mixture at 30-35 °C was then added hydrochloric acid in water (37%, 123.2 mmol, 10.1 mL, 12.02 g, 1.2 equiv.) portion-wise. Upon complete addition of HCl, the resulting mixture was held for 1 hour at 30-35 °C, followed by cooling to 0-5 °C and holding for 3 hours. The crystals were then collected by filtration, washed with isopropanol, dried with suction under nitrogen for 3 hours, and then further dried in a vacuum over at 50 °C overnight. The desired product (S)-2-hydroxy- 6-((4-(2-(2-hydroxyethyl)nicotinoyl)morpholin-3-yl)methoxy)benzaldehyde hydrochloride (compound 1a) was isolated in 81% yield (40.6 g) with a measured melting point of 190-191 °C.

[0197] 1H NMR (400 MHz, DMSO-d6) ppm 2.85-5.01 (m, 13 H), 6.56 (d, 1 H), 6.60-6.82 (m, 1 H), 7.38-7.62 (m, 1 H), 7.66-7.91 (m, 1 H), 8.07-8.50 (m, 1 H), 8.72-8.90 (m, 1 H), 10.04- 10.39 (m, 1 H), 11.44-11.97 (m, 1 H).

[0198] 13C NMR (100 MHz, DMSO-d6) ppm 25.6, 26.0, 35.5, 40.0, 43.8, 47.8, 48.6, 53.3, 59.9, 60.2, 62.5, 65.6-67.5 (m), 103.4, 104.1, 110.0, 110.3, 111.0, 111.4, 124.9-125.1 (m), 135.0-135.1 (m), 139.0, 139.3, 141.6, 142.3, 143.6, 153.1-154.0 (m), 161.2, 161.7, 162.8, 165.4- 165.7 (m), 194.1, 194.7. Step 7 – Synthesis of (S)-2-hydroxy-6-((4-(2-(2-hydroxyethyl)nicotinoyl)morpholin-3- yl)methoxy)benzaldehyde (compound 1)

[0199] To a 150 mL vessel was charged (S)-2-hydroxy-6-((4-(2-(2- hydroxyethyl)nicotinoyl)morpholin-3-yl)methoxy)benzaldehyde hydrochloride (compound 1a, 13 mmol, 5.60 g), ethyl acetate (54.0 mL, 48.6g) and water (22.0 mL, 22.0 g) to give a clear biphasic mixture. To this mixture was added trisodium citrate dihydrate (13.17 g, 44.78 mmol, 3.44 equiv.), and the resulting mixture was agitated at 25-40 °C for 30 minutes. The aqueous layer was then discarded, and the resulting organic layer was washed with water (17.0 mL, 17.0 g). The organic layer was then concentrated and purified by recrystallization from a solvent mixture of ethyl acetate and methyl tert-butyl ether. The desired product (S)-2-hydroxy-6-((4- (2-(2-hydroxyethyl)nicotinoyl)morpholin-3-yl)methoxy)benzaldehyde (compound 1) was isolated in 78% yield (3.99 g). Example 2 – Alternative Synthesis of Compound 2 according to Scheme 4Step 1 – Synthesis of (E)-1-(2-bromo-6-fluorophenyl)-N-(tert-butyl)methanimine (Compound 9)

[0200] To a 250 mL reaction vessel was added 2-bromo-6-fluorobenzaldehyde (36.5 g, 180 mmol) and 2-methyltetrahydrofuran (73 mL), stirred at rt to afford a colorless solution. tert- Butylamine (19.7 g, 28.5 mL, 270 mmol, 1.5 equiv.) was added as neat upon stirring. The resulting light-yellow solution was heated to 65 °C for about 2 hours. The reaction mixture was distilled down to 100 mL under 1 atm, and then subjected to constant-volume distillation at 1 atm, maintaining at 100 mL total volume while feeding 2-methyltetrahydrofuran (a total of 180 mL of 2-methyltetrahydrofuran was used). Reaction mixture was analyzed for KF (typically <0.1%). This 2-methyltetrahydrofuran solution, containing the desired product (E)-1-(2-bromo- 6-fluorophenyl)-N-(tert-butyl)methanimine (compound 9), was used without further purification. Alternatively, this solution could be further evaporated to remove all low boiling volatiles to afford the desired product compound 9 as a neat liquid in 83% yield.

[0201] 1H NMR (400 MHz, DMSO-d6) ppm: 1.33 (s, 9 H) 6.63 (d, J=8.59 Hz, 2 H) 7.20 - 7.37 (m, 1 H) 8.67 (d, J=3.12 Hz, 1 H). Step 2 – Synthesis of (S,E)-1-(2-bromo-6-(morpholin-3-ylmethoxy)phenyl)-N-(tert- butyl)methanimine (Compound 10)

