Process for preparing (s)-1-((s)-2-amino-3-(4-methoxyphenyl)propanoyl)-n-(4-(hydroxymethyl)phenethyl)-2-methylpyrrolidine-2-carboxamide and its intermediates

Abstract

Disclosed is a process for preparing (S)-1-((S)-2-amino-3-(4-methoxyphenyl)propanoyl)-N-(4-(hydroxymethyl)phenethyl)-2-methylpyrrolidine-2-carboxamide and its intermediates.

Description

25887 PROCESS FOR PREPARING (S)-1-((S)-2-AMINO-3-(4- METHOXYPHENYL)PROPANOYL)-N-(4-(HYDROXYMETHYL)PHENETHYL)-2- METHYLPYRROLIDINE-2-CARBOXAMIDE AND ITS INTERMEDIATES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 611,394 filed December 18, 2023, the entire contents of which are incorporated by reference herein. FIELD OF THE DISCLOSURE

[0002] The present disclosure relates to a process for preparing (S)-1-((S)-2-amino-3-(4- methoxyphenyl)propanoyl)-N-(4-(hydroxymethyl)phenethyl)-2-methylpyrrolidine-2- carboxamide and its intermediates. BACKGROUND

[0003] Peptides are ubiquitous in nature and are fundamental components of pharmaceutically active compounds; however, the practicality and economics of their chemical synthesis on manufacturing scale present significant challenges. In particular, chemo- and regioselectivity challenges arising from competing functionality of amino acids and peptides typically necessitate the use of orthogonal protecting groups and their subsequent removal, detracting from the ease and efficiency of processing. Current methodologies typically rely on the use of multiple orthogonal protecting groups, leading to additional deprotection and purification steps, thereby limiting their practical application for large-scale production. SUMMARY

[0004] The present disclosure is directed to a process for preparing a compound of Formula (X): H2N ,or a salt, hydrate, or solvate thereof. The synthesis comprises the steps of reacting compounds of Formulae (V), (VI), and (VIII): or salts,first intermediate.

[0005] The summary of the technology described herein is non-limiting and other features and advantages of the technology will be apparent from the following detailed description, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0006] FIG.1 is an X-ray powder diffraction pattern of a crystalline form of a hemi-sulfuric acid salt of the compound of Formula (X). The graph plots the intensity of the peaks as defined by counts per second versus the diffraction angle 2 theta (2θ) in degrees.

[0007] FIG.2 is an X-ray powder diffraction pattern of a crystalline form of a hydrochloric acid salt of the compound of Formula (X). The graph plots the intensity of the peaks as defined by counts per second versus the diffraction angle 2 theta (2θ) in degrees. DETAILED DESCRIPTION

[0008] The present disclosure pertains to a method to synthesize the compound of Formula (X) from readily available commercial starting materials. The synthesis of the compound of Formula (X) poses additional selectivity challenges due to the primary alcohol group, which may also react with electrophiles competitively to the desired amine group.

[0009] The present disclosure solves the shortcomings of the prior art via judicious choice of coupling conditions and employing a traceless, in situ masking strategy, which enables the highly regioselective coupling of the three building blocks without the need for additional protecting groups, maximizing process efficiency.

[0010] The present disclosure entails a carefully designed reaction sequence that enables the direct and selective amide coupling of the compound of Formula (V), the compound of Formula (VI), and the compound of Formula (VIII). Subsequently, deprotection and crystallization steps yield the compound of Formula (X) as a crystalline salt. This process not only exhibits remarkable efficiency but also demonstrates a high level of regioselectivity, ensuring the desired products are obtained with minimal unwanted side reactions. The disclosed method is versatileand compatible with a wide range of substrates containing unprotected nucleophiles such as alcohols and amines. Advantageously, this versatility expands its applicability to various derivatives and bioactive molecules.

[0011] In sum, the present disclosure introduces a groundbreaking method for selective amide coupling to produce short peptide derivatives, removing the necessity for protecting groups and propelling the field of peptide synthesis forward. The disclosed approach provides a more efficient, cost-effective, and versatile solution for the industrial-scale manufacturing of these biologically important molecules.

[0012] The present disclosure is directed to a novel, scalable synthesis of a compound of Formula (X): H2N , and or a pharmaceutically The synthesis comprisesthe steps of reacting compounds of Formulae (V), (VI), and (VIII): OH HN BocHN Me or salts, first

[0013] In an embodiment, the first intermediate is a compound of Formula (IX): BocHN or a pharmaceutically25887

[0014] In an embodiment, the instant process further comprises coupling the compounds of Formulae (V) and (VI) or the pharmaceutically acceptable salts, hydrates, or solvates thereof. In an embodiment, the coupling step comprises the steps of reacting the compounds of Formulae (V) and (VI) or the pharmaceutically acceptable salts, hydrates, or solvates thereof to form a second intermediate and reacting the second intermediate and the compound of Formula (VIII) or the pharmaceutically acceptable salt, hydrate, or solvate thereof to form the first intermediate.

[0015] In an embodiment, the second intermediate is a compound of Formula (VII): HN or a pharmaceutically

[0016] In an embodiment, the process further comprises the step of crystallizing the deprotected first intermediate to provide the compound of Formula (X) as a crystalline salt. In an embodiment, the crystalline salt is a hemi-sulfuric acid salt. In an embodiment, the crystalline salt is a hydrochloric acid salt.

[0017] In an embodiment, the process further comprises the step of crystallizing the deprotected first intermediate to provide a hydrate or solvate of the crystalline salt of compound of Formula (X). In a further embodiment, the process produces a hydrate of a crystalline hemi- sulfuric acid salt of a compound of Formula (X). In a further embodiment, the process produces a solvate of a crystalline hemi-sulfuric acid salt of a compound of Formula (X). In a further embodiment, the process produces a hydrate of a crystalline hydrochloric acid salt of a compound of Formula (X). In a further embodiment, the process produces a solvate of a crystalline hydrochloric acid salt of a compound of Formula (X).

