PROCESS OF MAKING 3«-HYDROXY-3p-METHOXYMETHYL-21-(l IMIDAZOLYL)-5a-PREGAN-20-ONE

TECHNICAL FIELD

[0001] The present disclosure relates to processes for preparing 3a-hydroxy-3P- methoxymethyl-21-(T-imidazolyl)-5a-pregnan-20-one and pharmaceutically acceptable salts thereof.

BACKGROUND

[0002] 3a-hydroxy-3P-methoxymethyl-21-(T-imidazolyl)-5a-pregnan-20- one (the compound of Formula (I)), is a synthetic neuroactive steroid. Its primary molecular target is the y- aminobutyric acid type A (GAB A- A) receptor, where it acts as a positive allosteric modulator (PAM) of channel function. The structural formula of the compound of Formula (I) appears below.

[0003] Neuroactive steroid GABA-A positive allosteric modulators (PAMs) have demonstrated clinical efficacy in treating several neurological diseases and conditions, including, for example, epilepsy, post-partum depression, and major depression.

[0004] The synthesis of the compound of Formula (I) is described in U.S. Application Publication Nos. 2004/034002 and 2009/0118248; a crystalline form of the compound of Formula (I) free base is described in U.S. Application Publication No. 2006/0074059; pharmaceutical compositions containing the compound of Formula (I) are described in U.S. Application Publication No. 2009/0131383. Crystalline polymorphs of salts of the compound of Formula (I) are described in U.S. Application Publication No. 2020/0071350, and hemicitrate salts of the compound of Formula (I) as well as crystalline forms thereof and processes for preparing such salts and crystalline forms are described in PCT Publication No. WO 2022/178000, all of which are hereby incorporated by reference in their entirety for all purposes. [0005] Current processes for synthesizing the compound of Formula (I) may suffer from low yields and high levels of impurities. These problems may be exacerbated upon process scale- up. Accordingly, there is a need to develop processes that increase the yield of the compound of Formula (I), particularly on an industrially useful scale, and provide the compound of Formula (I) with higher purity levels.

BRIEF SUMMARY

[0006] The present disclosure provides synthetic processes to manufacture 3a-hydroxy-3P- methoxymethyl-21-(r-imidazolyl)-5a-pregnan-20-one (the compound of Formula (I)). Additionally, the present disclosure provides methods of synthesizing salts of the compound of Formula (I). In some embodiments, the salt is a mono-citrate salt of the compound of Formula (I). In some embodiments, the salt is a hemi-citrate salt of the compound of Formula (I). In other embodiments, the salt is a hydrobromide, citrate, malate, maleate, mesylate, phosphate, tartrate, hydrochloride, tosylate, glucuronate, ethanesulfonate, fumarate, sulfate, napthalene-2-sulfonate, ascorbate, oxalate, napthalene-l,5-disulfonate, malonate, aminosalicylate, benzenesulfonate, isethionate, gentisate, l-hydroxy-2-napthoate, dichloroacetate, cyclamate, or ethane- 1 ,2-disulfonate salt of the compound of Formula (I).

[0007] The synthetic methods disclosed herein produce higher yields of the compound of Formula (I) than prior methods and are amenable to scale-up. Moreover, the processes disclosed herein result in the compound of Formula (I), and pharmaceutically acceptable salts thereof (e.g., the mono-citrate salt and the hemi-citrate salt), that have high purity levels.

[0008] In one aspect, provided herein is a method of preparing a compound of Formula (I): comprising reacting a compound of Formula (II): with imidazole in the presence of a phase-transfer catalyst under biphasic conditions to form a compound of Formula (I), wherein X is a leaving group. In certain embodiments, X is a halogen, an alkoxy, an imidate, a sulphonoloxy, an optionally substituted alkylsulfonyl, an optionally substituted alkenylsulfonyl, an optionally substituted arylsulfonyl, or a diazonuum, and in certain embodiments, X is a halogen such as bromine. Biphasic conditions generally require an aqueous layer and an organic layer that are immiscible. As set forth herein, it has been surprisingly discovered that the conversion of the compound of Formula (II) to the compound of Formula (I) under biphasic conditions (e.g., two immiscible liquid phases) results in higher levels of purity of the compound of Formula (I) than are produced when the reaction is carried out in a single phase.

[0009] Accordingly, in certain embodiments, the phase-transfer catalyst is an ammonium salt, such as a tetraalkylammonium salt, or a phosphonium salt, and in certain embodiments, the phase-transfer catalyst is tetrabutylammonium bromide. In certain embodiments, the phasetransfer catalyst is benzyl triethylammonium chloride, benzyl trimethylammonium chloride, benzyl tributylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium acetate, tetrabutylammonium hydroxide, tetraethyl ammonium bromide, tetrabutylammonium hydrogen sulfate, tetramethylammonium iodide, tetramethylammonium chloride, triethylbutyl ammonium bromide, tributylethyl ammonium bromide, tributylmethyl ammonium chloride, 2- chloroethylamine chloride HC1, bis(2-chloroethyl)amine HC1, 2-dimethylaminoethyl chloride HC1, 2-ethylaminoethyl chloride HC1, 3-dimethylaminopropyl chloride HC1, methylamine HC1, dimethylamine HC1, trimethylamine HC1, monoethylamine HC1, diethylamine HC1, triethylamine HC1, ethanolamine HC1, diethanolamine HC1, triethanolamine HC1, cyclohexylamine HC1, dicyclohexylamine HC1, cyclohexylamine HC1, diisopropylethylamine HC1, ethylenediamine HC1, aniline HC1, benzyltributylammonium bromide, dilauryldimethylammonium bromide, tetraethyl ammonium iodide, benzyltriethylammonium iodide, methyltrioctylammonium chloride, carbamylcholine chloride, hexadecyltributylphosphonium bromide, tributyl-n-octylphosphonium bromide, tetraethylphosphonium hexafluorophosphate, tetraethylphosphonium tetrafluoroborate, tributyl(cyanomethyl)phosphonium chloride, tetrakis(hydroxymethyl)phosphonium sulfate, tetraphenylphosphonium bromide, trans-2-butene-l,4-bis(triphenylphosphonium chloride), tributylhexylphosphonium bromide, (2-carboxyethyl)triphenylphosphonium bromide, tetrabutylphosphonium bromide, tetrabutylphosphonium chloride, or any combination thereof. [0010] According to certain embodiments, the reaction is performed using about 0.01 to about 0.2, such as about 0.1, molar equivalents of the phase-transfer catalyst. In certain embodiments, the reaction is performed using about 1 to about 5, such as about 1.2, molar equivalents of imidazole. In certain embodiments, the biphasic conditions comprise an organic solvent and an aqueous component, and in certain embodiments, at least one of the aqueous component or the organic solvent comprises an ionic liquid. In certain embodiments, the organic solvent comprises 1 -butanol, 2-butanol, butyl acetate, cyclohexane, chloroform, dichloroethane, dichloromethane, diethyl ether, diisopropyl ether, ethyl acetate, heptane, hexane, isooctane, methyl ethyl ketone, 2-methyltetrahydrofuran (2-MeTHF), methyl tert-butyl ether, pentane, trichloroethylene, toluene, xylene, or any combination thereof.

[0011] In certain embodiments, the reaction is performed in the presence of a base, such as cesium hydroxide, lithium hydroxide, potassium hydroxide, sodium hydroxide, ammonium hydroxide, or any combination thereof. In cetain embodiments, the reaction is performed using from about 1 to about 1.5, such as about 1.2, molar equivalents of the base. In some embodiments, the reaction is performed at room temperature.

[0012] In certain embodiments of the methods disclosed herein, the method further comprises adding an acid, such as citric acid, to the compound of Formula (I) to form a salt of the compound of Formula (I), such as a mono-citrate salt of the compound of Formula (I) or a hemi-citrate salt of the compound of Formula (I). In certain embodiments, the salt of the compound of Formula (I) is a hydrobromide, citrate, malate, maleate, mesylate, phosphate, tartrate, hydrochloride, tosylate, glucuronate, ethanesulfonate, fumarate, sulfate, napthalene-2- sulfonate, ascorbate, oxalate, nap thalene- 1,5 -disulf onate, malonate, aminosalicylate, benzenesulfonate, isethionate, gentisate, l-hydroxy-2-napthoate, dichloroacetate, cyclamate, or ethane- 1,2-disulf onate salt.

[0013] In some embodiments, the compound of Formula (II) is a compound of Formula (Ila): or a salt thereof.

[0014] The disclosure also provides methods of making a compound of Formula (Ila) by reacting a compound of Formula (III): with a brominating agent, wherein the brominating agent is not elemental bromine (Bn). In some embodiments, the brominating agent is copper (II) bromide, l,3-dibromo-5,5- dimethylhydantoin, N-bromosuccinimide, 4-(Dimethylamino)pyridine tribromide, carbon tetrabromide, phosphorous tribromide, 2,4,4,6-tetrabromocyclohex-2,5-dienone, pyridinium tribromide, or any combination thereof. In some embodiments, the brominating agent is N- bromosuccinimide or l,3-dibromo-5,5-dimethylhydantoin. In some embodiments, the brominating agent is l,3-dibromo-5,5-dimethylhydantoin. In certain embodiments, the reaction is performed using from about 0.5 to about 2.0 molar equivalents of l,3-dibromo-5,5- dimethylhydantoin, such as about 0.6 molar equivalents of l,3-dibromo-5,5- dimethylhydantoin, and in certain embodiments, the reaction is performed in the presence of an acid, such as sulfonic acid.

[0015] The disclosure also provides a method of preparing a compound of Formula (III) by reacting a compound of Formula (IV): with sodium methoxide (NaOMe) and trimethylsulfonium iodide (Me SOI) to obtain the compound of Formula (III). In some embodiments, the reaction is carried out in a single step. [0016] In another aspect, provided herein is a method of preparing a compound of Formula (I) comprising the following steps:

[0017] In some embodiments, the method of preparing the compound of Formula (I) comprises the steps of:

(i) reacting a compound of Formula (IV): with sodium methoxide and Me SOI to obtain a compound of Formula (III):

(ii) reacting the compound of Formula (III) with a brominating agent to obtain a compound of Formula (Ila): wherein the brominating agent is not Br ; (iii) reacting the compound of Formula (Ila) with imidazole under biphasic conditions in the presence of a phase-transfer catalyst to obtain the compound of Formula (I). [0018] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with citric acid to form a compound of Formula (V) (i.e., a mono-citrate salt of the compound of Formula (I)):

[0019] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with citric acid to form a compound of Formula (VI) (i.e., a hemi-citrate salt of the compound of Formula (I)):

[0020] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with hydrobromide to form a hydrobromide salt.

[0021] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with methanesulfonic acid to form a mesylate salt.

[0022] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with tartaric acid (e.g., L(+) -tartaric acid) to form a tartrate salt. [0023] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with fumaric acid to form a fumarate salt.

[0024] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with p-toluenesulfonic acid to form a tosylate salt. [0025] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with glucuronic acid (e.g., D-glucuronic acid) to produce a glucoronate salt.

[0026] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with ethanesulfonic acid to form an ethanesulfonate salt.

[0027] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with sulfuric acid to form a sulfate salt.

[0028] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with ascorbic acid to form a ascorbate salt.

[0029] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with naphthalene- 1,5-disulfonic acid tetrahydrate to form a napthalene-l,5-disulfonate salt.

[0030] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with benzenesulfonic acid to form a benzenesulfonate salt.

[0031] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with 2-hydroxyethanesulphonic acid to form an isethionate salt.

[0032] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with gentisic acid to form a gentisate salt.

[0033] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with l-hydroxy-2-napthoic acid to form a l-hydroxy-2- napthoate salt.

[0034] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with cyclamic acid to form a cyclamate salt.

[0035] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with ethane- 1,2-disulfonic acid to form a ethane- 1,2- disulfonate salt.

[0036] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with dichloroacetic acid to form a dichloroacetate salt.

[0037] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with malic acid (e.g., L-malic acid) to form a malate salt.