[0202] To a 250 mL reaction vessel was added compound 5 (6.07 g, 49.2 mmol, 1.05 equiv.) and 2-methyltetrahydrofuran (49 mL), stirred at room temperature to afford a light orange solution, then cooled to 10 °C. A solution of potassium tert-butoxide in THF (1 M, 56 mL, 56 mmol, 1.2 equiv.) was slowly added. The resulting solution was stirred at 22 °C for 1 h. A solution of compound 9 (12.1 g, 47 mmol, 1.0 equiv.) in 2-methyltetrahydrofuran (36 mL) wasadded slowly, which resulted in a thin slurry. Upon completion of addition, the reaction mixture was heated to 45 °C and held at 45 °C for 75 minutes. The reaction was stopped when UPLC indicated less than 1.2% of compound 9 remaining. This solution, containing the desired product (S,E)-1-(2-bromo-6-(morpholin-3-ylmethoxy)phenyl)-N-(tert-butyl)methanimine (compound 10), was used without further purification. An in-situ yield of 96.7% was calculated. For characterization purposes, a small sample was isolated by evaporating the solution to dryness to afford a neat liquid.

[0203] 1H NMR (400 MHz, DMSO-d6) ppm 1.25 (s, 9 H) 2.69 - 2.80 (m, 2 H) 2.94 - 3.03 (m, 1 H) 3.20 (t, J=10.03 Hz, 1 H) 3.35 (td, J=10.48, 3.00 Hz, 1H) 3.63 - 3.68 (m, 1 H) 3.76 - 3.93 (m, 3 H) 6.09 (s, 4 H) 7.06 (d, J=7.70 Hz, 1 H) 7.20 - 7.28 (m, 2 H) 8.28 (s, 1 H). Step 3a – Synthesis of (S)-2-(3-(3-((3-bromo-2-formylphenoxy)methyl)morpholine-4- carbonyl)pyridin-2-yl)ethyl benzoate (compound 2) via amidation

[0204] To a 100 mL reactor was charged compound 8 (2.98 g, 11.0 mmol, 1.05 equiv.) and 2- methyltetrahydrofuran (25 mL), followed by triethylamine (9.0 mL, 65 mmol, 6 equiv.) to provide a light-yellow solution and cooled to 0 °C. T3P (50% in Ethyl Acetate, 18.6 mL, 31.2 mmol, 3 equiv.) was then added in one portion, and the resulting mixture was warmed to room temperature and stirred for 50 min to provide a dark purple solution, and then cooled to 0 °C. A solution of compound 7 (5.00 g, 10.4 mmol) in 2-methyltetrahydrofuran (25 mL) was added and the resulting dark purple solution was warmed to 35 °C and stirred for 100 min, followed by the addition of water 30 mL and citric acid (30 mL). The resulting mixture was stirred at 35 °C for 45 min. The mixture was then extracted with ethyl acetate (30 mL), and the combined organic layers were washed with sodium bicarbonate (saturated aq.30 mL X 3) and brine, dried over magnesium sulfate, and filtered. The resulting solution was then concentrated under reduced vacuum to afford a brown foam. The residue was then purified by recrystallization in ethanol to provide the desired product (S)-2-(3-(3-((3-bromo-2-formylphenoxy)methyl)morpholine-4- carbonyl)pyridin-2-yl)ethyl (compound 2) with an isolated yield of 61.3% (3.84 g).Step 3b –Synthesis of (S)-2-(3-(3-((3-bromo-2-formylphenoxy)methyl)morpholine-4- carbonyl)pyridin-2-yl)ethyl benzoate (compound 2) via ring-opening of a lactone

[0205] To a solution of compound 10 (5.33 g, 11.1 mmol) and compound 4 (2.20 g, 14.4 mmol, 1.30 equiv.) in 2-methyltetrahydrofuran (80 mL) cooled to 0 °C under nitrogen was charged a solution of cyclohexylmagnesium chloride in toluene (1.3 M, 19.0 mL, 24.4 mmol, 2.2 equiv.) slowly. Internal temperature was maintained below 5 °C during the addition. Upon completion, the reaction mixture was stirred at 0-5 °C. Once reaction reaches completion (typically within 5 min after the addition of cyclohexylmagnesium chloride, monitored by UPLC), a solution of benzoic anhydride (7.70 g, 33.3 mmol, 3.0 equiv.) in 15 mL of 2- methyltetrahydrofuran was added while maintaining the reaction temperature below 8 °C. After the addition, the reaction mixture was warmed to 22 °C and stirred therein for 3 h. The reaction mixture was then treated with ammonium chloride (saturated aq, 50 mL X 2), and the organic layer was separated and then treated with citric acid (10wt% aq, 50 mL) at 32 °C. After 30 minutes, the organic layer was washed with sodium bicarbonate (saturated aq, 50 mL X 2), brine, dried over magnesium sulfate, filtered and evaporated to afford the desired product compound 2 as a crude red oil, which was purified by recrystallization from ethanol. The purified material was isolated by filtration and dried under vacuum to afford compound 2 in 37% yield (2.74 g). Example 3 – Alternative one-pot synthesis of Compound 1a from Compound 2

