Processes for making intermediates for isoindolinone inhibitors of the MDM2-p53 interaction having anticancer activity

Abstract

The present disclosure relates to processes for preparing synthetic intermediates for the synthesis of isoindolinone inhibitors of the MDM2-p53 interaction having anticancer activity.

Description

PROCESSES FOR MAKING INTERMEDIATES FOR ISOINDOLINONE INHIBITORS OF THE MDM2-P53 INTERACTION HAVING ANTICANCER ACTIVITYFIELD

[0001] The present disclosure relates to processes for preparing synthetic intermediates for the synthesis of isoindolinone inhibitors of the MDM2-p53 interaction having anticancer activity.BACKGROUND

[0002] (2.S\3.S)-3-(4-chlorophcnyl)-3-(( / ?)- 1 -(4-chlorophcnyl)-7-fhioro-5-((.S')- 1 -hydroxy- 1 -(tetrahydro- 2H-pyran-4-yl)propyl)-l-methoxy-3-oxoisoindolin-2-yl)-2 -methylpropanoic acid is a small molecule inhibitor of the MDM2-p53 interaction, useful for the treatment of various cancers such as liposarcoma, soft tissue sarcoma, osteosarcoma, oesophageal cancer, and certain pediatric malignancies including B-cell malignancies. There remains a need to develop facile processes for the efficient and selective preparation of this and other biologically active molecules.SUMMARY

[0003] An improved process is provided herein for the preparation of compounds useful as chiral synthetic intermediates in the synthesis of isoindolinone inhibitors of the MDM2-p53 interaction, such as (2S,3S)-3 -(4-chlorophenyl)-3 -(( / ?)- 1 -(4-chlorophenyl)-7-fluoro-5 -((.S')- 1 -hydroxy- 1 -(tetrahydro-2H- pyran-4-yl)propyl)-l-methoxy-3-oxoisoindolin-2-yl)-2 -methylpropanoic acid (hereinafter referred to as Compound VI), previously described in W02017055860A1. The process disclosed herein allows for early-stage chiral separation of intermediates, thereby reducing material waste and improving atom economy of the overall synthetic process.

[0004] Provided herein is a process for preparing compound I-S, or a salt thereof:comprising contacting compound II-SA, or a salt thereof;with compound III, or a salt thereof:under conditions suitable to provide compound I-S; wherein R1is H or a protecting group, and X is halo, Ci-6 alkoxy, Ce-io aryloxy, -N(Ra)(ORa), C4-10 heterocyclyl, C4-10 heteroaryl, or -O-C(O)-Ci-6 alkyl; wherein Rais a C1-6 alkyl; and wherein when R1is a protecting group, the process comprises a deprotection step after the contacting step to provide compound I-S.

[0005] Also provided herein is a process for providing an enantiomerically enriched composition comprising compound II-S:or salt thereof, comprising contacting a compound of formula IV, or a salt thereof:iv, with a chiral base, or a salt thereof, under conditions suitable to provide the enantiomerically enriched composition comprising compound II-S.

[0006] Also provided herein is a process for resolving a compound of formula IV:or salt thereof, to increase the proportion of the stereoisomer which is compound II-S:comprising contacting a compound of formula IV with a chiral base, or a salt thereof, under conditions suitable to increase the proportion of the stereoisomer which is compound II-S.

[0007] Also provided herein is a process for preparing a salt of compound II-S, represented by formulaII-SC:comprising contacting a compound of formula IV, or a salt thereof:under conditions suitable to provide compound II-SC.

[0008] Also provided herein is a process for preparing compound VI, or a salt thereof:the process comprising the steps of:(a) preparing compound I-S, or salt thereof:by the process disclosed herein; and(b) preparing compound VI, or a salt thereof, by using compound I-S as a starting material.

[0009] Also provided herein is a process for preparing compound VI, or a salt thereof:the process comprising the steps of:(c) preparing compound II-S , or a salt thereof:by the process disclosed herein; and(d) preparing compound VI or a salt thereof, by using compound II-S as a starting material.

[0010] Also provided herein is a process for preparing compound VI, or a salt thereof:the process comprising the steps of:(c) preparing compound II-S, or a salt thereof:by the process disclosed herein;(a) preparing compound I-S, or a salt thereof:by the process disclosed herein; and(b) preparing compound VI or a salt thereof, by using compound I-S as a starting material.

[0011] Provided herein is compound, or a salt thereof, selected from:

[0012] Also provided herein is Compound II-S, having the structure:

[0013] Also provided herein is salt of compound II-S, represented by formula II-SC:DESCRIPTIONDefinitions

[0014] As used in the present specification, the following words and phrases 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.

[0015] The term “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Thus, 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.

[0016] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 2.5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, to the term “about X” includes description of “X”.

[0017] Recitation of numeric ranges of values throughout the disclosure is intended to serve as a shorthand notation of referring individually to each separate value falling within the range inclusive of the values defining the range, and each separate value is incorporated in the specification as it were individually recited herein.

[0018] As used herein, the term “contacting” refers to the process of bringing into contact at least two distinct species such that they can react. It should be appreciated, however, that the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.

[0019] The term “reaction conditions” is intended to refer to the physical and / or environmental conditions under which a chemical reaction proceeds. Examples of reaction conditions include, but are not limited to, one or more of following: reaction temperature, solvent, pH, pressure, reaction time, mole ratio of reactants, the presence of a base or acid, one or more protecting groups, or catalyst, radiation, etc. Reaction conditions may be named after the particular chemical reaction in which the conditions are employed, such as, coupling conditions, hydrogenation conditions, acylation conditions, reduction conditions, etc. Reaction conditions for most reactions are generally known to those skilled in the art or can be readily obtained from the literature. Exemplary reaction conditions sufficient for performing the chemical transformations provided herein can be found throughout, and in particular, the examples below. It is also contemplated that the reaction conditions can include reagents in addition to those listed in the specific reaction.

[0020] The term “leaving group” refers to an atom or a group capable of being displaced by a nucleophile. Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), a sulfonic acid ester, such as toluene sulfonate (tosylate, -OTs), methanesulfonate (mesylate, -OMs), p-bromobenzenesulfonyloxy (brosylate, -OBs), OS(=O)2(CF2)3CF3 (nonaflate, -ONf), or trifluoromethane sulfonate (triflate, -OTf).

[0021] “Protecting group” refers to a moiety of a compound that masks or alters the properties of a functional moiety. “Deprotecting” or “deprotection” refers to a step removing the protecting group so as to restore the functional moiety to its original state. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See also Protective Groups in Organic Chemistry, Peter G. M. Wuts and Theodora W. Greene, 4th Ed., 2006. Protecting groups are often utilized to mask the reactivity of certain functional moieties, to assist in the efficiency of desired chemical reactions, e.g., making and breaking chemical bonds in an ordered and planned fashion. For example, a “carboxylic acid protecting group” refers to a protecting group useful for masking the carboxylic acid moiety, e.g., to render the carboxylic acid group unreactive during intermediate steps of a synthetic process. Exemplary carboxylic acid protecting groups include alkyl or benzyl protecting groups, such as methyl, ethyl, isopropyl, benzyl, or tert-butyl; silyl groups such as trimethylsilyl or 2- (trimethylsilyl)ethyl; and thioesters such as tert-butyl thioester. In some embodiments, the protecting group is tert-butyl. Exemplary alcohol protecting groups include alkyl groups such as methyl, ethyl, isopropyl, or tert-butyl; optionally substituted benzyl groups such as benzyl, p-methoxybenzyl, or p- nitrobenzyl; an ester such as acetyl or benzoyl; or a silyl group such as trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl chloride, or triisopropylsilyl.

[0022] “Silylating reagent” as used herein refers to a compound used to introduce silyl groups on a molecule, by replacing a proton on an alcohol, carboxylic acid, amine, thiol, or phosphate with a silyl ether. Silylating reagents are thus useful for installing silyl protecting groups. Non-limiting examples of silylating reagents include trimethylsilyl chloride, trimethylsilyl trifluoromethanesulfonate, triethylsilyl chloride, triethylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl chloride, tert- butyldimethylsilyl trifluoromethanesulfonate, tert-butyldiphenylsilyl chloride, tert-butyldiphenylsilyl trifluoromethane sulfonate, triisopropylsilyl chloride, or triisopropylsilyl trifluoromethanesulfonate.

[0023] The term “fluoride source” refers to a compound which is capable of providing a fluoride ion. Fluoride sources may be employed in the removal of various silyl protecting groups. Non-limiting examples of fluoride sources include sodium fluoride, potassium fluoride, cesium fluoride, pyridinium fluoride, and tetrabutylammonium fluoride.

[0024] The term “coupling agent” or an “activating agent” as defined herein refers to a chemical reactant that is capable of modifying an ester or carboxylic acid functional group to render it susceptible towards nucleophilic attack. Several types of activating agents are known in the art and include, for example, 2-Pyod 1 -oxide (HOPG), carbonyl diimidazole (e.g., JV,N'-dicyclohexylcarbodiimide (DCC), . '-dicyclopcntylcarbodiimidc. A'.N'-diisopropylcarbodiimidc (DIC), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), '-t-butyl- '-mcthylcarbodiimidc (BMC), JV-t-butyl-N- ethylcarbodiimide (BEC), l,3-bis(2,2-dimethyl-l,3-dioxolan-4-yhnethyl)carbodiimide (BDDC), etc.), anhydrides (e.g., symmetric, mixed, or cyclic anhydrides), activated ester forming agents (e.g., phenyl activated ester derivatives, p-hydroxamic activated ester, hexafluoroacetone (HF A), etc.), acylazole forming agents (acylimidazoles using CDI, acylbenzotriazoles, etc.), acyl azide forming agents, acid halide forming agents, phosphonium salts (HOBt, PyBOP, HOAt, etc.),aminium / uronium salts (e.g., tetramethyl aminium salts, bispyrrolidino aminium salts, bispiperidino aminium salts, imidazolium uronium salts, pyrimidinium uronium salts, uronium salts derived from N, N, A ’-trimethyl -A ’-phenylurea, morpholino-based aminium / uronium coupling reagents, antimoniate uronium salts, etc.), organophosphorus reagents (e.g., phosphinic and phosphoric acid derivatives), organosulfur reagents (e.g., sulfonic acid derivatives), triazine coupling reagents (e.g., 2-chloro-4,6-dimethoxy-l,3,5-triazine, 4-(4,6-dimethoxy- 1,3, 5 -triazin-2 -yl)-4 methylmorpholinium chloride, 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4 methylmorpholinium tetrafluoroborate, etc.), pyridinium coupling reagents (e.g., Mukaiyama’s reagent, pyridinium tetrafluoroborate coupling reagents, etc.), polymer-supported reagents (e.g., polymer-bound carbodiimide, polymer-bound TBTU, polymer-bound 2,4,6-trichloro-l,3,5-triazine, polymer-bound HOBt, polymer-bound HOSu, polymer-bound IIDQ, polymer-bound EEDQ, etc.), and the like.

[0025] “Methylation” as used herein refers to a form of alkylation, with a methyl group replacing a hydrogen atom. A “methylating agent” is a chemical substance capable of replacing a hydrogen atom with a methyl group. Non-limiting examples of methylating agents include methyl iodide, methyl trifluoromethane sulfonate, methylfluorosulfonate, methyl methane sulfonate, and the like.

[0026] As used herein, the term “salt” refers to a compound formed by the reaction of an acid and a base, resulting in the formation of a positively charged cation and a negatively charged anion. In general, a salt is defined as a compound that is formed by the combination of positively and negatively charged ions, where the charges of the ions result in a neutral compound. Salts can be either inorganic or organic. As used herein, the term “salt” includes partially or fully ionized salt forms. In some embodiments, the salt is fully ionized. In some embodiments, the salt 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 salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids, and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic 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, methane sulfonic acid, ethane sulfonic acid, p-toluene-sulfonic acid, salicylic acid, benzenesulfonic acid and the like. Likewise, pharmaceutically acceptable baseaddition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkyl amines (i.e., NITfalkyl)). dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (i.e., NH2(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkylE). tri(substituted alkyl) amines (i.e., N(substituted alkyl)’,), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl^), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl^, mono-, di- or tri- cycloalkyl amines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di- or tri- arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)s), or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, tert-butylamine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2- dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, N, A'-dibcnzylcthanc-1.2-diamine (benzathine), tris(hydroxymethyl)aminomethane (tromethamine), l-(2- hydroxyethyl)pyrrolidine (epoloamine), meglumine, arginine, lysine, and the like.

[0027] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March ’s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

[0028] The term “alkyl” as used herein, means a straight or branched, saturated hydrocarbon chain containing from 1 to 30 carbon atoms. The term “lower alkyl” or “Ci-6-alkyl” means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. The term “C1-3- alkyl” means a straight or branched chain hydrocarbon containing from 1 to 3 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, w-propyl. iso -propyl, w-butyl. secbutyl, zso-butyl, tert-butyl, w-pcntyl. isopentyl, neopentyl, w-hcxyl. 3 -methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, w-hcptyl. w-octyl. w-nonyl. and w-dccyl.

[0029] “Alkoxy” refers to the group “alkyl-O-”. Examples of alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and1.2-dimethylbutoxy .

[0030] The term “aryl” as used herein, refers to a phenyl group, or bicyclic aryl or tricyclic aryl fused ring systems. Bicyclic fused ring systems are exemplified by a phenyl group appended to the parentmolecular moiety and fused to a phenyl group. Tricyclic fused ring systems are exemplified by a phenyl group appended to the parent molecular moiety and fused to two other phenyl groups. Representative examples of bicyclic aryls include, but are not limited to, naphthyl. Representative examples of tricyclic aryls include, but are not limited to, anthracenyl. The monocyclic, bicyclic, and tricyclic aryls are connected to the parent molecular moiety through any carbon atom contained within the rings, and can be unsubstituted or substituted.