[0038] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with hydrochloric acid to form a hydrochloride salt. [0039] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with naphthalene- 1,5 -disulfonic acid hydrate to form a napthalene-l,5-disulfonate salt.

[0040] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with oxalic acid to form an oxalate salt.

[0041] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with 4-aminosalicylic acid to form an aminosalicylate salt.

[0042] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with maleic acid to form a maleate salt.

[0043] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with phosphoric acid to form a phosphate salt.

[0044] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with napthalene-2-sulfonic acid to form a napthalene-2- sulfonate salt.

[0045] In some embodiments, the compound of Formula (I) produced by the methods described herein can be reacted with malonic acid to form a malonate salt.

[0046] In certain embodiments, disclosed herein is a method of preparing a compound of Formula (VI): comprising:

(i) reacting a compound of Formula (IV): with sodium methoxide and trimethylsulfonium iodide (Me SOI) to obtain a compound of Formula (III):

(ii) reacting the compound of Formula (III) with a brominating agent to obtain a compound of Formula (Ila): wherein the brominating agent is not Br ;

(iii) reacting the compound of Formula (Ila) with imidazole in the presence of a phase-transfer catalyst to obtain a compound of Formula (I):

(I); and

(iv) reacting the compound of Formula (I) with citric acid to obtain the compound of Formula (VI).

[0047] In another aspect, provided herein is a composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)), wherein the composition is substantially free of a compound of Formula (VII):

(VII), or a salt thereof. The compound of Formula (VII) is also referred to as the C17-epimer of the compound of Formula (I). In some embodiments, the composition has less than about 2% by weight of the compound of Formula (VII), or a salt thereof. In some embodiments, the composition has less than about 1% by weight of the compound of Formula (VII), or a salt thereof. In certain embodiments, the percentage of a compound, such as a compound of Formula (VII), present in a composition can be monitored when measuring the chemical purity of the composition, e.g., by HPLC and as disclosed herein.

[0048] In another aspect, provided herein is a composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)), wherein the composition is substantially free of a compound of Formula (VIII): or a salt thereof. In some embodiments, the composition has less than about 0.15% of the compound of Formula (VIII), or a salt thereof.

[0049] In another aspect, provided herein is a composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)), wherein the composition is substantially free of a compound of Formula (IX):

(IX), or a salt thereof. In some embodiments, the composition has less than about 0.15% of the compound of Formula (IX), or a salt thereof.

[0050] In another aspect, provided herein is a composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)), wherein the composition is substantially free of a compound of Formula (X):

(X), or a salt thereof. In some embodiments, the composition has less than 1,000 parts per million (ppm) of the compound of Formula (X), or a salt thereof.

[0051] In another aspect, provided herein is a composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)), wherein the composition is substantially free of a compound of Formula (XI):

(XI), or a salt thereof. In some embodiments, the composition has less than 1,000 parts per million (ppm) of the compound of Formula (XI), or a salt thereof. DETAILED DESCRIPTION

I. Definitions

[0052] Unless defined otherwise, all terms of art, notations, and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art.

[0053] Throughout this disclosure, various aspects of the claimed subject matter are presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the claimed subject matter. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For instance, 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 dictate 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, 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. In some embodiments, two opposing and open ended ranges are provided for a feature, and in such description it is envisioned that combinations of those two ranges are provided herein. For example, in some embodiments, it is described that a feature is greater than about 10 units, and it is described (such as in another sentence) that the feature is less than about 20 units, and thus, the range of about 10 units to about 20 units is described herein.

[0054] The term “about” when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value). For example, “about 50” can mean 45 to 55, “about 25,000” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise or is inconsistent with such an interpretation. For example, in a list of numerical values such as “about 49, about 50, about 55, ...”, “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 52.5. Furthermore, the phrases “less than about” a value or “greater than about” a value should be understood in view of the definition of the term “about” provided herein. Similarly, the term “about” when preceding a series of numerical values or a range of values (e.g., “about 10, 20, 30” or “about 10-30”) refers, respectively to all values in the series, or the endpoints of the range.

[0055] The terms “effective amount” and “therapeutically effective amount” are used interchangeably in this disclosure and refer to an amount of a compound, or a salt, solvate or ester thereof, that, when administered to a patient, is capable of performing the intended result. For example, an effective amount of a salt of the compound of Formula (I) is that amount that is required to reduce at least one symptom of a disease or condition, such as depression, in a patient. The actual amount that comprises the “effective amount” or “therapeutically effective amount” will vary depending on a number of conditions including, but not limited to, the severity of the disorder, the size and health of the patient, and the route of administration. A skilled medical practitioner can readily determine the appropriate amount using methods known in the medical arts.

[0056] The terms “hemi-citrate salt of the compound of Formula (I)” and “the compound of Formula VI” are used herein interchangeably and refer to a compound having a molar ratio of the compound of Formula (I) to citrate of about 2: 1 and the formula

[0057] The term “isomer” refers to compounds having the same chemical formula but having different stereochemical formula, structural formula, or special arrangements of atoms. Examples of isomers include stereoisomers, diastereomers, enantiomers, conformational isomers, rotamers, geometric isomers, and atropisomers.

[0058] The terms “mono-citrate salt of the compound of Formula (I)” and “the compound of Formula V” are used herein interchangeably and refer to a compound having a molar ratio of the compound of Formula (I) to citrate of about 1 : 1 and the formula

[0059] The phrase “pharmaceutically acceptable” as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0060] The term “ppm” as used herein means “parts per million.” As used to refer to the compound of Formula (X) or the compound of Formula (XI), ppm means parts per million of one of these compounds in a particular sample.

[0061] The term “protic solvent” as used herein refers to a solvent or a solvent mixture that is capable of functioning as an acid for purposes of protonating any unreacted, strongly basic reaction intermediates. Non-limiting examples of protic solvents include water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1 -propanol, 2- propanol, 2-methoxy ethanol, 1 -butanol, 2-butanol, z-butyl alcohol, /-butyl alcohol, 2- ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, /-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, and the like.

[0062] The term “salts” as used herein embraces pharmaceutically acceptable salts commonly used to form addition salts of free bases. The nature of the salt is not critical provided that it is pharmaceutically acceptable. The term “salts” also includes solvates of addition salts, such as hydrates, as well as polymorphs of addition salts. Suitable pharmaceutically acceptable acid addition salts can be prepared from an inorganic acid or from an organic acid. In a salt, proton transfer occurs between the compound of Formula (I) free base and an organic acid or an inorganic acid. However, in some cases proton transfer is incomplete. In such cases, the compound of Formula (I) and the “co-former” molecules in the solid (i.e., “co-crystal”) interact through non-ionic forces such as hydrogen bonding.

[0063] Where an acid co-former is a solid at about 23 °C (i.e., room temperature) and there is no, or partial, proton transfer between the compound of Formula (I) and the acid co-former, a co-crystal of the co-former and the compound of Formula (I) is provided. As used herein, the term “salt” encompasses co-crystal forms of the compound of Formula (I).

[0064] As used herein, the term “in some embodiments,” “in other embodiments,” or the like, refers to embodiments of all aspects of the disclosure, unless the context clearly indicates otherwise.

[0065] The term “substantially similar” as used herein means an analytical spectrum, such as XRPD pattern, DSC thermogram, etc., which resembles the reference spectrum to a great degree. For example, one skilled in the art would be able to identify two XRPD patterns that are substantially similar by evaluating and comparing the overall patterns in both the peak locations and their intensity.

[0066] The term “treating” as used herein with regard to a patient, refers to improving at least one symptom of the patient’s disorder. Treating can be improving, or at least partially ameliorating a disorder.

[0067] The term “therapeutic effect” as used herein refers to a desired or beneficial effect provided by the method and/or the composition. For example, the method for treating depression provides a therapeutic effect when the method reduces at least one symptom of depression in a patient.

II. Synthetic Methods

Conversion of a Compound of Formula (II) to a Compound of Formula (I)

[0068] Prior methods of converting the compound of Formula (II) to the compound of Formula (I) involved nucleophilic reactions of the compound of Formula (II) (e.g., the compound of Formula (Ila)) with imidazole to produce the compound of Formula (I). This reaction has been shown to produce a dimer product, the compound of Formula (VIII), depicted below.

[0069] Efforts to control formation of the dimer (i.e., the compound of Formula (VIII)) through varying reaction conditions and amounts of reactants proved to be problematic. In general, even under optimized conditions using prior synthetic methods, the ratio of the compound of Formula (I) to the compound of Formula (VIII) following reaction was typically greater than about 9:1 but, for example, less than about 15:1. The compound of Formula (VIII) is difficult to remove from the final product upon purification.

[0070] Additionally, prior methods of converting the compound of Formula (Ila) to the compound of Formula (I) resulted in the production of other impurities that may be difficult to remove following product purification. For instance, using prior methods, the compound of Formula (IX), depicted below, consistently forms and is present in the final isolated product.

[0071] In accordance with the disclosure, it has now been discovered that converting the compound of Formula (II) (e.g., the compound of Formula (Ila)) to the compound of Formula (I) under biphasic conditions (e.g., two immiscible liquid phases) in the presence of a phase transfer catalyst produces the compound of Formula (I) in high yields with low levels of impurities. It has been surprisingly found that under the biphasic conditions disclosed herein, impurities, such as the compound of Formula (VIII), are removed as the reaction progresses. Moreover, the formation of the compound of Formula (IX) is minimized. Accordingly, these impurities are not present or are present at a minimal extent or in relatively small quantities in the isolated compound of Formula (I). Moreover, these impurities are not present in the purified salt forms of the compound of Formula (I) (e.g., hemi-citrate salt or mono-citrate salt) intended for administrations to patients in need thereof.

[0072] In one aspect, provided herein is a method of preparing a compound of Formula (I): comprising reacting a compound of Formula (II): with imidazole under biphasic conditions in the presence of a phase-transfer catalyst. In the compound of Formula (II), X is a suitable leaving group. In certain embodiments, X is a leaving group selected from a halogen, an alkoxy, an imidate, a sulphonoloxy, an optionally substituted alkylsulfonyl, an optionally substituted alkenylsulfonyl, an optionally substituted arylsulfonyl, and a diazonuum. In some embodiments, the leaving group X in the compound of Formula (II) is a halogen. In some embodiments, X is bromine.

[0073] In some embodiments, the compound of Formula (II) is a compound of Formula (Ila).

[0074] In some embodiments, the compound of Formula (II) is a compound of Formula (lib).

[0075] In some embodiments, the leaving group X in the compound of Formula (II) is an an optionally substituted alkylsulfonyl. In some embodiments, the compound of Formula (II) is a compound of Formula (lie). (lie), wherein Ts is a toluenesulfonyl (tosyl) group.

[0076] As used herein, the term “phase-transfer catalyst” refers to a catalyst that facilitates the migration of a reactant from one phase into another phase where reaction occurs. Any known phase-transfer catalyst may be used in the methods disclosed herein. In some embodiments, the phase-transfer catalyst is an ammonium salt. In some embodiments, the phase- transfer catalyst is a phosphonium salt. In some embodiments, the phase-transfer catalyst is a tetraalkylammonium salt. In some embodiments, the phase-transfer catalyst is selected from benzyl triethylammonium chloride, benzyl trimethylammonium chloride, benzyl tributylammonium chloride, tetrabutylammonium bromide (TBAB), tetrabutylammonium fluoride, tetrabutylammonium chloride (TBAC), tetrabutylammonium acetate, tetrabutylammonium hydroxide, tetraethyl ammonium bromide, tetrabutylammonium hydrogen sulfate, tetramethylammonium iodide, tetramethylammonium chloride, triethylbutyl ammonium bromide, tributylethyl ammonium bromide, tributylmethyl ammonium chloride, 2- chloroethylamine chloride HC1, bis(2-chloroethyl)amine HC1, 2-dimethylaminoethyl chloride HC1, 2-ethylaminoethyl chloride HC1, 3-dimethylaminopropyl chloride HC1, methylamine HC1, dimethylamine HC1, trimethylamine HC1, monoethylamine HC1, diethylamine HC1, triethylamine HC1, ethanolamine HC1, diethanolamine HC1, triethanolamine HC1, cyclohexylamine HC1, dicyclohexylamine HC1, cyclohexylamine HC1, diisopropylethylamine HC1, ethylenediamine HC1, aniline HC1, benzyltributylammonium bromide, dilauryldimethylammonium bromide, tetraethyl ammonium iodide, benzyltriethylammonium iodide, methyltrioctylammonium chloride, carbamylcholine chloride, hexadecyltributylphosphonium bromide, tributyl-n-octylphosphonium bromide, tetraethylphosphonium hexafluorophosphate, tetraethylphosphonium tetrafluoroborate, tributyl(cyanomethyl)phosphonium chloride, tetrakis(hydroxymethyl)phosphonium sulfate, tetraphenylphosphonium bromide, trans-2-butene-l,4-bis(triphenylphosphonium chloride), tributylhexylphosphonium bromide, (2-carboxyethyl)triphenylphosphonium bromide, tetrabutylphosphonium bromide, or tetrabutylphosphonium chloride. In some embodiments, the phase-transfer catalyst is TBAB. In some embodiments, the phase-transfer catalyst is TBAC.