[0018] In an embodiment, the compound of Formula (V) or the pharmaceutically acceptable salt, hydrate, or solvate thereof is prepared by deformylating a compound of Formula (IV): OH O or a pharmaceutically acceptable

[0019] In an embodiment, thethe pharmaceutically acceptable salt, hydrate, or solvate thereof is prepared by reducing a compound of Formula (III):or a pharmaceutically

[0020] In an embodiment, the compound of Formula (III) or the pharmaceutically acceptable salt, hydrate, or solvate thereof is prepared by reacting a compound of Formula (I): O or a pharmaceutically acceptablewith a compound of Formula (II): O or a pharmaceutically acceptable salt,thereof.

[0021] The present disclosure is also directed to a compound of Formula (X) or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0022] In an embodiment, the present disclosure is directed to a crystalline form of the compound (S)-1-((S)-2-amino-3-(4-methoxyphenyl)propanoyl)-N-(4- (hydroxymethyl)phenethyl)-2-methylpyrrolidine-2-carboxamide. In an embodiment, the present disclosure is directed to a hemi-solvate crystalline form of the compound (S)-1-((S)-2-amino-3- (4-methoxyphenyl)propanoyl)-N-(4-(hydroxymethyl)phenethyl)-2-methylpyrrolidine-2- carboxamide. In an embodiment, the present disclosure is directed to a solvate crystalline form of the compound (S)-1-((S)-2-amino-3-(4-methoxyphenyl)propanoyl)-N-(4- (hydroxymethyl)phenethyl)-2-methylpyrrolidine-2-carboxamide.

[0023] In an embodiment, the present disclosure is directed to an isolated crystalline form of the compound (S)-1-((S)-2-amino-3-(4-methoxyphenyl)propanoyl)-N-(4- (hydroxymethyl)phenethyl)-2-methylpyrrolidine-2-carboxamide. In an embodiment, the present disclosure is directed to an isolated hemi-solvate crystalline form of the compound (S)-1-((S)-2- amino-3-(4-methoxyphenyl)propanoyl)-N-(4-(hydroxymethyl)phenethyl)-2-methylpyrrolidine-2- carboxamide. In an embodiment, the present disclosure is directed to an isolated solvate crystalline form of the compound (S)-1-((S)-2-amino-3-(4-methoxyphenyl)propanoyl)-N-(4- (hydroxymethyl)phenethyl)-2-methylpyrrolidine-2-carboxamide.

[0024] In an embodiment, the present disclosure is directed to an anhydrous crystalline form of the compound (S)-1-((S)-2-amino-3-(4-methoxyphenyl)propanoyl)-N-(4- (hydroxymethyl)phenethyl)-2-methylpyrrolidine-2-carboxamide. In an embodiment, the present disclosure is directed to an anhydrous hemi-solvate crystalline form of the compound (S)-1-((S)- 2-amino-3-(4-methoxyphenyl)propanoyl)-N-(4-(hydroxymethyl)phenethyl)-2-methylpyrrolidine- 2-carboxamide. In an embodiment, the present disclosure is directed to an anhydrous solvate crystalline form of the compound (S)-1-((S)-2-amino-3-(4-methoxyphenyl)propanoyl)-N-(4- (hydroxymethyl)phenethyl)-2-methylpyrrolidine-2-carboxamide.

[0025] In an embodiment, the X-ray powder diffraction pattern of a crystalline form of a hemi- sulfuric acid salt of the compound of Formula (X) can include one or more peaks from Table 1.

[0026] In an embodiment, the X-ray powder diffraction pattern of the crystalline form of a hemi-sulfuric acid salt of the compound of Formula (X) has an X-ray diffraction pattern substantially similar to that set forth in FIG.1.

[0027] In an embodiment, the crystalline form of a hemi-sulfuric acid salt of the compound of Formula (X) is characterized by an X-ray powder diffraction pattern having peaks, expressed in degrees-2-theta at angles of (±0.2º) measured using CuKα radiation, selected from the group consisting of about 5.50 and 19.27_° 2θ. In a further embodiment, the crystalline form of a hemi- sulfuric acid salt of the compound of Formula (X) is characterized by an X-ray powder diffraction pattern having peaks, expressed in degrees-2-theta at angles of (±0.2º) measured using CuKα radiation, selected from the group consisting of about 5.50, 18.13, 19.27, 19.47, and 21.62 ° 2θ. In a further embodiment, the crystalline form of a hemi-sulfuric acid salt of the compound of Formula (X) is characterized by an X-ray powder diffraction pattern having peaks, expressed in degrees-2-theta at angles of (±0.2º) measured using CuKα radiation, selected from the group consisting of about 5.50, 7.72, 8.65, 9.41, 10.16, 10.93, 11.01, 12.19, 13.88, 14.40, 14.96, 15.41, 16.00, 16.38, 17.34, 17.63, 17.77, 18.13, 18.60, 19.27, 19.47, 19.69, 20.39, 21.13, 21.62, 22.18, 22.62, 23.42, 24.38, 24.75, 25.02, 25.91, 26.20, 27.42, 28.71, 28.99, 29.30, 29.55, 30.23, 31.35, 32.51, 32.78, 33.42, 34.56 ° 2θ.

[0028] In another embodiment, the crystalline hemi-sulfuric acid salt form of the compound of Formula (X) is characterized by an X-ray powder diffraction pattern having peaks shown in Table 1 (expressed in degrees-2-theta at angles ±0.2º).

[0029] In an embodiment, the X-ray powder diffraction pattern of a crystalline form of a hydrochloric acid salt of the compound of Formula (X) has an X-ray diffraction pattern substantially similar to that set forth in FIG.2.