[0206] In a 100 mL reactor under nitrogen was charged Compound 2 (10.0 g, 18.1 mmol, 1 equiv.), copper(I) iodide (0.035 g, 0.18 mmol, 0.01 equiv.), 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl)picolinamide (ligand, 0.187 g, 0.724 mmol, 0.04 equiv.), anhydrous ethanol (30.0 mL), and a degassed solution of potassium phosphate tribasic monohydrate (8.67 g, 36.1 mmol, 2 equiv.) in water (10.0 mL). Sodium ascorbate (0.036 g, 0.18 mmol, 0.01 equiv.) was then added and the resulting mixture was heated at 50 °C for 3.5 hours. The reaction mixture was then cooled to 20 °C followed by addition of more potassium phosphate tribasic monohydrate (4.33 g, 18.1 mmol, 1 equiv.) and methanol (30.0 mL), and the resulting mixture was heated to 50 °C. After 15 hours, the reaction mixture was cooled to 20 °C followed by addition of water (50 mL) and hydrochloric acid (12 M, 5.5 mL). The resulting mixture was then evaporated under vacuum to remove methanol and ethanol to give the crude residue, which was then extracted with ethyl acetate. The organic layers were combined and concentrated to provide the crude residue, which was dissolved in tetrahydrofuran (50 mL) and heated to 35 °C, followed by slow and portion-wise addition of hydrochloric acid (12 M, 1.78 mL) over about 1.5 hours. After about 3.5 hours, the mixture was cooled to 0 °C for 1 hour and the desired product was collected by filtration and dried under vacuum at 60 °C overnight. The desired product compound 1a was isolated in 87% yield (7.07 g) in 98.3% purity. Example 4 – Alternative synthesis of Compound 1 according to Scheme 5Step 1 – Synthesis of 1-bromo-2-(dimethoxymethyl)-3-fluorobenzene (Compound 11)

[0207] To a 500 mL glass reactor with overhead stirring at 25°C was charged 150 mL (3 mL / g) of methylcyclohexane, 96.0 g of 2-bromo-6-fluorobenzaldehyde (1.10 equiv.), and 6.52 g of toluenesulfonic acid monohydrate (0.08 equiv.). Then 90 mL of trimethylorthoacetate (1.65 equiv.) was added slowly, and the mixture was stirred for 60 minutes. The volume of the reaction mixture was then reduced to a volume of about 100 -150 mL (2-3 mL / g) to produce a solution containing the desired product Compound 11, which was used in the next step without further purifications. Step 1a – Alternative Synthesis of Compound 11

[0208] Alternatively, Compound 11 can be synthesized according to the following procedure.

[0209] To a 1000 mL glass reactor with overhead stirring at 25 °C was charged 400 mL of methanol (8 mL / g), 96.0 g of 2-bromo-6-fluorobenzaldehyde (1.10 equiv.), and 8.2 g of toluenesulfonic acid monohydrate (0.10 equiv.), and the resulting reaction mixture was stirred for 16 hr at 25 °C. The reaction mixture was then quenched with the addition of 11.2 mL of N,N-diisopropylethylamine (0.15 equiv.), followed by the addition of 700 mL of methylcyclohexane (14 mL / g), and resulting mixture was then reduced to a volume of 100 -150 mL (2-3 mL / g), to produce a solution containing the desired product Compound 11, which was used in the next step without further purification. Step 2 – Synthesis of (S)-3-((3-bromo-2-(dimethoxymethyl)phenoxy)methyl)morpholine (Compound 12)

[0210] To a solution containing Compound 11 at 40 °C was added 25 mL of tetrahydrofuran (0.5 mL / g) and 309 mL of 20% Potassium tert-butoxide in THF (1.20 equiv.). Compound 5 (50.0 g) was then added and the resulting mixture was heated to 80 °C and held for 6 hr. The mixture was then cooled to 40 °C, followed by the addition of 150 mL of water (3 mL / g). The resulting mixture was then vigorously mixed, and the lower layer was removed, followed by the addition of 150 mL of 20% NaCl in water (3 mL / g) and 200 mL of methylcyclohexane (4 mL / g). The reaction mixture was then vigorously mixed again, and the lower layer was again removed. The resulting mixture was then distilled at 0.3 bar to a volume of 100-150 mL (3 mL / g), followed by the addition of 400 mL of methylcyclohexane (8 mL / g). The resulting mixture was again distilled at 0.3 bar to a volume of 300 mL (6 mL / g), cooled to 40 °C, followed by the addition of seed crystals. After stirring for 1 hr, the mixture was cooled to 10 °C and stirred for an additional 4 hr. The mixture was then filtered to collect the residue, which was washed twith 100 mL of methylcyclohexane (2 mL / g) twice. The isolated residue was then dried under vacuum to provide the desired Compound 12 in 84% yield (128.5 g).

[0211] 1H NMR (600 MHz, DMSO-d6) 7.24 – 7.18 (m, 1H), 7.18 (dd, J = 8.0, 1.4 Hz, 1H), 7.04 (dd, J = 8.0, 1.4 Hz, 1H), 5.69 (s, 1H), 3.90 – 3.85 (m, 2H), 3.83 (dd, J = 10.8, 3.1 Hz, 1H), 3.67 (dt, J = 11.0, 2.9 Hz, 1H), 3.40 – 3.34 (m, 1H), 3.32 (d, J = 1.2 Hz, 6H), 3.25 (dd, J = 10.8, 9.3 Hz, 1H), 3.04 (dtt, J = 8.4, 5.6, 2.8 Hz, 1H), 2.81 (dt, J = 12.2, 2.7 Hz, 1H), 2.76 (ddd, J = 12.2, 10.2, 3.2 Hz, 1H), 2.53 (s, 1H).