[0031] An “aryloxy” as used herein, refers to an oxygen atom substituted with any aryl group, such as phenoxy or naphthoxy, which may be optionally substituted.

[0032] The term “benzyl” as used herein refers to -C b-phcnyl. which may be unsubstituted or substituted, as defined herein.

[0033] “Carboxyl ester” or “ester” refer to both -OC(O)RXand -C(O)ORX, wherein Rxis alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0034] The term “halogen” or “halo” as used herein, means Cl, Br, I, or F.

[0035] “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., C1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8 heteroaryl), 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[l,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, thiophenyl (i.e., thienyl), 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[l,5-a]pyridinyl, and imidazo[l,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.

[0036] The term “heterocycle” or “heterocyclic” as used herein, means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle. The monocyclic heterocycle is a three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. The three- or four-membered ring contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S. The five-membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The six-membered ring contains zero, one or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. The seven- and eight-membered rings contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3- dithiolanyl, 1,3-dithianyl, l,3-dimethylpyrimidine-2,4(lH,3H)-dione, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, 1,2-thiazinanyl, 1,3- thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a spiro heterocycle group, or a bridged monocyclic heterocycle ring system in which two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms. Representative examples of bicyclic heterocycles include, but are not limited to, benzopyranyl, benzothiopyranyl, chromanyl, 2,3 -dihydrobenzofuranyl, 2,3- dihydrobenzothienyl, 2,3-dihydroisoquinoline, 2-azaspiro[3.3]heptan-2-yl, azabicyclo [2.2. l]heptyl (including 2- azabicyclo [2.2. l]hept-2-yl), 2,3-dihydro-lH-indolyl, isoindolinyl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl. Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused to a phenyl group, or a bicyclic heterocycle fused to a monocyclic cycloalkyl, or a bicyclic heterocycle fused to a monocyclic cycloalkenyl, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle in which two non-adjacent atoms of the bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms. Examples of tricyclic heterocycles include, but are not limited to, octahydro-2, 5-epoxypentalene, hexahydro-2H-2,5- mcthanocyclopcnta| / ) |fiiran. hexahydro- lH-l,4-methanocyclopenta[c] furan, aza-adamantane (1- azatricyclo[3.3.1.13,7]decane), and oxaadamantane (2-oxatricyclo[3.3.1.13,7]decane). The monocyclic, bicyclic, and tricyclic heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the rings, and can be unsubstituted or substituted.

[0037] The term “substituted” used herein means any of the above groups wherein at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to alkyl, aryl, alkoxy, aryloxy, halo, heteroaryl, heterocyclyl, hydroxy, or -Si(Ry)3, wherein each Ryis independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0038] The term “acid” refers to a chemical species that donate protons. Acidic compounds may be organic compounds such as carboxylic acids and sulfonic acids, inorganic compounds such as sulfuric acid, hydrochloric acid, nitric acids, and phosphoric acid, and may be classified as strong or weak.

[0039] The term “base” refers to a chemical species that can accept protons. Basic compounds may be organic compounds such as basic amines, inorganic compounds such as metal hydroxides and carbonates, and may be classified as strong or weak.

[0040] The term “inorganic base” as used herein generally refers to sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Non- limiting examples include phosphates such as potassium phosphate (mono-, di-, or tribasic), sodium phosphate (mono-, di-, or tribasic), ammonium phosphate (mono-, di-, or tribasic); acetates such as potassium acetate, sodium acetate and ammonium acetate; formates such as potassium formate and sodium formate; carbonates such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate; and alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide.

[0041] The term “amine base” as used herein generally refers to a primary, secondary, or tertiary amine, such as an alkyl amine, dialkyl amine, trialkyl amine, nitrogen-containing heterocycle, or nitrogencontaining heteroaryl, wherein each of which is optionally substituted, e.g., by alkyl.

[0042] The compounds of the disclosure, or their pharmaceutically acceptable salts include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (.S')- or, as (D)- or (L)- for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (.S)-. or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and / or fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0043] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers, or mixtures thereof, and includes “enantiomers,” which refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.

[0044] ‘ ‘Enantiomeric excess,” sometimes abbreviated to “ee,” is a measurement of the purity of a chiral chemical entity, and refers to the degree to which a particular enantiomer is present in greater amounts than the other enantiomer. A racemic mixture has an ee of 0%, while a completely pure chiral enantiomer has an ee of 100%. A chemical substance which has an ee of greater than 50% is sometimes referred to as “enantiomerically enriched”. In some embodiments, the enantiomerically enriched composition comprises an enantiomeric excess of an enantiomer greater than 50%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%. In some embodiments, the enantiomerically enriched composition comprises an enantiomeric excess of an enantiomer greater than 90%. In some embodiments, the enantiomerically enriched composition comprises an enantiomeric excess of an enantiomer greater than 95%.

[0045] In some embodiments, the enantiomeric excess of an enantiomer is greater than 50%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%. In some embodiments, the enantiomeric excess of an enantiomer is greater than 90%. In some embodiments, enantiomeric excess of an enantiomer is greater than 95%.

[0046] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0047] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.

[0048] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub- combination. All combinations of the embodiments pertaining to the disclosure are embraced by the present disclosure and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace subject matter that are, for example, compounds that are stable compounds (i.e., compounds that can be made, isolated, characterized, and tested for biological activity). In addition, all sub- combinations of the various embodiments and elements thereof (e.g., elements of the chemical groups listed in the embodiments describing suchvariables) are also embraced by the present disclosure and are disclosed herein just as if each and every such sub-combination was individually and explicitly disclosed herein.Processes

[0049] The processes described herein provide compounds that are synthetic intermediates for the synthesis of isoindolinone inhibitors of the MDM2-p53 interaction having anticancer activity.

[0050] Provided herein is a process for preparing compound I-S, or a salt thereof:comprising contacting compound II-SA, or a salt thereof:with compound III, or a salt thereof:under conditions suitable to provide compound I-S; wherein R1is H or a protecting group, and X is halo, Ci-6 alkoxy, Ce-io aryloxy, -N(Ra)(0Ra), C4-10 heterocyclyl, C4-10 heteroaryl, or -O-C(O)-Ci-6 alkyl; wherein Rais a C1-6 alkyl; and wherein when R1is a protecting group, the process comprises a deprotection step after the contacting step to provide compound I-S.

[0051] In some embodiments, provided is a process for preparing compound I-R, or a salt thereof:comprising contacting compound II-RA, or a salt thereof:with compound III, or a salt thereof:under conditions suitable to provide compound I-R, wherein R1is H or a protecting group, and X is halo, Ci-6 alkoxy, Ce-io aryloxy, -N(Ra)(ORa), C4-10 heterocyclyl, C4-10 heteroaryl, or -O-C(O)-Ci-6 alkyl; wherein Rais a C1-6 alkyl; and wherein when R1is a protecting group, the process comprises a deprotection step after the contacting step to provide compound I-R.

[0052] In some embodiments, X is halo. In some embodiments, X is F, Cl, Br, or I.

[0053] In some embodiments, X is Cl.

[0054] In some embodiments, X is C1-6 alkoxy. In some embodiments, X is methoxy. In some embodiments, X is ethoxy. In some embodiments, X is w-propoxy. In some embodiments, X is isopropoxy. In some embodiments, X is tert-butoxy.

[0055] In some embodiments, X is Ce-io aryloxy. In some embodiments, X is phenoxy.

[0056] In some embodiments, X is -N(Ra)(ORa), wherein Rais a C1-6 alkyl. In some embodiments, X is -N(CH3)(OCH3).

[0057] In some embodiments, X is C4-10 heterocyclyl. In some embodiments, X is 2-pyrrolyl.

[0058] In some embodiments, X is C4-10 heteroaryl. In some embodiments, X is 2-thiopyridine.

[0059] In some embodiments, X is -O-C(O)-Ci-6 alkyl. In some embodiments, X is -O-C(O)CH3. In some embodiments, X is -O-C(O)C(CH3)3.

[0060] In some embodiments, R1is H. In some embodiments, R1is a protecting group.

[0061] In some embodiments, when R1is a protecting group, the protecting group is a C1-6 alkyl, an optionally substituted benzyl, a silyl group, or -C(O)R, wherein each R is a C1-6 alkyl group or a phenyl.

[0062] In some embodiments, when R1is a protecting group, the protecting group is a C1-6 alkyl group. In some embodiments, when R1is a protecting group, the protecting group is methyl. In some embodiments, when R1is a protecting group, the protecting group is ethyl. In some embodiments, the protecting group is isopropyl. In some embodiments, when R1is a protecting group, the protecting group is tert-butyl.

[0063] In some embodiments, when R1is a protecting group, the protecting group is an optionally substituted benzyl. In some embodiments, when R1is a protecting group, the protecting group is benzyl. In some embodiments, when R1is a protecting group, the protecting group is p-methoxybenzyl. In some embodiments, when R1is a protecting group, the protecting group is p- nitrobenzyl.

[0064] In some embodiments, when R1is a protecting group, the protecting group is -C(O)R wherein each R is a Ci-6 alkyl group or a phenyl. In some embodiments, when R1is a protecting group, the protecting group is -C(O)CH3. In some embodiments, when R1is a protecting group, the protecting group is -C(O)-phenyl.

[0065] In some embodiments, when R1is a protecting group, the protecting group is a silyl group. In some embodiments, when R1is a protecting group, the protecting group is -SiR,. wherein each R is independently a Ci-6 alkyl group or a phenyl. In some embodiments, when R1is a protecting group, the protecting group is trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl chloride, or triisopropylsilyl.

[0066] In some embodiments, when R1is a protecting group, the protecting group is trimethylsilyl.

[0067] In some embodiments, the conditions suitable to provide compound I-S or compound I-R comprise a base.

[0068] In some embodiments, the base is an organolithium base. In some embodiments, the base is lithium diisopropylamide, lithium bis(trimethylsilyl)amide, lithium tetramethylpiperidide, methyllithium, isopropyllithium, w-butyllithium. scc-biityllithium. tert-butyllithium, w-hcxyllithium. or phenyllithium.

[0069] In some embodiments, the base is w-butyllithium.

[0070] In some embodiments, the conditions suitable to provide compound I-S or compound I-R further comprise a solvent. In some embodiments, the conditions suitable to provide compound I-S or compound I-R further comprise a solvent at a temperature of about -40 °C to about -100 °C. In some embodiments, the conditions suitable to provide compound I-S or compound I-R further comprise a solvent at a temperature of about -60 °C to about -80 °C.

[0071] In some embodiments, the solvent is an ethereal solvent, a hydrocarbon, or a combination thereof. In some embodiments, the solvent is diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, or tert-butyl methyl ether, pentane, hexane, heptane, octane, petroleum ether, benzene, toluene, xylene, or a combination thereof.

[0072] In some embodiments, the solvent is an ethereal solvent. In some embodiments, the solvent is a combination of an ethereal solvent and a hydrocarbon.

[0073] In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is 2- methyltetrahydrofuran .

[0074] In some embodiments, the conditions suitable to provide compound I-S or compound I-R, or a salt thereof, comprise a base and a solvent. In some embodiments, the conditions comprise w-butyllithium and tetrahydrofuran. In some embodiments, the conditions suitable to provide compound I-S or compound I-R comprise w-butyllithium and tetrahydrofuran at a temperature of about -60 °C to about -80 °C.

[0075] In some embodiments, the process for preparing compound I-S or compound I-R, or a salt thereof, further comprises isolation of compound I-S or compound I-R by slurry from a solvent. In some embodiments, the solvent is a hydrocarbon. In some embodiments, the hydrocarbon is pentane, hexane, heptane, octane, petroleum ether, benzene, toluene, xylene, or a combination thereof.

[0076] In some embodiments, the solvent is heptane. In some embodiments, the solvent is toluene.

[0077] In some embodiments, the process further comprises recrystallization of compound I-S or compound I-R from a solvent. In some embodiments, the solvent is a hydrocarbon, an ethereal solvent, a ketone, a nitrile, an ester, an amide, a sulfoxide, a halogenated solvent, or a combination thereof. In some embodiments, the solvent is pentane, hexane, heptane, octane, petroleum ether, benzene, toluene, xylene, diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran, 2- methyltetrahydrofuran, cyclopentyl methyl ether, tert-butyl methyl ether, acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, isopropyl acetate, A'.A'-dimcthylfonnamidc. N,N- dimethylacetamide, dimethylsulfoxide, dichloromethane, 1 ,2-dichloroethane, chlorobenzene, or a combination thereof.

[0078] In some embodiments, the solvent is a hydrocarbon. In some embodiments, the hydrocarbon is pentane, hexane, heptane, octane, petroleum ether, benzene, toluene, xylene, or a combination thereof.

[0079] In some embodiments, the solvent is an ethereal solvent. In some embodiments, the ethereal solvent is diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran, 2 -methyltetrahydrofuran, cyclopentyl methyl ether, or tert-butyl methyl ether, or a combination thereof.

[0080] In some embodiments, the solvent is a ketone. In some embodiments, the solvent is acetone or methyl ethyl ketone.

[0081] In some embodiments, the solvent is a nitrile. In some embodiments, the solvent is acetonitrile.

[0082] In some embodiments, the solvent is an ester. In some embodiments, the solvent is ethyl acetate or isopropyl acetate.

[0083] In some embodiments, the solvent is an amide. In some embodiments, the solvent is N,N- dimethylformamide or N, '-dim ethyl acetamide.

[0084] In some embodiments, the solvent is a sulfoxide. In some embodiments, the solvent is dimethylsulfoxide .

