Process for preparing n-aminoalkylated tryptophan compounds

Abstract

The present invention relates to processes useful in the synthesis of aminohexyl compounds, such as a compound of Formula I or a salt, hydrate and / or solvate thereof, as well as methods for the preparing a compound of Formula I and intermediates used to make a compound of Formula I. The present invention presents a novel method for the selective alkylation of tryptophan analogues, eliminating the need for protecting groups and advancing the field of tryptophan analogue synthesis.

Description

PROCESS FOR PREPARING N-AMINOALKYLATED TRYPTOPHAN COMPOUNDSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 611,847 filed December 19, 2023, the entire contents of which are incorporated by reference herein.BACKGROUND

[0002] Tryptophan and its related analogues are ubiquitous in nature, serving as essential components in various biologically active molecules. However, their preparation, particularly at a scale conducive to economic viability, poses significant challenges. Current synthetic methods often involve the intricate use of protecting groups and their subsequent removal, including orthogonal protecting groups due to the high degree of functionality inherent in these molecules.

[0003] One of the central difficulties in the synthesis of tryptophan analogues lies in the lack of precedent for the selective functionalization of the indole nitrogen without the employment of protecting groups. Existing methodologies typically require complex and time-consuming steps, limiting their practicality for large-scale production.

[0004] This present invention is directed to an unprecedented process that is a significant advancement in the field of tryptophan analogue synthesis.SUMMARY

[0005] The present invention relates to processes useful in the synthesis of N-aminoalkylated tryptophan compounds, such as a compound of Formula Ior a salt, hydrate and / or solvate thereof, as well as intermediates used to make a compound of Formula I or a salt, hydrate and / or solvate thereof.

[0006] The present invention pertains to a method for the selective alkylation of tryptophan analogues without the need for protecting groups. The long-standing challenges have beenaddressed by introducing a novel approach to selectively alkylate tryptophan analogues with both saturated and unsaturated electrophiles possessing nucleophilic residues, such as amines or alcohols, in a single step. The method developed herein eliminates the need for protecting groups, streamlining the synthesis process, enhancing its efficiency and permitting scalability.

[0007] The instant invention also is directed to a robust method for the synthesis of l-amino-6- bromohexane, based on the Delepine reaction, utilizing the readily available hexamethylenetetramine (HMTA) as an amine source. Amination with HMTA results in a reactive crystallization which prevents over-amination, allowing for stoichiometric amounts of reagents to be used.

[0008] The present invention presents a novel method for the selective alkylation of tryptophan analogues and advances the field of tryptophan analogue synthesis. The process offers a more efficient, cost-effective, and versatile solution for the large-scale production of these biologically significant molecules.

[0009] 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.

[0010] The summary 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.DETAILED DESCRIPTION

[0011] The present disclosure is directed to a compound of Formula I:or a salt, solvate and / or hydrate thereof, as well as methods for preparing intermediates used in the manufacturing of a compound of Formula I, or a salt, hydrate and / or solvate thereof.

[0012] In an embodiment, the process for preparing a compound of Formula I:or a salt, solvate and / or hydrate thereof, comprises the steps of: a) combining Compound 3, or a salt, solvate, and / or hydrate thereof,and Compound 2, or a salt, solvate, and / or hydrate thereof,29 in the presence of a base, wherein X is selected from a halide; and b) isolating a compound of Formula I, or a salt, solvate and / or hydrate thereof.

[0013] In a further embodiment, one or more solvents are present when combining Compound 3, or a salt, solvate, and / or hydrate thereof, with Compound 2, or a salt, solvate, and / or hydrate thereof.

[0014] In a second embodiment, the instant invention is directed to a process for preparing a compound of Formula Ior a salt, solvate and / or hydrate thereof, further comprising the steps of preparing Compound 22 or a salt, solvate and / or hydrate thereof wherein X is selected from a halide, by: a) mixing hexamethylenetetramine, a first solvent and a dihalogenated hexane to obtain Compound 1, or salt, solvate and / or hydrate thereof,wherein X and Y are independently selected from a halide; and b) reacting Compound 1. or solvate and / or hydrate thereof, with a second solvent and an additive selected from hydrogen bromide or acetyl bromide to obtain Compound 2, or a salt, solvate or hydrate thereof.In a further embodiment, the process for preparing Compound 2’2' or a salt, solvate or hydrate thereof comprises the steps of: a) mixing hexamethylenetetramine, a first solvent and 1 ,6-dibromohexane to obtain Compound 1A, or solvate and / or hydrate thereof.b) reacting Compound 1A, or a solvate and / or hydrate thereof, with a second solvent and an additive selected from hydrogen bromide or acetyl bromide to produce a resulting mixture containing Compound 2’, or a salt, solvate and / or hydrate thereof; and c) adding a third solvent to the resulting mixture to obtain a Compound 2’, or a salt, solvate and / or hydrate thereof.