[0212] 13C NMR (151 MHz, DMSO-d6) 157.8, 130.8, 125.7, 125.1, 122.0, 112.4, 103.0, 69.3, 68.8, 66.9, 55.1 (d, J = 1.1 Hz), 53.3, 44.8.

[0213] HRMS (ESI+): calc. for C14H21BrNO4+(M+H): 346.0648, found: 346.0648 (error +0.0 ppm). Step 3 – Synthesis of (S)-2-(3-(3-((3-bromo-2-formylphenoxy)methyl)morpholine-4- carbonyl)pyridin-2-yl)ethyl benzoate (Compound 2) from Compounds 12 and 8

[0214] To a 100 mL glass reactor with overhead stirring at 10 °C was added 50 mL (5 mL / g) of acetone, 5 mL of water (0.5 mL / g), 14.7 g of Compound 12 (1.15 equiv.), and 10 g of Compound 8. Then, 13.3 g of 2-chloro 1-methylpyiridinium toluenesulfonate (1.20 equiv.) was also added, followed by the addition of 11.6 mL of N,N-diisopropylethylamine (1.80 equiv.). The mixture was then stirred for 2 hours, then heated to 35 °C and held for 12 hours, during which a residue precipitated out of solution. An additional 20 mL (2 mL / g) of acetone and 25 mL water (2.5 mL / g) was added to further precipitate the residue, and the resulting mixture was cooled to 0 °C and granulated for 4-24 hours. The reaction mixture was then filtered and the isolated residue was washed twice with a mixture of 8 mL acetone (0.8 mL / g) and 17 mL of isopropanol (1.7 mL / g). The residue was then dried under vacuum to provide the desired product Compound 2 in 81% yield (16.6 g). Step 4 – One-Pot Synthesis of (S)-2-hydroxy-6-((4-(2-(2-hydroxyethyl)nicotinoyl)morpholin-3- yl)methoxy)benzaldehyde hydrochloride (Compound 1a) from Compound 2

[0215] To a 200 L reactor was charged methanol (5 L, 0.43 vol.) followed by purging the reactor 4 times with nitrogen. USP Water (34.5 L, 3.00 vol.) was then charged followed by potassium phosphate tribasic monohydrate (14.6 kg, 3.00 equiv.) at a stirring rate of 120 RPM. After complete dissolution, methanol (51.8 L, 4.50 vol.) was charged followed by the sequential addition of Compound 2 (11.5 kg, 1.00 equiv.) and the ligand 6-hydroxy-N-(4-hydroxy-2,6- dimethylphenyl)picolinamide (0.23 kg, 0.04 equiv.). The reactor was rinsed with methanol (5.75L, 0.50 vol.) and purged 4 times with nitrogen. The reactor was then charged with sodium ascorbate (0.04 kg, 0.01 equiv.) and copper iodide (0.04 kg, 0.01 equiv.) before heating the reaction mixture to an internal temperature of 50 °C (+ / - 5 °C) over a period of 1 hour. The reactor was held at 50 °C (+ / - 5 °C) for NLT 4.0 hours before cooling to 20 °C (+ / - 5 °C) and the bottom aqueous layer was removed. The organic layer was then charged USP water (40.3 L, 3.50 vol.) followed by hydrochloric acid, 35-37% (5.96 L, 3.50 equiv.) while maintaining a temperature of Tr=20 °C (+ / - 5 °C) at a stirring rate of 120 RPM. The resulting homogenous solution was distilled under vacuum to 6.5V. The reactor was then charged with ethyl acetate (92.0 L, 8.00 vol.) followed by a solution of potassium phosphate tribasic monohydrate (4.88 kg, 1.00 equiv.) in USP water (11.5 L, 1.00 vol.). The mixture was then charged with 2- mercaptonicotinic acid (0.32 kg, 0.10 equiv.) and rinsed with ethyl acetate (23.0 L, 2.00 vol.). After stirring for NLT 30 minutes at 120 RPM, the bottom aqueous layer was removed and the top organic layer was distilled to 5V. Isopropanol (115 L, 10.0 vol.) was then charged, and the resulting mixture was distilled to 5.0V. Isopropanol (115 L, 10.0 vol.) was then charged again, and the resulting mixture was distilled to 7.5V. The resulting solution was analyzed by KF and then charged with USP Water (5.75 L, 0.50 equiv.) and warmed to 35 °C (+ / - 5 °C) at a stirring speed of 120 RPM. The reactor was then charged a solution of hydrochloric acid, 35-37% (2.04 L, 1.20 equiv.) in isopropanol (23 L, 2.00 vol.) dropwise until a pH target of 2.5 was reached. After reaching pH 2.5, Compound 1a (0.04 kg, 0.35 wt.%) seed was added to the reactor followed by charging the remaining acidic IPA solution over NLT 1 hour at 35 °C (+ / - 5 °C). After completing the charge, the slurry was held at 35 °C (+ / - 5 °C) for NLT 2 hours before cooling to 10 °C (+ / - 5 °C) over a period of NLT 50 minutes. The slurry was held at 10 °C (+ / - 5 °C) for NLT 2.0 hours before being filtered. The resulting residue was washed twice with a cold and mixed solution of isopropanol (21.9 L) and water (1.15 L) and once with cold isopropanol (23.0 L). The residue was dried with nitrogen for NLT 30 minutes and the solid was dried under nitrogen at 60 °C (+ / - 5 °C) to provide the desired Compound 1a in 83% isolated yield, 99.15% purity and 99.5% potency with a measured melting point of solid of 193 °C.