[0085] In some embodiments, the solvent is a halogenated solvent. In some embodiments, the solvent is dichloromethane, 1,2-dichloroethane, or chlorobenzene.

[0086] In some embodiments, the solvent is a hydrocarbon. In some embodiments, the solvent is an ethereal solvent. In some embodiments, the solvent is a combination of a hydrocarbon and an ethereal solvent.

[0087] In some embodiments, the solvent is a combination of heptane and tetrahydrofuran.

[0088] In some embodiments, the process for preparing compound I-S or compound I-R further comprises recrystallization of compound I-S or compound I-R from a combination of heptane and tetrahydrofuran.

[0089] In some embodiments, provided is a process for preparing compound I-S, or a salt thereof:comprising contacting compound II-SA, or a salt thereof:with compound III, or a salt thereof:in the presence of w-butyllithium in tetrahydrofuran at a temperature of about -60 °C to about -80 °C, to provide compound I-S; wherein R1is a protecting group, and X is Cl; optionally followed by recrystallization of compound I-S, or a salt thereof, from a combination of heptane and tetrahydrofuran.

[0090] In some embodiments, provided is a process for preparing compound I-R, or a salt thereof:comprising contacting compound II-RA, or a salt thereof:with compound III, or a salt thereof:in the presence of w-butyllithium in tetrahydrofuran at a temperature of about -60 °C to about -80 °C, to provide compound I-R; wherein R1is a protecting group, and X is Cl; optionally followed by recrystallization of compound I-R, or a salt thereof, from a combination of heptane and tetrahydrofuran.

[0091] In some embodiments, the process further comprises a protection step comprising converting compound II-S:or a salt thereof, under conditions suitable to provide compound II-SA:or a salt thereof; wherein R1is a protecting group.

[0092] In some embodiments, the process further comprises a protection step comprising converting compound II-R:or a salt thereof, under conditions suitable to provide compound II-RA:or a salt thereof; wherein R1is a protecting group.

[0093] In some embodiments, when R1is a protecting group, the protecting group is a Ci-6 alkyl, an optionally substituted benzyl, a silyl group, or -C(O)R, wherein each R is a Ci-6 alkyl group or a phenyl.

[0094] In some embodiments, when R1is a protecting group, the protecting group is a Ci-6 alkyl group. In some embodiments, when R1is a protecting group, the protecting group is methyl. In some embodiments, when R1is a protecting group, the protecting group is ethyl. In some embodiments, when R1is a protecting group, the protecting group is isopropyl. In some embodiments, when R1is a protecting group, the protecting group is tert-butyl.

[0095] In some embodiments, when R1is a protecting group, the protecting group is an optionally substituted benzyl. In some embodiments, when R1is a protecting group, the protecting group is benzyl. In some embodiments, when R1is a protecting group, the protecting group is p- methoxybenzyl. In some embodiments, when R1is a protecting group, the protecting group is p- nitrobenzyl.

[0096] In some embodiments, when R1is a protecting group, the protecting group is -C(O)R wherein each R is a Ci-6 alkyl group or a phenyl. In some embodiments, when R1is a protecting group, the protecting group is -C(O)CH3. In some embodiments, when R1is a protecting group, the protecting group is -C(O)-phenyl.

[0097] In some embodiments, when R1is a protecting group, the protecting group is a silyl group. In some embodiments, when R1is a protecting group, the protecting group is -SiR ,. wherein each R is independently a Ci-6 alkyl group or a phenyl. In some embodiments, when R1is a protecting group, the protecting group is trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, / crt-biityldiphcnylsilyl chloride, or triisopropylsilyl.

[0098] In some embodiments, when R1is a protecting group, the protecting group is trimethylsilyl.

[0099] In some embodiments, when R1is a protecting group, the protection step comprises a silylating reagent. In some embodiments, the silylating reagent is trimethylsilyl chloride, trimethylsilyl trifluoromethanesulfonate, triethylsilyl chloride, triethylsilyl trifluoromethanesulfonate, tertbutyldimethylsilyl chloride, tert-butyldimethylsilyl trifluoromethanesulfonate, tert-butyldiphenylsilyl chloride, tert-butyldiphenylsilyl trifluoromethanesulfonate, triisopropylsilyl chloride, triisopropylsilyl trifluoromethanesulfonate, trimethylsilylimidazole, l-(tert- butyldimethylsilyl)imidazole, hexamethyldisilazane, A'-mcthyl-A'-(trimcthylsilyl)trifluoroacctamidc. JV-tert-butyldimethylsilyl-JV-methyltrifluoroacetamide, V,O-bis(trimethylsilyl)acetamide, or N,O- bis(tert-butyldimethylsilyl)acetamide.

[0100] In some embodiments, the silylating reagent is trimethylsilyl trifluoromethanesulfonate.

[0101] In some embodiments, the protection step further comprise a base. In some embodiments, the base is an amine base. In some embodiments, the base is triethylamine, diisopropylethyl amine, tributyl amine, JV-methylmorpholine, pyridine, 4-dimethylaminopyridine, or JV-methylimidazole.

[0102] In some embodiments, the base is triethylamine.

[0103] In some embodiments, the protection step further comprise a solvent. In some embodiments, the protection step further comprise a solvent at a temperature of about -20 °C to about 20 °C. In some embodiments, the protection step further comprise a solvent at a temperature of about -10 °C to about10 °C. In some embodiments, the protection step further comprise a solvent at a temperature of about -5 °C to about 5 °C.

[0104] In some embodiments, the solvent is polar aprotic solvent or a halogenated solvent. In some embodiments, the solvent is dichloromethane, 1,2-dichloroethane, chlorobenzene, acetonitrile, ethyl acetate, isopropyl acetate, AA'-dimcthylformamidc. AA'-dimcthylacctamidc. A-mcthyl-2- pyrrolidone, dimethyl sulfoxide, or a combination thereof.

[0105] In some embodiments, the solvent is a halogenated solvent. In some embodiments, the solvent is dichloromethane, 1,2-dichloroethane, or chlorobenzene, or a combination thereof.

[0106] In some embodiments, the solvent is dichloromethane.

[0107] In some embodiments, the protection step comprises a silylating reagent and a base, and a solvent. In some embodiments, the protection step comprises trimethylsilyl trifluoromethanesulfonate, triethylamine, and dichloromethane. In some embodiments, the protection step comprises trimethylsilyl trifluoromethanesulfonate, triethylamine, and dichloromethane at a temperature of about -10 °C to about 10 °C. In some embodiments, the protection step comprises trimethylsilyl trifluoromethanesulfonate, triethylamine, and dichloromethane at a temperature of about -5 °C to about 5 °C.

[0108] In some embodiments, the process for preparing compound I-S further comprises a protection step comprising contacting compound II-S:or a salt thereof, with trimethylsilyl trifluoromethane sulfonate and triethylamine in dichloromethane at a temperature of about -5 °C to about 5 °C, to provide compound II-SA:or a salt thereof; wherein R1is trimethylsilyl.

[0109] In some embodiments, the process for preparing compound I-R further comprises a protection step comprising contacting compound II-R:or a salt thereof, with trimethylsilyl trifluoromethane sulfonate and triethylamine in dichloromethane at a temperature of about -5 °C to about 5 °C, to provide compound II-RA:or a salt thereof; wherein R1is trimethylsilyl.

[0110] In some embodiments, R1is a protecting group and the process for preparing compound I-S further comprise a deprotection step after the contacting step to provide compound I-S.[oni] In some embodiments, the deprotection step comprises converting a compound of formula I-SA, or a salt thereof:to compound I-S, or a salt thereof, under conditions suitable to provide compound I-S, wherein R1is a protecting group.

[0112] In some embodiments, R1is a protecting group and the process for preparing compound I-R further comprise a deprotection step after the contacting step to provide compound I-R.

[0113] In some embodiments, the deprotection step comprises converting a compound of formula I-RA, or a salt thereof:to compound I-R, or a salt thereof, under conditions suitable to provide compound I-R, wherein R1is a protecting group.

[0114] In some embodiments, the protecting group R1is a Ci-6 alkyl, an optionally substituted benzyl, a silyl group, or -C(O)R, wherein each R is a Ci-6 alkyl group or a phenyl.

[0115] In some embodiments, the protecting group R1is a Ci-6 alkyl group. In some embodiments, the protecting group is methyl. In some embodiments, the protecting group R1is ethyl. In someembodiments, the protecting group R1is isopropyl. In some embodiments, the protecting group R1is tert-butyl.

[0116] In some embodiments, the protecting group R1is an optionally substituted benzyl. In some embodiments, the protecting group R1is benzyl. In some embodiments, the protecting group R1is p- methoxybenzyl. In some embodiments, the protecting group R1is -nitrobenzyl.

[0117] In some embodiments, the protecting group R1is -C(O)R wherein each R is a Ci-6 alkyl group or a phenyl. In some embodiments, the protecting group R1is -C(O)CH3. In some embodiments, the protecting group R1is -C(O)-phenyl.

[0118] In some embodiments, the protecting group R1is a silyl group. In some embodiments, the protecting group R1is -SiR ,. wherein each R is independently a Ci-6 alkyl group or a phenyl. In some embodiments, the protecting group R1is trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tertbutyldiphenylsilyl chloride, or triisopropylsilyl.

[0119] In some embodiments, the protecting group R1is trimethylsilyl.

[0120] In some embodiments, the deprotection step comprises an acid or a fluoride source. In some embodiments, the acid or fluoride source is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, -toluene sulfonic acid, tetrabutylammonium fluoride, cesium fluoride, or potassium fluoride.

[0121] In some embodiments, the deprotection step comprises a fluoride source. In some embodiments, the fluoride source is tetrabutylammonium fluoride, pyridinium fluoride, sodium fluoride, potassium fluoride, or cesium fluoride.

[0122] In some embodiments, the deprotection step comprises an acid. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, or -toluenesulfonic acid.

[0123] In some embodiments, acid is phosphoric acid.

[0124] In some embodiments, the deprotection step further comprises a solvent. In some embodiments, the deprotection step further comprises a solvent at a temperature of about 20 °C to about 50 °C. In some embodiments, the deprotection step further comprises a solvent at a temperature of about 30 °C to about 50 °C, for example about 30 °C to about 40 °C.

[0125] In some embodiments, the solvent is an ethereal solvent. In some embodiments, the solvent is diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran, 2 -methyltetrahydrofuran, cyclopentyl methyl ether, or tert-butyl methyl ether, or a combination thereof.

[0126] In some embodiments, the solvent is tetrahydrofuran.

[0127] In some embodiments, the deprotection step comprises an acid and a solvent. In some embodiments, the deprotection step comprises phosphoric acid and tetrahydrofuran. In some embodiments, the deprotection step comprises phosphoric acid and tetrahydrofuran at a temperature of about 30 °C to about 50 °C, for example 30 °C to about 40 °C.

[0128] In some embodiments, the deprotection step is followed by isolation of compound I-S or compound I-R by slurry in a solvent. In some embodiments, the solvent is a hydrocarbon. In some embodiments,the solvent is pentane, hexane, heptane, octane, petroleum ether, benzene, toluene, or xylene. In some embodiments, the solvent is heptane or toluene.

[0129] In some embodiments, the process for preparing compound I-S further comprises a deprotection step comprising converting a compound of formula I-SA, or a salt thereof:to compound I-S, or a salt thereof, in the presence of phosphoric acid in tetrahydrofuran at a temperature of about 30 °C to about 50 °C, for example 30 °C to about 40 °C; wherein R1is trimethylsilyl, optionally followed by isolation of compound I-S by slurry in heptane or toluene.

[0130] In some embodiments, the process for preparing compound I-R further comprises a deprotection step comprising converting a compound of formula I-RA, or a salt thereof:to compound I-R, or a salt thereof, in the presence of phosphoric acid in tetrahydrofuran at a temperature of about 30 °C to about 50 °C, for example 30 °C to about 40 °C; wherein R1is trimethylsilyl, optionally followed by isolation of compound I-R by slurry in heptane or toluene.

[0131] Also provided herein is a process for providing an enantiomerically enriched composition comprising compound II-S:or salt thereof, comprising contacting a compound of formula IV, or a salt thereof:with a chiral base, or a salt thereof, under conditions suitable to provide the enantiomerically enriched composition comprising compound II-S.

[0132] Also provided herein is a process for providing an enantiomerically enriched composition comprising compound II-R:or salt thereof, comprising contacting a compound of formula IV, or a salt thereof:with a chiral base, or a salt thereof, under conditions suitable to provide the enantiomerically enriched composition comprising compound II-R.

[0133] Also provided herein is a process for resolving a compound of formula IV:iv, or salt thereof, to increase the proportion of the stereoisomer which is compound II-S:comprising contacting a compound of formula IV with a chiral base, or a salt thereof, under conditions suitable to increase the proportion of the stereoisomer which is compound II-S.

[0134] Also provided herein is a process for resolving a compound of formula IV:or salt thereof, to increase the proportion of the stereoisomer which is compound II-R:comprising contacting a compound of formula IV with a chiral base, or a salt thereof, under conditions suitable to increase the proportion of the stereoisomer which is compound II-R.