[0030] In an embodiment, the X-ray powder of the crystalline form of a hydrochloric acid salt of the compound of Formula (X) is characterized by an X-ray powder diffraction pattern having peaks, expressed in degrees-2-theta at angles of (±0.2º) measured using CuKα radiation, selected from the group consisting of about 6.71 and 13.17° 2θ. In an embodiment, the X-ray powder of the crystalline form of a hydrochloric acid salt of the compound of Formula (X) is characterized by an X-ray powder diffraction pattern having peaks, expressed in degrees-2-theta at angles of (±0.2º) measured using CuKα radiation, selected from the group consisting of about 6.71, 13.17, 16.30, and 19.16° 2θ. In an embodiment, the X-ray powder of the crystalline form of a hydrochloric acid salt of the compound of Formula (X) is characterized by an X-ray powder diffraction pattern having peaks, expressed in degrees-2-theta at angles of (±0.2º) measured using CuKα radiation, selected from the group consisting of of about 6.71, 12.90, 13.37, 14.01, 15.65, 16.10, 16.30, 17.49, 17.96, 18.60, 19.16, 19.71, 20.10, 21.01, 22.01, 22.65, 23.42, 24.61, 24.88, 26.18, 35.11 ° 2θ.

[0031] In another embodiment, the crystalline form of a hydrochloric acid salt of the compound of Formula (X) is characterized by an X-ray powder diffraction pattern having peaks shown in Table 2 (expressed in degrees-2-theta at angles ±0.2º).

[0032] In an embodiment, the synthesis of a compound of Formula (V) commences with condensation of 4-bromobenzaldehyde (Formula (I)) with N-vinyl formamide (Formula (II)). The reaction can be mediated by a palladium catalyst to form an enamide (Formula (III)). In addition to the palladium catalyst, the reaction can involve a base. In addition to the palladium catalyst, the reaction can involve a solvent. In addition to the palladium catalyst, the reaction can involve other necessary reagents. The enamide can be isolated as a crystalline solid. The crystalline solid can be obtained via seeding or in the absence of seeding. O O O H H O Hlimiting examples of solvents used in the synthesis of the compound of Formula (III) include EtOAc, DMF, THF, IPAc, PhMe, and DME. Non-limiting examples of bases used in the synthesis of the compound of Formula (III) include DIPEA, triethylamine, tripropylamine, tri-n-butylamine, and tri-n-octylamine. Other non-limiting examples of reagents used in the synthesis of the compound of Formula (III) include t-Bu3P-HBF4 and n-Bu4NBr.

[0034] The synthesis of the compound of Formula (III) is carried out at a temperature ranging from about 50 ºC to about 100 ºC, from about 60 ºC to about 90 ºC, from about 70 ºC to about 80 ºC, or from about 70 ºC to about 75 ºC. In an embodiment, the synthesis of the compound of Formula (III) is carried out at a temperature of about 73 ºC.

[0035] In an embodiment, reduction of the enamide (Formula (III)) via palladium-catalyzed hydrogenation results in a formamide (Formula (IV)). In addition to the palladium catalyst, the reaction can involve a solvent. In addition to the palladium catalyst, the reaction can involve other necessary reagents. The reduction reaction can be a single or a double reduction reaction. H

[0036] compound of Formula (IV) include Pd / C and Pd(OH)2 / C. Non-limiting examples of solvents used in the synthesis of the compound of Formula (IV) include water, 1-PrOH, methanol, isopropanol, and n-butanol. Other non-limiting examples of reagents used in the synthesis of the compound of Formula (IV) include triethylamine and hydrogen gas.

[0037] The synthesis of the compound of Formula (IV) is carried out at a temperature ranging from about 10 ºC to about 70 ºC, from about 20 ºC to about 60 ºC, from about 30 ºC to about 50 ºC, or from about 35 ºC to about 45 ºC. In an embodiment, the synthesis of the compound of Formula (IV) is carried out at a temperature of about 40 ºC.

[0038] The formamide (Formula (IV)) undergoes acid-mediated deformylation to provide a crystalline Phe salt (Formula (V)), which is isolated directly by filtration. In addition to the deformylating agent, the reaction can involve a solvent. The crystalline Phe salt can exist as a hydrochloric acid salt. The crystalline Phe salt can be obtained via seeding or in the absence of seeding. OH OH NH2

[0039] Advantageously, compared to literature routes to synthesizing phenethylamine, the two- step process for synthesizing Formula (V) from Formula (III) is more concise and avoids the use of hazardous reagents such as lithium aluminum hydride, cyanide, and nitromethane.

[0040] Non-limiting examples of the deformylating agent used in the synthesis of the compound of Formula (V) include PivCl, NaOH, HCl, and methanesulfonic acid. Non-limiting examples of the solvent used in the synthesis of the compound of Formula (V) include 1-PrOH, methanol, isopropanol, and n-butanol.

[0041] The synthesis of the compound of Formula (V) is carried out at a temperature ranging from about 10 ºC to about 90 ºC, from about 20 ºC to about 80 ºC, from about 30 ºC to about 70 ºC, from about 40 ºC to about 60 ºC, or from about 45 ºC to about 55 ºC. In an embodiment, the synthesis of the compound of Formula (V) is carried out at a temperature of about 50 ºC.

[0042] Amide coupling of Formula (V) with amino acid MePro (Formula (VI)) is achieved via an N-carboxyanhydride intermediate, formed through condensation of MePro with CDI (used as a coupling agent). In addition to the coupling agent, the reaction can involve a base. In addition to the coupling agent, the reaction can involve a solvent. The MePro can exist as a hydrochloric acid solvate salt. HN OH Me

[0043] An CDI to give an N-is not isolated, but reacted further with the compound of Formula (V) to give the compound of Formula (VII). OH NH2O25887

[0044] Advantageously, this method avoids the need for protecting groups to couple the free amino acid selectively with the ambident nucleophile Phe (Formula (V)) with >99:1 selectivity. The MePro-Phe intermediate (Formula (VII)) is then crystallized and isolated by filtration. The MePro-Phe intermediate can exist as a hydrochloric acid salt. The crystalline MePro-Phe intermediate can be obtained via seeding or in the absence of seeding.