[0216] 1H NMR (400 MHz, DMSO-d6) ppm 2.85-5.01 (m, 13 H), 6.56 (d, 1 H), 6.60-6.82 (m, 1 H), 7.38-7.62 (m, 1 H), 7.66-7.91 (m, 1 H), 8.07-8.50 (m, 1 H), 8.72-8.90 (m, 1 H), 10.04- 10.39 (m, 1 H), 11.44-11.97 (m, 1 H).

[0217] 13C NMR (100 MHz, DMSO-d6) ppm 25.6, 26.0, 35.5, 40.0, 43.8, 47.8, 48.6, 53.3, 59.9, 60.2, 62.5, 65.6-67.5 (m), 103.4, 104.1, 110.0, 110.3, 111.0, 111.4, 124.9-125.1 (m), 135.0-135.1 (m), 139.0, 139.3, 141.6, 142.3, 143.6, 153.1-154.0 (m), 161.2, 161.7, 162.8, 165.4- 165.7 (m), 194.1, 194.7.Step 5 – Synthesis of (S)-2-hydroxy-6-((4-(2-(2-hydroxyethyl)nicotinoyl)morpholin-3- yl)methoxy)benzaldehyde (Compound 1) from Compound 1a

[0218] To a 1L glass reactor with overhead stirring was added water (110 mL), followed by Compound 1a (1 equiv.), and then charged with ethyl acetate (552 mL), and the reaction mixture was then stirred at 300 RPM and 20 °C. In a separate container was charged with trisodium citrate dihydrate (76.1 g, 2 equiv.) and water (110 mL), and the resulting mixture was warmed to 30-40 °C to dissolve the solids. This solution of trisodium citrate dihydrate in water was then charged to the 1L glass reactor with Compound 1a solution over 10 min. Salt break is exothermic which increased the reaction mixture temperature by 4 °C of solution. The reacter was stirred at 300 rpm for NLT 60 min while maintaining the temperature at 20 °C. The stirring was then stopped and the reaction mixture was allowed to settle for NLT 15min. The layers were then separated and the upper layer was transferred to a 1L reactor, to which was added water (166 mL) to this solution and stirred for NLT 5min at 300 RPM and 20 °C. Stirring was then turned off and the reaction mixture was allowed to settle. The layers were again separated and the upper layer was transferred to another 1L reactor, which was charged with activated charcoal Darco G-60 (2.76 g) and stirred for 10 min. The resulting mixture was then filtered through celite Diatomaceous Earth, Flux-calcinated (27.6 g). The celite bed was then rinsed with ethyl acetate (300 mL), and the organic layers were combined and then filtered. The resulting mixture was then vacuum distilled to azeotropically dry the reaction mixture. The reaction mixture was then stirred at 257 RPM and heated to 45 °C, followed by addition of Compound 1 seed (2.5 g). After about 30 minutes, the reaction mixture was charged with methyl tert-butyl ether (700 mL) over 8 h using dosing pump. The resulting slurry was then held at 45 °C for NLT 2h. The slurry was then colled to 10 °C over NMT 2 h and the stirring speed was increased to 400 RPM. The slurry was then cooled to 0 °C over NMT 2 h, and then held at 0 °C for NLT 12 h. The slurry was then filtered and washed with 75 mL of methyl tert-butyl ether (75 mL). The collectedsolids were then dried at 70 °C until residual ethyl acetate and methyl tert-butyl ether are NMT 0.5%. The desired Compound 1 was obtained in about 83% yield with 99.68% purity. Example 5 – Alternative synthesis of Compound 2 via neopentyl glycol acetal protection according to Scheme 6Compound 13

[0219] To a reactor with overhead mechanical stirring at 25 °C was added toluene (40 mL), 2- bromo-6-fluorobenzaldehyde (7.62 g, 37.6 mmol, 1.10 equiv.), 2,2-dimethyl-1,3-propanediol (4.09 g, 39.3 mmol, 1.15 equiv.), and p-toluenesulfonic acid monohydrate (260 mg, 1.37 mmol, 0.04 equiv). The resulting reaction mixture was then flushed with N2, and heated to 100 °C for 30 min, and then cooled to 25 °C. The reaction mixture was then concentrated under vacuum to about 20 mL of solution containing the desired product 2-(2-bromo-6-fluorophenyl)-5,5- dimethyl-1,3-dioxane (Compound 13), which was used in the next step without further purification. Step 2 – Synthesis of (S)-3-((3-bromo-2-(5,5-dimethyl-1,3-dioxan-2- yl)phenoxy)methyl)morpholine (Compound 14)

