Process for preparing lipidated peptide and its intermediates

Abstract

The instant invention is directed to an efficient and scalable process for synthesizing a crystalline lipidated peptide, such as a compound of Formula I, wherein A- represents an anion thereof, and a process for preparing intermediate compounds useful to generate a compound of Formula I. The invention is also directed to compounds of Formula I and salts and zwitterions thereof. The invention is further directed to intermediate compounds useful in the preparation of compounds of Formula I, and salts and zwitterions thereof, as well as crystalline solid forms of these compounds.

Description

PROCESS FOR PREPARING LIPID ATED PEPTIDE AND ITS INTERMEDIATESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 667,244, filed July 3. 2024. the entire contents of which are incorporated by reference herein.FIELD OF USE

[0002] The present disclosure relates to a process for preparing a cry stalline lipidated peptide, such as a compound of Formula I,I wherein -A represents an anion thereof, and a process for preparing intermediates to make a compound of Formula I.BACKGROUND

[0003] Peptides are ubiquitous in nature and are fundamental components of many 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 ty pically leading to additional deprotection and purification steps, thereby limiting their practical application for large-scale production.

[0004] The introduction of a lipid sidechain containing a quaternary ammonium salt into a peptide further increases the challenge to synthesize and isolate pure compounds. Purification of peptides can be challenging, and cry stallization is an attractive and efficient method. Thecounterion of the quaternary ammonium must be chemically managed in order to use crystallization as a means for purification and isolation.SUMMARY

[0005] The instant disclosure is directed to an efficient and scalable process for synthesizing a crystalline form of a compound of Formula I,I wherein -A represents an anion thereof, which contains a lipid sidechain. This compound is a lipidated dipeptide derivative containing 2,3-Diamino-propionic acid (DAP) and L-alanine (DAP-Ala). The disclosure also provides salts and zwitterions of compounds of Formula I, such as the compound of Formula la. The disclosure further provides crystalline solid forms of these compounds.

[0006] The present disclosure also relates to intermediate compounds useful in the preparation of the compound of Formula I, and salts and zwitterions thereof, and to processes for preparing such intermediates and salts and zwitterions thereof. The disclosure further provides crystalline solid forms of these intermediate compounds.

[0007] The process of the instant invention prepares a compound of Formula I utilizing only two protecting groups. This process focuses on making chemically defined quaternary ammonium salts that are crystalline and allow the isolation of pure compounds.

[0008] The present disclosure solves the shortcomings of prior art processes via judicious choice of coupling conditions and protecting groups which enables the highly selective coupling of the three building blocks without the need for additional isolation, maximizing process efficiency.

[0009] The judicious selection of protecting groups and reagents minimizes the isolation of intermediates and enables the chemical control of the counter-anion in the lipid chain. This strategy can be expanded to various derivatives and bioactive molecules.

[0010] The present disclosure introduces a method for preparing a compound of Formula I to produce short peptide derivatives, removing the necessity for systematic isolation of intermediates 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.

[0011] Other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples and appended claims.

[0012] The summaiy of the technology described above is non-limiting and other features and advantages of the technology will be apparent from the following detailed description, and from the claims.BRIEF DESCRIPTIONS OF THE DRAWINGS

[0013] FIG. 1 is an X-ray powder diffraction pattern of crystalline Form I of Formula IA.

[0014] FIG. 2 is an X-ray powder diffraction pattern of crystalline Form II of Compound 4A.

[0015] FIG. 3 is an X-ray powder diffraction pattern of cry stalline Form III of Compound 4A.

[0016] FIG. 4 is an X-ray powder diffraction pattern of crystalline Form IV of Compound 4A.

[0017] FIG. 5 is an X-ray powder diffraction pattern of crystalline Form V of Compound 5.

[0018] FIG. 6 is an X-ray powder diffraction pattern of crystalline Form VI of Compound 5.DETAILED DESCRIPTION

[0019] The present disclosure pertains to novel, scalable synthesis for preparing crystalline form of a compound of Formula I:or a salt or zwiterion thereof, wherein “-A” represents an anion of Formula I. This compound is a lipidated DAP -Ala dipeptide derivative.

[0020] In a first embodiment, the process for preparing a compound of Formula I comprises the steps of: a) combining Compound 5:with isopropyl alcohol (IP A) and Acid A2 to obtain Compound 6:b) combining succinic anhydride and a first amine base with Compound 6 to obtain a solution containing a compound of Formula I; and c) isolating a compound of Formula I.

[0021] In particular embodiments, in step b), the first amine base is combined with Compound 6 before the succinic anhydride is added to this combination.

[0022] In a further embodiment of the first embodiment. Acid A2 is methanesulfonic acid (MsOH, or MSA), and A2‘ is mesylate or MsO". In a further embodiment of the first embodiment, the first amine base is triethylamine (TEA).

[0023] In a further embodiment, the process further comprises adding Acid A3 to the solution containing a compound of Formula I from step b) above, wherein Acid A3 is selected from 1,2- Ethanedisulfonic acid (EDSA), hydrochloric acid (HC1), and MsOH. In some embodiments, A3 is EDSA. In particular embodiments, A3 is EDSA dihydrate.

[0024] In second embodiment, the disclosure is directed to a process for preparing a compound of Formula I A:comprising the steps of: a) combining Compound 5 with IPA and Acid A2, wherein Acid A2 is MsOH; b) adding succinic anhydride and a first amine base; c) adding Acid A3, wherein Acid A3 is EDSA; and d) isolating a crystalline compound of Formula IA.

[0025] In a third embodiment, the disclosure is directed to a process for preparing a crystalline Compound 5 comprising the steps of: a) combining Compound 2and trimethylamine to obtain a solution containing Compound 33 b) mixing the solution containing Compound 3 with HC1, terephthalic acid, and a second amine base to obtain Compound 4A:c) combining Acid Al, water, and a water-soluble solvent with Compound 4A to obtain a solution containing Compound 4Bd) reacting Boc-conj ugated alanine (Boc-Ala) and a coupling reagent to obtain an activated Alanine (Ala) reaction mixture; e) combining the activated Ala reaction mixture from step d) with a solution containing Compound 4B, a tri-alkyl amine base, a polar aprotic solvent and antisolvent to obtain Compound 5; and f) isolating a cry s tall ine Compound 5.