[0045] Non-limiting examples of the coupling agent used in the synthesis of the compound of Formula (VII) include CDI and DSC. Non-limiting examples of the solvent used in the synthesis of the compound of Formula (VII) include AcCl, IPA, DMF, NMP, MeCN, THF, and IPAc. Non-limiting examples of the base used in the synthesis of the compound of Formula (VII) include DIPEA and TEA.

[0046] The synthesis of the compound of Formula (VII) is carried out at a temperature ranging from about -30 ºC to about 50 ºC, from about -20 ºC to about 40 ºC, from about -10 ºC to about 30 ºC, from about -5 ºC to about 25 ºC, or from about 0 ºC to about 20 ºC.

[0047] Coupling of the monomer Boc-MeTyr (Formula (VIII)) to MePro-Phe (Formula (VII)) is achieved through EDC-mediated amide coupling, which results in the protected Formula (IX). In addition to the coupling agent, the reaction can involve a nucleophilic additive. In addition to the coupling agent, the reaction can involve a base. In addition to the coupling agent, the reaction can involve a solvent. HN BocHN ofchloride. Non-limiting examples of the nucleophilic additive used in the synthesis of the compound of Formula (IX) include HOPO and Oxyma. Non-limiting examples of the solvent used in the synthesis of the compound of Formula (IX) include BSA, MTBE, DMF, DMAc, and MeCN. Non-limiting examples of the base used in the synthesis of the compound of Formula (IX) include DIPEA and TEA.

[0049] The synthesis of the compound of Formula (IX) is carried out at a temperature ranging from about 0 ºC to about 70 ºC, from about 10 ºC to about 60 ºC, from about 20 ºC to about 5025887 ºC, or from about 30 ºC to about 40 ºC. In an embodiment, the synthesis of the compound of Formula (IX) is carried out at a temperature of about 35 ºC.

[0050] The crude stream is then treated with deprotecting agents to provide Formula (X). Non- limiting examples of deprotecting agents include methansulfonic acid and iso-butyryl chloride. In an embodiment, methanesulfonic acid is used to achieve deprotection and provide Formula (X), which is then crystallized and isolated to provide the corresponding sulfuric acid salt or hemi- sulfuric acid salt. In addition or alternative to the deprotecting agent, the reaction can involve other types of acids. In addition to the deprotecting agent, the reaction can involve a solvent. The crystalline sulfuric acid salt or crystalline hemi-sulfuric acid salt can further exist as a hydrate form. In an embodiment, iso-butyryl chloride is used to achieve deprotection and provide Formula (X), which is then crystallized and isolated to provide the corresponding hydrochloric acid salt. The crystalline hydrochloric acid salt can further exist as a 2-BuOH solvate or a 2- BuOH hemi-solvate form. Other crystalline salts of Formula (X) include but are not limited to hydrochloride, hydrobromide, tosylate, edisylate, D-tartrate and oxalate salts. The crystalline salts of Formula (X) can be obtained via seeding or in the absence of seeding. BocHN H2N Formula(X) of the acid used in the synthesis of the compound of Formula (X) include HCl, H2SO4, MsOH, and (iso- butyryl chloride + 2-BuOH).

[0052] The synthesis of the compound of Formula (X) is carried out at a temperature ranging from about 0 ºC to about 90 ºC, from about 10 ºC to about 80 ºC, from about 20 ºC to about 70 ºC, from about 30 ºC to about 60 ºC, from about 40 ºC to about 50 ºC, or from about 45 ºC to about 50 ºC. In an embodiment, the synthesis of the compound of Formula (IX) is carried out at a temperature of about 45 ºC or about 50 ºC.

[0053] All of the steps of the above processes are optionally but preferably conducted with agitation (e.g., stirring).

[0054] An example synthesis scheme of Formula (X) is shown in the following.25887 Step 1 Heck Step 2a - Reduction t- P- OBocHN BocHN HN 0.525887 - Hterms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0057] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well-known and commonly employed in the art.

[0058] As used herein, the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.25887

[0059] As used herein, the term “about” in quantitative terms refers to plus or minus 10% of the value it modifies (rounded up to the nearest whole number if the value is not sub-dividable, such as a number of molecules or nucleotides).

[0060] All ranges disclosed herein are inclusive of the recited endpoint and independently combinable (for example, the range of “from 50 mg to 500 mg” is inclusive of the endpoints, 50 mg and 500 mg, and all the intermediate values). The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value; they are sufficiently imprecise to include values approximating these ranges and / or values.

[0061] As used herein, the term “comprising” may include the embodiments “consisting of” and “consisting essentially of.” The terms “comprise(s),” “include(s),” “having,” “has,” “may,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients / steps and permit the presence of other ingredients / steps. However, such description should be construed as also describing compositions or processes as “consisting of” and “consisting essentially of” the enumerated components, which allows the presence of only the named components or compounds, along with any acceptable carriers or fluids, and excludes other components or compounds.

[0062] The compounds of the present disclosure may contain one or more asymmetric centers and can thus occur as “stereoisomers” including racemates and racemic mixtures, enantiomeric mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the scope of this disclosure. The present disclosure is meant to comprehend all such isomeric forms of these compounds. When bonds to the chiral carbon are depicted as straight lines in the formulae of the disclosure, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within a given formula. For example, Formula (X) shows the structure of the compound with the designation of specific stereochemistry. When the compounds of the present disclosure contain one chiral center, the term “stereoisomer” includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixture.

[0063] The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed25887 herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

[0064] The compounds of the present disclosure which contain olefinic double bounds, unless specified otherwise, are meant to include both E and Z geometric isomers.

[0065] Some of the compounds described herein may exist as tautomers which have different points of attachment of hydrogen accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed by the compounds of the present disclosure.

[0066] Some of the compounds described herein may exist as atropisomers when the rotational energy barrier around a single bond is sufficiently high to prevent free rotation at a given temperature, thus allowing isolation of individual conformers with distinct properties. The individual atropisomers as well as mixtures thereof are encompassed by the compounds of the present disclosure. When resolved, individual atropisomers can be designated by established conventions such as those specified by the International Union of Pure Applied Chemistry (IUPAC) 2013 Recommendations.