[0220] To a solution containing Compound 13 at 50 °C was added Compound 5 (4.00 g, 34.1 mmol, 1.00 equiv.) and potassium tert-butoxide (20 wt% in THF, 30.9 mL, 51.2 mmol, 1.50 equiv.), and the resulting mixture was heated to reflux (80-85 °C). After about 16 hours, the reaction mixture was cooled to 50 °C, and aqueous sodium bicarbonate (saturated, 20 mL, 22.8 mmol, 0.67 equiv.) was added. The resulting mixture was then vigorously stirred, and the layers were separated. To the organic layer was then added aqueous sodium bicarbonate (5 wt%, 20 mL, 12.3 mmol, 0.36 equiv.), which the resulting mixture was vigorously stirred again and the layers were separated again. The resulting organic layer was then distilled to about 40 mL of solution and the temperature of the resulting solution was adjusted to 75 °C. After 30 min at 75 °C, n-heptane (20 mL) was added dropwise. Upon completion of the addition of n-heptane, the resulting mixture was cooled to 25 °C. The mixture was filtered, the reactor was rinsed twice with 85:15 n-heptane:toluene (v / v) (2 x 4 mL), and the residue was collected. After drying in a vacuum oven, the desired product Compound 14 was obtained in 82% yield (10.82 g, 28.01 mmol).

[0221] 1H NMR (400 MHz, DMSO-d6): 7.26-7.16 (m, 2H); 7.07-7.01 (dd, 7.9 Hz, 1.3 Hz, 1H); 5.93-5.90 (s, 1H); 3.97-3.90 (dd, 9.5 Hz, 5.6 Hz, 1H); 3.86-3.78 (m, 2H); 3.71-3.63 (app d, 11.1 Hz, 3H); 3.60-3.53 (dd, 11.5 Hz, 1.9 Hz, 2H); 3.43-3.35 (td, 10.5 Hz, 2.9 Hz, 1H); 3.24-3.17 (app t, 9.4 Hz, 1H); 3.13-3.04 (m, 1H); 2.84-2.69 (m, 2H); 2.65-2.55 (br s, 1H); 1.34-1.29 (s, 3H); 0.77-0.72 (s, 3H).

[0222] 13C NMR (100 MHz, DMSO-d6): 158.1, 131.3, 125.6, 124.7, 122.6, 112.7, 100.4, 77.4, 77.3, 69.7, 68.7, 66.9, 53.4, 44.9, 30.1, 23.3, 21.4.

[0223] HRMS (ESI+): calc. for C17H25BrNO4+(M+1): 386.0961, found: 386.0963 (error +0.48 ppm). Step 3 – Synthesis of (S)-2-(3-(3-((3-bromo-2-formylphenoxy)methyl)morpholine-4- carbonyl)pyridin-2-yl)ethyl benzoate (Compound 2) from Compounds 14 and 8

[0224] To a reactor with overhead mechanical stirring at 25 °C was added acetonitrile (30 mL), Compound 8 (3.00 g, 11.1 mmol, 1.00 equiv.), Compound 14 (4.49 g, 11.6 mmol, 1.05 equiv.), and 4-methylmorpholine (2.10 equiv.). After stirring the resulting mixture for 5 min at 25 °C, 2- chloro-1-methylpyridinium p-toluenesulfonate (3.98 g, 13.3 mmol, 1.20 equiv.) was added. After stirring at 25 °C for 4 h, HCl (1 M in water, 22.1 mL, 22.1 mmol, 2.00 equiv.) was added followed by propionaldehyde (1.58 mL, 22.1 mmol, 2.0 equiv.). After stirring at 25 °C for 12 h, 4-methylmorpholine (1.83 mL, 16.6 mmol, 1.50 equiv.) was added and the resulting mixture stirred for 2 h. Seed crystal of Compound 2 (0.01 equiv.) may be used to aid nucleation. The slurry was allowed to granulate for 1 h, followed by addition of 4-methylmorpholine (1.22 mL, 11.1 mmol, 1.00 equiv.). The resulting mixture was stirred for 30 min, followed by addition of water (45 mL) over 30 min, and the resulting slurry was stirred for 12 h at 25 °C. The slurry was filtered, the reactor was washed twice with 3:1 water:acetonitrile (v / v) (2 x 15 mL), and the residue was collected and dried in a vacuum oven. The desired product Compound 2 was isolated in 95% yield (5.79 g, 10.3 mmol).

[0225] Alternatively, butyl vinyl ether can be used instead of propionaldehyde in the procedure described above.