[0026] In some embodiments of step c), a mixture of Compound 4B and a corresponding compound having 2 anions, Compound 4B*, is generated. In various embodiments. Compound 4B predominates in said mixture.In a further embodiment of the third embodiment, the second amine base is N,N- Diisopropylethylamine (DIPEA).

[0027] In a further embodiment of the third embodiment, Acid Al is trifluoroacetic acid (TFA) and the water-soluble solvent is acetonitrile (MeCN).

[0028] In a further embodiment of the third embodiment, the coupling reagent is 1,1'- Carbonyldiimidazole (CDI).

[0029] In some embodiments of the third embodiment, the polar aprotic solvent is MeCN and the antisolvent is IP Ac.

[0030] In a further embodiment, the tri-alkyl amine base is TEA. In a further embodiment, the tri-alkyl amine base is DIPEA. In some embodiments, an MeCN polar aprotic solvent, IP Ac antisolvent, and DIPEA tri-alkyl amine base is used.

[0031] In the embodiments of the instant invention, the processes of the disclosure may be conducted in a single vessel, as a “one-pot” process. Alternatively, the steps may be conducted sequentially. For clarity, it should be noted that any of the steps and reactions of the instant invention may occur simultaneously, or sequentially, unless otherwise specifically designated. In embodiments, the intermediate products may optionally be isolated.

[0032] In an embodiment, the invention is directed to a compound of Formula I:wherein “-A” represents an anion. In a further embodiment, the invention is directed to a cry stalline form of a compound of Formula I.

[0033] In an embodiment, a compound of Formula IA is provided:IAThe disclosure also provides salts and zwitterions of a compound of Formula IA.

[0034] Alternatively, a compound of Formula IA can be depicted as:An equivalent depiction of the structure of Fonnula IA is shown below:IA

[0035] In a further embodiment, the invention is directed to a crystalline form of a compound of Formula TA. The crystalline form of a compound of Formula IA described herein is a hemi- EDSA salt. The hemi-EDSA salt anhydrate of a compound of Formula IA is a crystalline material and is designated Form I (anhydrate). Form I may be obtained by preparing EDSA slurry’, followed by filtering and washing with 2: 1 IPA / THF and dried under vacuum.

[0036] In an embodiment, Form I (anhydrate) is characterized by an X-ray powder diffraction containing 20 values measured using CuKa radiation selected from the group consisting of about 7.96, about 13.36, and about 18.79° 20. The PXRD spectrum of Form I is illustrated in Figure 1. In certain embodiments, Form I (anhydrate) is characterized by an X-ray powder diffraction containing 20 values measured using CuKa radiation selected from the group consisting of about 7.96, about 10.66, about 13.36, about 17.97, about 18.79 , and about 19.54° 20. In certain embodiments, Form I (anhydrate) is characterized by an X-ray powder diffraction containing at least 3 20 values measured using CuKa radiation selected from the group consisting of about2.22. about 5.28. about 7.96. about 9.42. about 10.16. about 10.66, about 11.48, about 13.36. about 15.28, about 16.08, about 17.97, about 18.79, about 19.04, about 19.54, about 21.52, about 21.78, about 24.26, about 24.75, about 27.01, about 27.31, about 28.93, about 29.81, about 30.06, about 32.61, about 33.69, about 35.39, about 38.09, and about 38.78° 29.

[0037] In an embodiment, the invention is directed to Compound 2., or a salt or zwitterion thereof.

[0038] In an embodiment, the invention is directed to Compound 3,or a salt or zwiterion thereof. In a further embodiment, the invention is directed to a crystalline form of Compound 4A that is one of Form II, Form III or Form IV, each being a hydrate. In particular embodiments, Form II of Compound 4A is provided. As such, crystalline forms of Compound 4A are provided having an X-ray powder diffraction patern substantially similar to that set forth in Figure 2.

[0040] In an embodiment, Form II (hydrate) is characterized by an X-ray powder diffraction containing 20 values measured using CuKa radiation selected from the group consisting of about 5.93, about 11.91 and about 24.55° 20. In certain embodiments, Form II is characterized by an X-ray powder diffraction containing at least 3 29 values measured using CuKa radiation selected from the group consisting of about 5.93, about 11.91, about 12.92, about 19.65, about 24.55 and about 26.54° 20. In certain embodiments, Form II is characterized by an X-ray powder diffraction containing at least 3 20 values measured using CuKa radiation selected from the group consisting of about 5.93, about 6.02, about 8.11, about 9.00, about 11.10, about 11.91. about 12.92, about 15.73, about 16.38. about 17.25. about 18.00, about 18.55, about 19.05. about 19.42, about 19.65, about 20.51, about 21.32, about 21.93, about 22.60, about 22.98, about 23.22, about 23.65, about 24.03, about 24.55, about 24.84, about 25.38, about 26.20, about 26.54, about 27.07, about 27.88, about 29.46, about 30.16, about 31.07, about 31.40, about 31.82, about 32.17, about 33.08, about 34.88, about 35.48. about 36.55, about 37.02, about 37.67, about 38.66. about 39.15, and about 39.41° 20.

[0041] In an embodiment, Form III (hydrate) is characterized by an X-ray powder diffraction containing 20 values measured using CuKa radiation selected from the group consisting of about 8.84, about 23.21, and about 23.56° 20. In certain embodiments, Form III (hydrate) is characterized by an X-ray powder diffraction containing at least 3 20 values measured using CuKa radiation selected from the group consisting of about 8.84, about 16.34, about 20.43, about 22.51, about 23.21, and about 23.56° 20. In certain embodiments, Form III (hydrate) is characterized by an X-ray powder diffraction containing at least 3 20 values measured using CuKa radiation selected from the group consisting of about 6.02. about 8. 17. about 8.84. about 1 1.83, about 13.03, about 15.10, about 16.34, about 16.62, about 16.83, about 17.63, about 18.21, about 19.08, about 19.43, about 20.43, about 21.15, about 21.40, about 21.67, about 22.04, about 22.51, about 23.21, about 23.56, about 24.06, about 24.26, about 24.60. about 24.94, about 25.21, about 25.90, about 26.97, about 27.46. about 28.04, about 28.28, about 29.30, about 30.03. about 30.59, about 31.18, about 33.57, about 34.24, about 36.84, about 37.52, about 38.34, and about 39.14° 20.