[0067] In the compounds of the present disclosure, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present disclosure as described and claimed herein is meant to include all suitable isotopic variations of the compounds of the present disclosure and embodiments thereof. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H, also denoted herein as D). Protium is the predominant25887 hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates.

[0068] The term “salts” refers to salts prepared from acceptable bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particular embodiments include the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates. Salts derived from organic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylene-diamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0069] When the compound of the present disclosure is basic, salts may be prepared from acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particular embodiments include the citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids. If a compound of the present disclosure simultaneously contains acidic and basic groups in the molecule, the disclosure also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). Salts can be obtained from the compounds of the present disclosure by customary methods which are known to the person skilled in the art, for example, by combination with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange from other salts. The present disclosure also includes all salts of the compounds which, owing to low physiological compatibility, are not directly suitable25887 for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0070] Furthermore, the compounds of the present disclosure may exist in amorphous form and / or one or more crystalline forms, and as such all amorphous and crystalline forms and mixtures thereof of the compounds of the present disclosure, including the Examples, are intended to be included within the scope of the present disclosure. In addition, some of the compounds of the present disclosure may form solvates with water (i.e., a hydrate) or common organic solvents such as but not limited to ethyl acetate or isobutyl alcohol, or solvents such as but not limited to hydrochloric acid or sulfuric acid. Such solvates and hydrates, particularly the pharmaceutically acceptable solvates and hydrates, of the present compounds are likewise encompassed within the scope of this disclosure, along with unsolvated and anhydrous forms.

[0071] The term “substantially similar” used in reference to X-ray powder diffraction patterns means that the X-ray powder diffraction pattern of a polymorph may display “batch to batch” variations due to differences in the types of equipment used for the measurements, and fluctuations in both experimental conditions (e.g. purity and grain size of the sample) and instrumental settings (e.g. X-ray wavelengths; accuracy and sensitivity of the diffractometer; and “instrumental drift”) normally associated with the X-ray diffraction measurement. Due to these variations, the same polymorph may not contain X-ray powder diffraction peaks at exactly the same positions or intensities shown in the figures disclosed herein. Accordingly, the term “about” used in reference to the peaks in an X-ray powder diffraction pattern takes into account these variations and a skilled artisan would readily appreciate the scope.

[0072] Throughout the synthetic schemes and examples, abbreviations and acronyms may be used with the following meanings unless otherwise indicated: Ac = acetyl; Am = amyl; t-AmOH = tert-amyl alcohol; aq = aqueous; Boc = tert-butoxycarbonyl; BSA = bis(trimethylsilyl)acetamide; Bu = butyl; i-BuCOCl = iso-butyryl chloride; t-Bu3P Pd G2 = chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)] palladium(II); t-Bu3P Pd G3 = methanesulfonato(tri-tert-butylphosphino)(2'-amino-1,1'-biphenyl-2-yl)palladium(II); CDI = 1,1′- carbonyldiimidazole; D = deuterium; DMAc = N,N-dimethylacetamide; DIPEA = i-Pr2NEt = N,N-diisopropylethylamine; DME = dimethyl ether; DMF = dimethylformaide; DMSO = dimethyl sulfoxide; DSC = N,N′-disuccinimidyl carbonate; EDC = N-(3-dimethylaminopropyl)- N′-ethylcarbodiimide; Et = ethyl; EtOAc = ethyl acetate; HOPO = 2-pyrinidnol 1-oxide; IPA = 2- propanol; IPAc = isopropyl acetate; Me = methyl; MeCN = acetonitrile; MePro = methyl proline; MsOH = methanesulfonic acid; MTBE = tert-butyl methyl ether; NCA = N-carboxyanhydride; NMP = 1-methyl-2-pyrrolidone; NMR = nuclear magnetic resonance; Oxyma = ethyl25887 cyanohydroxyiminoacetate; Pd / C = palladium on carbon; Ph == phenyl; PhMe = toluene; Phe = phenethylamine; PivCl = pivaloyl chloride; Pr = propyl; Pro = proline; TCFH = chloro- N,N,N′,N′-tetramethylformamidinium hexafluorophosphate; TEA = triethylamine; THF = tetrahydrofuran; Tyr = tyrosine; T3P = propanephosphonic acid anhydride. EXAMPLES

[0073] The following examples are meant to be illustrative and should not be construed as further limiting the disclosure in any way. In some embodiments, the final product may be further modified, for example, by manipulation of substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art. In some embodiments, the order of carrying out the foregoing reaction schemes and examples may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided so that the disclosure might be more fully understood. Example 1: Synthesis of (E)-N-(4-formylstyryl)formamide ((III)) O PdCl2(MeCN)2O O H

[0074] To a mixture of 4-bromobenzaldehyde ((I), 100 g, 539 mmol)bromide (1.76 g, 5.39 mmol) in EtOAc (700 mL) was added bis(acetonitrile) dichloropalladium(II) (0.280 g, 1.08 mmol) and tri-tert-butylphosphonium tetrafluoroborate (0.344 g, 1.19 mmol). The mixture was sparged with nitrogen, tri-n-propylamine (92.7 g, 647 mmol) added, and the resulting mixture was warmed to 70 °C and aged for 30 minutes. N- vinylformamide ((II), 54.8 g, 755 mmol) was added, and the resulting solution was aged at 70 °C for 18 h. The reaction mixture was cooled to 40 °C, and washed twice with NaHSO4(3% aq, 300 mL). The combined aqueous layers were extracted with EtOAc (500 mL) at 40 °C, and the combined organic extracts were washed twice with NaCl (5% aq, 200 mL) at 40 °C. The organics were treated with activated carbon (10.0 g) before being filtered through CELITE® and concentrated in vacuo to 500 mL at 50 °C. The batch was then seeded, and 500 mL xylenes were added to crystallize the batch while distilling at 50 °C under reduced pressure to maintain constant volume. The batch was then cooled to 20 °C and filtered. The cake was washed with25887 EtOAc / xylenes (1:4, 3 x 200 mL) and dried under vacuum to afford (E)-N-(4- formylstyryl)formamide ((III), 71.0 g, 97 wt%, 73% yield) as a crystalline beige solid.