[0135] In some embodiments, the chiral base isL-valinol,L-lysine,L-arginine,(-)-quinine,(-)-cinchonidine, quinidine,(+)-dehydroabietylamine,(.S')-(-)-a-mcthyl-bcnzylaminc.(R)-(-)- 1 ,2,3 ,4-tetrahydro- 1 -naphthylamine,(R)-(-)- 1 -cyclohexylethylamine,(R)-(+)- 1 -( 1 -naphthyl)ethylamine,( / ?)-(+)- W-dimcthyl- 1 -( 1 -naphthyl)ethylamine,1 -(4-methoxyphenyl)ethanamine,(R)-(+)-P-methylphenethylamine,( l / ?.2 / ?)-(-)-diaminocyclohcxanc.(.S')-(-)-2-am ino-3 -phenyl- 1 -propanol,(<$)-(-)- 1 -(4-bromophenyl)ethylamine,(-)-bis[(S)-l-phenylethyl]amine,(S)-(-)-V V-dimethyl- 1 -phenyl -ethylamine,( / ?. / ?)-(+)-hydrobcnzoin.( lR,2R)-(+)- 1 ,2-diphenylethylenediamine,( I / ?.2.S')-(+)-ci s- 1 -amino-2 -indanol,( \R.2R)-(-)-lrans- 1 -amino-2 -indanol,(.S'..S')-(-)-2-am ino- 1 ,2-diphenylethanol, or( I / ?.2.S')-(-)-2-am ino- 1 ,2-diphenylethanol,( IS, 2 / ?)-(+)-2 -amino- 1 ,2-diphenylethanol, or a salt of each thereof.

[0136] In some embodiments, the chiral base is ( l / ?.2 / ?)-(+)- l .2-diphcnylcthylcncdiaminc. (lS,2R)-(+)- 2-amino-l,2-diphenylethanol, or ( I / ?.2.S')-(-)-2-amino- 1 ,2-di phenyl ethanol. In some embodiments, the chiral base is ( l / ?.2 / ?)-(+)- l .2-diphcnylcthylcncdiaminc. In some embodiments, the chiral base is ( l / ?.2S)-(-)-2-amino- l .2-diphcnylcthanol. In some embodiments, the chiral base is (lS,2R)-(+)-2- amino- 1 ,2-diphenylethanol .

[0137] In some embodiments, the enantiomerically enriched composition comprises an enantiomeric excess of a (.S')-cnantiomcr of compound II-S greater than 50%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%In some embodiments, the enantiomerically enriched composition comprises an enantiomeric excess of a (.S')-cnantiomcr of compound II-S greater than 90%.

[0138] In some embodiments, the enantiomerically enriched composition comprises an enantiomeric excess of a (.S')-cnantiomcr of compound II-S greater than 95%.

[0139] In some embodiments, the enantiomerically enriched composition comprises an enantiomeric excess of a (.S')-cnantiomcr of compound II-S greater than 98%.

[0140] In some embodiments, the enantiomerically enriched composition comprises an enantiomeric excess of a (R)-enantiomer of compound II-R greater than 50%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%.

[0141] In some embodiments, the enantiomerically enriched composition comprises an enantiomeric excess of a (R)-enantiomer of compound II-R greater than 90%.

[0142] In some embodiments, the enantiomerically enriched composition comprises an enantiomeric excess of a (R)-enantiomer of compound II-R greater than 95%.

[0143] In some embodiments, the enantiomerically enriched composition comprises an enantiomeric excess of a (R)-enantiomer of compound II-R greater than 98%.

[0144] In some embodiments the proportion of the stereoisomer which is compound II-S after resolving the compound of formula IV is greater than 50%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%.

[0145] In some embodiments, the proportion of the stereoisomer which is compound II-S after resolving the compound of formula IV step is greater than 90%.

[0146] In some embodiments, the proportion of the stereoisomer which is compound II-S after resolving the compound of formula IV is greater than 95%.

[0147] In some embodiments, the proportion of the stereoisomer which is compound II-S after resolving the compound of formula IV is greater than 98%.

[0148] In some embodiments, the proportion of the stereoisomer which is compound II-R after resolving the compound of formula IV is greater than 50%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%.

[0149] In some embodiments, the proportion of the stereoisomer which is compound II-R after resolving the compound of formula IV is greater than 90%.

[0150] In some embodiments, the proportion of the stereoisomer which is compound II-R is after resolving the compound of formula IV greater than 95%.

[0151] In some embodiments, the proportion of the stereoisomer which is compound II-R after resolving the compound of formula IV is greater than 98%.

[0152] In some embodiments, conditions suitable to provide the enantiomerically enriched composition comprising compound II-S or compound II-R, or conditions suitable to resolve a compound of formula IV to increase the proportion of compound II-S or compound II-R, further comprise a solvent. In some embodiments, the solvent is a ketone, an alcohol, a polar aprotic solvent, an ethereal solvent, a halogenated solvent, a hydrocarbon, water, or a combination thereof. In some embodiments, the solvent is acetone, methyl ethyl ketone, methyl isobutyl ketone, methanol, ethanol, isopropanol, butanol, acetonitrile, ethyl acetate, isopropyl acetate, W-dimcthyl formamide, W-dimcthyl acetamide, dimethyl sulfoxide, V-methyl pyrrolidine, diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran, 2 methyltetrahydrofuran, cyclopentyl methyl ether, tert-butyl methyl ether, dichloromethane, 1,2-dichloroethane, chlorobenzene, water, pentane, hexane, heptane, octane, petroleum ether, benzene, toluene, xylene, or a combination thereof.

[0153] In some embodiments, the solvent is a ketone. In some embodiments, the ketone is acetone, methyl ethyl ketone, methyl isobutyl ketone, or a combination thereof.

[0154] In some embodiments, the solvent is an alcohol. In some embodiments, the alcohol is methanol, ethanol, isopropanol, butanol, or a combination thereof.

[0155] In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the polar aprotic solvent is acetonitrile, ethyl acetate, isopropyl acetate, W-dimcthyl formamide, N,N- dimethyl acetamide, dimethyl sulfoxide, V-methyl pyrrolidine, or a combination thereof.

[0156] In some embodiments, the solvent is an ethereal solvent. In some embodiments, the ethereal solvent is diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran, 2 methyltetrahydrofuran, cyclopentyl methyl ether, tert-butyl methyl ether, or a combination thereof.

[0157] In some embodiments, the solvent is a halogenated solvent. In some embodiments, the halogenated solvent is dichloromethane, 1,2-dichloroethane, chlorobenzene, or a combination thereof.

[0158] In some embodiments, the solvent is a hydrocarbon. In some embodiments, the hydrocarbon is pentane, hexane, heptane, octane, petroleum ether, benzene, toluene, xylene, or a combination thereof.

[0159] In some embodiments, the solvent is a ketone, a polar aprotic solvent, a hydrocarbon, water, or a combination thereof. In some embodiments, the solvent is acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, isopropyl acetate, heptane, water, or a combination thereof. In some embodiments, the solvent is isopropyl acetate, a combination of methyl ethyl ketone and heptane, or a combination of acetonitrile and water.

[0160] In some embodiments, the solvent is isopropyl acetate. In some embodiments, the solvent is a combination of methyl ethyl ketone and heptane. In some embodiments, the solvent is a combinationof acetonitrile and water. In some embodiments, the solvent is selected from isopropyl acetate and a combination of acetonitrile and water.

[0161] In some embodiments, provided is a process for providing an enantiomerically enriched composition comprising compound II-S:or salt thereof, comprising contacting a compound of formula IV, or a salt thereof:with (17?,2S)-(-)-2-amino-l,2-diphenylethanol in a solvent selected from isopropyl acetate, a combination of methyl ethyl ketone, and a combination of acetonitrile and water, to provide the enantiomerically enriched composition comprising compound II-S.

[0162] In some embodiments, provided is a process for providing an enantiomerically enriched composition comprising compound II-R:or salt thereof, comprising contacting a compound of formula IV, or a salt thereof:iv, with ( IS, 2R)-(+)-2 -amino- 1,2-diphenylethanol in a solvent selected from isopropyl acetate, a combination of methyl ethyl ketone, and a combination of acetonitrile and water, to provide the enantiomerically enriched composition comprising compound II-R.

[0163] In some embodiments, provided is a process for resolving a compound of formula IV:or salt thereof, to increase the proportion of the stereoisomer which is compound II-S:comprising contacting a compound of formula IV with ( l / ?.2S)-(-)-2 -amino- 1,2-diphenylethanol in a solvent selected from isopropyl acetate, a combination of methyl ethyl ketone and heptane, and a combination of acetonitrile and water. In some embodiments, the solvent is selected from isopropyl acetate and a combination of acetonitrile and water.

[0164] In some embodiments, provided is a process for resolving a compound of formula IV:or salt thereof, to increase the proportion of the stereoisomer which is compound II-R:or salt thereof, comprising contacting a compound of formula IV with ( IS, 2R)-(+)-2 -amino- 1,2- diphenylethanol in a solvent selected from isopropyl acetate, a combination of methyl ethyl ketone and heptane, and a combination of acetonitrile and water.

[0165] Also provided herein is a process for preparing a salt of compound II-S, represented by formulaII-SC:comprising contacting a compound of formula IV, or a salt thereof:with a compound of formula V-S, or a salt thereof:under conditions suitable to provide compound II-SC.

[0166] Also provided herein is a process for preparing a salt of compound II-R, represented by formulaII-RC:comprising contacting a compound of formula IV, or a salt thereof:under conditions suitable to provide compound II-RC.

[0167] In some embodiments, the conditions suitable to provide compound II-SC or compound II-RC further comprise a solvent. In some embodiments, the solvent is a ketone, an alcohol, a polar aprotic solvent, an ethereal solvent, a halogenated solvent, a hydrocarbon, water, or a combination thereof. In some embodiments, the solvent is acetone, methyl ethyl ketone, methyl isobutyl ketone, methanol, ethanol, isopropanol, butanol, acetonitrile, ethyl acetate, isopropyl acetate, V '-dimcthyl formamide, N, '-dimcthyl acetamide, dimethyl sulfoxide, '-mcthyl pyrrolidine, diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran, 2 -methyltetrahydrofuran, cyclopentyl methyl ether, tert-butyl methyl ether, dichloromethane, 1,2-dichloroethane, chlorobenzene, water, pentane, hexane, heptane, octane, petroleum ether, benzene, toluene, xylene, or a combination thereof.

[0168] In some embodiments, the solvent is a ketone, a polar aprotic solvent, a hydrocarbon, water, or a combination thereof. In some embodiments, the solvent is acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, isopropyl acetate, heptane, water, or a combination thereof. In some embodiments, the solvent is isopropyl acetate, a combination of methyl ethyl ketone and heptane, or a combination of acetonitrile and water.

[0169] In some embodiments, the solvent is isopropyl acetate. In some embodiments, the solvent is a combination of methyl ethyl ketone and heptane. In some embodiments, the solvent is a combinationof acetonitrile and water. In some embodiments, the solvent is selected from isopropyl acetate and a combination of acetonitrile and water.

[0170] In some embodiments, the process for preparing compound II-SC or compound II-RC further comprises recrystallization from a solvent. In some embodiments, the solvent is water, a hydrocarbon, a polar aprotic solvent, or a combination thereof. In some embodiments, the solvent is water, pentane, hexane, heptane, octane, petroleum ether, benzene, toluene, xylene, acetonitrile, ethyl acetate, isopropyl acetate, N, '-dimcthyl formamide, N, '-dimcthyl acetamide, dimethyl sulfoxide, '-mcthyl pyrrolidine, or a combination thereof.

[0171] In some embodiments, the solvent is a combination of water and a polar aprotic solvent. In some embodiments, the solvent is a combination of water and acetonitrile.

[0172] In some embodiments, provided is a process for preparing a salt of compound II-S, represented by formula II-SC:in a solvent selected from isopropyl acetate, a combination of methyl ethyl ketone and heptane, and a combination of acetonitrile and water, to provide compound II-SC; optionally followed by recrystallization of compound II-SC in a combination of acetonitrile and water.

[0173] In some embodiments, provided is a process for preparing a salt of compound II-R, represented by formula II-RC:II-RC,comprising contacting a compound of formula IV, or a salt thereof:in a solvent selected from isopropyl acetate, a combination of methyl ethyl ketone and heptane, and a combination of acetonitrile and water, to provide compound II-RC; optionally followed by recrystallization of compound II-RC in a combination of acetonitrile and water.

[0174] In some embodiments, the process for preparing compound II-SC further comprises contacting compound II-SC with a base under conditions suitable to provide compound II-S, or a salt thereof:

[0175] In some embodiments, the process for preparing compound II-RC further comprises contacting compound II-RC with a base under conditions suitable to provide compound II-R, or a salt thereof:

[0176] In some embodiments, the process for resolving a compound of formula IV to increase the proportion of the stereoisomer which is compound II-S comprises by contacting compound II-SC with a base under conditions suitable to provide compound II-S, or a salt thereof:

[0177] In some embodiments, the process for resolving a compound of formula IV to increase the proportion of the stereoisomer which is compound II-RC comprises by contacting compound II-RC with a base under conditions suitable to provide compound II-R, or a salt thereof:

[0178] In some embodiments, the base is an inorganic base. In some embodiments, the base is sodium phosphate mono / di / tribasic, lithium phosphate mono / di / tribasic, potassium phosphate mono / di / tribasic, calcium phosphate mono / di / tribasic, magnesium phosphate mono / di / tribasic, tetramethylammonium phosphate mono / di / tribasic, or tetrabutylammonium phosphate mono / di / tribasic.

[0179] In some embodiments, the base is potassium phosphate tribasic.

[0180] In some embodiments, the conditions suitable to provide compound II-S or compound II-R further comprise a solvent. In some embodiments, the solvent is water, a halogenated solvent, or a combination thereof. In some embodiments, the solvent is water, dichloromethane, 1,2- dichloroethane, chlorobenzene, or a combination thereof.

[0181] In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is a combination of dichloromethane and water.

[0182] In some embodiments, the process for preparing compound II-S or compound II-R further comprises recrystallization from a solvent. In some embodiments, the solvent is water, a hydrocarbon, an ethereal solvent, or a combination thereof. In some embodiments, the solvent is water, pentane, hexane, heptane, petroleum ether, benzene, toluene, diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, tert-butyl methyl ether, or a combination thereof.