[0042] In an embodiment, Form IV (hydrate) is characterized by an X-ray powder diffraction containing 20 values measured using CuKa radiation selected from the group consisting of about 6.03, about 12.02, and about 19.71° 20. In certain embodiments, Form IV (hydrate) is characterized by an X-ray powder diffraction containing at least 3 20 values measured using CuKa radiation selected from the group consisting of about 6.03. about 12.02, about 17.93, about 19.45, about 19.71 and about 20.51° 20. In certain embodiments, Form IV (hydrate) is characterized by an X-ray powder diffraction containing at least 3 20 values measured using CuKa radiation selected from the group consisting of about 2.10, about 6.03, about 7.97, about 8.12, about 8.44, about 9.08. about 9.95. about 11.05, about 12.02, about 12.93, about 15.74. about 16.43, about 17.30, about 17.93, about 18.62, about 19.03, about 19.45, about 19.71, about 20.51, about 21.02, about 21.68, about 21.98, about 22.56, about 23.37, about 24.20, about 24.54, about 24.99, about 25.48, about 26.20, about 26.68, about 27.99, about 29. 12, about 30.24, about 31.09, about 31.69, and about 34.93° 20.

[0043] In some aspects, Compound 4B is provided:wherein “-A1” represents an anion. In some embodiments, salts and zwitterions of Compound 4B are provided.

[0044] In some aspects, Compound 4B* is provided:wherein “-A1” represents an anion. In some embodiments, salts and / or zwitterions of Compound 4B* are provided.

[0045] In particular embodiments, Compounds 4C and 4C*, and salts and / or zwitterions thereof, are provided:Compounds 4C and 4C* represents the embodiments of 4B and 4B*, respectively, wherein AC is trifluoroacetate (TFA).

[0046] In some aspects, Compound 5 is provided:5In some embodiments, salts and / or zwitterions of Compound 5 are provided.

[0047] In a further embodiment, the invention is directed to a crystalline form of Compound 5 selected from Form V or Form VI. In particular embodiments, Form V of Compound 5 is provided. As such, crystalline forms of Compound 5 are provided having an X-ray powder diffraction pattern substantially similar to that set forth in Figure 5.

[0048] In an embodiment, Form V (hydrate) is characterized by an X-ray powder diffraction containing at least 3 20 values measured using CuKa radiation selected from the group consisting of about 8.06, about 9.42, and about 18.91° 20. In certain embodiments, Form V (hydrate) ischaracterized by an X-ray powder diffraction containing at least 3 20 values measured using CuKa radiation selected from the group consisting of about 8.06, about 9.42, about 13.12, about 16.57, about 18.91 and about 28.53° 20. In certain embodiments, Form V (hydrate) is characterized by an X-ray powder diffraction containing at least 3 20 values measured using CuKa radiation selected from the group consisting of about 8.06. 9.42, 11.76, 12.74. 13. 12, 14.33, 15.65, 16.57, 17.13, 17.83, 18.34, 18.91, 20.05, 21.19, 21.91, 23.09, 23.61, 24.36, 24.66, 25.24, 25.63, 26.65, 28.53, 32.84, and about 35.81° 20.

[0049] In an embodiment, Form VI is characterized by an X-ray powder diffraction containing at least 3 20 values measured using CuKa radiation selected from the group consisting of about7.90, about 8.86 and about 9.48° 20. In certain embodiments. Form VI is characterized by an X- ray powder diffraction containing at least 3 20 values measured using CuKa radiation selected from the group consisting of about 7.90, about 8.86 and about 9.48, about 13.16, about 15.88, and about 20.70° 20. In certain embodiments. Form VI is characterized by an X-ray powder diffraction containing at least 3 20 values measured using CuKa radiation selected from the group consisting of about 7.90, 8.86, 9.48, 11.05, 11.81, 12.48, 12.80, 13.16, 14.04, 14.39, 14.87, 15.66, 15.88, 16.40, 17.29, 17.80, 18.99, 20.34, 20.70, 20.93, 21.85, 22.22, 23.32, 23.93, 25.59,26.90, 28.32, 29.39, 30.05, 31.20, 32.13, 33.61, 34.81, 35.95, and about 37.90° 20.

[0050] In an embodiment, Compound 6 is provided:6 wherein A2‘ represents an anion. In some embodiments, salts and / or zwitterions of Compound 6 are provided.

[0051] In an embodiment, Compound 6* is provided. Compound 6* represents the embodiment wherein A2‘ is MsO’.In some embodiments, salts and / or zwitterions of Compound 6* are provided.

[0052] In some embodiments, a compound selected from Compound 6*, 4C, and 4C* is provided. In some embodiments, salts and / or zwitterions of Compounds 6*, 4C, and 4C* are provided.Characterization of Crystalline Forms

[0053] In certain embodiments, the crystalline forms provided herein are identifiable on the basis of characteristic peaks in an X-ray powder diffraction analysis. X-ray powder diffraction (PXRD) is a scientific technique using X-ray diffraction on powder, microcrystalline, or other solid materials for structural characterization of solid materials. X-ray powder diffraction studies are widely used to characterize molecular structures, crystallinity, and polymorphism.

[0054] It should also be noted that when a term is used more than once, such as base or acid, the definition at each instance is independent of a prior selection. For example, the same, or a different, amine base may be chosen for each step of the process independently of a previous selection.Definitions

[0055] Listed below are definitions of various terms used herein. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0056] 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.