[0075] 1H NMR (500 MHz, DMSO-d6) δ Rotamer 1 (major): 10.51 (d, J = 10.3 Hz, 1H), 9.92 (s, 1H), 8.19 (s, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.64 (dd, J = 14.7, 10.5 Hz, 1H), 7.59 (d, J = 8.3 Hz, 2H), 6.33 (d, J = 14.7 Hz, 1H). Rotamer 2 (minor): 10.44 (t, J = 10.7 Hz, 1H), 9.91 (s, 1H), 8.48 (d, J = 10.6 Hz, 1H), 7.83 – 7.78 (m, 2H), 7.73 – 7.65 (m, 1H), 7.53 (d, J = 8.3 Hz, 2H), 6.08 (d, J = 14.3 Hz, 1H).13C NMR (126 MHz, DMSO-d6) δ 192.59, 192.48, 164.70, 159.84, 143.81, 143.38, 134.58, 134.15, 130.88, 130.52, 126.21, 125.69, 125.30, 112.18, 109.47. Example 2: Synthesis of 2-(4-(hydroxymethyl)phenyl)ethan-1-aminium chloride ((V)) ClNH2in 1-PrOH (500 mL) and water (10.0 mL) was added palladium on carbon (5% wt / wt, 54% water wet) (5.40 g, 1.37 mmol Pd), and triethylamine (7.40 mL, 53.1 mmol). The reactor was pressurized with 130 psi of hydrogen, warmed to 40 °C and vigorously agitated for 18 h. The reaction mixture was vented and filtered over CELITE®. The cake was washed with 1- PrOH / H2O (98:2, 300 mL). The combined filtrate and washes were collected, KF adjusted to 2- 4%, then cooled to 10 °C.

[0077] A solution of HCl was prepared by slow addition of PivCl (128 g, 1.06 mol) to 1-PrOH (191 mL, 2.55 mol) at 0-20 °C. The resulting solution was aged at 0 °C for 1 h, then added slowly to the crude solution of EF-formamide ((IV)). The resulting solution was warmed to 50 °C and aged for 1 h. The batch was then seeded, aged at 50 °C for a further 13 h, then cooled to 40 °C, and MTBE (800 mL) was added over 2 h. The resulting slurry was cooled to 20 °C before being filtered, and the cake washed with MTBE / 1-PrOH (1:1, 3 x 300 mL) and dried under vacuum to afford 2-(4-(hydroxymethyl)phenyl)ethan-1-aminium chloride ((V), 92.2 g, 99 wt%, 90% yield) as a white crystalline solid.

[0078] 1H NMR (500 MHz, DMSO-d6) δ 8.24 (s, 3H), 7.27 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 5.21 (s, 1H), 4.47 (s, 2H), 2.99 (br s, 3H), 2.90 (dd, J = 9.8, 6.0 Hz, 3H).13C NMR (126 MHz, DMSO-d6) δ 141.46, 136.15, 128.77, 127.21, 63.06, 33.10.25887

[0079] Example 3: Synthesis of (S)-2-((4-(hydroxymethyl)phenethyl)carbamoyl)-2- methylpyrrolidin-1-ium chloride ((VII)) O, g, 295 mmol) in NMP (150 mL) at 0 °C was added 1,1′-carbonyldiimidazole (CDI, 53.4 g, 329 mmol) portion-wise, maintaining the temperature below 10 °C. The reaction mixture was aged at 0 °C for 2 h before 2-propanol (6 mL) was added. This mixture was then transferred over 2 h to a separate vessel containing a slurry of 2-(4-(hydroxymethyl)phenyl)ethan-1-aminium chloride ((V), 50.0 g, 98.9 wt%, 264 mmol) and N,N-diisopropylethylamine (92 mL, 527 mmol) in MeCN (250 mL) at 0 °C. Piperidine (6.5 mL) and 2-propanol (50 mL) were then charged, and the batch was aged at 0 °C for additional 1 h before being heated to 40 °C and seeded. A solution of HCl was prepared in a separate vessel by slow addition of AcCl (46.8 mL) to 2-propanol (150 mL) at 0-20 °C. The resulting HCl solution was aged at 20 °C for 1 h before being charged over 4 h to the main batch, which was then cooled to 0 °C. The batch was then filtered, and the cake was washed with 2-propanol (3 x 200 mL) and dried under vacuum to provide (S)-2-((4- (hydroxymethyl)phenethyl)-carbamoyl)-2-methylpyrrolidin-1-ium chloride ((VII), 72.2 g, 97 wt%, 89% yield) as a crystalline white solid.

[0081] 1H NMR (500 MHz, DMSO-d6) δ 8.60 (t, J = 5.5 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 5.14 (t, J = 5.6 Hz, 1H), 4.45 (d, J = 5.5 Hz, 2H), 3.43 – 3.30 (m, 2H), 3.21 – 3.11 (m, 2H), 2.75 (t, J = 7.0 Hz, 2H), 2.15 – 2.09 (m, 1H), 1.99 – 1.86 (m, 2H), 1.71 – 1.61 (m, 1H), and 1.52 (s, 3H) ppm.13C NMR (125 MHz, DMSO) δ 170.6, 140.4, 137.3, 128.4, 126.4, 68.7, 62.6, 43.9, 40.7, 35.3, 34.3, 22.4, and 21.2 ppm.