[0183] In some embodiments, the solvent is 2-methyltetrahydrofuran, heptane, or a combination thereof. In some embodiments, the solvent is 2-methyltetrahydrofuran and heptane. In some embodiments, the solvent is 2-methyltetrahydrofuran.

[0184] In some embodiments, the process for preparing compound II-S further comprises contacting compound II-SC with potassium triphosphate basic in dichloromethane to provide compound II-S, or a salt thereof:optionally followed by recrystallization of compound II-S in a combination of 2- methyltetrahydrofuran, heptane or a combination thereof.

[0185] In some embodiments, the process for preparing compound II-R further comprises contacting compound II-RC with potassium triphosphate basic in dichloromethane to provide compound II-R, or a salt thereof:optionally followed by recrystallization of compound II-R in 2-methyltetrahydrofuran, heptane or a combination thereof.

[0186] In some embodiments, resolving a compound of formula IV to increase the proportion of the stereoisomer which is compound II-RC is followed by contacting compound II-SC with potassium triphosphate basic in dichloromethane to provide compound II-S, or a salt thereof:optionally followed by recrystallization of compound II-S in 2-methyltetrahydrofuran, heptane or a combination thereof.

[0187] In some embodiments, resolving a compound of formula IV to increase the proportion of the stereoisomer which is compound II-RC is followed by contacting compound II-RC with potassium triphosphate basic in dichloromethane to provide compound II-R, or a salt thereof:optionally followed by recrystallization of compound II-R in 2-methyltetrahydrofuran, heptane or a combination thereof.

[0188] In some embodiments, provided herein is a process for preparing compound VI, or a salt thereof:the process comprising the steps of:(a) preparing compound I-S, or salt thereof:by the process disclosed herein; and(b) preparing compound VI, or a salt thereof, by using compound I-S as a starting material.

[0189] Also provided herein is a process for preparing compound VI, or a salt thereof:the process comprising the steps of:(c) preparing compound II-S, or a salt thereof:by the process disclosed herein; and(d) preparing compound VI or a salt thereof, by using compound II-S as a starting material.

[0190] Also provided herein is a process for preparing compound VI, or a salt thereof:the process comprising the steps of:(c) preparing compound II-S, or a salt thereof:by the process disclosed herein;(a) preparing compound I-S, or a salt thereof:by the process disclosed herein; and(b) preparing compound VI or a salt thereof, by using compound I-S as a starting material.

[0191] In some embodiments, step (b) comprises contacting compound I-S, or salt thereof:with a compound of formula VII, or a salt thereof:under conditions suitable to provide compound VIA, or a salt thereof:followed by a methylation step to provide compound VIB, or a salt thereof:followed by deprotection to provide compound VI, wherein R2is a protecting group.

[0192] In some embodiments, the salt of the compound of formula VII is an acid salt. In some embodiments, the salt of the compound of formula VII is a hydrochloric acid salt, a toluenesulfonic acid salt, a benzenesulfonic acid salt, a methanesulfonic acid salt, a trifluoracetic acid salt, a trifluoromethanesulfonic acid salt, a phosphoric acid salt, or a sulfuric acid salt.

[0193] In some embodiments, the salt of the compound of formula VII is a hydrochloride salt or a benzenesulfonic acid salt.

[0194] In some embodiments, the salt of the compound of formula VI is a sodium, potassium, calcium, magnesium, ammonium, tert-butylamine, diethylamine, 2-dimethylaminoethanol (deanol), N,N- dibenzylethane-l,2-diamine (benzathine), tris(hydroxymethyl)aminomethane (tromethamine), l-(2- hydroxyethyl)pyrrolidine (epoloamine), meglumine, arginine, or lysine salt.

[0195] In some embodiments, the salt of the compound of formula VI is a sodium salt. In some embodiments, the salt of the compound of formula VI is a tris(hydroxymethyl)aminomethane (tromethamine) salt. In some embodiments, the salt of the compound of formula VI is a l-(2- hydroxyethyl)pyrrolidine (epolamine) salt. In some embodiments, the salt of the compound of formula VI is a 2-dimethylaminoethanol (deanol) salt.

[0196] In some embodiments, the protecting group R2is Ci-6 alkyl, benzyl, Si(Ci-6 alkyl)’,, or Si(Ci-6 alkyl)3-Ci-6 alkyl.

[0197] In some embodiments, the protecting group R2is a Ci-6 alkyl group. In some embodiments, the protecting group R2is methyl. In some embodiments, the protecting group is R2ethyl. In some embodiments, the protecting group R2is isopropyl. In some embodiments, the protecting group R2is tert-butyl.

[0198] In some embodiments, the protecting group R2is benzyl.

[0199] In some embodiments, the protecting group R2is -Si(Ci-6 alkyl)3. In some embodiments, the protecting group R2is trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, or triisopropylsilyl. In some embodiments, the protecting group R2is trimethylsilyl.

[0200] In some embodiments, the protecting group R2is Si(Ci-6 alkyl)3-Ci-6 alkyl. In some embodiments, the protecting group R2is (trimethylsilyl)ethyl, (triethylsilyl)ethyl, or (tert-butyldimethylsilyl)ethyl. In some embodiments, the protecting group R2is (trimethylsilyl)ethyl.

[0201] In some embodiments, the conditions suitable to provide compound VIA, further comprise a coupling agent. In some embodiments, the coupling agent is W'-dicyclohcxylcarbodiimidc (DCC), W'-dicyclopcntylcarbodiimidc. W'-diisopropylcarbodiimidc (DIC), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), A'-t-butyl-A'-mcthylcarbodiimidc (BMC), JV-t-butyl-JV- ethylcarbodiimide (BEC), l,3-bis(2,2-dimethyl-l,3-dioxolan-4-yhnethyl)carbodiimide (BDDC), 2- pyridinol-1 -oxide (HOPO), 1 -hydroxybenzotriazole (HOBt), l-hydroxy-7-azabenzotriazole (HOAt), benzotriazol- 1 -yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), hexafluorophosphate nenzotriazole tetramethyluronium (HBTU), hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU), or a combination thereof.

[0202] In some embodiments, the coupling agent is a combination of l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC) and 2-pyridinol-l -oxide (HOPO).

[0203] In some embodiments, the conditions suitable to provide compound VIA further comprise a base. In some embodiments, the base is an amine base. In some embodiments, the base is triethylamine, diisopropylethyl amine, tributyl amine, '-mcthylmorpholinc. pyridine, 4-dimethylaminopyridine, or '-mcthy 1 imidazole. In some embodiments, the base is 4-dimethylaminopyridine or a combination of 4-dimethylaminopyridine and diisopropylethyl amine. In some embodiments, the base is a combination of 4-dimethylaminopyridine and diisopropylethyl amine

[0204] In some embodiments, the conditions suitable to provide compound VIA further comprise a solvent. In some embodiments, the solvent is a halogenated solvent or a polar aprotic solvent. In some embodiments, the solvent is dichloromethane, 1,2-dichloroethane, chlorobenzene, or acetonitrile. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is acetonitrile. In some embodiments, the conditions suitable to provide compound VIA comprise acetonitrile at a temperature of about 40 °C to about 60 °C.

[0205] In some embodiments, the conditions suitable to provide compound VIA comprise a coupling agent, a base, and a solvent. In some embodiments, the conditions suitable to provide compound VIA comprise a combination of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 2-pyridinol- 1 -oxide (HOPO), a base, and a solvent. In some embodiments, the conditions suitable to provide compound VIA, comprise a combination of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 2-pyridinol-l -oxide (HOPO), 4-dimethylaminopyridine, diisopropylethyl amine, and a solvent. In some embodiments, the conditions suitable to provide compound VIA comprise a combination of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 2-pyridinol-l -oxide (HOPO), 4- dimethylaminopyridine, diisopropylethyl amine, and dichloromethane. In some embodiments, the conditions suitable to provide compound VIA comprise a combination of l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC) and 2-pyridinol-l -oxide (HOPO), 4- dimethylaminopyridine, diisopropylethyl amine, and acetonitrile. In some embodiments, the conditions suitable to provide compound VIA comprise a combination of l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC) and 2-pyridinol-l -oxide (HOPO), 4-dimethylaminopyridine, diisopropylethyl amine, and acetonitrile at a temperature of about 40 °C to about 60 °C.

[0206] In some embodiments, the methylation step comprises a methylating agent. In some embodiments, the methylating agent is methyl iodide, methyl trifluoromethanesulfonate, methylfluorosulfonate, methyl methanesulfonate, dimethyl sulfate, trimethyloxonium tetrafluoroborate, or trimethylsilyldiazomethane .

[0207] In some embodiments, the methylating agent is methyl trifluoromethanesulfonate.

[0208] In some embodiments, the methylation step further comprises a base. In some embodiments, the base is an alkoxide base. In some embodiments, the alkoxide base is sodium methoxide, lithium methoxide, potassium methoxide, magnesium methoxide, calcium methoxide, sodium ethoxide, lithium ethoxide, potassium ethoxide, magnesium ethoxide, calcium ethoxide, sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, calcium tert-butoxide.

[0209] In some embodiments, the base is sodium tert-butoxide, lithium tert-butoxide, or potassium tert- butoxide. In some embodiments, the base is lithium tert-butoxide.

[0210] In some embodiments, the methylation step further comprises a solvent. In some embodiments, the solvent is an ethereal solvent. In some embodiments, the solvent is diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran, 2 -methyltetrahydrofuran, cyclopentyl methyl ether, or tert-butyl methyl ether, or a combination thereof. In some embodiments, the solvent is tetrahydrofuran.

[0211] In some embodiments, the methylation step comprises a methylating agent, a base, and a solvent. In some embodiments, the methylation step comprises methyl trifluoromethanesulfonate, a base, and a solvent. In some embodiments, the methylation step comprises methyl trifluoromethanesulfonate, lithium tert-butoxide, and a solvent. In some embodiments, the methylation step comprises methyl trifluoromethane sulfonate, lithium tert-butoxide, and tetrahydrofuran.

[0212] In some embodiments, the methylation step is carried out at a temperature of -60°C to -80 °C, for example -70 °C to - 80 °C.

[0213] In some embodiments, the methylation step comprises methyl trifluoromethanesulfonate, lithium tert-butoxide, and tetrahydrofuran at a temperature of -60 °C to -80 °C.

[0214] In some embodiments, the deprotection step comprises an acid or a fluoride source. In some embodiments, the acid or fluoride source is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, tetrabutylammonium fluoride, pyridinium fluoride, sodium fluoride, potassium fluoride, or cesium fluoride.

[0215] In some embodiments, the deprotection step comprises a fluoride source. In some embodiments, the fluoride source is cesium fluoride. In some embodiments, the fluoride source is tetrabutylammonium fluoride.

[0216] In some embodiments, the deprotection step further comprises a solvent. In some embodiments, the solvent is polar aprotic solvent. In some embodiments, the solvent is acetonitrile, ethyl acetate, isopropyl acetate, N, JV-dimethylformamide, N,N dimethylacetamide, JV-methyl-2-pyrrolidone,dimethyl sulfoxide, 2-methyl tetrahydrofuran or a combination thereof. In some embodiments, the solvent is W-dimcthylfonnamidc. In some embodiments, the solvent is acetonitrile or 2-methyl tetrahydrofuran. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is 2-methyl tetrahydrofuran.

[0217] In some embodiments, the deprotection step comprises a fluoride source that is tetrabutylammonium fluoride and a solvent that is acetonitrile or 2-methyl tetrahydrofuran. In some embodiments, the deprotection step comprises tetrabutylammonium fluoride and 2-methyl tetrahydrofuran. In some embodiments, the deprotection step comprises a fluoride source that is tetrabutylammonium fluoride and a solvent that is acetonitrile.

[0218] In some embodiments, provided is a process for preparing compound VI, or a salt thereof:the process comprising the steps of:(c) preparing compound II-S , or a salt thereof:by the process disclosed herein;(a) preparing compound I-S, or a salt thereof:by the process disclosed herein; and(b) preparing compound VI, or a salt thereof, by contacting compound I-S, or salt thereof, with a compound of formula VII, or a salt thereof:in the presence of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 2-pyridinol-l -oxide (HOPO), diisopropylethyl amine and 4-dimethylaminopyridine in dichloromethane, to provide compound VIA, or a salt thereof:followed by a methylation step comprising methyl trifluoromethane sulfonate and lithium tert- butoxide in tetrahydrofuran to provide compound VIB, or a salt thereof:followed by a deprotection step comprising cesium fluoride in W-dimcthylfonnamidc to provide compound VI, or a salt thereof, wherein R2is (trimethylsilyl)ethyl.

[0219] In some embodiments, provided is a process for preparing compound VI, or a salt thereof:the process comprising the steps of:(c) preparing compound II-S, or a salt thereof:by the process disclosed herein;(a) preparing compound I-S, or a salt thereof:by the process disclosed herein; and(b) preparing compound VI, or a salt thereof, by contacting compound I-S, or salt thereof, with a compound of formula VII, or a salt thereof:in the presence of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 2-pyridinol-l -oxide (HOPO), diisopropylethyl amine and 4-dimethylaminopyridine in acetonitrile, to provide compound VIA, or a salt thereof:followed by a methylation step comprising methyl trifluoromethane sulfonate and lithium tert- butoxide in tetrahydrofuran to provide compound VIB, or a salt thereof:followed by a deprotection step comprising tetrabutylammonium fluoride in acetonitrile, to provide compound VI, or a salt thereof, wherein R2is (trimethylsilyl)ethyl.Compounds

[0220] In certain embodiments, the disclosure provides for intermediate compounds that are useful in the processes described herein.