[0057] As used herein, the word “antisolvenf ' refers to a solvent (e.g. a liquid) that reduces the solubility of a compound in a solution, leading to precipitation or crystallization of thecompound. A desired compound is typically less soluble in an antisolvent than in the primary solvent in which it has been dissolved.

[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. As used herein, including the appended claims, the singular forms of words such as “a,” “an,” and “the,” include their corresponding plural references unless the context clearly dictates otherwise.

[0059] As used herein, the terms “at least one” item or “one or more” item each include a single item selected from the list as well as mixtures of two or more items selected from the list.

[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. As an example, temperature ranges, percentages, ranges of equivalents, and the like described herein include the upper and lower limits of the range and any value in the continuum there between. “About” when used to modify a numerically defined parameter (e.g.. the temperature, or the length of time for a reaction, as described herein) means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter; where appropriate, the stated parameter may be rounded to the nearest whole number. For example, a temperature of about 30°C may vary between 25°C and 35°C. In addition, the term “or,” as used herein, denotes alternatives that may, where appropriate, be combined; that is, the term “or” includes each listed alternative separately.

[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 be depicted with negative or positive formal charges. In various embodiments, these compounds exist in a charged state in a solution.In solution, any of the disclosed charged compounds may exist in a different protonation, anionic and / or zwitterionic state than that depicted. As such, zwitterions of any of the disclosed compounds are provided.

[0063] 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 IA 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.

[0064] The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed 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.

[0065] The compounds of the present disclosure which contain olefinic double bounds, unless specified otherwise, are meant to include both E and Z geometric isomers.

[0066] 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.

[0067] 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.

[0068] 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 predominant 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.

[0069] 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, JV.A'-dibenzylethylene-diamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, A-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0070] 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, ethanedisulfonic fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic (MSA), mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, terephthalic, p- toluenesulfonic acid, and the like. Additional examples of such acids include aryl sulfonic acids, such as but not limited to / ?-toluenesulfomc acid, 3-methyl-toluenesulfonic acid, 2-methyl- toluenesulfonic acid, benzenesulfonic acid, 2-naphthalene sulfonic acid, 2,6-naphtalene sulfonic acid, as well as hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, hippuric acid, adipic acid, phenyl acetic acid, trimethylacetic acid, tetrafluoroboric acid, tetraphenylboric acid, trifluoroacetic acid (TFA), maleic acid, fumaric acid, oxalic acid, or camphorsulfonic acid. Particular embodiments include EDSA, MSA. TFA, TEA, terephthalic, hippuric. adipic and hydrochloric. 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 suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0071] 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 thepharmaceutically acceptable solvates and hydrates, of the present compounds are likewise encompassed within the scope of this disclosure, along with unsolvated and anhydrous forms.

[0072] The preparation of the pharmaceutically acceptable salts and other ty pical pharmaceutically acceptable salts is more fully described by Berg et al., “Pharmaceutical Salts,’' J. Pharm. Sci., 1977:66: 1-19.

[0073] In each embodiment, the first amine base and second amine base are independently selected from pyridine, triethylamine (TEA), DIPEA, and the like.

[0074] In an embodiment, Acid Al is selected from TFA, MsOH, and HC1.

[0075] In each embodiment, Acid A2 is independently selected MsOH, HC1, sulfuric acid, TFA, and EDSA.

[0076] In an embodiment, Acid A3 is selected from EDSA HC1, and MsOH.

[0077] In an embodiment, a water-soluble solvent is selected from MeCN, DMF, DMAc, NMP, THF, acetone and the like.

[0078] In a further embodiment of the third embodiment, the coupling reagent is CDI, HATU, EDC, and DCC

[0079] In an embodiment, the polar aprotic solvent is selected from MeCN, DMF, NMP, DMAc, acetone, THF and the like.

[0080] In an embodiment, an antisolvent is selected from IP Ac. MTBE, toluene, hexane, EtOAc, Me-THF and the like.

[0081] Exemplary methods and materials are described herein, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure. The materials, methods, and examples are illustrative only and not intended to be limiting.GENERIC SCHEME2. Anti-SolventFormula IFormula IA

[0082] In various embodiments of the Generic Scheme, a molar equivalent of about 0.85, 0.95, 1.0, 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 of Acid Al is added to Compound 4A. In some embodiments of the Generic Scheme, after addition of Acid Al to Compound 4A, a mixture of Compounds 4B and 4B* is generated. In some embodiments, 4B and 4B:i!are present in the mixture. In some embodiments, 4B predominates. In some embodiments. 4B and 4B* are present in approximate ratios of 10: 1, 8: 1, 6: 1, 5: 1, 4: 1, 7:2, 3: 1, 5:2, 2: 1, 3:2 or 1 : 1 (w / w).

[0083] In embodiments of the above Scheme for which Acid Al is TFA, after addition of the TFA to Compound 4A, a mixture of Compounds 4C and 4C* is generated. In some embodiments, 4C and 4C* are present in the mixture. In some embodiments, 4C predominates. In some embodiments, 4C and 4C* are present in approximate ratios of 10: 1, 8: 1. 6: 1, 5: 1, 4: 1, 7:2. 3: 1, 5:2, 2: 1, 3:2 or 1 : 1.