[0082] Example 4: Synthesis of hemi-sulfuric acid solvate-monohydrate of (S)-1-((S)-2-amino- 3-(4-methoxyphenyl)propanoyl)-N-(4-(hydroxymethyl)phenethyl)-2-methylpyrrolidine-2- carboxamide ((X))25887acid ((VIII), 50.6 g, 171 mmol), (S)-2-((4-(hydroxymethyl)phenethyl)carbamoyl)-2-methylpyrrolidin- 1-ium chloride ((VII), 50 g, 155 mmol, 92.8 wt%), and 2-pyridinol 1-oxide (3.52 g, 31.0 mmol) in MTBE (200 mL) was added N,N-diisopropylethylamine (13.6 mL, 78 mmol) followed by N,O-bis(trimethylsilyl)acetamide (26.9 mL, 109 mmol) at 20-35 °C. The slurry was then warmed to 35 °C and a solution of EDC (35.7 g, 186 mmol) and N,N-diisopropylethylamine (46.3 mL, 264 mmol) in MeCN (200 mL, held at 35 °C) was then added over 6 h. The batch was aged for a further 10 h before being diluted with MTBE (150 mL). The biphasic mixture was washed with H2SO4 (5% aq, 2 x 100 mL). The organics were diluted with water (80 mL), then MsOH (18.2 mL, 279 mmol) was added. The biphasic mixture was aged at 50 °C for 16 h before being cooled to 25 °C. Tert-amyl alcohol (250 mL) and NaOH (10% aq, 200 mL) were charged, and the biphasic mixture was agitated for 3 h. The layers were separated, and the organic layer was washed with Na2SO4 (10% aq, 150 mL). The organics were concentrated to ~350 mL under vacuum at 50 °*C. Further, tert-amyl alcohol (300 mL) was charged and the batch was concentrated to about 350 mL under vacuum at 50 °C, before being adjusted to 40 °C. In a separate vessel, a solution of sulfuric acid (50 wt% aq, 10.9 mL, 78 mmol) in tert-amyl alcohol (150 mL) was prepared. Approximately 20% of the sulfuric acid solution was charged to the main batch over 1 h, which was then seeded and aged. The remaining sulfuric acid solution was25887 charged over 8 h, followed by MTBE (275 mL) over 3 h. The slurry was cooled to 25 °C, filtered, and the cake was washed with t-AmOH / MTBE / H2O (2:1:0.1 v / v / v, 2 x 150 mL), and dried under vacuum to provide (S)-1-((S)-2-amino-3-(4-methoxyphenyl)propanoyl)-N-(4- (hydroxymethyl)phenethyl)-2-methylpyrrolidine-2-carboxamide hemisulfate hydrate ((X), 65.5 g, 82% yield).

[0084] 1H NMR (500 MHz, D2O) δ 7.32 (d, J = 7.9 Hz, 2H), 7.25 (d, J = 8.0 Hz, 4H), 6.99 (d, J = 8.5 Hz, 2H), 4.55 (s, 2H), 4.43 (t, J = 7.1 Hz, 1H), 3.80 (s, 3H), 3.78 – 3.72 (m, 1H), 3.56 – 3.41 (m, 2H), 3.37 – 3.27 (m, 1H), 3.12 (dd, J = 14.4, 6.5 Hz, 1H), 2.95 (dd, J = 14.4, 7.7 Hz, 1H), 2.81 (t, J = 6.8 Hz, 2H), 2.04 – 1.92 (m, 1H), 1.91 – 1.73 (m, 3H), 1.51 (s, 3H).13C NMR (126 MHz, D2O) δ 175.02, 166.98, 158.56, 138.51, 138.49, 130.93, 129.20, 127.67, 126.11, 114.57, 68.11, 63.62, 55.41, 53.26, 48.50, 40.66, 38.83, 34.76, 34.24, 23.23, 19.87.

[0085] Example 5: Synthesis of mono-hydrochloric acid hemi-2-butyl alcohol solvate of (S)-1- ((S)-2-amino-3-(4-methoxyphenyl)propanoyl)-N-(4-(hydroxymethyl)phenethyl)-2- methylpyrrolidine-2-carboxamide ((X)) Cl BocHN H H2Nthen added slowly to a crude solution of tert-butyl ((S)-1-((S)-2-((4- (hydroxymethyl)phenethyl)carbamoyl)-2-methylpyrrolidin-1-yl)-3-(4-methoxyphenyl)-1- oxopropan-2-yl)carbamate ((IX), 27.0 g, 50.8 mmol) in 2-BuOH (108 mL) at 45 °C. The reaction solution was aged at 45 °C then seeded with (X). The resulting slurry was aged at 45 °C then cooled to 40 °C and MTBE (135 mL) was added dropwise over 3 h. The slurry was then cooled to room temperature before being filtered. The wet cake was washed with MTBE / 2-BuOH (2:1, 2 x 80 mL) and dried under vacuum to provide (S)-1-((S)-2-amino-3-(4- methoxyphenyl)propanoyl)-N-(4-(hydroxymethyl)phenethyl)-2-methylpyrrolidine-2- carboxamide chloride 2-BuOH hemisolvate ((X), 23.3 g, 89% yield) as a white crystalline solid.25887

[0087] 1H NMR (500 MHz, D2O) δ 7.35 (d, J = 7.9 Hz, 2H), 7.32 – 7.25 (m, 4H), 7.03 (d, J = 8.5 Hz, 2H), 4.58 (s, 2H), 4.46 – 4.40 (m, 1H), 3.88 – 3.73 (m, 4.5H), 3.62 – 3.53 (m, 1H), 3.52 – 3.44 (m, 1H), 3.44 – 3.35 (m, 1H), 3.16 (dd, J = 14.5, 6.0 Hz, 1H), 2.97 – 2.75 (m, 3H), 2.07 – 1.95 (m, 1H), 1.95 – 1.76 (m, 3H), 1.58 – 1.40 (m, 4H), 1.18 (d, J = 6.3 Hz, 1.5H), 0.91 (t, J = 7.5 Hz, 1.5H).13C NMR (126 MHz, D2O) δ 175.1, 166.9, 158.6, 138.6, 138.4, 130.9, 129.3, 127.7, 126.1, 114.6, 69.4, 68.1, 63.6, 55.4, 53.4, 48.5, 40.6, 38.8, 34.6, 34.2, 30.8, 23.3, 21.4, 19.8, 9.2. Example 6: Method for Obtaining X-Ray Powder Diffraction Patterns

[0088] Powder X-ray Diffraction data were acquired on a Panalytical X-pert Pro PW3040 System configured in the Bragg-Brentano configuration and equipped with a Cu radiation source with monochromatization to Kα achieved using a Nickel filter. A fixed slit optical configuration was employed for data acquisition. Data were acquired between 2 and 40° 2θ. Samples were prepared by gently pressing powdered sample onto a shallow cavity zero background silicon holder.