[0221] It can be appreciated that the straight bolded or dashed bond is used to indicate relative stereochemistry, and the wedged bolded or dashed bond is used to indicate absolute stereochemistry. Where the composition is identified as enantiomerically enriched, it is intended that the composition comprises more than 50% of a single enantiomer, or at least about 55%, or at least about 60%, or at least about 65%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 97%, or about 99% ee. Where the compound is identified as a single stereoisomer, it is intended that there is an enantiomeric excess of more than 50%, or at least about 55%, or at least about 60%, or at least about 65%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 97%, or about 99% ee.

[0222] Provided herein is a compound, or a salt thereof, of formula I-SA:wherein R1is H or a protecting group.

[0223] Also provided herein is a compound, or a salt thereof, of formula II-SA:wherein R1is H or a protecting group.

[0224] Provided herein is a compound, or a salt thereof, of formula I-RA:wherein R1is H or a protecting group.

[0225] Also provided herein is a compound, or a salt thereof, of formula II-RA:wherein R1is H or a protecting group.

[0226] In some embodiments, R1is H. In some embodiments, R1is a protecting group.

[0227] In some embodiments, when R1is a protecting group, the protecting group is a Ci-6 alkyl, an optionally substituted benzyl, a silyl group, or -C(O)R, wherein each R is a Ci-6 alkyl group or a phenyl.

[0228] In some embodiments, when R1is a protecting group, the protecting group is a Ci-6 alkyl group. In some embodiments, when R1is a protecting group, the protecting group is methyl. In some embodiments, when R1is a protecting group, the protecting group is ethyl. In some embodiments, when R1is a protecting group, the protecting group is isopropyl. In some embodiments, when R1is a protecting group, the protecting group is tert-butyl.

[0229] In some embodiments, when R1is a protecting group, the protecting group is an optionally substituted benzyl. In some embodiments, when R1is a protecting group, the protecting group is benzyl. In some embodiments, when R1is a protecting group, the protecting group is p- methoxybenzyl. In some embodiments, when R1is a protecting group, the protecting group is p- nitrobenzyl.

[0230] In some embodiments, when R1is a protecting group, the protecting group is -C(O)R wherein each R is a Ci-6 alkyl group or a phenyl. In some embodiments, when R1is a protecting group, the protecting group is -C(O)CH3. In some embodiments, when R1is a protecting group, the protecting group is -C(O)-phenyl.

[0231] In some embodiments, when R1is a protecting group, the protecting group is a silyl group. In some embodiments, when R1is a protecting group, the protecting group is -SiR,. wherein each R is independently a Ci-6 alkyl group or a phenyl. In some embodiments, when R1is a protecting group,the protecting group is trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl chloride, or triisopropylsilyl.

[0232] In some embodiments, when R1is a protecting group, the protecting group is trimethylsilyl.

[0233] Provided herein is a compound, or a salt thereof, selected from:

[0234] Provided herein is a compound, or a salt thereof, selected from:

[0235] Also provided herein is a compound, or a salt thereof, of formula I-SB:

[0236] Also provided herein is a compound, or a salt thereof, of formula I-RB:

[0238] Also provided herein is a compound, or a salt thereof, of formula II-R:

[0239] Also provided herein is a compound, or a salt thereof, of formula II-SB:

[0240] Also provided herein is a compound, or a salt thereof, of formula II-RB:

[0241] Also provided herein is a compound, or a salt thereof, of formula II-SC:

[0242] Also provided herein is a compound, or a salt thereof, of formula II-RC:

[0243] It is appreciated that certain features described herein, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features described herein, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.EXAMPLES

[0244] The compounds of the disclosure may be prepared 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 compounds described 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. Unless otherwise noted, the starting materials for the following reactions may be obtained from commercial sources.

[0245] Chiral purity was measured by chiral HPLC analysis performed on an Agilent 1260 series LC system with a UV / Vis detector (254 nm or 280 nm) using CHIRALPAK IG-3 150x4.6 mm, 3 pm column at a flow rate of 0.8 mL / min with 0. 1% v / v trifluoroacetic acid in w-hcptanc solution (Mobile phase A) and ethanol (Mobile phase B) under isocratic conditions with the use of 15%, 10%, or 5% Mobile phase B.

[0246] Achiral HPLC was performed on an Agilent 1260 series LC system with a UV / Vis detector (210 nm, 220 nm or 230 nm) using the following conditions: i) Agilent ZORBAX Eclipse XDB C18, 4.6x50 mm, 1.8 pm column at a flow rate of 1.0 mL / min with 0.05% v / v trifluoroacetic acid in water (Mobile phase A) and 0.05% v / v trifluoroacetic acid in MeCN (Mobile phase B) at a gradient of 0.0 min: 10% Mobile phase B; 12.0 min: 95% Mobile phase B; 15.0 min: 95% Mobile phase B; and 15.1 min: 10% Mobile phase B; ii) Xbridge C18 4.6x150 mm, 3.5 pm column at a flow rate of 1.0 mL / min with 10 mM ammonium acetate in water (Mobile phase A) and MeCN (Mobile phase B) at a gradient of 0.0 min: 5% Mobile phase B; 6.0 min: 50% Mobile phase B; 9.0 min: 95% Mobile phase B; 17.0 min: 95% Mobile phase B; and 17.1 min: 5% Mobile phase B; iii) Agilent ZORBAX Eclipse XDB Cl 8, 4.6x50 mm, 1.8 pm column at a flow rate of 1.2 mL / min with 0.05% v / v trifluoroacetic acid in water (Mobile phase A) and 0.05% v / v trifluoroacetic acid in MeCN (Mobile phase B) at a gradient of 0.0 min: 10% Mobile phase B; 6.0 min: 95% Mobile phase B; 8.0 min: 95% Mobile phase B; and 8.1 min: 10% Mobile phase B.

[0247] List of abbreviations and acronymsAbbreviation Meaning° C degrees CelsiusACN / MeCN acetonitrile w-BuLi M-butyllithiumDCM dichloromethaneDMSO dimethylsulfoxideHC1 hydrochloric acidHPLC high performance liquid chromatographyH3PO4 phosphoric acid ee enantiomeric excess equiv equivalentIPAc isopropyl acetateIR infrared spectroscopyKF Karl FischerKHSO4 potassium hydrogen sulfate mL / L milliliter / literLOD loss on dryingMEK methyl ethyl ketoneMeTHF 2-methyltetrahydrofuranNaCl sodium chlorideTHF tetrahydrofuranTMS trimethylsilylVol volume equivalentsNMR abbreviations br = broad d = doublet dd = doublet of doublets ddd = doublet of doublet of doublets dt = doublet of triplets m = multiplet q = quartet s = singlet t = tripletExample 1: Preparation of (A)-3-fluoro-5-(l-hydroxy-l-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid (17?,2A)-2-amino-l,2-diphenylethan-l-ol salt (Compound II-SC) using MEK and w-heptane

[0248] A solution was obtained by mixing 3-fluoro-5-(l-hydroxy-l-(tetrahydro-2H-pyran-4- yl)propyl)benzoic acid (120 g, 1.0 equiv), (lR,2S)-2-amino-l,2-diphenylethan-l-ol (90.66 g, 1.0 equiv) and MEK (840 m , 7 Vol) at ambient temperature. w-Hcptanc was added to the solution and the resultant solution was stirred until the crystallization was deemed complete. The slurry was fdtered, and the fdter cake was washed with a mixture of MEK and w-hcptanc in three portions. Thewet solids were dried under vacuum to provide 73.57 g (yield: 35%) of (S)-3 -fluoro-5-(l -hydroxy- 1- (tetrahydro-2H-pyran-4-yl)propyl)benzoic acid ( 1R, 2S)-2 -amino- 1,2-diphenylethan-l-ol salt with 99.4% ee and 99% purity by achiral HPLC.Example 2: Preparation of (A)-3-fluoro-5-(l-hydroxy-l-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid (17?,2iS)-2-amino-l,2-diphenylethan-l-ol salt (Compound II-SC) using IPAc

[0249] A mixture of 3 -fluoro-5-(l -hydroxy- l-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid (1.0 equiv), ( \R.2S)-2 -amino- 1,2-diphenylethan-l-ol (1.05 equiv) and IPAc (8 Vol) was stirred under nitrogen for 0.5 hours to give a clear solution. Water (0.3 equiv) and seeds of (S)-3 -fluoro-5-(l -hydroxy- 1- (tetrahydro-2H-pyran-4-yl)propyl)benzoic acid ( \R.2S)-2 -amino- 1,2-diphenylethan-l-ol salt were added. The cloudy mixture was stirred for a few hours. Water (1.2 equiv) was added dropwise. The slurry was aged and fdtered. The cake was washed with a mixture of IPAc and water and dried under vacuum at about 45 °C. The crude salt contains about 90-94% of the desired enantiomer as determined by HPLC. The crude salt can further be purified by dissolving it in IPAc (20 Vol) at about 65 °C, adding water (2 equiv) and seeds. The slurry was stirred at 20 °C for several hours and filtered. The cake was washed with IPAc and dried under vacuum to give 88% yield of (.S)-3-fluoro-5-( I -hydroxy- l-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid ( 1R, 2S)-2 -amino- 1,2-diphenylethan-l-ol salt with 99% ee.Example 3: Preparation of (A)-3-fluoro-5-(l-hydroxy-l-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid (lR,2S)-2-amino-l,2-diphenylethan-l-ol salt (Compound II-SC) using ACN and water

[0250] 3 -Fluoro-5-(l -hydroxy- l-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid (1.0 equiv), ( \R.2S)-2- amino- 1,2-diphenylethan-l-ol (1.05 equiv), and ACN (15 Vol to 20 Vol relative to 3-fluoro-5-(l- hydroxy-l-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid) were heated to 40±5 °C. Water and seeds were sequentially added to the solution to give a cloudy mixture. After stirring a few hours at 40±5 °C, the mixture was cooled to 20±5 °C and stirred to ripen the crystallization mixture. The slurry was filtered, the cake was washed with a mixture of acetonitrile / water and then dried to give (.S)-3-fluoro- 5-( 1 -hydroxy- 1 -(tetrahydro -2H-pyran-4-yl)propyl)benzoic acid ( 1R, 2S)-2 -amino- 1 ,2-diphenylethan- l-ol salt with > 88% ee as determined by HPLC.Example 4: Preparation of (A)-3-fluoro-5-(l-hydroxy-l-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid (l / ?,2iS)-2-amino-l,2-diphenylethan-l-ol salt (Compound II-SC) using ACN and water (1.67 kg scale)

[0251] 3 -Fluoro-5-(l -hydroxy- l-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid (2.1 kg, 1.0 equiv), ( 17?, 2S)-2 -amino- 1,2-diphenylethan-l-ol (1.67 kg, 1.05 equiv), and ACN (42 L, 20 Vol relative to 3- fluoro-5-(l -hydroxy- l-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid) were heated to 40±5 °C to give a clear solution. Water (1.05 kg, 2.5% v / v) and (.S)-3-fluoro-5-( l -hydroxy- l-(tetrahydro-2H- pyran-4-yl)propyl)benzoic acid ( 17?, 25)-2 -amino- 1,2-diphenylethan-l-ol salt seeds were sequentially added to the solution to give a cloudy mixture. The mixture was stirred at 40±5 °C for about 1 hour and then cooled over 2 hours to 20±5 °C. The slurry was aged and filtered. The filter cake was washed with a mixture of acetonitrile-water and dried under vacuum at 45±5 °C. (.S)-3-Fluoro-5-( I -hydroxy-I -(tctrahydro-2H-py ran -4-yl )propy I (benzoic acid ( l / ?.2.S')-2-amino- l .2-diphcnylcthan- l -ol salt (1.72 kg, 45% yield) was obtained as a hydrate with 97.2% ee and 100% purity as determined by HPLC.Example 5: Preparation of (A)-3-fluoro-5-(l-hydroxy-l-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid (17?,2iS)-2-amino-l,2-diphenylethan-l-ol salt (Compound II-SC) using IPAc (1.98 kg scale)

[0252] 3 -Fluoro-5-(l -hydroxy- l-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid (2.5 kg, 1.0 equiv), ( 17?, 2S)-2 -amino- 1,2-diphenylethan-l-ol (1.98 kg, 1.05 equiv) and IPAc (200 L, 8 Vol) were stirred at 20±5 °C. Water (48 g, 0.3 equiv) and (.S')-3-fluoro-5-( l -hydroxy- l-(tetrahydro-2H-pyran-4- yl)propyl)benzoic acid ( 1 ?, 2S)-2 -amino- 1,2-diphenylethan-l-ol salt seeds were added to the solution to give a cloudy mixture. After stirring the mixture for 2 hours, water (191.3 g, 1.2 equiv) was added dropwise to the mixture. The slurry was aged and filtered. The filter cake was washed with a mixture of IPAc / water. The wet solid (3.5 kg, yield: 53% (corrected by LOD). LOD: 34%, with 87.1% ee) was used in recrystallization.Example 6: Recrystallization of (A)-3-fluoro-5-(l-hydroxy-l-(tetrahydro-2H-pyran-4- yl)propyl)benzoic acid (17?,2A)-2-amino-l,2-diphenylethan-l-ol salt (Compound II-SC) using ACN and water

[0253] Crude wet (.S)-3-fluoro-5-( I -hydroxy- l-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid ( l / ?.2.S)-2- amino- 1,2-diphenylethan-l-ol salt (3.21 kg wet, 2.12 kg on dry basis, 1.0 equiv) was mixed with ACN (10.6 L, 5 Vol), heated to 55±5 °C and stirred for at least 1 hour to dissolve. Water (0.35 kg) was added slowly to the solution at 55±5 °C (turned cloudy), and then seeds were added at 55±5 °C. The slurry was cooled to 20±5 °C at 10-15 °C / hour, stirred for 2 hours and filtered. The filter cake was washed with a mixture of ACN / water and dried to give 1.85 kg (S)-3 -fluoro-5-(l -hydroxy- 1- (tetrahydro-2H-pyran-4-yl)propyl)benzoic acid ( 17?, 2S)-2 -amino- 1,2-diphenylethan-l-ol salt with 100% purity and 99.4% ee by HPLC.Example 7: Preparation of (A)-3-fluoro-5-(l-hydroxy-l-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid (Compound II-S)

[0254] (.S)-3-Fluoro-5-( I -hydroxy- l-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid ( l / ?.2.S)-2-amino- 1,2-diphenylethan-l-ol salt (1.7 kg, 1.0 equiv) and DCM (17 L, 10 Vol) were stirred under nitrogen atmosphere. The solution was treated with aqueous 10% K3PO4 (11.05 L, 6.5 Vol) to adjust pH to ~II. The mixture was stirred for least 2 hours, layers were separated, and the aqueous phase was washed with DCM (17 L, 10 Vol). The aqueous phase was mixed with MeTHF (8.5 L, 5 Vol), adjusted the pH to ~2 by adding 3M HC1 aqueous solution and stirred. The layers were separated, and the organic phase was washed with 20% brine solution (8.5 L, 5 Vol). The organic layer was concentrated with addition of MeTHF to remove most of the water. w-Hcptanc (6.8 L, 4 Vol) was added slowly into the solution. The resultant slurry was stirred for at least 1 hour, seeds were added and the slurry was stirred for at least 1 hour. ^-Heptane (10.2 L, 6 Vol) was slowly added, and the slurry was aged. The slurry was concentrated under reduced pressure to a final volume of 6-8 Vol to give MeTHF content of not more than 10%. The slurry was cooled to 0±5 °C, stirred for a few hours, and filtered. The cake was washed with w-hcptanc and dried under vacuum at 45±5 °C to provide 868 g (93%yield) of solid (.S')-3-fluoro-5-( I -hydroxy- l-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid with 100% purity and 96.6% ee by HPLC.