[0084] In particular embodiments, in the final step of the General Scheme, 1 ,2-Ethanedisulfonic acid (EDSA) dihydrate is added to generate Formula IA:Formula IAABBREVIATIONSMEASUREMENTS: eq. / equiv. Equivalent mg Milligram min minutes h hours ml. mL MilliliterL LiterM MolarMHz Megahertz v / v by volume w / w by weight wt% weight percent mmHg millimeters of Mercury psi pounds per square inchNMR nuclear magnetic resonanceAla AlanineBoc tert-Butyloxy carbonylCDI 1, 1 '-CarbonyldiimidazoleDCC DicyclohexylcarbodiimideDAP (2R)-2,3-Diaminopropionic acidDIPEA N,N-DiisopropylethylamineDMAc N.N-DimethylacetamideDMF DimethylformamideEDC 1 -Ethyl-3-(3-dimethylaminopropyl)carbodiimideEDS A 1 ,2-Ethanedisulfonic acid DihydrateHATU Hexafluorophosphate Azabenzotriazole Tetramethyl UroniumIPA Isopropyl alcoholIP Ac Isopropyl AcetateMeCN AcetonitrileMe3N TrimethylamineMSA, MsOH methanesulfonic acidMe-THF 2-MethyltetrahydrofuranMTBE Methyl tert-butyl etherNMP N-methylmorpholinePXRD X-ray Powder DiffractionTEMPO (2,2,6,6-Tetramethylpiperidin-l-yl)oxylTFA Trifluoroacetic acidTEA TriethylamineTHF tetrahydrofuran

[0085] Additional abbreviations may be defined throughout this disclosure.EXAMPLES

[0086] The following examples are meant to be illustrative and should not be construed as further limiting. The contents of the figures and all references, patents, and published patent applications cited throughout this application are expressly incorporated herein by reference.EXAMPLE 16-Chlorohexanol 1

[0087] In a cylindrical vessel under nitrogen, 6-chlorohexanol (100 g. 0.73 mol, 1 eq) was charged to a stirring solution of sodium dihydrogen phosphate dihydrate (285 g, 1.83 mol, 2.5 eq) in 600 mL (6 vol) water at 20 °C. 800 mL (8 vol) IP Ac, TEMPO (5.7 g, 0.07 mol, 0.05 eq) and 10% sodium hypochlorite solution (52.1 g, 0.04 mol, 0.1 eq) was sequentially charged to the vessel. The resulting biphasic mixture was stirred at 20 °C for 30 min. Aqueous sodium chlorite solution (449 g, containing 99 g sodium chlorite, 1.10 mol, 1.5 eq) was charged slowly to maintain batch temperature below 25 °C. The resulting mixture was agitated for 10 h. 20 wt% sodium sulfite solution (100 g, 1 vol) was charged slowly to quench the reaction. After phase separation, the organic layer was collected and extracted with 1.2 M sodium bicarbonate solution twice (9 + 3 vol). The resulting aqueous layers were combined, and the pH was adjusted to 3-5 by addition of 2 M HC1 (750 g). The resulting aqueous solution was extracted with 500 mL IP Ac twice (2x 5 vol). The combined organic layers were washed with 300 mL (3 vol) pure water. The resulting organic solution was concentrated under vacuum to afford Compound 1 (6- chlorohexanoic acid) as a solution (35 wt% in IPAc).EXAMPLE 2

[0088] In a cylindrical vessel under nitrogen, Compound 1 in IPAc (100 g. 0.664 mol, 1 eq) and 400 mL (4 vol) DMF was distilled under vacuum below 40 °C to remove IPAc (residual IPAc < 10%). CDI (102 g, 0.63 mol, 0.95 eq) was added portion-wise while maintaining batch temperature between 20-30 °C. The resulting mixture was agitated for 2 h at 25 °C. TEA (168 g, 1.66 mol, 2.5 eq) and Boc-D-DAP-OH (133 g, 0.65 mol, 0.98 eq) were charged. The resulting mixture was agitated for 4 h at 25 °C. Water (800 mL) was charged to quench the reaction. 2 M HC1 was charged slowly to adjust pH to 4.1-4.6. The resulting mixture was agitated at 20 °C for 1 h, and the pH was adjusted to 2.0-3.5 by charging 2 M HC1 slowly. The resulting slurry wasfiltered, and the filter cake was washed with 400 mL DMF / water (1 / 5, v / v) and 2x 400 mL water. The wet cake was dried below 55 °C under vacuum, to provide Compound 2 as solids.EXAMPLE 2A

[0089] In a cylindrical vessel under nitrogen, Compound 1 in IP Ac (100 g, 0.664 mol, 1 eq) and 400 mL (4 vol) DMF was distilled under vacuum below 40 °C to remove IP Ac (residual IP Ac < 10%). CDI (102 g, 0.63 mol, 0.95 eq) was added portion-wise while maintaining batch temperature between 20-30 °C. The resulting mixture was agitated for 2 h at 25 °C. TEA (168 g, 1.66 mol, 2.5 eq) and Boc-D-DAP-OH (133 g, 0.65 mol, 0.98 eq) were charged. The resulting mixture was agitated for 4 h at 25 °C. Water (800 mL) was charged to quench the reaction. 2 M HC1 was charged slowly to adjust pH to 4.1-4.6. Compound 2 (1 g, 1 wt%) was charged as seed. The resulting mixture was agitated at 20 °C for 1 h. and the pH was adjusted to 2.0-3.5 by charging 2 M HC1 slowly. The resulting slurry was filtered, and the filter cake was washed with 400 mL DMF / water (1 / 5, v / v) and 2x 400 mL water. The wet cake was dried below 55 °C under vacuum, to provide Compound 2 as solids. 'H NMR (400 MHz, Chloroform-J) 5 6.53 (s, 1H), 6. 11 (s, OH), 4.24 (q. J= 4.3 Hz. 1H), 3.83 (s, 1H), 3.56 (t, J= 6.6 Hz, 2H), 2.29 (t, J= 7.5 Hz, 4H), 1.75 (ddt, J = 49.0, 15.3, 7.1 Hz, 3H), 1.54 (m, 2H), 1.48 (s, 9H).EXAMPLE 3

[0090] In a pressure vessel, Compound 2 (100 g, 0.297 mol, 1 eq) and 30% aqueous MeaN solution (410 g, 2.08 mol, 7 eq) was heated at 50 °C for 18 h and aged until reaching >99 % conversion. The reaction mixture was cooled to 25 °C and distilled to 2.2 vol below 55 °C under vacuum with nitrogen bubbling. The concentrated reaction mixture was diluted with 50 mL water to afford Compound 3 as a solution.3