[0077] In some embodiments, the reaction is performed using from about 0.01 to about 0.20 molar equivalents of the phase-transfer catalyst per one molar equivalent of the compound of Formula (II). In some embodiments, the reaction is performed using from about 0.05 to about 0.15 molar equivalents of the phase-transfer catalyst per one molar equivalent of the compound of Formula (II). In some embodiments, the reaction is performed using about 0.01 molar equivalents per one molar equivalent of Formula (II). In some embodiments, the reaction is performed using about 0.05 molar equivalents per one molar equivalent of Formula (II). In some embodiments, the reaction is performed using about 0.10 molar equivalents of the phasetransfer catalyst per one molar equivalent of Formula (II). In some embodiments, the reaction is performed using about 0.15 molar equivalents per one molar equivalent of Formula (II). In some embodiments, the reaction is performed using about 0.20 molar equivalents per one molar equivalent of Formula (II).

[0078] In some embodiments, the reaction is performed using from about 1.0 to about 5.0 molar equivalents of imidazole per one molar equivalent of the compound of Formula (II). In some embodiments, the reaction is performed using from about 1.0 to about 3.0 molar equivalents of imidazole per one molar equivalent of the compound of Formula (II). In some embodiments, the reaction is performed using from about 1.0 to about 1.5 molar equivalents of imidazole per one molar equivalent of the compound of Formula (II). In some embodiments, the reaction is performed using from about 1.0 to about 1.2 molar equivalents of imidazole per one molar equivalent of the compound of Formula (II). In some embodiments, the reaction is performed using about 1.0 molar equivalent of imidazole per one molar equivalent of the compound of Formula (II). In some embodiments, the reaction is performed using about 1.2 molar equivalents of imidazole per one molar equivalent of the compound of Formula (II). In some embodiments, the reaction is performed using about 1.5 molar equivalents of imidazole per one molar equivalent of the compound of Formula (II). In some embodiments, the reaction is performed using about 2.0 molar equivalents of imidazole per one molar equivalent of the compound of Formula (II). In some embodiments, the reaction is performed using about 3.0 molar equivalents of imidazole per one molar equivalent of the compound of Formula (II). In some embodiments, the reaction is performed using about 4.0 molar equivalents of imidazole per one molar equivalent of the compound of Formula (II). In some embodiments, the reaction is performed using about 5.0 molar equivalents of imidazole per one molar equivalent of the compound of Formula (II). [0079] The reactions are performed using a biphasic system, wherein the biphasic system comprises an aqueous component and an organic solvent. In some embodiments, the aqueous component is water. In some embodiments, the aqueous component contains dissolved inorganics. In some embodiments, the aqueous component contains sodium chloride. In some embodiments, the aqueous component contains about 0-20% sodium chloride. In some embodiments, the organic solvent is butanol, butyl acetate, cyclohexane, chloroform, dichloroethane, dichloromethane, diethyl ether, diisopropyl ether, ethyl acetate, heptane, hexane, isooctane, methyl ethyl ketone, 2-methyltetrahydrofuran (2-MeTHF), methyl tert-butyl ether, pentane, trichloroethylene, toluene, or xylene. In some embodiments, the organic solvent is toluene or 2-MeTHF. In some embodiments, the organic solvent is 2-MeTHF. In some embodiments, at least one of the aqueous component or the organic solvent is an ionic liquid. In some embodiments, both the aqueous component and the organic solvent are ionic liquids. As used herein, the term “ionic liquid” refers to a salt in the liquid state and usually refers to compounds composed largely of ions with a melting point below a designated temperature, such as, for example, a melting point below about 100 °C. Ionic liquids may also be referred to in the art as, for example, liquid electrolytes, ionic fluids, or liquid salts.

[0080] In some embodiments, the reaction is performed in the presence of a base. In some embodiments, the base is an inorganic base. In some embodiments, the base is selected from cesium hydroxide, lithium hydroxide, potassium hydroxide, sodium hydroxide, or ammonium hydroxide. In some embodiments, the base comprises sodium hydroxide. In some embodiments, the reaction is performed using from about 1.0 to about 1.5 molar equivalents of the base per one molar equivalent of Formula (II). In some embodiments, the reaction is performed using from about 1.2 to about 1.4 molar equivalents of the base per one molar equivalent of Formula (II). In some embodiments, the reaction is performed using from about 1.1 to about 1.3 molar equivalents of the base per one molar equivalent of Formula (II). In some embodiments, the reaction is performed using about 1.0 molar equivalent of the base per one molar equivalent of Formula (II). In some embodiments, the reaction is performed using about 1.1 molar equivalents of the base per one molar equivalent of Formula (II). In some embodiments, the reaction is performed using about 1.2 molar equivalents of the base per one molar equivalent of Formula (II). In some embodiments, the reaction is performed using about 1.3 molar equivalents of the base per one molar equivalent of Formula (II). In some embodiments, the reaction is performed using about 1.4 molar equivalents of the base per one molar equivalent of Formula (II). In some embodiments, the reaction is performed using about 1.5 molar equivalents of the base per one molar equivalent of Formula (II). [0081] In some embodiments, the reaction is performed at a temperature of about 0 °C to about 50 °C. In some embodiments, the reaction is performed at a temperature of about 0 °C to about 40 °C. In some embodiments, the reaction is performed at a temperature of about 0 °C to about 30 °C. In some embodiments, the reaction is performed at a temperature of about 0 °C to about 20 °C. In some embodiments, the reaction is performed at a temperature of about 20 °C to about 50 °C. In some embodiments, the reaction is performed at a temperature of about 20 °C to about 40 °C. In some embodiments, the reaction is performed at a temperature of about 20 °C to about 35 °C. In some embodiments, the reaction is performed at room temperature.

[0082] In some embodiments, the reaction time is from about 1 hour to about 20 hours. In some embodiments, the reaction time is from about 1 hour to about 10 hours. In some embodiments, the reaction time is from about 3 hours to about 7 hours.

[0083] In some embodiments, after the biphasic reaction is performed, the reaction mixture is purified. In some embodiments, the purification comprises the steps of:

(i) separating the organic solvent from the aqueous component of the reaction mixture;

(ii) washing the organic solvent with a pH buffer (e.g., a solution of NaH2PO4); and

(iii) washing the organic solvent with an aqueous solution (e.g., a solution of NaCl). [0084] In some embodiments, the reaction produces the compound of Formula (I) at a yield of greater than about 80%. In other embodiments, the reaction produces the compound of Formula (I) at a yield of greater than about 90%. In other embodiments, the reaction produces the compound of Formula (I) at a yield of greater than about 95%. In other embodiments, the reaction produces the compound of Formula (I) at a yield of greater than about 98%. In some embodiments, the reaction produces the compound of Formula (I) at a yield of from about 80% to about 98%. In other embodiments, the reaction produces the compound of Formula (I) at a yield of from about 85% to about 95%. In other embodiments, the reaction produces the compound of Formula (I) at a yield of from about 90% to about 95%.

[0085] In another aspect, provided herein is a method of preparing a salt of the compound of Formula (I), comprising adding an acid to a solution of the compound of Formula (I) in an organic solvent. Any acid suitable for forming a salt of the compound of Formula (I) may be used. In some embodiments, the acid is selected from acetic acid, citric acid, maleic acid, succinic acid, ascorbic acid, hydrobromic acid, sulfuric acid, or phosphoric acid. In some embodiments, the acid is citric acid. [0086] In some embodiments, the salt of the compound of Formula (I) is isolated via crystallization. In some embodiments, the crystallization is performed in the presence of an antisolvent. In some embodiments, the antisolvent is methyl tert-butyl ether.

[0087] In some embodiments, the salt of the compound of Formula (I) is a compound of Formula (V):

(V).

The compound of Formula (V) is also known as the mono-citrate salt of the compound of Formula (I), and it has a molar ratio of the compound of Formula (I) to citrate of about 1:1. The compound of Formula (V) can be prepared from the compound of Formula (I) as described in, for example, U.S. Application Publication No. 2020/0071350.

[0088] In another aspect, provided herein is a composition comprising the compound of Formula (V), wherein the compound of Formula (V) is produced using the methods described herein.

[0089] In some embodiments, the salt of the compound of Formula (I) is a compound of Formula (VI):

The compound of Formula (VI) is also known as the hemi-citrate salt of the compound of Formula (I), and it has a molar ratio of the compound of Formula (I) to citrate of about 2:1. The compound of Formula (VI) can be prepared from the compound of Formula (I) as described herein. [0090] In another aspect, provided herein is a composition comprising the compound of Formula (VI), wherein the compound of Formula (VI) is produced using the methods described herein.

[0091] In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VIII) or a salt thereof of more than about 15:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VIII) or a salt thereof of more than about 20:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VIII) or a salt thereof of more than about 30:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VIII) or a salt thereof of more than about 50:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VIII) or a salt thereof of more than about 100:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VIII) or a salt thereof of more than about 500:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VIII) or a salt thereof of more than about 1,000:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VIII) or a salt thereof of more than about 2,500:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VIII) or a salt thereof of more than about 5,000:1.

[0092] In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VIII) or a salt thereof of from about 15:1 to about 5,000:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VIII) or a salt thereof of from about 20: 1 to about 2,500:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VIII) or a salt thereof of from about 20: 1 to about 1,000:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VIII) or a salt thereof from about 20:1 to about 500:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (V) or a salt thereof of from about 50:1 to about 500:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VIII) or a salt thereof of from about 50:1 to about 100:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce the compound of Formula (I) or a pharmaceutically acceptable salt thereof that is substantially free of the compound of Formula (VIII) or a salt thereof.

[0093] In all embodiments set forth in the preceding paragraph, the compound of Formula (I) produced in accordance with the disclosure can be isolated or further reacted to form a salt (e.g., a compound of Formula (V) or a compound of Formula (VI)). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup is substantially free of the compound of Formula (VIII). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 2% of the compound of Formula (VIII). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 1.5% of the compound of Formula (VIII). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 1% of the compound of Formula (VIII). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 0.5% of the compound of Formula (VIII). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 0.25% of the compound of Formula (VIII). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 0.1% of the compound of Formula (VIII). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 0.05% of the compound of Formula (VIII). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 0.01% of the compound of Formula (VIII). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 0.005% of the compound of Formula (VIII). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 0.0005% of the compound of Formula (VIII). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes from about 0.0005% to about 2% of the compound of Formula (VIII). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes from about 0.005% to about 2% of the compound of Formula (VIII). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes from about 0.05% to about 2% of the compound of Formula (VIII). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes from about 0.05% to about 1% of the compound of Formula (VIII). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes from about 0.5% to about 2% of the compound of Formula (VIII). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes from about 0.5% to about 1% of the compound of Formula (VIII). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes from about 0.1% to about 0.5% of the compound of Formula (VIII). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes from about 0.1% to about 1% of the compound of Formula (VIII). In certain embodiments, the percentage of a compound, such as a compound of Formula (VIII), can be measured when measuring the chemical purity of a compound of Formula I.