[0226] HRMS (ESI+): calc. for C27H26BrN2O6+(M+1): 553.0969, found: 553.0985 (error: +2.87 ppm). Example 6 – Powder X-Ray Diffraction (PXRD) Collection and Analysis of Compound 2

[0227] Data Collection: Powder X-ray diffraction (PXRD) analysis was conducted using aBruker AXS D8 Endeavor diffractometer equipped with a Cu radiation source (K average). Themotorized divergence slits were set at a continuous illumination of 15 mm. Diffracted radiation was detected by a LYNXEYE XE-T detector, with the position sensitive detector (PSD) opening set at 4.10 degrees. The X-ray tube voltage and amperage were set to 40 kV and 40 mA respectively. Data was collected in the Theta-Theta goniometer from 3.0 to 50.0 degrees 2-Theta using a step size of 0.02 degrees and a step time of 0.24 second. The antiscatter screen was set toa fixed distance of 1.5 mm. Samples were rotated at 15 RPM during collection. A sample was placed in a silicon low background sample holder and smoothed with a glass slide. The powder pattern was collected at room temperature using Bruker DIFFRAC Plus software.

[0228] Data Analysis: Data analysis was performed by EVA diffract plus software. Using the Peak Search algorithm in the EVA software, peaks identified with a threshold value of 1 were initially selected. To ensure validity, adjustments were manually made, if needed. The output of automated assignments was visually checked, and peak positions were adjusted to the peak maximum. Peaks with relative intensity of 3.0% were generally chosen. Typically, the peaks which were not resolved or were consistent with noise were not selected. A typical errorassociated with the peak position from PXRD is up to + / - 0.2° 2 (USP-941).

[0229] Results: The PXRD of Compound 2 Form 1 is shown in FIG.1.

[0230] Table 2 below summarizes the observed PXRD peaks for crystalline Compound 2Form 1 from 3° 2 to 40° 2 .Table 2 – Observed PXRD peaks for Compound 2 Form 1* Angle Relative Angle Relative Angle Relative (°2 )Intensity (%)(°2 )Intensity (%)(°2 )Intensity (%) 5.1 4 19.4 20 27.3 5 7.2 23 20.2 10 27.7 5 8.4 16 20.4 28 28.1 14 8.9 16 21.0 10 29.1 5 12.0 3 21.8 17 29.7 15 14.0 9 22.4 5 30.1 16 14.3 7 22.7 7 31.5 4 15.2 9 23.5 14 31.9 5 15.4 6 23.7 100 32.2 3 16.6 19 24.1 50 33.9 6 16.8 12 24.6 10 34.4 7 17.1 23 25.2 30 35.9 7 17.3 31 25.4 40 37.1 5 17.9 6 25.8 11 18.3 11 26.0 10 19.0 7 26.9 20* A typical error associated with the peak position from PXRD is up to + / - 0.2° 2 (USP-941)

[0231] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0232] The inventions illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising”, “including,” “containing”, etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed.

[0233] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In case of conflict, the present specification, including definitions, will control.

Claims

WHAT IS CLAIMED:

1. A compound of Formula A:or a salt thereof, wherein: R1is H or Bz; and R2is H, F, Cl, Br, I, OTf, OTs, or OMs.

2. The compound of claim 1, wherein R1is Bz.

3. The compound of claim 1, wherein R2is Br or I.

4. A compound according to the formula of Compound 2:or a salt thereof.

5. A crystalline Compound 2 Form 1 having the formula:,characterized by a powder X-ray diffractogram comprising diffraction peaks 17.3 ± 0.2, 23.7 ±0.2, 24.1 ± 0.2, 25.2 ± 0.2, and 25.4 ± 0.2 as determined on a diffractor using Cu-Kradiation.

6. The crystalline Compound 2 Form 1 of claim 5, wherein the powder X-ray diffractogram further comprises diffraction peaks 7.2 ± 0.2, 17.1 ± 0.2, 19.4 ± 0.2, 20.4 ± 0.2, and 26.9 ± 0.2 °2 as determined on a diffractor using Cu-K radiation.

7. The crystalline Compound 2 Form 1 of claim 5 or 6, wherein the crystalline Compound 2 Form 1 is characterized by the powder X-ray diffractogram as substantially shown in FIG.

1.

8. A process for preparing Compound 1:comprising: (i) contacting Compound 2:with a catalyst in a solvent to form Compound 3:(ii) contacting Compound 3 with a base in a solvent to form a mixture; (iii) contacting the mixture after step (ii) with hydrochloric acid solution in a solvent to form Compound 1a HCl salt:; and (iv) contacting Compound 1a with sodium citrate in a solvent to form Compound 1.

9. A process for preparing Compound 1:comprising: (i) contacting Compound 2:with a catalyst and a base in a solvent to form a mixture; (ii) contacting the mixture after step (i) with hydrochloric acid solution in a solvent to form Compound 1a HCl salt:; and (iii) contacting Compound 1a with sodium citrate in a solvent to form Compound 1.

10. The process of claim 8 or 9, wherein the catalyst comprises copper.

11. The process of any one of claims 8-10, wherein the catalyst further comprises a ligand.

12. The process of any one of claims 8-11, wherein the catalyst comprises copper iodide and 6- hydroxy-N-(4-hydroxy-2,6-dimethylphenyl)picolinamide.

13. The process of claim 11, wherein the ratio of copper iodide to 6-hydroxy-N-(4-hydroxy-2,6- dimethylphenyl)picolinamide is from about 1:5 to about 1:

1.