[0091] In a cylindrical vessel under nitrogen, 35% HC1 (72.5 g, 0.695, 2.5 eq) was charged slowly into a stirring solution of Compound 3 in water (100 g, 0.278 mol, 1 eq) while maintaining temperature at 15-25 °C. The resulting reaction mixture was agitated at 22 °C for 16 h, before cooling down to 0 °C. Terephthalic acid (43.9 g, 0.264 mol. 0.95 eq) and DIPEA (158 g, 1.22 mol, 4.4 eq) were charged slowly to the reaction mixture while maintaining temperature below 5 °C. The resulting mixture was warmed up to 10 °C and agitated for 3 h. DMAc (400 mb (4 vol)) was added, and the resulting mixture was cooled to 0 °C and agitated overnight until a slurry had formed. DMAc (350 mb (3.5 vol)) and IPA (750 mL (7.5 vol)) was added slowly. The resulting slurry mixture was agitated at 0 °C for 10 h before filtration at 0 °C. The filtrate cake was washed with 210 g water / DMAc / IPA (1 / 4 / 4, v / v / v) and 200 ml (2 vol) IPA. The wet cake was dried under vacuum below 60 °C to afford Compound 4A as solids.EXAMPLE 4A

[0092] In a cylindrical vessel under nitrogen, 35% HC1 (72.5 g, 0.695, 2.5 eq) was charged slowly into a stirring solution of Compound 3 in water (100 g, 0.278 mol, 1 eq) while maintaining temperature at 15-25 °C. The resulting reaction mixture was agitated at 22 °C for 16 h, before cooling down to 0 °C. Terephthalic acid (43.9 g, 0.264 mol, 0.95 eq) and DIPEA (158 g, 1.22 mol, 4.4 eq) were charged slowly to the reaction mixture while maintaining temperature below 5 °C. The resulting mixture was warmed up to 10 °C and agitated for 3 h. DMAc (400 mL (4 vol)) and Compound 4A seed (0.1 g) was added, and the resulting mixture was cooled to 0 °C and agitated for 3 h. DMAc (350 mL (3.5 vol)) and IPA (750 mL (7.5 vol)) was then added slowly. The resulting slurry mixture was agitated at 0 °C for 10 h before filtration at 0 °C. The filtrate cake was washed with 210 g water / DMAc / IPA (1 / 4 / 4, v / v / v) and 200 ml (2 vol) IPA. The wet cake was dried under vacuum below 60 °C to afford compound 4A as a solid. ‘H NMR (400MHz, Deuterium Oxide) 5 7.79 (s. 2H), 3.79 (dd, J = 6.7. 3.6 Hz. 1H), 3.64 (dd, J = 14.9, 3.6 Hz, 1H), 3.48 (dd, J= 14.9, 6.7 Hz, 1H), 3.20 - 2.99 (m, 2H), 2.92 (s, 9H), 2.14 (t, J= 7.5 Hz, 2H), 1.65 - 1.51 (m, 2H), 1.46 (p, J= 7.6 Hz, 2H), 1.15 (p, J= 7.6 Hz, 2H).13C NMR (101 MHz, Deuterium Oxide) 5 177.91, 174.66, 171.89, 138.70, 128.68, 66.28. 55.02, 52.87 - 52.47 (m), 39.81, 35.06. 24.87, 24.41, 21.94.Boc-Ala

[0093] To a solution of MeCN (4.00 L). water (0.18 L). and TFA (0.40 L, 3.50 mol).Compound 4A (1.00 kg, 2.92 mol) was added at 25 °C. The reaction mixture was aged at 25 °C for 2 hours. The resulting slurry was filtered to remove terephthalic acid, and this waste cake was washed with 98.8: 1.2 MeCN:Water (1.50 L). The resulting filtrates of Compound 4B were charged to a clean vessel and cooled to 0 °C.

[0094] In a separate vessel, to a solution of IPAc (1.80 L) and MeCN (0.36 L), CDI (0.64 kg, 3.94 mol) was added at 25 °C. The slurry was cooled to 0 °C. To the slurry, Boc-L-Ala (0.75 kg, 3.94 mol) was added at 0 °C. The Activated Ala reaction mixture was aged at 0 °C for 2 hours, then added to the solution containing Compound 4B.

[0095] Form II (hydrate) of Compound 4A was obtained by preparing a slurry of crude Compound 4A in any one of the following solvents: ethyl acetate, isopropanol, acetone, di chloromethane, MeCN, THF, 1 -propanol, DMAc, ethanol, 2-methyl THF, cyclopen tylmethyl ether (CPME), toluene, methanol, and DMSO / H2O; followed by air drying to afford a crystalline solid. In some aspects, a slurry is formed at 50 °C. In some aspects, a slurry is formed at 25 °C. In some aspects, a slurry is formed at 6 °C. Form II was characterized by PXRD. The PXRD spectrum is illustrated in Figure 2.

[0096] Form III (hydrate) of Compound 4A was obtained by preparing a slurry of crude Compound 4A in acelonilrile / FbO 9: 1 ratio (v / v), followed by air drying to afford a crystalline solid. Form III was characterized by PXRD, and the PXRD spectrum is illustrated in Figure 3. Form IV (hydrate) of compound 4A may be obtained by heating Form III to 160 °C at a rate of 10 °C per minute. The PXRD spectrum of Form IV is illustrated in Figure 4.

[0097] The resulting crude solution containing Compound 5 was warmed to 25 °C, and DIPEA (1.02 L, 5.84 mmol) was charged over 30 minutes and the batch was aged for overnight. To the resulting slurry, IPAc (14.00 L) was added over 6 hours. The slurry was cooled to 0 °C and aged for 1 hour. The resulting white slurry was filtered, and the cake washed with 3: 1 IPAc:MeCN + 0.45% water (2.00 L) and followed by pure IPAc (2.00 L). The wet cake was dried under vacuum at 50 °C to afford Compound 5 as a crystalline solid. In an alternate embodiment of this exemplary method, the wet cake was dried under vacuum at ambient temperature to afford Compound 5 as a crystalline solid.