[0089] Tables 1-2 provide the major 2θ peaks and d-spacings for each of the crystalline forms of the compound of Formula (X). Table 1: Diffraction peaks and corresponding d-spacings for crystalline form of the hemi-sulfuric acid salt of the compound of Formula (X).25887 ° ÅTable 2: Diffraction peaks and corresponding d-spacings for crystalline for of the hydrochloric acid salt of the compound of Formula (X). Peak Number Position [°2θ] d-spacing [Å]

[0090] The d ic embodimentsand examples described herein. Indeed, various modifications of the disclosure in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

[0091] All figures and references (e.g., publications or patents or patent applications) cited herein are incorporated herein by reference in their entirety and for all purposes to the same25887 extent as if each individual reference (e.g., publication or patent or patent application) was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the following claims.

Claims

25887 WHAT IS CLAIMED IS:

1. A process for preparing a compound of Formula (X): H2N or a salt, hydrate, orreacting compounds of Formulae (V), (VI), and (VIII): OH HN BocHN or salts,deprotecting the first intermediate, wherein the first intermediate is a compound of Formula (IX): BocHN or a salt, hydrate, or2. The process of claim 1, wherein the reacting step comprises the steps of: reacting the compounds of Formulae (V) and (VI) or the salts, hydrates, or solvates thereof to form a second intermediate; and reacting the second intermediate and the compound of Formula (VIII) or the salt, hydrate, or solvate thereof to form the first intermediate, wherein the second intermediate is a compound of Formula (VII):25887or a salt, hydrate, or solvate 3. The process of Claim 1 or 2, further comprising the step of: crystallizing the deprotected first intermediate to provide the compound of Formula (X) as a crystalline salt.

4. The process of claim 3, wherein the crystalline salt is a crystalline hemi-sulfuric acid salt.

5. The process of claim 3, wherein the crystalline salt is a crystalline hydrochloric acid salt.

6. The process of any one of claims 1-5, wherein the compound of Formula (V) or the salt, hydrate, or solvate thereof is prepared by deformylating a compound of Formula (IV): or a salt, hydrate, or solvate7 The process of claim 6, wherein the compound of Formula (IV) or the salt, hydrate, or solvate thereof is prepared by reducing a compound of Formula (III): or a salt, hydrate, or solvate8. The process of claim 7, wherein the compound of Formula (III) or the salt, hydrate, or solvate thereof is prepared by reacting a compound of Formula (I):25887or a salt, hydrate, or solvate thereof (II): O or a salt, hydrate, or solvate thereof.

9. A compound of Formula (X): H2N or a salt, hydrate, or10. A crystalline form of the compound of Claim 9, or a salt, hydrate or solvate thereof.

11. The crystalline form of Claim 10, wherein the crystalline form is of the hemi-sulfuric acid salt of the compound of Formula (X), or a hydrate or solvate thereof.

12. The crystalline form of Claim 10, wherein the crystalline form is of the hydrochloric acid salt of the compound of Formula (X), or a hydrate or solvate thereof.

13. The process of Claim 8, wherein a palladium catalyst, a base and a solvent are present when reacting the compound of Formula (I) or a salt, hydrate, or solvate thereof with a compound of Formula (II) or a salt, hydrate, or solvate thereof, wherein a) the palladium catalyst is selected from Pd(OAc)2, t-Bu3P Pd G2, t-Bu3P Pd G3, and PdCl2(MeCN)2; b) the solvent is selected from EtOAc, DMF, THF, IPAc, PhMe, and DME; and25887 c) the base is selected from DIPEA, triethylamine, tripropylamine, tri-n-butylamine, and tri-n-octylamine.

14. The process of Claim 9 or 13, wherein a reagent is optionally present and is selected from t-Bu3P-HBF4 and n-Bu4NBr.

15. The process of Claim 7, wherein a palladium catalyst and a solvent are present when reducing the compound of Formula (III) and the palladium catalyst is selected from Pd / C and Pd(OH)2 / C and the solvent is selected from water, 1-PrOH, methanol, isopropanol, and n- butanol.

16. The process of Claim 7 or 15, wherein a reagent is optionally present and is selected from triethylamine and hydrogen gas.

17. The process of Claim 6, wherein the deformylating agent is selected from PivCl, NaOH, HCl, and methanesulfonic acid.

18. The process of Claim 2, further comprising the steps of condensing the compound of Formula VI with a coupling agent, optionally in the presence of a base and a solvent, to form an N-carboxyanhydride intermediate, and reacting said intermediate with the compound of Formula (V) to give the compound of Formula (VII).

19. The process of Claim 18, further comprising the step of crystallizing and isolating the compound of Formula (VII).

20. The process of Claims 18 or 19, wherein the coupling agent is selected from CDI and DSC; the solvent is selected from AcCl, IPA, DMF, NMP, MeCN, THF, and IPAc; and the base is selected from DIPEA and TEA.

21. The process of Claim 1 or 2, further comprising the reacting a compound of Formula (VII) with a compound of Formula (VIII) in the presence of a coupling agent, a nucleophile additive, a solvent and a base wherein: the coupling agent is selected from EDC, TCFH, T3P, diethyl chlorophosphite, and diphenylphosphinic chloride; the nucleophilic additive is selected from HOPO and Oxyma; the25887 solvent is selected from BSA, MTBE, DMF, DMAc, and MeCN; and the base is selected from DIPEA and TEA.

22. The process of Claim 1, further comprising deprotecting the compound of Formula (IX) using a deprotecting agent, wherein the deprotecting agent is selected from methansulfonic acid and iso-butyryl chloride.

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