14. The process of any one of claims 8-13, further comprising: contacting a compound of Formula B:wherein: R3is adamantylR4is C1-C6alkyl or aryl; and R5and R6are each independently hydrogen or C1-C6alkyl; with a compound of Formula C:wherein R7is OH or Cl, to form Compound 2.

15. The process of any one of claims 8-13, further comprising: contacting a compound of Formula B:wherein:R5and R6are each independently hydrogen or C1-C6 alkyl; with: (a) a Grignard reagent; (b) compound 4:(c) benzoyl chloride or benzoyl anhydride, to form Compound 2.

16. The process of claim 14 or 15, wherein R3 is, and R5 and R6 are each independentlymethyl.

17. The process of any one of claims 14-16, wherein R4is methyl or phenyl.

18. The process of claim 14, wherein R7is OH.

19. The process of any one of claims 8-13, further comprising: contacting a compound of Formula L:wherein: R14and R15are each independently H or C1-C6alkyl; or R14and R15, taken together with the oxygen atom to which they are attached to, form a 3- to 8- membered heterocycloalkyl, wherein the 3- to 8-membered heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 instances of C1-C6 alkyl; with a compound of Formula C:wherein R7is OH or Cl, to from Compound 2.

20. The process of claim 19, wherein R14and R15are each independently C1-C6alkyl.

21. The process of claim 19 or 20, wherein the compound of Formula L is compound 14 according to the formula:or a salt thereof.

22. A process of making Compound 1:Compound 1 comprising: (i) contacting a compound of Formula EFormula Ewherein R8and R9are each independently selected from F, Cl, Br, and I, with a compound of Formula F: Formula F wherein: R10is adamantylR11is C1-C6 alkyl or aryl; and R12and R13are each independently hydrogen or C1-C6 alkyl; to form a compound of Formula G:Formula G (ii) contacting a compound of Formula G with Compound 5:to form a compound of Formula HFormula H (iii) contacting a compound of Formula H with a compound of Formula C:wherein R7is OH or Cl rm a compound of Formula J:; (iv) contacting a compound of Formula J with a catalyst in a solvent to form a mixture; (v) contacting the solution from step (iv) with a base in a solvent to form Compound 3: ;(vi) contacting Compound 3 with hydrochloric acid solution in a solvent to form Compound 1a HCl salt:; and (vii) contacting Compound 1a with sodium citrate in a solvent to form Compound 1.

23. The process of claim 22, wherein the catalyst of step (iv) comprises copper iodide and 6- hydroxy-N-(4-hydroxy-2,6-dimethylphenyl)picolinamide.

24. The process of claim 23, wherein the ratio of copper iodide to 6-hydroxy-N-(4-hydroxy-2,6- dimethylphenyl)picolinamide is from about 1:5 to about 1:

1.

25. A process of making Compound 1:comprising: (i) contacting a compound of Formula EFormula E wherein R8and R9are each independently selected from F, Cl, Br, and I, with a reagent and an acid to form a compound of Formula K:wherein: R14and R15are each independently H or C1-C6 alkyl; or R14and R15, taken together with the oxygen atom to which they are attached to, form a 3- to 8- membered heterocycloalkyl, wherein the 3- to 8-membered heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 instances of C1-C6 alkyl; (ii) contacting a compound of Formula K with Compound 5:to form a compound of Formula L(iii) contacting a compound of Formula L with a compound of Formula C:wherein R7is OH or Cl to form a compound of Formula J:; wherein R8is selected from F, Cl, Br, and I (iv) contacting a compound of Formula J with a catalyst and a base in a solvent to form a mixture (v) contacting the mixture after step (iv) with hydrochloric acid solution in a solvent to form Compound 1a HCl salt:; and (vi) contacting Compound 1a with sodium citrate in a solvent to form Compound 1.

26. The process of claim 25, wherein the reagent of step (i) is selected from methanol, trimethylorthoacetate, and 2,2-dimethyl-1,3-propanediol.

27. The process of claim 25 or 26, wherein the reagent of step (i) is trimethylorthoacetate or methanol.

28. The process of any one of claims 25-27, wherein the catalyst of step (iv) comprises copper.

29. A process of making Compound 1:comprising: (i) contacting 2-bromo-6-fluorobenzaldehyde with methanol or trimethylorthoacetate, and toluenesulfonic acid monohydrate to form Compound 11 according to the formula:; (ii) contacting Compound 11 with Compound 5 according to the formula:and potassium tert-butoxide to form Compound 12 according to the formula:Compound 12 ;(iii) contacting Compound 12 with Compound 8 according to the formula:and 2-chloro 1-methylpyiridinium toluenesulfonate to form Compound 2 according to the formula:; (iv) contacting Compound 2 with a copper catalyst, a ligand, and a base in a solvent to form a mixture; (v) contacting the mixture after step (iv) with hydrochloric acid solution in a solvent to form Compound 1a HCl salt:; and (vi) contacting Compound 1a with sodium citrate in a solvent to form Compound 1.

30. The process of claim 29, wherein the ligand is 6-hydroxy-N-(4-hydroxy-2,6- dimethylphenyl)picolinamide.

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