[0098] Form V (hydrate) of Compound 5 was obtained by preparing a slurry of crude Compound 5 in any one of the following solvents: ethyl acetate, isopropanol, acetone, dichloromethane, MeCN, THF, ethanol, 2-methyl THF, CPME, toluene, MTBE, IPAc, and DMSO / H2O; followed by air drying to afford a crystalline solid. In particular embodiments, the solvent IPAc and / or MeCN is used in the slurry. In some aspects, a slurry is formed at 50 °C. Insome aspects, a slurry is formed at 25 °C. In some aspects, a slurry is formed at 6 °C. Form V was characterized by PXRD. The PXRD spectrum is illustrated in Figure 5.

[0099] Form VI (hydrate) of Compound 5 was obtained by preparing a slurry of crude Compound 5 in methanol, followed by air drying to afford a cry stalline solid. Form VI was characterized by PXRD. The PXRD spectrum is illustrated in Figure 6.EXAMPLE 5AAlternative Process for Compound 5

[0100] To a solution of MeCN (4.00 L). water (0.18 L). and TFA (0.40 L, 3.50 mol).Compound 4A (1.00 kg, 2.92 mol) was added at 25 °C. The reaction mixture was aged at 25 °C for 2 hours. The resulting slurry was filtered to remove terephthalic acid, and this waste cake was washed with 98.8: 1.2 MeCN:Water (1.50 L). The resulting filtrates of Compound 4B were charged to a clean vessel and cooled to 0 °C.

[0101] In a separate vessel, to a solution of IPAc (1.80 L) and MeCN (0.36 L), CDI (0.64 kg, 3.94 mol) was added at 25 °C. The slurry was cooled to 0 °C. To the slurry, Boc-L-Ala (0.75 kg, 3.94 mol) was added at 0 °C. The Activated Ala reaction mixture was aged at 0 °C for 2 hours, then added to the solution containing Compound 4B.

[0102] The resulting crude solution containing Compound 5 was warmed to 25 °C, and DIPEA (1.02 L, 5.84 mmol) was charged over 30 minutes and the batch was aged for 1 hour. Compound 5 seed (5 g, 0.5 wt%) was charged, and the batch was aged overnight. To the resulting slurry', IPAc (14.00 L) was added over 6 hours. The slurry was cooled to 0 °C and aged for 1 hour. The resulting white slurry’ was filtered and the cake washed with 3: 1 IPAc: MeCN + 0.45% water (2.00 L) and followed by pure IPAc (2.00 L). The wet cake was dried under vacuum at 50 °C to afford Compound 5 as a cry stalline solid.JH NMR (400 MHz, D2O) 5: 4.50 - 4.30 (m, 1H), 4.10 (q, J= 7.2 Hz, 1H), 3.85 - 3.38 (m, 2H). 3.39 - 3.27 (m. 2H), 3.13 (s. 9H), 2.29 (t, J= TA Hz, 2H), 1.94 - 1.76 (m, 2H), 1.67 (p, J= 7.5 Hz, 2H), 1.54 - 1.29 (m, 14H).13C NMR (101 MHz, D2O) 5: 176.82, 175.60, 175.42, 157.38, 81.48, 66.43 (t, J=2.6 Hz), 54.85, 52.81 (t, J=4.0 Hz), 50.77, 41.17, 35.44, 27.66, 24.98, 24.72, 22.04, 17.08. *Triplets in carbon spectra are due to the 14N coupling constant from trimethylammonium group.

[0103] Step A: To a solution of Compound 5 (1.0 kg. 2.32 mol) in IPA (10 L). MSA (0.75 L, 11.6 mol) was added at 25 °C. The reaction mixture was aged at 55 °C for 24 h and the resulting crude solution of Compound 6 was cooled to 0 °C. To the reaction mixture, TEA (1.75 L, 12.5 mol) was added slowly to maintain contents at 0 °C followed by addition of Succinic Anhydride(0.30 kg. 3.02 mol) . The slurry was then warmed to 25 °C and aged for at least 1 h to afford a solution containing a compound of Formula I.

[0104] Step B: In a separate vessel, a solution of EDSA was prepared by dissolving EDSA (0.37 kg, 1.62 mol) in IPA (3.7 L) at 25 °C for at least 1 h.

[0105] Step C: The resulting crude solution containing a compound of Formula I, was heated to52.5 °C. To the batch, 0.275 eq EDSA solution (0.638 mol) and aged overnight until a slurry is formed. To the resulting slurry', 0.275 eq EDSA solution was charged slowly over 5 h. The batch was then increased to 62.5 °C and aged for 2 h followed by cooling down the batch to 52.5 °C over 3 h. THF (5.5 L) was charged over 5 h to maintaining batch temperature at 52.5 °C. The batch was then cooled to 20 °C over 4 h. To further improve liquor losses, an additional 0. 15 eq EDSA solution is added to the slurry' over 3 h. The resulting white slurry was filtered, and the cake washed with 2: 1 IPA / THF (2: 1, 2 x 8 L) and dried under vacuum to afford a compound of Formula IA as a crystalline solid.EXAMPLE 6AAlternative Process for a Compound of Formula I and Formula IA

[0106] Step A: To a solution of Compound 5 (1.0 kg. 2.32 mol) in IPA (10 L). MSA (0.75 L,11.6 mol) was added at 25 °C. The reaction mixture was aged at 55 °C for 24 h and the resulting crude solution of Compound 6 was cooled to 0 °C. To the reaction mixture, TEA (1.75 L, 12.5 mol) w as added slowly to maintain contents at 0 °C followed by addition of Succinic Anhydride (0.30 kg, 3.02 mol). The slurry was then warmed to 25 °C and aged for at least 1 h to afford a solution containing a compound of Formula I.

[0107] Step B: In a separate vessel, a solution of EDSA was prepared by dissolving EDSA (0.37 kg, 1.62 mol) in IPA (3.7 L) at 25 °C for at least 1 h.