[0255] A second batch with higher ee of 99.8% by HPLC was also prepared.Example 8: Preparation of (A)-3-fluoro-5-(l-(tetrahydro-2H-pyran-4-yl)-l-((trimethylsilyl)oxy)propyl)benzoic acid (Compound II-SB)

[0256] A solution of (.S')-3-fluoro-5-( I -hydroxy- l-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid (830 g, 1.0 equiv) and DCM (8.3 L, 10 Vol) was cooled to 0±5 °C. Triethylamine (0.83 kg, 2.8 equiv) was added to the solution followed by trimethylsilyltriflate (1.57 kg, 2.4 equiv) slowly to the solution at 0±5 °C. HPLC analysis showed the reaction to be complete. Water (8.3 L, 10 Vol) was added keeping temperature at 10±5 °C. The mixture was stirred for at least 0.5 hours at 10±5 °C, and then the layers were separated. The DCM phase was washed sequentially with the 0.5M KHSCL solution (8.3 L, 10 Vol) and water (8.3 L, 10 Vol). The DCM layer was concentrated under reduced pressure until a final volume of 3.5-4.5 Vol (2.9 - 3.7 L) remained. The solution was cooled to 20±5 °C and w-hcptanc (8.3 L, 10 Vol) was added followed by (.S)-3-fluoro-5-( l -(tctrahydro-2H-pyran-4-yl)- l - ((trimethylsilyl)oxy)propyl)benzoic acid seeds. The slurry was stirred and concentrated to a final volume of 5.5 to 7.5 Vol (4.6 - 6.2 L) to remove DCM. The slurry was cooled to 20±5 °C, aged and filtered. The filter cake was washed with w-hcptanc. and dried at 45±5 °C under vacuum to give 934 g (89.6% yield) of solid (S)-3-fluoro-5-(l-(tetrahydro-2H-pyran-4-yl)-l- ((trimethylsilyl)oxy)propyl)benzoic acid with 100% purity and 98.6% ee by HPLC.

[0257] A second batch with 99.3% purity and 100% ee was also prepared.Example 9: Preparation of (A)-2-(4-chlorobenzoyl)-3-fluoro-5-(l-hydroxy-l-(tetrahydro-2H-pyran- 4-yl)propyl)benzoic acid (Compound I-S) using toluene isolation

[0258] To THF (6.75 L, 15 Vol) at -75 °C to -40 °C was added w-BuLi (1.16 L, 2.5 M, 2.3 equiv) slowly, maintaining the temperature. A solution of (.S)-3-fluoro-5-( l -(tctrahydro-2H-pyran-4-yl)- l - ((trimethylsilyl)oxy)propyl)benzoic acid (450 g, 1.0 equiv) in THF (2.25 L, 5 Vol) was slowly added maintaining the temperature at -70±5 °C. The mixture was stirred for about 1 hour at -70±5 °C. A solution of 4-chlorobenzoyl chloride (256 g, 1.15 equiv) in THF (0.9 L, 2 Vol) was added and stirred for 0.5 hour at -70±5 °C. A second batch of (.S)-3-fluoro-5-( l -(tctrahydro-2H-pyran-4-yl)- l - ((trimethylsilyl)oxy)propyl)benzoic acid (450 g) was similarly processed and the reaction mixtures were combined to into a 900 g batch for the next step.

[0259] The mixture was warmed to -20 °C to 0 °C and treated with H3PO4 (85 wt% in water, 526.5 g, 5.0 equiv). The mixture was adjusted to about 35 °C and stirred until less than 2% of the starting material remained by HPLC. The mixture was diluted with toluene (9 L, 10 Vol) after cooling to 20±5 °C, washed twice with 4% aq. NaCl (2 x 9 L, 2 x 10 Vol) and once with water (9 L, 10 Vol). Then, the organic phase was concentrated under reduced pressure at 45±5 °C to a final volume near 8±0.5 Vol. Toluene (9 L, 10 Vol) was added to the mixture and adjusted to 45±5 °C. The solution was seeded with (.S')-2-(4-chlorobcnzoy I )-3 -fluoro-5 -( 1 -hydroxy- 1 -(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid and aged at 45±5 °C. The slurry was distilled under reduced pressure at 45±5 °C to a final volumenear 9±0.5 Vol. The slurry was aged at 45±5 °C, cooled to 20±5 °C over 1 hour, then stirred for 1 hour at 20±5 °C. The slurry was fdtered, and the cake washed with toluene. The wet solid was dried at 45±5 °C under vacuum to give 821.5 g of solid (S)-2-(4-chlorobenzoyl)-3 -fluoro-5 -(1 -hydroxy- 1- (tetrahydro-2H-pyran-4-yl)propyl)benzoic acid (LOD: 0.7%) with 93.5% purity. This material was further recrystallized.Example 10: Preparation of (iS)-2-(4-chlorobenzoyl)-3-fluoro-5-(l-hydroxy-l-(tetrahydro-2H- pyran-4-yl)propyl)benzoic acid (Compound I-S) using THF and w-heptane recrystallization

[0260] Crude (.S')-2-(4-chlorobcnzoy I )-3 -fluoro-5 -( 1 -hydroxy- 1 -(tetrahydro-2H-pyran-4- yl)propyl)benzoic acid (760 g, 1.0 equiv) was added to THF (3.8 L, 5.0 Vol) under nitrogen atmosphere. The mixture was heated to 45±5 °C and stirred for a few hours. ^-Heptane (11.4 L, 15 Vol) was slowly added to the solution at 45±5 °C followed by (.S)-2-(4-chlorobcnzoyl)-3 -fluoro-5 -(1- hydroxy-l-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid seeds. The slurry was stirred for at least 2 hours at 45±5 °C, gradually cooled over 3 hours to 20±5 °C, aged, cooled to 0±5 °C and stirred for a few hours. The slurry was centrifuged and washed with w-hcptanc. The wet cake was dried under vacuum at 45±5 °C with a nitrogen sweep to afford 761 g of solid (LOD 7.4%) as a THF solvate with 98.5% purity by achiral HPLC.Example 11: Preparation of (iS)-2-(4-chlorobenzoyl)-3-fluoro-5-(l-hydroxy-l-(tetrahydro-2H- pyran-4-yl)propyl)benzoic acid (Compound I-S) using w-heptane slurry to desolvate THF

[0261] To the THF solvate of (.S)-2-(4-chlorobcnzoyl)-3 -fluoro-5 -(1 -hydroxy- l-(tetrahydro-2H-pyran -4- yl)propyl)benzoic acid (761 g) was added to w-hcptanc (7.6 L, 10 Vol) under nitrogen. The slurry was stirred for a few hours at 20±5 °C and centrifuged. The wet cake was washed with w-hcptanc and dried under vacuum at 45±5 °C with a nitrogen sweep to afford 577 g of solid (.S)-2-(4-chlorobcnzoyl)-3- fluoro-5-(l -hydroxy- l-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid with 98.5% purity and 100% ee by HPLC.Example 12: Preparation of (iS)-2-(4-chlorobenzoyl)-3-fluoro-5-(l-hydroxy-l-(tetrahydro-2H- pyran-4-yl)propyl)benzoic acid (Compound I-S) using w-heptane isolation

[0262] To THF (6.0 L, 15 Vol) at -75 °C to -65 °C was added w-BuLi (2.54 M, 2.2 equiv) slowly, maintaining the temperature. A solution of (S)-3 -fluoro-5 -(l-(tetrahydro-2H-pyran-4-yl)-l- ((trimethylsilyl)oxy)propyl)benzoic acid (400 g, 1.0 equiv) in THF (2 L, 5 Vol) was slowly added maintaining temperature at -70±5 °C. The mixture was stirred for 1 hour at -70±5 °C. A solution of 4-chlorobenzoyl chloride (226 kg, 1.15 equiv) in THF (0.8 L, 2 Vol) was added and stirred for 0.5 hour at -70±5 °C. A second batch of (S)-3 -fluoro-5 -(l-(tetrahydro-2H-pyran-4-yl)-l- ((trimethylsilyl)oxy)propyl)benzoic acid (400 g) batch was similarly processed and the reaction mixtures were combined at this stage for the deprotection of TMS group.

[0263] The mixture was warmed to -20 °C to 0 °C and treated with H3PO4 (85 wt% in water, 0.468 kg, 5.0 equiv). The mixture was adjusted to 35±5 °C and stirred until the reaction was deemed complete. The mixture was diluted with w-hcptanc (8 L, 10 Vol) after cooling to 20±5 °C, washed twice with 4% aqueous NaCl (2 X 8 L, 2 x 10 Vol) and once with water (8 L, 10 Vol). Then, the organic phasewas concentrated under reduced pressure at 45±5 °C to a final volume near 10 Vol (THF content -28.5%). Calculated amount of THF (1.72 L, 2.15 Vol) was added and w-hcptanc (6.28 L, 7.85 Vol) was slowly added at 45±5 °C to adjust THF content approximately 25% v / v). The mixture turned cloudy, and the slurry was stirred for 1 hour, cooled to 20±5 °C over 1 hour, aged, cooled to 0±5 °C, and stirred for a few hours at 0±5 °C. The slurry was filtered, and the cake was washed with n- heptane. The wet cake was dried under vacuum at 45±5 °C with a nitrogen sweep to give 720.3 g of (.S')-2-(4-chlorobcnzoy I )-3 -fluoro-5 -( 1 -hydroxy- 1 -(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid as a solid with 98.5% purity, 100% ee by HPLC and LOD 0.5%.Example 13: Recrystallization of (N)-2-(4-chlorobenzoyl)-3-fluoro-5-(l-hydroxy-l-(tetrahydro-2H- pyran-4-yl)propyl)benzoic acid (Compound I-S) using w-heptane isolation

[0264] Crude (.S')-2-(4-chlorobcnzoy I )-3 -fluoro-5 -( 1 -hydroxy- 1 -(tetrahydro-2H-pyran-4- yl)propyl)benzoic acid with 98.5% achiral purity (360 g) was added to THF (1.8 L, 5 Vol). The mixture was heated to 45±5 °C and stirred for a few hours. ^-Heptane (5.4 L, 15 Vol) was added slowly at 45±5 °C followed by (.S')-2-(4-chlorobcnzoyl)-3 -fluoro-5 -(1 -hydroxy- l-(tetrahydro-2H- pyran-4-yl)propyl)benzoic acid seeds and the slurry was stirred for at least 2 hours. Then the slurry was cooled over 3 hours to 20±5 °C, aged, cooled to 0±5 °C, and stirred for 3 hours. The slurry was centrifuged and washed with w-hcptanc. The wet cake was suspended in w-hcptanc (3.6 L, 10 Vol) and stirred for at least 3 hours at 20±5 °C. The slurry was centrifuged and washed with w-hcptanc. The wet cake was dried under vacuum at 45±5 °C with a nitrogen sweep to provide 341.9 g of (S)-2- (4-chlorobenzoyl)-3-fluoro-5-(l-hydroxy-l-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid as a solid with 99.4% achiral purity and 100% ee by HPLC (LOD 0.62%, water content measured by KF titration 0.02%).

[0265] Representative characterization data for the compounds are shown in the table below.

[0266] 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 disclosure belongs.

[0267] The embodiments 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 embodiments claimed.

[0268] 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.

[0269] It is to be understood that while the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.

Claims

What is Claimed is:

1. A process for preparing compound I-S, or a salt thereof:comprising contacting compound II-SA, or a salt thereof;with compound III, or a salt thereof:under conditions suitable to provide compound I-S, wherein R1is H or a protecting group, and X is halo, Ci-6 alkoxy, Ce-io aryloxy, -N(Ra)(ORa), C4-10 heterocyclyl, C4-10 heteroaryl, or -O-C(O)-Ci-6 alkyl; wherein Rais a C1-6 alkyl; and wherein when R1is a protecting group, the process comprises a deprotection step after the contacting step to provide compound I-S.