[0094] The disclosure also provides pharmaceutical compositions (e.g., compositions for oral administration) comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof that is substantially free of or comprises a minimal amount of the compound of Formula (VIII) or a salt thereof. In some embodiments, the pharmaceutical composition comprises less than about 0.15% by weight of the compound of Formula (VIII) or a salt thereof. In some embodiments, the pharmaceutical composition comprises less than about 0.12% by weight of the compound of Formula (VIII) or a salt thereof. In some embodiments, the pharmaceutical composition comprises less than about 0.10% by weight of the compound of Formula (VIII) or a salt thereof. In some embodiments, the pharmaceutical composition comprises less than about 0.08% by weight of the compound of Formula (VIII) or a salt thereof. In some embodiments, the pharmaceutical composition comprises less than about 0.05% by weight of the compound of Formula (VIII) or a salt thereof. In some embodiments, the pharmaceutical composition comprises less than about 0.01% by weight of the compound of Formula (VIII) or a salt thereof. In some embodiments, the pharmaceutical composition less than about 0.005% by weight of the compound of Formula (VIII) or a salt thereof. In some embodiments, the pharmaceutical composition less than about 0.0005% by weight of the compound of Formula (VIII) or a salt thereof. In some embodiments, the pharmaceutical composition comprises from about 0.0005% to about 0.15% by weight of the compound of Formula (VIII) or a salt thereof. In some embodiments, the pharmaceutical composition comprises from about 0.005% to about 0.15% by weight of the compound of Formula (VIII) or a salt thereof. In some embodiments, the pharmaceutical composition comprises from about 0.005% to about 0.10% by weight of the compound of Formula (VIII) or a salt thereof. In some embodiments, the pharmaceutical composition comprises from about 0.005% to about 0.10% by weight of the compound of Formula (VIII) or a salt thereof. In some embodiments, the pharmaceutical composition comprises from about 0.005% to about 0.05% by weight of the compound of Formula (VIII) or a salt thereof. In some embodiments, the pharmaceutical composition is substantially free of the compound of Formula (VIII) or a salt thereof. In some of the foregoing embodiments, the pharmaceutical composition comprises a mono-citrate salt of the compound of Formula (I) (i.e., the compound of Formula (V)). In some of the foregoing embodiments, the pharmaceutical composition comprises a hemi-citrate salt of the compound of Formula (I) (i.e., the compound of Formula (VI)).

[0095] In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a salt thereof to the compound of Formula (IX) or a salt thereof of more than about 15:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (IX) or a salt thereof of more than about 20:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (IX) or a salt thereof of more than about 30:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (IX) or a salt thereof of more than about 50:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a salt thereof to the compound of Formula (IX) or a salt thereof of more than about 100:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a salt thereof to the compound of Formula (IX) or a salt thereof of more than about 500:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a salt thereof to the compound of Formula (IX) or a salt thereof of more than about 1,000:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a salt thereof to the compound of Formula (IX) or a salt thereof of more than about 2,500:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (IX) or a salt thereof of more than about 5,000:1.

[0096] In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (IX) or a salt thereof of from about 15:1 to about 5,000:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (IX) or a pharmaceutically acceptable salt thereof of from about 20:1 to about 2,500. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (IX) or a salt thereof of from about 20:1 to about 1,000:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (IX) or a salt thereof of from about 20:1 to about 500:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (IX) or a salt thereof of from about 50:1 to about 500:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (IX) or a salt thereof of from about 50:1 to about 100:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce the compound of Formula (I) or a pharmaceutically acceptable salt thereof that is substantially free of the compound of Formula (IX) or a salt thereof.

[0097] In all embodiments set forth in the preceding paragraphs, the compound of Formula (I) produced in accordance with the disclosure can be isolated or further reacted to form a salt (e.g., a compound of Formula (V) or a compound of Formula (VI)). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup is substantially free of the compound of Formula (IX). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 2% of the compound of Formula (IX). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 1.5% of the compound of Formula (IX). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 1% of the compound of Formula (IX). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 0.5% of the compound of Formula (IX). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 0.25% of the compound of Formula (IX). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 0.1% of the compound of Formula (IX). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 0.05% of the compound of Formula (IX). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 0.01% of the compound of Formula (IX). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 0.005% of the compound of Formula (IX). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 0.0005% of the compound of Formula (IX). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes from about 0.0005% to about 2% of the compound of Formula (IX). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes from about 0.005% to about 2% of the compound of Formula (IX). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes from about 0.05% to about 2% of the compound of Formula (IX). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes from about 0.05% to about 1% of the compound of Formula (IX). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes from about 0.5% to about 2% of the compound of Formula (IX). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes from about 0.5% to about 1% of the compound of Formula (IX). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes from about 0.1% to about 0.5% of the compound of Formula (IX). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes from about 0.1% to about 1 % of the compound of Formula (IX). In certain embodiments, the percentage of a compound, such as a compound of Formula (IX), can be measured when measuring the chemical purity of a compound of Formula I.

[0098] The disclosure also provides pharmaceutical compositions (e.g., compositions for oral administration) comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof that is substantially free of or comprises a minimal amount of the compound of Formula (IX) or a salt thereof. In some embodiments, the pharmaceutical composition comprises less than about 0.15% by weight of the compound of Formula (IX) or a salt thereof. In some embodiments, the pharmaceutical composition comprises less than about 0.12% by weight of the compound of Formula (IX) or a salt thereof. In some embodiments, the pharmaceutical composition comprises less than about 0.10% by weight of the compound of Formula (IX) or a salt thereof. In some embodiments, the pharmaceutical composition comprises less than about 0.08% by weight of the compound of Formula (IX) or a salt thereof. In some embodiments, the pharmaceutical composition comprises less than about 0.05% by weight of the compound of Formula (IX) or a salt thereof. In some embodiments, the pharmaceutical composition comprises less than about 0.01% by weight of the compound of Formula (IX) or a salt thereof. In some embodiments, the pharmaceutical composition less than about 0.005% by weight of the compound of Formula (IX) or a salt thereof. In some embodiments, the pharmaceutical composition less than about 0.0005% by weight of the compound of Formula (IX) or a salt thereof. In some embodiments, the pharmaceutical composition comprises from about 0.0005% to about 0.15% by weight of the compound of Formula (IX) or a salt thereof. In some embodiments, the pharmaceutical composition comprises from about 0.005% to about 0.15% by weight of the compound of Formula (IX) or a salt thereof. In some embodiments, the pharmaceutical composition comprises from about 0.005% to about 0.10% by weight of the compound of Formula (IX) or a salt thereof. In some embodiments, the pharmaceutical composition comprises from about 0.005% to about 0.10% by weight of the compound of Formula (IX) or a salt thereof. In some embodiments, the pharmaceutical composition comprises from about 0.05% to about 0.10% by weight of the compound of Formula (IX) or a salt thereof. In some embodiments, the pharmaceutical composition comprises from about 0.005% to about 0.05% by weight of the compound of Formula (IX) or a salt thereof. In some embodiments, the pharmaceutical composition is substantially free of the compound of Formula (IX) or a salt thereof. In some of the foregoing embodiments, the pharmaceutical composition comprises a mono-citrate salt of the compound of Formula (I) (i.e., the compound of Formula (V)). In some of the foregoing embodiments, the pharmaceutical composition comprises a hemi-citrate salt of the compound of Formula (I) (i.e., the compound of Formula (VI)).

[0099] In another embodiment, the biphasic reactions performed in accordance with the discosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VIII) or a salt thereof and a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (IX) or a salt thereof according to any of the preceding embodiments set forth above.

[0100] In other embodiments, the biphasic reactions performed in accordance with the disclosure provide a compound of Formula (I) that is substantially free of or includes a minimal amount of the compound of Formula (VIII) or a salt thereof and that is substantially free of or includes a minimal amount of the compound of Formula (IX) or a salt thereof. In some embodiments, the amounts of the compound of Formula (VIII) or a salt thereof and the compound of Formula (IX) are as set forth in the embodiments above.

[0101] In other embodiments, the disclosure provides pharmaceutical compositions (e.g., compositions for oral administration) comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof that is substantially free of or comprises a minimal amount of the compound of Formula (VIII) or a salt thereof and that is substantially free of or comprises a minimal amount of the compound of Formula (IX) or a salt thereof. In some embodiments, the amounts of the compound of Formula (VIII) or a salt thereof and the compound of Formula (IX) in the pharmaceutical compositions are as set forth in the embodiments above.

[0102] In another aspect, provided herein is a composition comprising the compound of Formula (I), wherein the composition is substantially free of a compound of Formula (VII): or a salt thereof. It has been found that formation of the compound of Formula (VII) (also referred to as the “C17-epimer”) can be minimized by controlling the amount of base present in the biphasic reaction. For instance, using about 1.2 molar equivalents of sodium hydroxide minimizes the production of the compound of Formula (VII). [0103] In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VII) or a salt thereof of more than about 15:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VII) or a salt thereof of more than about 20:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VII) or a salt thereof of more than about 30:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VII) or a salt thereof of more than about 50:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VII) or a salt thereof of more than about 100:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VII) or a salt thereof of more than about 500:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VII) or a salt thereof of more than about 1,000:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VII) or a salt thereof of more than about 2,500:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VII) or a salt thereof of more than about 5,000:1.

[0104] In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VII) or a salt thereof of from about 15:1 to about 5,000:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VII) or a salt thereof of from about 20: 1 to about 2,500:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VII) or a salt thereof of from about 20: 1 to about 1,000:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VII) or a salt thereof of from about 30: 1 to about 1,000:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VII) or a salt thereof of from about 20: 1 to about 500:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VII) or a salt thereof of from about 20: 1 to about 100:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VII) or a salt thereof of from about 50: 1 to about 500:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VII) or a salt thereof of from about 50: 1 to about 200:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VII) or a salt thereof of from about 50: 1 to about 100:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce a ratio of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the compound of Formula (VII) or a salt thereof of from about 100:1 to about 200:1. In some embodiments, the biphasic reactions performed in accordance with the disclosure produce the compound of Formula (I) or a pharmaceutically acceptable salt thereof that is substantially free of the compound of Formula (VII) or a salt thereof.

[0105] In all embodiments set forth in the preceding paragraphs, the compound of Formula (I) produced in accordance with the disclosure can be isolated or further reacted to form a salt (e.g., a compound of Formula (V) or a compound of Formula (VI)). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup is substantially free of the compound of Formula (VII). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 2% of the compound of Formula (VII). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 1.5% of the compound of Formula (VII). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula

(VI)) following reaction and workup includes less than about 1% of the compound of Formula

(VII). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 0.5% of the compound of Formula (VII). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 0.25% of the compound of Formula (VII). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 0.1% of the compound of Formula (VII). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 0.05% of the compound of Formula (VII). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula

(VI)) following reaction and workup includes less than about 0.01% of the compound of Formula (VII). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 0.005% of the compound of Formula (VII). In other embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes less than about 0.0005% of the compound of Formula (VII). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes from about 0.0005% to about 2% of the compound of Formula (VII). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes from about 0.005% to about 2% of the compound of Formula

(VII). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes from about 0.05% to about 2% of the compound of Formula (VII). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes from about 0.05% to about 1% of the compound of Formula (VII). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes from about 0.5% to about 2% of the compound of Formula (VII). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes from about 0.5% to about 1% of the compound of Formula (VII). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes from about 0.1% to about 0.5% of the compound of Formula (VII). In certain embodiments, the isolated compound of Formula (I) or salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)) following reaction and workup includes from about 0.1% to about 1% of the compound of Formula (VII). In certain embodiments, the percentage of a compound, such as a compound of Formula (VII), can be measured when measuring the chemical purity of a compound of Formula I.