[0108] Step C: The resulting crude solution containing a compound of Formula I, was heated to 52.5 °C. To the batch. 0.275 eq EDSA solution (0.638 mol) and aged overnight until a slurry is formed. Seeds of compound IA were added, and aged for at least 30 minutes. To the resulting slurry', 0.275 eq EDSA solution was charged slowly over 5 h The batch was then increased to 62.5 °C and aged for 2 h followed by cooling down the batch to 52.5 °C over 3 h. THF (5.5 L) was charged over 5 h to maintaining batch temperature at 52.5 °C. The batch was then cooled to 20 °C over 4 h. To further improve liquor losses, an additional 0.15 eq EDSA solution is added to the slurry' over 3 h. The resulting white slurry was filtered, and the cake washed with 2: 1 IPA / THF (2: 1, 2 x 8 L) and dried under vacuum to afford a compound of Formula IA as a cry stalline solid. 'H NMR (500 MHz. 1: 1 CD3CN / D2O): 5 5.48 (hept, J = 6.2 Hz, 1H), 4.95 (dd, J = 8.0, 4.8 Hz, 1H), 4.77 - 4.71 (m. 1H), 4.15 (dd, J = 14.1, 4.8 Hz, 1H), 3.91 (dd, J = 14.1, 8.0 Hz, 1H). 3.79 -3.71 (m, 2H), 3.64 (s, 2H). 3.55 (s, 9H). 3.22 - 2.97 (m, 4H). 2.71 (t. J = 7.5 Hz. 2H), 2.30 - 2.20 (m, 2H), 2.10 (p, J= 7.4 Hz, 2H), 1.83 (dd, J= 15.3, 7.5 Hz, 5H), 1.78 - 1.70 (m, 6H).13C NMR (125 MHz, 1:1 CD3CN / D2O): 5 176.68, 176.52, 175.05, 174.46, 170.77, 70.86, 66.81, 53.31, 53.28, 53.25, 53.21, 50.08, 47.17, 40.02, 35.71, 30.42, 29.49, 25.52, 25.16, 22.55, 21.35, 21.34. 17.19.Example 7 : Method for Obtaining X-Ray Powder Diffraction Paterns

[0109] 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 Ka achieved using a Nickel filter. A fixed slit optical configuration was employed for data acquisition. Data were acquired between 2 and 40° 20. Samples were prepared by gently pressing powdered sample onto a shallow cavity zero background silicon holder.

[0110] Tables 1-6 provide the major 29 peak positions (“Pos.”) and d-spacings for each of the isolated cry stalline forms described herein. “Rel. Int.’' refers to relative intensities.Table T. Diffraction peaks and corresponding d-spacings for crystalline Form ITable 2'. Diffraction peaks and corresponding d-spacings for cry stalline Form IITable 3: Diffraction peaks and corresponding d-spacings for crystalline Form IIITable 4\ Diffraction peaks and corresponding d-spacings for crystalline Form IVTable 5: Diffraction peaks and corresponding d-spacings for crystalline Form VTable 6: Diffraction peaks and corresponding d-spacings for cry stalline Form VI

Claims

CLAIMSWhat is claimed is:

1. A process for preparing a compound of Formula I,l wherein -A represents an anion, comprising the steps of: a) combining Compound 55 with 1PA and Acid A2 to obtain Compound 66 b) combining succinic anhydride and a first amine base with Compound 6 to obtain a solution comprising a compound of Formula I; and c) isolating a compound of Formula I.

2. The process according to Claim 1. wherein Acid A2 is MsOH, and A2- is mesylate orMsO".

3. The process according to Claim 1, wherein the first amine base is TEA.

4. The process according to Claim 1, wherein the process further comprises adding Acid A3 to the solution comprising a compound of Formula I from step b), wherein Acid A3 is selected from EDSA. HC1, and MsOH.

5. A process for preparing a compound of Formula I A:IA comprising the steps of: a) combining Compound 5 with IPA and Acid A2, wherein Acid A2 is MsOH; b) adding succinic anhydride and a first amine base; c) adding Acid A3, wherein Acid A3 is EDSA; and d) isolating a crystalline compound of Formula IA.

6. The process according to Claim 1, wherein the process further comprises preparing a crystalline Compound 5 comprising the steps of: a) combining Compound 22 and trimethylamine to obtain a solution comprising Compound 3b) mixing the solution comprising Compound 3 with HC1, terephthalic acid and a second amine base to obtain Compound 4Ac) combining Acid Al, water, and a water-soluble solvent with Compound 4A to obtain a solution comprising Compound 4Bd) reacting Boc-Ala and a coupling reagent to obtain an activated Ala reaction mixture; e) combining the activated Ala reaction mixture from step d) with a solution comprising Compound 4B, a tri-alkyl amine base, apolar aprotic solvent and antisolvent to obtain Compound 5; and f) isolating a crystalline Compound 5.

7. The process according to Claim 6, wherein the second amine base is DIPEA.

8. The process according to Claim 6, wherein the Acid Al is TFA and the water-soluble solvent is MeCN.

9. The process according to Claim 6, wherein the coupling reagent is CDI.

10. The process according to Claim 6, wherein the polar aprotic solvent is MeCN and the antisolvent is IP Ac.

11. A compound of Formula 1:I or a salt or zwitterion thereof, wherein -A represents an anion.

12. The compound of Claim 11, wherein the compound has the structure set forth in Formula IA:IA or a salt or zwitterion thereof.

13. A crystalline form of the compound of Claim 12, characterized by an X-ray powder diffraction pattern including peaks at about 7.96, about 13.36, and about 18.79 degrees 20, wherein the X-ray powder diffraction pattern is obtained using a Cu Ka radiation source (1.54 A).

14. The crystalline form of the compound of Claim 12 having an X-ray powder diffraction pattern substantially similar to that set forth in FIG. 1.or a salt or zwitterion thereof.

16. A compound selected fromor a salt or zwitterion thereof.

17. The compound of Claim 15, wherein the compound isor a salt or zwitterion thereof.

18. A crystalline form of the compound of Claim 17 having an X-ray powder diffraction pattern substantially similar to that set forth in FIG. 2.

19. The compound of Claim 15, wherein the compound is5 or a salt or zwitterion thereof.

20. A crystalline form of the compound of Claim 19 having an X-ray powder diffraction pattern substantially similar to that set forth in FIG. 5.

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