2. The process of claim 1, wherein X is Cl.

3. The process of claim 1 or 2, wherein the conditions comprise an organolithium base.

4. The process of claim 3, wherein the organolithium base is lithium diisopropylamide, lithium bis(trimethylsilyl)amide, lithium tetramethylpiperidide, methyllithium, isopropyllithium, w-butyllithium. scc-biityllithium. tert-butyllithium, w-hcxyllithium. or phenyllithium.

5. The process of claim 3 or claim 4, wherein the base is w-butyllithium.

6. The process of any one of claims 1-5, wherein the conditions further comprise a solvent that is an ethereal solvent, a hydrocarbon, or a combination thereof.

7. The process of any one of claims 1-5, wherein the conditions further comprise a solvent selected from diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, or tert-butyl methyl ether, pentane, hexane, heptane, octane, petroleum ether, benzene, toluene, xylene, and combinations thereof.

8. The process of claim 6 or claim 7, wherein the solvent is tetrahydrofuran or 2- methyltetrahydrofuran, for example tetrahydrofuran.

9. The process of any one of claims 1-8, wherein the conditions comprise cooling to a temperature of about -50 °C to about -100 °C, for example about -60 °C to -80 °C.

10. The process of any one of claims 1-9, wherein the conditions further comprise recrystallization of compound I-S from a solvent selected from water, a hydrocarbon, an ethereal solvent, a ketone, a nitrile, an ester, an amide, a sulfoxide, a halogenated solvent, and combinations thereof.

11. The process of any one of claims 1-9, wherein the conditions further comprise recrystallization of compound I-S from a solvent selected from water, pentane, hexane, heptane, octane, petroleum ether, benzene, toluene, xylene, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, methyl ethyl ketone, acetonitrile, acetone, isopropyl acetate, ethyl acetate, N, A-dimethylformamide, N,N- dimethylacetamide, dimethylsulfoxide, dichloromethane, 1,2-dichloroethane, chlorobenzene, and combinations thereof.

12. The process of claim 10 or claim 11, wherein the solvent is a combination of heptane and tetrahydrofuran.

13. The process of claim 1, wherein the process further comprises a protection step comprising converting compound II-S:or a salt thereof, under conditions suitable to provide compound II-SA:or salt thereof; wherein R1is a protecting group.

14. The process of claim 13, wherein the protection step comprises a silylating reagent.

15. The process of claim 14, wherein the silylating reagent is trimethylsilyl chloride, trimethylsilyl trifluoromethanesulfonate, triethylsilyl chloride, triethylsilyl trifluoromethanesulfonate, tertbutyldimethylsilyl chloride, tert-butyldimethylsilyl trifluoromethanesulfonate, tert-butyldiphenylsilyl chloride, tert-butyldiphenylsilyl trifluoromethanesulfonate, triisopropylsilyl chloride, triisopropylsilyl trifluoromethanesulfonate, trimethylsilylimidazole, 1 -(tert-butyldimethylsilyl)imidazole, hexamethyldisilazane, A-mcthyl-A-(trimcthylsilyl)trifluoroacctamidc. A-tert-butyldimethylsilyl-N- methyltrifluoroacetamide, N, 62-bi s (tri m ethyl si lyl )acetamide, or N, O-bis(tert- butyldimethylsilyl)acetamide .

16. The process of claim 14 or claim 15, wherein the silylating reagent is trimethylsilyl trifluoromethane sulfonate .

17. The process of any one of claims 1 to 16, wherein R1is a protecting group and the process further comprises a deprotection step after the contacting step to provide compound I-S.

18. The process of claim 17, wherein the deprotection step comprises an acid or a fluoride source.

19. The process of claim 18, wherein the acid or fluoride source is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, p- toluenesulfonic acid, tetrabutylammonium fluoride, pyridinium fluoride, sodium fluoride, potassium fluoride, or cesium fluoride.

20. The process of claim 18 or claim 19, wherein the acid is phosphoric acid.

21. The process of any one of claims 1-20, wherein R1is -SiR ,. wherein each R is independently a Ci- 6 alkyl group or a phenyl.

22. The process of any one of claims 1-21, wherein R1is trimethylsilyl, triethylsilyl, tert- butyldimethylsilyl, tert-butyldiphenylsilyl chloride, or triisopropylsilyl.

23. The process of any one of claims 1-22, wherein R1is trimethylsilyl.

24. A process for providing an enantiomerically enriched composition comprising compound II-S:or salt thereof, comprising contacting a compound of formula IV, or a salt thereof:with a chiral base, or a salt thereof, under conditions suitable to provide the enantiomerically enriched composition comprising compound II-S.

25. A process for resolving a compound of formula IV:iv, or salt thereof, to increase the proportion of the stereoisomer which is compound II-S:comprising contacting a compound of formula IV with a chiral base, or a salt thereof, under conditions suitable to increase the proportion of the stereoisomer which is compound II-S.

26. The process of claim 24 or 25, wherein the chiral base isL-valinol,L-lysine,L-arginine,(-)-quinine,(-)-cinchonidine, quinidine,(+)-dehydroabietylamine,(.S')-(-)-a-mcthyl-bcnzylaminc.1 ,2,3 ,4-tetrahydro- 1 -naphthylamine,1 -cyclohexylethylamine,(7?)-(+)- 1 -( 1 -naphthyl)ethylamine,( / ?)-(+)-N.N-dimcthyl- 1 -( 1 -naphthyl)ethylamine,1 -(4-methoxyphenyl)ethanamine,(R)-(+)-P-methylphenethylamine,(17?,27?)-(-)-diaminocyclohexane,(.S')-(-)-2-am ino-3 -phenyl- 1 -propanol,(5)-(-)-l -(4-bromophenyl)ethylamine,(-)-bis | (.S')- 1 -phenylethyl] amine,(.S')-(-)-A. '-dimcthyl- 1 -phenyl -ethylamine, ( / ?, / ?)-(+)-hydrobcnzoin.( 1 R,2R)-(+)- 1 ,2-diphenylethylenediamine,( 1 R,2S)-(+)-cis- 1 -amino-2 -indanol,( lR,2R)-(-)-trans- 1 -amino-2 -indanol,(.S'..S')-(-)-2-am ino- 1 ,2-diphenylethanol, or( I / ?.2.S')-(-)-2-am ino- 1 ,2-diphenylethanol, or a salt of each thereof.

27. The process of any one of claims 24 to 26, wherein the chiral base is (17?,27?)-(+)-l,2- diphenylethylenediamine or ( l / ?.2.S')-(-)-2-amino- l .2-diphcnylcthanol.

28. The process of any one of claims 24 or 26 to 27, wherein the enantiomerically enriched composition comprises an enantiomeric excess of a (.S')-cnantiomcr of compound II-S greater than 90%.

29. The process of claim 28, wherein the enantiomerically enriched composition comprises an enantiomeric excess of a (.S')-cnantiomcr of compound II-S greater than 95%.

30. The process of any one of claims 25 to 27, wherein the proportion of the stereoisomer which is compound II-S is increased to greater than 90%.

31. The process of claim 30, wherein the proportion of the stereoisomer which is compound II-S is increased to greater than 95%.

32. A process for preparing a salt of compound II-S, represented by formula II-SC:comprising contacting a compound of formula IV, or a salt thereof:with a compound of formula V-S, or a salt thereof:under conditions suitable to provide compound II-SC.

33. The process of claim 32, wherein the process further comprises contacting compound II-SC with a base under conditions suitable to provide compound II-S, or a salt thereof:

34. The process of claim 33, wherein the base is sodium phosphate monobasic, sodium phosphate dibasic, sodium phosphate tribasic, lithium phosphate monobasic, lithium phosphate dibasic, lithium phosphate tribasic, potassium phosphate monobasic, potassium phosphate dibasic, potassium phosphate tribasic, calcium phosphate monobasic, calcium phosphate dibasic, calcium phosphate tribasic, magnesium phosphate monobasic, magnesium phosphate dibasic, magnesium phosphate tribasic, tetramethylammonium phosphate monobasic, tetramethylammonium phosphate dibasic, tetramethylammonium phosphate tribasic, tetrabutylammonium phosphate monobasic, tetrabutylammonium phosphate dibasic or tetrabutylammonium phosphate tribasic.

35. The process of claim 34, wherein the base is potassium phosphate tribasic.

36. The process of any one of claims 24 to claim 32, wherein the conditions further comprise a solvent selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, methanol, ethanol, isopropanol, butanol, acetonitrile, ethyl acetate, isopropyl acetate, W-dimcthyl formamide, W-dimcthyl acetamide, dimethyl sulfoxide, V-methyl pyrrolidine, tetrahydrofuran, methyl tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, chlorobenzene, water, pentane, hexane, heptane, octane, petroleum ether, benzene, toluene, xylene, and combinations thereof.

37. The process of claim 36, wherein the solvent is isopropyl acetate, a combination of methyl ethyl ketone and w-hcptanc. or a combination of acetonitrile and water.

38. The process of any one of claims 32 to 36, further comprising recrystallization of compound II-SC from a solvent selected from water, pentane, hexane, heptane, octane, petroleum ether, benzene, toluene, xylene, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, methyl ethyl ketone, acetonitrile, acetone, isopropyl acetate, ethyl acetate, and combinations thereof.

39. The process of claim 38, wherein the solvent is a combination of acetonitrile and water.

40. The process of any one of claims 33 to 39, further comprising recrystallization of compound II-S from a solvent selected from water, pentane, hexane, heptane, petroleum ether, benzene, toluene, diethyl ether, diisopropyl ether, 1 ,4-dioxane, tetrahydrofuran, 2 methyltetrahydrofuran, cyclopentyl methyl ether, tert-butyl methyl ether, and combinations thereof.

41. The process of claim 40, wherein the solvent is 2-methyltetrahydrofuran, heptane, or a combination thereof.

42. A process for preparing compound VI, or a salt thereof:the process comprising the steps of:(a) preparing compound I-S, or salt thereof:by the process of any one of claims 1-23; and(b) preparing compound VI, or a salt thereof, by using compound I-S as a starting material.

43. A process for preparing compound VI, or a salt thereof:the process comprising the steps of:(c) preparing compound II-S , or a salt thereof:by the process according to any one of claims 24-41; and(d) preparing compound VI or a salt thereof, by using compound II-S as a starting material.

44. A process for preparing compound VI, or a salt thereof:the process comprising the steps of:(c) preparing compound II-S, or a salt thereof:by the process according to any one of claims 24-41;(a) preparing compound I-S, or a salt thereof:by the process according to any one of claims 1-23; and(b) preparing compound VI or a salt thereof, by using compound I-S as a starting material.

45. The process of claim 42 or 44, wherein step (b) is a coupling step that comprises contacting compound I-S, or a salt thereof, with a compound of formula VII, or a salt thereof:under conditions suitable to provide compound VIA, or a salt thereof:followed by a methylation step to provide compound VIB, or a salt thereof:followed by deprotection to provide compound VI, wherein R2is a protecting group.

46. The process of claim 45, wherein the salt of the compound of formula VII is a hydrochloride salt or benzenesulfonic acid salt.

47. The process of claim 45 or 46, wherein R2is Ci-6 alkyl, benzyl, Si(Ci-6 alkyl ) or Si(Ci-6 alkyl)3- Ci-6 alkyl.

48. The process of claim 47, wherein R2is (trimethylsilyl)ethyl.

49. The process of any one of claims 45 to 48, wherein the coupling step conditions comprise a coupling agent.

50. The process of claim 49, wherein the coupling agent is A V -dicyclohexylcarbodiimide (DCC),A V -dicyclopentylcarbodiimide,-diisopropylcarbodiimide (DIC), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), N-t-butyl-A-mcthylcarbodiimidc (BMC), JV-t-butyl-JV- ethylcarbodiimide (BEC), l,3-bis(2,2-dimethyl-l,3-dioxolan-4-yhnethyl)carbodiimide (BDDC), 2- pyridinol-1 -oxide (HOPO), 1 -hydroxybenzotriazole (HOBt), l-hydroxy-7-azabenzotriazole (HOAt), benzotriazol- 1 -yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) , hexafluorophosphate nenzotriazole tetramethyl uronium (HBTU), hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU), or a combination thereof.

51. The process of claim 49 or claim 50, wherein the coupling agent is a combination of l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC) and 2-pyridinol-l -oxide (HOPO).

52. The process of any one of claims 49 to 51, wherein the coupling step conditions further comprise 4-dimethylaminopyridine and diisopropylethyl amine.

53. The process of any one of claims 49 to 52, wherein the coupling step conditions further comprise a solvent that is acetonitrile, optionally wherein the coupling step is performed at a temperature of about 40 °C to about 60 °C.

54. The process of any one of claims 45 to 53, wherein the methylation step comprises a methylating agent selected from methyl iodide, methyl trifluoromethanesulfonate, methylfluorosulfonate, methyl methanesulfonate, dimethyl sulfate, trimethyloxonium tetrafluoroborate, and trimethylsilyldiazomethane; and a base.

55. The process of claim 54, wherein the methylating agent is methyl trifluoromethanesulfonate.

56. The process of claim 54 or 55, wherein the base is lithium tert-butoxide, sodium tert-butoxide, or potassium tert-butoxide.

57. The process of any one of claims 45 to 56, wherein the deprotection step comprises a fluoridesource that is tetrabutylammonium fluoride and a solvent that is acetonitrile or 2-methyl tetrahydrofuran.

58. A compound, or a salt thereof, selected from:

59. Compound II-S, having the structure:

60. A salt of compound II-S, represented by formula II-SC:

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