[0106] The disclosure also provides pharmaceutical compositions (e.g., compositions for oral administration) comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof that is substantially free of or comprises a minimal amount of the compound of Formula (VII) or a salt thereof. In some embodiments, the composition comprises less than about 2% by weight of the compound of Formula (VII) or a salt thereof. In some embodiments, the composition comprises less than about 1.5% by weight of the compound of Formula (VII) or a salt thereof. In some embodiments, the composition comprises less than about 1.0% by weight of the compound of Formula (VII) or a salt thereof. In some embodiments, the composition comprises less than about 0.5% by weight of the compound of Formula (VII). In some embodiments, the composition comprises less than about 0.45%, less than about 0.4%, less than about 0.35%, less than about 0.3%, less than about 0.25%, less than about 0.2, or less than about 0.15% by weight of the compound of Formula (VII). In some embodiments, the composition comprises less than about 0.10% by weight of the compound of Formula (VII) or a salt thereof. In some embodiments, the composition comprises less than about 0.08% by weight of the compound of Formula (VII) or a salt thereof. In some embodiments, the composition comprises less than about 0.06% by weight of the compound of Formula (VII) or a salt thereof. In some embodiments, the composition comprises less than about 0.04% by weight of the compound of Formula (VII) or a salt thereof. In some embodiments, the composition comprises less than about 0.02% by weight of the compound of Formula (VII) or a salt thereof. In some embodiments, the composition comprises less than about 0.01% by weight of the compound of Formula (VII) or a salt thereof. In some embodiments, the composition comprises less than about 0.005% by weight of the compound of Formula (VII) or a salt thereof. In some embodiments, the composition comprises less than about 0.0005% by weight of the compound of Formula (VII) or a salt thereof. In some embodiments, the composition comprises from about 0.0005% to about 2% by weight of the compound of Formula (VII) or a salt thereof. In some embodiments, the composition comprises from about 0.005% to about 2% by weight of the compound of Formula (VII) or a salt thereof. In some embodiments, the composition comprises from about 0.05% to about 2% by weight of the compound of Formula (VII) or a salt thereof. In some embodiments, the composition comprises from about 0.5% to about 2% by weight of the compound of Formula (VII) or a salt thereof. In some embodiments, the composition comprises from about 0.5% to about 1.5% by weight of the compound of Formula (VII) or a salt thereof. In some embodiments, the composition comprises from about 0.5% to about 1.0% by weight of the compound of Formula (VII) or a salt thereof. In some embodiments, the composition comprises from about 0.1% to about 0.5% by weight of the compound of Formula (VII) or a salt thereof. In some embodiments, the composition comprises from about 1% to about 2% by weight of the compound of Formula (VII) or a salt thereof. In some embodiments, the composition is substantially free of a compound of Formula (VII) or a salt thereof. In some of the foregoing embodiments, the pharmaceutical composition comprises a mono-citrate salt of the compound of Formula (I) (i.e., the compound of Formula (V)). In some of the foregoing embodiments, the pharmaceutical composition comprises a hemi-citrate salt of the compound of Formula (I) (i.e., the compound of Formula (VI)).

Conversion of a Compound of Formula (I) to a Compound of Formula (VI)

[0107] A hemi-citrate salt of the compound of Formula (I) (i.e., the compound of Formula (VI)) may be prepared, for example, by mixing the compound of Formula (I) free base and citric acid in a suitable solvent to provide the compound of Formula (I) salt as a suspension in the suitable solvent. In some embodiments, about a 2:1 ratio of the compound of Formula (I) freebase to citric acid are mixed. In some embodiments, the suitable solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, or methyl ferf-butyl ether. In some embodiments, the hemi-citrate salt of the compound of Formula (I) (and crystalline forms thereof) may be prepared by slow evaporation, slow cooling, or antisolvent addition to the mixture of the compound of Formula (I) free base and citric acid. [0108] In some embodiments, a hemi-citrate salt (and crystalline forms thereof) of the compound of Formula (I) is prepared from a mono-citrate salt of the compound of Formula (I) (i.e., the compound of Formula (V)).

[0109] In some embodiments, the method of preparing a hemi-citrate salt of the compound of Formula (I) (i.e., the compound of Formula (VI)) comprises: (a) dissolving a mono-citrate salt of the compound of Formula (I) in a C1-C3 alcohol; and (b) adding the solution of Step (a) to water to provide the hemi-citrate salt of the compound of Formula (I). In some embodiments, the method further comprises a Step (c) of isolating and drying the hemi-citrate salt of the compound of Formula (I). In some embodiments, the present method is used to prepare a crystalline form of a hemi-citrate salt of the compound of Formula (I).

[0110] In some embodiments, the C1-C3 alcohol is methanol, ethanol, or isopropanol. In some embodiments, the C1-C3 alcohol is methanol or ethanol. In some embodiments, the C1-C3 alcohol is methanol. In some embodiments, the C1-C3 alcohol is an alcohol with a water activity greater than about 0.75.

[0111] In some embodiments, the mono-citrate salt of the compound of Formula (I) is dissolved in C1-C2 alcohol. In some embodiments, the C1-C2 alcohol is methanol. In some embodiments, the C1-C2 alcohol is ethanol.

[0112] In some embodiments, the method of preparing a hemi-citrate salt of the compound of Formula (I) comprises: (a) suspending a mono-citrate salt of the compound of Formula (I) in water; and (b) isolating the hemi-citrate salt of the compound of Formula (I). In some embodiments, the method further comprises drying the hemi-citrate salt of the compound of Formula (I). In some embodiments, the present method is used to prepare a crystalline form of a hemi-citrate salt of the compound of Formula (I).

[0113] In some embodiments, the present disclosure provides further methods of making crystalline forms of a hemi-citrate salt of the compound of Formula (I). For example, in some embodiments, the hemi-citrate salt of the compound of Formula (I) is suspended in a suitable solvent for a time sufficient to provide a suspension of a crystalline form of the hemi-citrate salt of the compound of Formula (I).

[0114] In some embodiments, a hemi-citrate salt of the compound of Formula (I) is dissolved in a suitable solvent to provide a solution, and a crystalline form of the hemi-citrate salt of the compound of Formula (I) is precipitated from the solution. In some embodiments, a hemi- citrate salt of the compound of Formula (I) is dissolved by heating a mixture of the hemi-citrate salt of the compound of Formula (I) and a suitable solvent. In some embodiments, a crystalline form of the hemi-citrate salt of the compound of Formula (I) is precipitated from the solution by cooling the solution. In some embodiments, the crystalline form of the hemi-citrate salt of the compound of Formula (I) is precipitated from the solution by adding an anti-solvent (i.e., a solvent that decreases the solubility of the crystalline form of the hemi-citrate salt of the compound of Formula (I) in the solution). In some embodiments, a crystalline form of the hemi-citrate salt of the compound of Formula (I) is precipitated from the solution by evaporating a portion of the suitable solvent from the solution. In some embodiments, the crystalline form of the hemi-citrate salt is crystalline Form I. In some embodiments, the suitable solvent comprises water.

[0115] In some embodiments, the suitable solvent comprises a non-protic solvent. In some embodiments, the non-protic solvent comprises at least one solvent selected from dimethylformamide (DMF), dimethylacetamide (DMAC), l,3-dimethyl-3,4,5,6-tetrahydro- 2(l//)-pyrimidinone (DMPU), l,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, methyl ethyl ketone (MEK), hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N- dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, hexamethylphosphoramide, diethoxymethane, tetrahydrofuran, toluene, 1,3-dioxane, 1,4- dioxane, furan, diethyl ether, tetrahydropyran, diisopropyl ether, dibutyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, or /-butyl methyl ether. In some embodiments, the non-protic solvent is acetone. In some embodiments, the non-protic solvent is ethyl acetate. In some embodiments, the non-protic solvent is acetonitrile.

[0116] In some embodiments, the suitable solvent comprises a protic solvent. In some embodiments, the protic solvent comprises at least one solvent selected from water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1 -propanol, 2- propanol, 2-methoxy ethanol, 1 -butanol, 2-butanol, z-butyl alcohol, r-butyl alcohol, 2- ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, r-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, and glycerol. In some embodiments, the protic solvent comprises a mixture of 2-propanol and water.

[0117] In some embodiments, the suitable solvent is a single solvent. In some embodiments, the solvent is a mixture of solvents. In some embodiments, the suitable solvent is a mixture of a protic solvent and a non-protic solvent. [0118] In certain embodiments, the hemi-citrate salt of the compound of Formula (I) (or crystalline form of the hemi-citrate salt) is isolated after it is prepared. The isolation of the hemi-citrate salt (or crystalline form of the hemi-citrate salt) of the compound of Formula (I) may be accomplished using methods such as filtration, decantation, centrifugation, or other suitable separation technique.

[0119] In certain embodiments, the isolated hemi-citrate salt of the compound of Formula (I) (or crystalline form of the hemi-citrate salt) is optionally washed with a liquid such as an antisolvent, acetonitrile, methanol, ethanol, ethyl acetate, methyl ethyl ketone, acetone, tetrahydrofuran, or a combination thereof.

[0120] In some embodiments, the hemi-citrate salt of the compound of Formula (I) e.g., a compound of Formula (V) or a compound of Formula (VI) prepared by the embodiments above is substantially pure. For example, in some embodiments, the chemical purity of the hemi- citrate salt of the compound of Formula (I) is at least about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99.0 %, about 98%, about 97%, about 96%, or about 95% pure. Chemical purity may be determined using methods known to those skilled in the art. For example, chemical purity may be determined by HPLC chromatography, such as the use of HPLC chromatography with a suitable solvent and column detecting a wavelength of 210 nm. In some embodiments, the chemical purity is determined on a weight percent basis. In some embodiments, the chemical purity is determined on an area under the curve basis.

[0121] In some embodiments, the hemi-citrate salt of the compound of Formula (I) prepared by the embodiments above is crystalline. In certain embodiments, the crystalline hemi-citrate salt of the compound of Formula (I) (e.g., a compound of Formula (V) or a compound of Formula (VI) prepared by the embodiments above is substantially pure. For example, in some embodiments, the polymorphic purity of the crystalline hemi-citrate salt of the compound of Formula (I) is at least about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99.0%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, or about 50% pure. Polymorphic purity may be determined using methods known to those skilled in the art (including, among others, X-ray powder crystallography as described in Shah, B., et al., Analytical techniques for quantification of amorphous/crystalline phases in pharmaceutical solids, J. Pharm. Sci. 2006, 95(8), pages 1641-1665 which is hereby incorporated by reference in its entirety). Conversion of a Compound of Formula (III) to a Compound of Formula (Ila)

[0122] In another aspect, provided herein is a method of preparing a compound of Formula

(Ila) by reacting a compound of Formula (III): with a brominating agent to obtain the compound of Formula (Ila), wherein the brominating agent is not Br2. It has been found that use of bromine may result in the production of undesired dibrominated by-products, such as the compound of Formula (X) and/or a compound of Formula (XI).

[0123] In some embodiments, the brominating agent is selected from copper (II) bromide, 1,3- dibromo- 5 , 5 -dimethylhydantoin, N -bromosuccinimide, 4- (Dimethy lamino)pyridine tribromide, carbon tetrabromide, phosphorous tribromide, 2,4,4,6-tetrabromocyclohex-2,5- dienone, or pyridinium tribromide. In some embodiments, the brominating agent is N- bromosuccinimide or l,3-dibromo-5,5-dimethylhydantoin. In some embodiments, the brominating agent is l,3-dibromo-5,5-dimethylhydantoin.

[0124] In some embodiments, the reaction is performed using about 0.5 to about 2 molar equivalents of l,3-dibromo-5,5-dimethylhydantoin. In some embodiments, the reaction is performed using about 0.5 to about 1.5 molar equivalents of l,3-dibromo-5,5- dimethylhydantoin. In some embodiments, the reaction is performed using about 0.5 to about 1 molar equivalent of l,3-dibromo-5,5-dimethylhydantoin. In some embodiments, the reaction is performed using about 0.5 to about 0.8 molar equivalents of l,3-dibromo-5,5- dimethylhydantoin. In some embodiments, the reaction is performed using about 0.5 molar equivalents of l,3-dibromo-5,5-dimethylhydantoin. In some embodiments, the reaction is performed using about 0.6 molar equivalents of l,3-dibromo-5,5-dimethylhydantoin. In some embodiments, the reaction is performed using about 0.8 molar equivalents of l,3-dibromo-5,5- dimethylhydantoin. In some embodiments, the reaction is performed using about 1.0 molar equivalent of l,3-dibromo-5,5-dimethylhydantoin. In some embodiments, the reaction is performed using about 1.5 molar equivalents of l,3-dibromo-5,5-dimethylhydantoin. In some embodiments, the reaction is performed using about 2.0 molar equivalents of l,3-dibromo-5,5- dimethylhydantoin. [0125] In some embodiments, the reaction is performed in the presence of an acid. In some embodiments, the acid is sulfonic acid. In some embodiments, the acid is methanesulfonic acid.

[0126] In some embodiments, the reaction is performed using about 0.1 to about 0.5 molar equivalents of acid, such as sulfonic acid or methanesulfonic acid. In some embodiments, the reaction is performed using about 0.1 to about 0.4 molar equivalents of acid, such as sulfonic acid or methanesulfonic acid. In some embodiments, the reaction is performed using about 0.1 to about 0.3 molar equivalents of acid, such as sulfonic acid or methanesulfonic acid. In some embodiments, the reaction is performed using about 0.1 to about 0.2 molar equivalents of acid, such as sulfonic acid or methanesulfonic acid. In some embodiments, the reaction is performed using about 0.5 molar equivalents of acid, such as sulfonic acid or methanesulfonic acid. In some embodiments, the reaction is performed using about 0.4 molar equivalents of acid, such as sulfonic acid or methanesulfonic acid. In some embodiments, the reaction is performed using about 0.3 molar equivalents of acid, such as sulfonic acid or methanesulfonic acid. In some embodiments, the reaction is performed using about 0.2 molar equivalents of acid, such as sulfonic acid or methanesulfonic acid. In some embodiments, the reaction is performed using about 0.1 molar equivalents of acid, such as sulfonic acid or methanesulfonic acid. In some embodiments, the reaction is performed using about 0.2 molar equivalents of sulfonic acid. In some embodiments, the reaction is performed using about 0.2 molar equivalents of methanesulfonic acid.

[0127] In some embodiments, the reaction is performed using a solvent selected from ethyl acetate or methanol. In some embodiments, the reaction is performed using methanol as the solvent.

[0128] In another aspect, provided herein is a composition comprising the compound of Formula (Ila), wherein the compound of Formula (Ila) is produced using the methods described herein.

[0129] In another aspect, provided herein is a composition comprising the compound of Formula (Ila), wherein the composition is substantially free of a compound of Formula (X): or a salt thereof, and/or a compound of Formula (XI): or a salt thereof.

[0130] Following conversion of the compound of Formula (III) to the compound of Formula (Ila), the compound of Formula (Ila) can be converted to the compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)). In some embodiments, the isolated compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)), is substantially free of the compound of Formula (X), or a salt thereof. In some embodiments, the isolated compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)), is substantially free of the compound of Formula (XI), or a salt thereof. In some embodiments, the isolated compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)), is substantially free of the compound of Formula (X), or a salt thereof, and the compound of Formula (XI), or a salt thereof.

[0131] The disclosure also provides pharmaceutical compositions comprising Formula (I), or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)), that are substantially free of or contain minimal amounts of the compound of Formula (X). In some embodiments, the compositions comprise less than about 5,000 ppm of the compound of Formula (X). In other embodiments, the compositions comprise less than about 2,500 ppm of the compound of Formula (X). In other embodiments, the compositions comprise less than about 1,000 ppm of the compound of Formula (X). In other embodiments, the compositions comprise less than about 500 ppm of the compound of Formula (X). In other embodiments, the compositions comprise less than about 100 ppm of the compound of Formula (X). In other embodiments, the compositions comprise less than about 50 ppm of the compound of Formula (X).

[0132] The disclosure also provides pharmaceutical compositions comprising Formula (I), or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)), that are substantially free of or contain minimal amounts of the compound of Formula (XI). In some embodiments, the compositions comprise less than about 5,000 ppm of the compound of Formula (XI). In some embodiments, the compositions comprise less than about 2,500 ppm of the compound of Formula (XI). In other embodiments, the compositions comprise less than about 1,000 ppm of the compound of Formula (XI). In other embodiments, the compositions comprise less than about 500 ppm of the compound of Formula (XI). In other embodiments, the compositions comprise less than about 100 ppm of the compound of Formula (XI). In other embodiments, the compositions comprise less than about 50 ppm of the compound of Formula (XI).

[0133] The disclosure also provides pharmaceutical compositions comprising Formula (I), or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (V) or a compound of Formula (VI)), that are substantially free of or contain minimal amounts of both the compound of Formula (X) and the compound of Formula (XI). In some embodiments, the compositions comprise less than about 5,000 ppm of the compound of Formula (X) and less than about 5,000 ppm of the compound of Formula (XI). In some embodiments, the compositions comprise less than about 2,500 ppm of the compound of Formula (X) and less than about 2,500 ppm of the compound of Formula (XI). In some embodiments, the compositions comprise less than about 1 ,000 ppm of the compound of Formula (X) and less than about 1 ,000 ppm of the compound of Formula (XI). In some embodiments, the compositions comprise less than about 500 ppm of the compound of Formula (X) and less than about 500 ppm of the compound of Formula (XI). In some embodiments, the compositions comprise less than about 100 ppm of the compound of Formula (X) and less than about 100 ppm of the compound of Formula (XI). In some embodiments, the compositions comprise less than about 50 ppm of the compound of Formula (X) and less than about 50 ppm of the compound of Formula (XI).

Conversion of a Compound of Formula (IV) to a Compound of Formula (III) [0134] In another aspect, provided herein is a method of preparing the compound of Formula (III) by reacting a compound of Formula (IV): under suitable conditions to provide the compound of Formula (III). [0135] In some embodiments, provided herein is a method of preparing the compound of Formula (III) by first converting the compound of Formula (IV) to a compound of Formula (XII): through an epoxidation process. In some embodiments, the compound of Formula (IV) is converted to the compound of formula (XII) through Corey epoxidation with trimethylsulfonium iodide (Me SOI) and potassium tert-butoxide (KOf-Bu). In some embodiments, the reaction is performed using from about 1.0 to about 2.0 molar equivalents of Me SOI. In some embodiments, the reaction is performed using from about 1.0 to about 1.5 molar equivalents of Me SOI. In some embodiments, the reaction is performed using from about 1.0 to about 1.3 molar equivalents of Me SOI. In some embodiments, the reaction is performed using from about 1.0 to about 1.2 molar equivalents of Me SOI. In some embodiments, the reaction is performed using about 1.0 molar equivalent of Me SOI. In some embodiments, the reaction is performed using about 1.1 molar equivalents of Me SOI. In some embodiments, the reaction is performed using about 1.2 molar equivalents of Me SOI. In some embodiments, the reaction is performed using about 1.3 molar equivalents of Me SOI. In some embodiments, the reaction is performed using about 1.4 molar equivalents of Me SOI. In some embodiments, the reaction is performed using about 1.5 molar equivalents of Me SOI. In some embodiments, the reaction is performed using about 2.0 molar equivalents of Me SOI.

[0136] The compound of Formula (XII) can be isolated and converted to the compound of Formula (III) through the addition of sodium methoxide (NaOMe). In some embodiments, the reaction is performed using about 1.0 to about 5.0 molar equivalents of sodium methoxide. In some embodiments, the reaction is performed using about 1.2 to about 5.0 molar equivalents of sodium methoxide. In some embodiments, the reaction is performed using about 1.5 to about 4.0 molar equivalents of sodium methoxide. In some embodiments, the reaction is performed using about 2.0 to about 3.0 molar equivalents of sodium methoxide. In some embodiments, the reaction is performed using about 1.0 molar equivalent of sodium methoxide. In some embodiments, the reaction is performed using about 1.2 molar equivalents of sodium methoxide. In some embodiments, the reaction is performed using about 1.5 molar equivalents of sodium methoxide. In some embodiments, the reaction is performed using about 2.0 molar equivalents of sodium methoxide. In some embodiments, the reaction is performed using about 3.0 molar equivalents of sodium methoxide. In some embodiments, the reaction is performed using about 4.0 molar equivalents of sodium methoxide. In some embodiments, the reaction is performed using about 5.0 molar equivalents of sodium methoxide. In some embodiments, the reaction is performed at a temperature between about 60 °C and about 80 °C. In some embodiments, the reaction temperature is about 60 °C. In some embodiments, the reaction temperature is about 65 °C. In some embodiments, the reaction temperature is about 68 °C. In some embodiments, the reaction temperature is about 70 °C. In some embodiments, the reaction temperature is about 75 °C. In some embodiments, the reaction temperature is about 80 °C. The overall process for converting the compound of Formula (IV) to the compound of

[0137] The reactions detailed above may require isolation of the compound of Formula (XII) prior to synthesis of the compound of Formula (III). Owing to the added step of isolating the compound of Formula (XII) and the high cost of KOf-Bu as an epoxidation base, removing the isolation step would produce a significant improvement to the overall process. The disclosure provides methods of synthesizing a compound of Formula (III) from a compound of Formula (IV) without further comprising a step of isolating a compound of Formula (XII). Accordingly, in certain embodiments disclosed herein, the compound of Formula (IV) can be converted to a Compound of Formula (III) in a single step.

[0138] In a particular embodiment, the epoxidation of the compound of Formula (IV) can be carried out with sodium methoxide (NaOMe) rather than KOf-Bu as an epoxidation base. Since NaOMe is used both for the epoxidation and the ring-opening step, the compound of Formula (IV) can be directly converted to the compound of Formula (III) without isolating the compound of Formula (XII).

[0139] Accordingly, in one aspect, the disclosure provides a method of producing a compound of Formula (XII) comprising reacting a compound of Formula (IV) with NaOMe and Me SOI to produce a compound of Formula (XII). In some embodiments, the reaction conditions can be chosen so that the compound of Formula (XII) converts to the compound of Formula (III) without isolation of the compound of Formula (XII).

[0140] In some embodiments where the compound of Formula (IV) is converted to the compound of Formula (III) in a single step in accordance with the disclosure, the reaction is carried out in the presence of tetrahydrofuran (THF). In some embodiments, the reaction is carried out in an alcohol. In some embodiments, the reaction is carried out in methanol. It has been found that in certain embodiments, the use of methanol as a solvent results in increased yields of the compound of Formula (III).

[0141] In some embodiments where the compound of Formula (IV) is converted to the compound of Formula (III) in a single step in accordance with the disclosure, an excess of NaOMe is used. In some embodiments, more than about 2.0 molar equivalents of NaOMe is used per one molar equivalent of the compound of Formula (IV). In some embodiments, more than about 2.5 molar equivalents of NaOMe is used per one molar equivalent of the compound of Formula (IV). In some embodiments, more than about 3.0 molar equivalents of NaOMe is used per one molar equivalent of the compound of Formula (IV). In some embodiments, more than about 3.5 molar equivalents of NaOMe is used per one molar equivalent of the compound of Formula (IV). In some embodiments, more than about 4.0 molar equivalents of NaOMe is used per one molar equivalent of the compound of Formula (IV). In some embodiments, from about 2.5 molar equivalents to about 3.5 molar equivalents of NaOMe is used per one molar equivalent of the compound of Formula (IV). In some embodiments, from about 2.0 molar equivalents to about 4.0 molar equivalents of NaOMe is used per one molar equivalent of the compound of Formula (IV). In some embodiments, from about 3.0 molar equivalents to about 4.0 molar equivalents of NaOMe is used per one molar equivalent of the compound of Formula (IV). In some embodiments, about 3.5 molar equivalents of NaOMe is used per one molar equivalent of the compound of Formula (IV).

General Synthetic Schemes

[0142] In another aspect, provided herein is a method of preparing a compound of Formula (I) comprising the steps:

The compound of Formula (I) can be converted to a pharmaceutically acceptable salt using methods disclosed herein. In some embodiments, the compound of Formula (IV) is converted to a compound of Formula (III) in a single step, as set forth herein.

[0143] In some embodiments, a compound of Formula (VI) can be produced as shown in the schematic below:

EXAMPLES

Example 1: Conversion of a Compound of Formula (IV) to a Compound of Formula (III) [0144] Various conditions were evaluated to convert the compound of Formula (IV) to the compound of Formula (III) according to the following reaction scheme:

The reaction was performed either using a two-step process or a one-step process.

Two-Step Process [0145] In the two-step process, the compound of Formula (XII) was isolated, purified, and subsequently subjected to ring-opening conditions to provide the compound of Formula (III). The process conditions are provided in entries 1 and 2 of Table 1, below. In the two stepprocess, 25 grams of the compound of Formula (XII) was reacted with 1.1 molar equivalents of trimethylsulfonium iodide (Me SOI) and 1.09 molar equivalents of potassium tert-butoxide (KOf-Bu). Following aqueous workup of the epoxidation reaction mixture, the compound of Formula (XII) was crystallized from MeOH/THF to provide an isolated yield of the compound of Formula (XII) of 84.2% (see entry 1 of Table 1).

[0146] Following the isolation of the compound of Formula (XII), exposure of the compound of Formula (XII) to NaOMe in methanol at elevated temperature allowed for the ring-opening of the epoxide and production the compound of Formula (III). Following completion of the reaction at 60-68 °C, the resulting suspension is a mixture of diastereomers at C17. The temperature of the bulk reaction mixture was therefore lowered to 35-40 °C in order to equilibrate the stereocenter at C17 and provide an enriched diastereomeric ratio (d.r.) of 97:3 favoring the P-isomer of the compound of Formula (III). Following equilibration, acidification of the reaction mixture, aqueous workup, and crystallization from EtOAc/heptane, the compound of Formula (III) was provided at a yield of 84.2% (see Entry 2 of Table 1).

Single Step Process

[0147] A variety of feasibility experiments were conducted to improve the process manufacturing route to the compound of Formula (III). With a goal of consolidating the reagents used in the process and due to the high cost of KOf-Bu, NaOMe was employed as the base for both the generation of the active epoxidation reagent and the ring opening of the resultant epoxide (see Entry 3 of Table 1). In this experiment, the equilibration procedure and workup procedure for the compound of Formula (III) was not changed. It was found that NaOMe could be used as an appropriate base for this reaction, and the compound of Formula (III) was isolated in 51.7% yield over two steps, with the elimination of isolating the compound of Formula (XII).

[0148] The relatively low isolated yield in Entry 3 of Table 1 was attributed to the THF used in the epoxidation reaction mixture increasing the solubility of the compound of Formula (III) in the ring-opening reaction mixture and increasing mother liquor losses in the crystallization. To circumvent this issue, MeOH rather than THF was evaluated for as the solvent for the epoxidation mixture, while maintaining the same 2-portion addition of NaOMe and the same workup procedures for the compound of Formula (III) (see Entry 4 of Table 1). The compound of Formula (III) was isolated in a higher yield of 77.3% in this experiment, indicating that MeOH was an appropriate solvent for both epoxidation and ring-opening.

[0149] Ideally, the epoxidation reaction should tolerate excess base in the reaction mixture. The reaction procedure would be more convenient if only 1 charge of NaOMe was required, and the ring-opening reaction could be conducted simultaneously with the epoxidation of the compound of Formula (IV). In the original development of the two-step process, the levels of impurities were found to increase with additional KOf-Bu. However the effect was not expected to be as significant in this case due to the lower basicity of NaOMe. Moreover, the reaction mixture was left at elevated temperature, and the compound of Formula (IV) was directly charged, rather than the previous process of cooling to ambient conditions after generation of the active sulfur-ylide. When this experiment was conducted with excess NaOMe and pre-formation of the active epoxidation reagent (see Entry 5 of Table 1), full conversion of the compound of Formula (IV) was observed after 1 hour at elevated temperature. The epoxide intermediate (the compound of Formula (XII)) was not observed in appreciable quantities in the reaction mixture under these conditions. Following equilibration and cooling the reaction mixture, an improved workup procedure was explored to remove an extraction: the suspension was quenched by the addition of water (IV), directly filtered, and washed with water to remove excess Me SOI and inorganic salts. The compound of Formula (III) was isolated in 84.8% yield with an additional 12.4% of material isolated from the filtrate upon addition of excess water.

[0150] Finally, the pre-formation of the epoxidation reagent by heating Me SOI and NaOMe prior to the addition of the compound of Formula (IV) was found to not be necessary. When all reagents were added at ambient conditions followed by heating the reaction mixture, the reaction proceeded in full conversion, and the compound of Formula (III) was isolated in 91.1% yield on a 5 g scale after quenching the reaction mixture with 5 V of water (see Entry 6 of Table 1),

Table 1: Epoxidation and Ring- Opening Conditions

Scaled-up Single Step Process

[0151] Based on the reaction conditions and methods set forth in the studies described above, the following protocol was used to synthesize the compound of Formula (III) from the compound of Formula (IV):

1. Charged methanol, the compound of Formula (IV), and trimethylsulfoxonium iodide to a dry and N2 flushed reactor of appropriate size.

2. Charged sodium methoxide solution (typical addition rate 10 mL/min) keeping batch solution at no more than 35 °C.

3. The mixture was heated to 65-70 °C and aged for no less than 2 hours. After approximately 30 minutes at temperature the majority of solids in the reaction mixture had dissolved.

4. The reaction was cooled to 30-40 °C (target: 35 °C) and then aged for no less than 8 hours. In this experiment the reaction mixture was aged overnight for 19 hours.

5. The resulting suspension was cooled to 20-30 °C and neutralized by the addition of 85% w/w H3PO4 as a solution in water. The batch temperature was kept at no more than 35 °C (typical addition rate 10 mL/min).

6. The mixture was heated to 65-70 °C and stirred for no less than 1 hour.

7. The resulting suspension was cooled to 20-30 °C and then stirred for no less than 3 hours.

8. The suspension was filtered and washed with MeOH/Water (5/3 v/v; 3 volumes total) and water (3 volumes).

9. The wet cake was dried at no more than 60-70 °C under vacuum. No decomposition at temperatures <70 °C over prolonged drying periods were observed. The isolated yield for the 300 g scale experiment was 96.2%.

Example 2: Conversion of a Compound of Formula (III) to a Compound of Formula

(Ila) Using Elemental Bromine

[0152] Bromination of the compound of Formula (III) with elemental bromine yielded the compound of Formula (Ila). The reaction resulted in the production of undesirable levels of dibrominated products (including the compound of Formula (X) and the compound of Formula

(XI)).

Example 3: Conversion of a Compound of Formula (III) to a Compound of Formula (Ila) using Alternative Bromination Methods

[0153] An alternative protocol was targeted for the bromination that would address problems with elemental bromine (e.g., safety and handling) while at least maintaining a comparable yield, if not improving upon it. A variety of different brominating agents were evaluated in the reaction. Two particular brominating agents, DMDMH and NBS, were identified as particularly useful agents to effect the conversion of the compound of Formula (III) to the compound of Formula (Ila). The compound of Formula (III) was reacted with 0.6 equivalents of DBDMH and 0.2 equivalents of p-TsOH in methanol, which produced 94% conversion by HPLC in 4 hours with minimal side product formation. To further expand upon the solvents screened in the initial reagent studies, the bromination using DBDMH/p-TsOH was performed in isopropyl acetate, toluene, and isopropanol at the same stoichiometry (1.2 equiv. DBDMH, 0.2 equiv. p-TsOH) and concentration (20 vol) as the EtOAc/2-MeTHF/MeOH runs discussed above. As shown in Table 2, isopropyl acetate gave a comparable reaction rate to ethyl acetate, but with additional formation of the same late-eluting impurity observed at low levels in ethyl acetate. Toluene gave a similar profile to ethyl acetate, but the formation of several very large peaks in the HPLC chromatogram suggested that toluene itself was being brominated. As a result, the reaction stalled due to depletion of active DBDMH. The reaction in isopropanol was sluggish and gave a large amount of an unidentified impurity.

Table 2: DBDMH bromination solvent screen results

[0154] Following analysis of the purity profile of the isolated products by HPLC (see Example 9), it was determined that certain impurities were present in the isolated product, including the compound of Formula (VII) (the C17-epimer of the compound of Formula (I)) and dibrominated impurities (the compound of Formula (X) and the compound of Formula (XI)). It was determined that reactions conducted in methanol produced lower amounts of these impurities than other solvents. Moreover, reactions conducted at room temperature produced lower amounts of these impurities than when the reactions were conducted at higher temperatures. Additionally, to minimize formation of the C17-epimer and dibrominated byproducts, the stoichiometric ratio of the compound of Formula (III) to DBDMH was investigated. It was determined that using approximately 0.6 equivalents of DBDMH provided the lowest levels of the C17-epimer and dibrominated byproducts, while still achieving full conversion to the compound of Formula (Ila). Fewer equivalents (e.g., 0.55 equivalents) of DBDMH gave improved purity profiles, although product yield was slightly lower. The results of the DBDMH stoichiometry study is shown in Table 3.

Table 3: DBDMH stoichiometry screen results

(I") (HA)

[0155] Based on the reaction conditions and methods set forth in the studies described above, the following protocol was used to synthesize the compound of Formula (Ila) from the compound of Formula (III).

1. The compound of Formula (III), methanol, and methanesulfonic acid were charged to a dry reactor of appropriate size fitted with an overhead stirrer and stirred.

2. The compound 1,3 -dibromo- 5, 5 -dimethylhydantoin was charged to the reactor (note: reaction is exothermic (temperature rise from 25 °C to 32 °C over 15 min was observed at 26 g scale in an non-jacketed reactor); permissible to add in a single portion or portionwise, depending on cooling capacity of reactor jacket.

3. The mixture was aged at 25 °C for no longer than 30 minutes. When the compound of Formula (I) was nearly completely consumed, the mixture became homogeneous.

4. The reaction mixture was quenched by addition of sodium bisulfite 1.2% w/w in water. The resultant suspension was stirred for no longer than 30 minutes.

5. The mixture was concentrated to 5 vol at no more than 45 °C to remove methanol.

6. The reaction mixture was charged with methyl tert-butyl ether (MTBE) and stirred until all solids had dissolved (no longer than 30 min). 7. The organic layer was washed with deionized water.

8. The organic layer was concentrated to 6 vol under vacuum at no more than 40 °C.

9. The concentrated organic layer was charge with a first portion (6 vol) of heptanes and concentrated to 6 vol under vacuum at no more than 40 °C. Solids began to precipitate during the swap.

10. The concentrated organic layer was further charged with a second portion (6 vol) of heptanes and concentrated to 6 vol under vacuum at no more than 40 °C.

11. The suspension was cooled to 0°C and stirred for no less than 2 hours.

12. The suspension was filtered, and the wet cake was washed with a pre-cooled (0 °C) third portion (2 vol) of heptanes.

13. The solids were dried under vacuum at no more than 60 °C for no less than 6 hours to afford the compound of Formula (Ila). The overall yield was approximately 85%.

Example 4: Synthesis of Dibrominated Reaction By-products

[0156] For the purpose of producing samples of the two dibrominated reaction byproducts (compound of Formula (X) and compound of Formula (XI)), a sample of the compound of Formula (Ila) was subjected to the reaction conditions with an excess of DBDMH. After 18.5 hours, complete consumption of the compound of Formula (Ila) was observed with production of both the compound of Formula (X) and the compound of Formula (XI), as well as a tribrominated product not observed in the bromination of the compound of Formula (III) (identified by MS). The compound of Formula (XI) was isolated by precipitation from a concentrated acetonitrile solution of the crude product, while the compound of Formula (X) was purified chromatographically.

[0157] The structures of the two compounds were confirmed by NMR, with the most downfield signals providing the key information. In the compound of Formula (X), two doublets coupled to each other and integrating to 1 appear at 4.38 and 4.15 ppm, representing diastereotopic a-protons bound to the same carbon. In the compound of Formula (XI) , a singlet integrating to 1 appears at 5.87 ppm, indicating a single proton at the a position shifted significantly downfield by two geminal bromines. A triplet appearing at 3.01 ppm, indicating the single proton at the other a-position, coupled to the two adjacent protons on the 5- membered ring. Example 5: Attempted Amination of the Compound of Formula (III) with Imidazole

[0158] Initial attempts to convert the compound of Formula (III) into the compound of Formula (I) were focused on using ' H-imidazole as nucleophile (Table 3.3.1). The major issue with using unactivated imidazole was a formation of the dimer byproduct (i.e., the compound of Formula (VIII)). Reported conditions (Steroids 2006, 71, 77-82) in THF at 60 °C with 2 eq. of imidazole produced about 1/1 ratio (LCAP at 220 nm) of compound of Formula (I)/dimer. Lowering reaction temperature and increasing relative amount of imidazole allowed significant improvement of the yield of the desired product. For instance, reaction in acetone at 40 °C with 3 eq. of imidazole gave a mixture of the compound of Formula (I) and dimer in 80/20 ratio. The reaction stayed homogeneous until completion, but solids precipitated out after stirring the reaction mixture overnight at room temperature. The product was filtered and analyzed by HPLC and ^! H NMR. NMR showed a clean mixture of the compound of Formula (I) and dimer in 9/1 molar ratio (based on the integration for C17 proton: 2.6 ppm for the compound of Formula (I) and 2.7 ppm for dimer). Thus, 80/20 LCAP at 220 nm corresponds to about 9/1 molar ratio of the compound of Formula (I) /dimer.

Table 4: Summary of attempted reaction of the compound of Formula (Ila) with imidazole Example 6: Synthesis of the compound of Formula (I) under PTC Conditions

[0159] Initial optimization studies for the phase transfer catalyzed (PTC) conditions are summarized in Table 5. Commonly used inorganic solvents were tested in toluene and 2- MeTHF in the presence of tetrabutylammonium bromide (TBAB) as a phase transfer catalyst. Experiments were done with 0.5 g of the compound of Formula (Ila) in 2 ml organic solvent and 2 ml water. The reaction reached complete conversion in 3 hours with KOH as a base.

Only trace amounts of the dimer were observed by LC/MS. A control experiment with no TBAB gave a very slow reaction. Reaction with potassium carbonate (K2CO3) was much slower and gave the dimer as a major product. Both LiOH and NaOH worked well to clean the reaction profile with a low amount of dimer impurity.

Table 5: Initial optimization of the Compound of Formula (I) Synthesis under PTC conditions

Table 5: Initial PTC conditions to Synthesize the Compound of Formula (I)

[0160] Initially with the biphasic solution, reactions in toluene quickly turned into a thick slurry as the compound of Formula (I) precipitated out due to the low solubility in toluene. Switching to 2-MeTHF as a reaction solvent significantly improved the reaction rate due to a better mixing, and no product precipitation was observed, making it possible to easily move to the work-up step. [0161] The next set of optimization/ranging studies was focused on amounts of imidazole, sodium hydroxide, and TBAB loading. The results of these studies are shown in Table 6. All experiments were done in 8 vol of 2-MeTHF, which is the minimum amount of solvent required to keep the compound of Formula (I) in solution at the end of the reaction based on solubility data. Using a larger excess of imidazole and base provided faster reaction (2 hours) but also resulted in epimerization at C17 center. Lowering the catalyst loading to 5% or 1% slowed down the reaction rate, and a significant amount of epoxide intermediate was observed at the end. Thus, 10% TBAB loading is recommended. No difference was noticed between using 5%, 10% sodium chloride solution, or pure water as the aqueous phase.

Table 6: Range studies under PTC conditions

[0162] Epimerization over time was observed in all experiments when greater than 1.5 eq. of sodium hydroxide was used. Lowering the amount of base to 1.2 eq. reduced the formation of the C17-epimer while giving comparable yield and product purity. As shown in Table 6, isolated product yields of greater than 90% can be achieved using PTC processes in accordance with the disclosure.

Example 7: Dimer Experiments

[0163] The dimer (compound of Formula (VIII)) was submitted to the standard reaction conditions as shown below:

HPLC indicated dimer decomposition, and the main fate products were the compound of Formula (I) and the C17-epimer.

[0164] The organic layer from the reaction was separated, 7% NathPCU was added, and the mixture was heated to 40 °C. The reaction mixture was stirred at 40 °C and sampled at 1, 2, and 20 hours. The compound of Formula (I) concentration was constant in the first two samples, but some decreasing was observed in 20 hours. Impurity with rt 4.2 min (m/z 495) was gone in 20 hours, while the dimer suddenly reappeared at a quite high level (1.7% in 20 hours). Afterwards, the organic layer was separated and washed with 10% NaCl.

[0165] The mono-citrate of the compound of Formula (I) was crystallized as usual. The dimer was partially rejected by crystallization, but it was present at 0.7% in isolated product. Thus, prolonged exposure to NaH ₂ PC>4 at elevated temperature should be avoided because of the potential instability of the compound of Formula (I) and dimer formation. [0166] In the next stress experiment, the organic layer from the reaction was separated, washed with 7% NaFbPCU, and then 10% NaCl was added. The mixture was stirred at 40 °C and sampled at 1, 2, and 20 hours. The compound of Formula (I) did not change throughout the experiment. Interestingly, the impurity rt 4.2 (m/z 495) is not stable under those conditions, and it completely decomposed in 20 hours. No accumulation of dimer was observed in this case. The compound of Formula (I) mono-citrate was crystallized in high purity.

Example 8A: Crystallization of the Hemi-Citrate Salt of the Compound of Formula (I) [0167] An initial attempt to crystallize the hemi-citrate salt of the compound of Formula (I) directly from the stream of crude compound of Formula (I) in wet 2-MeTHF was done by the addition of 0.5 equivalents of citric acid to the solution. Crystallization of the hemi-citrate salt of the compound of Formula (I) occurred quickly at room temperature without seeding. Product was obtained in high purity (99.4% LCAP). Yield loss in mother liquors was estimated to be about 12%.

[0168] Ranging experiments on citric acid (0.4-0.7 equivalents relative to the compound of Formula (I) in free base form) were performed in order to maximize recovery. Crystallizations were performed at room temperature, and slurries were sampled in 4 hours and 1 day. Based on the yield loss in mother liquors, the best recovery was achieved when 0.6 equivalents of citric acid was charged. The LC purity of isolated hemi-citrate salt of of the compound of Formula (I) was similar in all cases at 99.5%. XRPD showed the same crystalline pattern as the overdried hemi-citrate for all samples.

Example 8B: Crystallization and Purification of the Hemi-Citrate Salt of the Compound of Formula (I)

[0169] Crude hemi-citrate salt of the compound of Formula (I) (1.1 kg) was charged into a RE54C reactor, followed by 2.2 L of methanol. The temperature was set to 20/25 °C, and the reaction mixture was stirred for 10 minutes. Purified water (12.1 kg) was added to the reactor slowly over the course of 35 minutes. After addition of 1.6 vol of water, solid began to precipitate. A ring of product was formed around the impeller stirrer shaft. Massive precipitation was observed, suggesting that the amount of water added was in excess of the amount needed to induce precipitation.

[0170] X-ray analysis was performed on the solid obtained at the beginning of the crystallization, and the pattern was concordant with the hemi-citrate salt of the compound of Formula (I). The mixture was then stirred at 20/25 °C for 4 hours. The loss yield product in mother liquors was analyzed at different aging times. At To, the loss product in mother liquors was 62 g (6.9%). After 1.5 hours, the loss product was 55 g (5.0%), and after 3 hours, the loss product was 52 g (4.7%). By 4 hours, the loss product was 48 g (4.4%), which was consistent with expections based on laboratory tests of about 4.0%.

[0171] The suspension contained in the reactor was filtered through a FV03 filter for 5 minutes. Foam formation was observed. After filtration, a ring of product was observed at the bottom of the reactor. The mother liquors were recirculated, and most of the solid from the ring was thereby removed. The cake was washed with purified water (1.1 kg), and drying was performed at 30 °C in a forced air oven. The product was determined to have 6.3% water based on Karl Fischer titration.

[0172] HPLC was performed on the resulting product, using the HPLC methods set forth in Tables 7A and 7B below. HPLC results from Method 1 confirmed 99.87% of the compound of Formula (I), 0.02% epimer, and 0.09% dimer, with no detectable quantity of imidazole or intermediates. HPLC results from Method 2 confirmed 99.53% of the compound of Formula (I), 0.05% epimer, 0.21% contaminant, and 0.13% dimer, with no detectable quantity of intermediates. HPLC was likewise performed on the crude product starting material, using HPLC Method 1 set forth in Table 7 A. The HPLC results on the crude starting material confirmed 99.63% of the compound of Formula (I), 0.77% imidazole, 0.13% epimer, 0.11% dimer, and no detectable quantity of intermediates.

Table 7A - HPLC Method 1

Table 7B - HPLC Method 2

[0173] Additionally, further analysis was conducted on the resulting product, including residue on ignition (ROI), content of citrate, imidazole content, and residual solvents, as shown below in Table 8.

Table 8 - Assay Analysis of the Compound of Formula (I)

[0174] X-Ray powder diffraction analysis was also performed on the product, and the pattern was consistent with the hemi-citrate salt of a compound of the Formula (I).

[0175] The wet cake was dried in the laboratory under various conditions, including use of vacuum ranging from 100-200 mbar and from 300-500 mbar, as well as at temperatures of 45 °C, 35 °C, and room temperature. It was determined that under vacuum conditions of 100-200 mbar, the product dries below 3% regardless of temperature. At vacuum pressure of 300-500 mbar, the product may become over-dried, especially at room temperature. Under forced air conditions, regardless of temperature (30-45 °C) there appeared to be no risk of over-drying the product (below about 3.3%). Thus, forced air oven-drying at 30 °C may be used.

Example 9: HPLC Methods

[0176] The following HPLC methods were used for various aspects of development for the compound of Formula (I) and pharmaceutically acceptable salts thereof:

• HPLC Method A: Method for conversion of the compound of Formula (IV) to the compound of Formula (III)

• HPLC Method A: Method for conversion of the compound of Formula (III) to the compound of Formula (Ila)

• HPLC Method A: Method for conversion of the compound of Formula (Ila) to the compound of Formula (I) Example 10 - Scale-up of Recrystallization of the Hemi-Citrate Salt of the Compound of Formula (I)

[0177] A 40 g scale recrystallization of the hemi-citrate sesquihydrate salt of Formula (I) in MeOH/IFO was performed. In the scale-up, 40 g of the hemi-citrate monohydrate salt of the compound of Formula (I) and 308 mL (7.7 vol) of MeOH/H ₂ O (85:15, v/v) were added to a 1 L Atlas Reactor. The starting concentration was 130 mg of Formula (I)/mL solvent. The mixture was agitated (700 rpm) at 20 °C to dissolve the Formula I. The solution was then cooled to 10 °C over 20 minutes (0.5 °C/min). At 10 °C, an antisolvent (83 mL water) was added over 13 minutes (Me0H/H20 v/v, 67:33).

[0178] A minimal quantity of seeds of the hemi-citrate monohydrate salt of Formula (I) (20 mg, 0.05 wt %) was added at MeOH/IFO (1:1, 0.2 mL, between the homogeneous and heterogeneous nucleation points with relatively high super-saturation). 481 mL of water was then added over 70 minutes, such that the total water addition time was 83 minutes. The solution was agitated for 1 hour at 10 °C. The end slurry was filtered at 5 psi, and washed with 3:7 (v/v) MeOH/fFO (80 mL, 2 vol) at room temperature. The wet cake was then washed with water (2 x 40 mL, 2 vol) at room temperature, and the wet cake was dried by ambient vac -pull (20-25 °C, 45-50% RH) for 1 hour. The solids were further dried in a full vacuum oven at 60 °C. The operating conditions aimed to promote heterogeneous nucleation for more uniform small product particle size distribution with minimized solvent occlusion. The experimental conditions and results for the hemi-citrate sesquihydrate salt of Formula (I) recrystallization at 40 g scale are shown below in Table 9. Production of the hemi-citrate sesquihydrate salt of Formula (I) was confirmed by XRPD. Polarized light microscopy images of the final slurry and dried solids showed large rod-shaped crystals with minimal agglomeration, but smaller in size than the products from seeding and recrystallization at 20 °C.

Table 9