[0015] In a third embodiment, the instant invention is directed to a process for preparing a compound of Formula Ior a salt, solvate or hydrate thereof, further comprising the steps of: a) mixing a polar solvent, a base, and Compound 3, or salt, solvate and / or hydrate thereof,to obtain a mixture; b) combining Compound 2’, or salt, solvate or hydrate thereof,with the mixture to produce a reaction mixture; c) adding an acid to adjust the pH of the reaction mixture to 3 to 9; and d) adding an antisolvent to the reaction mixture to obtain a compound of Formula I or a salt, solvate and / or hydrate thereof.

[0016] In the third embodiment, alternatively, the reaction mixture from step c can be cooled to obtain a compound of Formula I, or a salt, solvate and / or hydrate thereof.

[0017] In a fourth embodiment, the instant invention is directed to a process for preparing a compound of Formula I or a salt, solvate or hydrate thereof, comprising the steps of: a) mixing hexamethylenetetramine. 1,6-dibromohexane and a first solvent to create a first slurry; b) heating the first slurry to above about 20°C to obtain Compound 1Ac) adding Compound 1A to a mixture containing a second solvent and an additive selected from hydrogen bromide or acetyl bromide; d) adding a third solvent to obtain a first mixture containing Compound 2*or a solvate and / or hydrate thereof, wherein A is selected from an anion; e) mixing an acid and a third solvent to obtain a first solution; f) combining the first mixture containing Compound 2* with the first solution to obtain a second slurry containing Compound 2* , or a solvate and / or hydrate thereof; g) filtering the slurry containing Compound 2* , or a solvate or hydrate thereof, to obtain crystalline Compound 2*; h) mixing a polar solvent, a base, and Compound 3 to obtain a second mixture; i) adding crystalline Compound 2*, or a solvate and / or hydrate thereof, to the second mixture to produce a third mixture;j) adding an acid to adjust the pH to between 3 and 9 of the third mixture; k) adding an antisolvent to the third mixture to obtain a resulting slurry containing a compound of Formula I, or a salt, solvate and / or hydrate thereof; and l) isolating a compound of Formula I, or a salt, solvate or hydrate thereof, from the resulting slurry.

[0018] In the fourth embodiment, alternatively, the third mixture from step j can be cooled to below about 20°C obtain a resulting slurry containing compound of Formula I, or a salt, solvate and / or hydrate thereof.

[0019] In a fifth embodiment, the instant invention is directed to a process for preparingCompound 4A:comprising the steps of: a) mixing hexamethylenetetramine, 1 ,6-dibromohexane and a first solvent to create a first slurry, wherein the first solvent is selected from THF, acetone, or dimethylcarbonate; b) filtering the first slurry to obtain Compound 1A; c) adding Compound 1A to a mixture containing methanol and acetyl bromide to obtain a resulting mixture; d) adding a third solvent to the resulting mixture to obtain a first mixture containingCompound 2*or a solvate and / or hydrate thereof, wherein A is selected from an anion and the third solvent is selected from MeCN or 2-MeTHF;e) distilling the first mixture to obtain a second slurry containing Compound 2* or a solvate and / or hydrate thereof; f) filtering the second slurry to obtain the filtrate containing Compound 2* or a solvate and / or hydrate thereof; g) mixing p-toluenesulfonic acid hydrate and a third solvent to obtain a first solution, wherein the third solvent is MeCN, 2-MeTHF or a mixture of MeCN / triethylamine; h) combining the filtrate containing Compound 2*, or a solvate and / or hydrate thereof, with the first solution to obtain a third slurry', which contains Compound 2Ai) filtering the third slurry' containing Compound 2A to obtain Compound 2A; j) mixing NMP, a base, and Compound 3 to obtain a second mixture; k) adding Compound 2A from step i with the second mixture of step j to produce a third mixture; l) adding a solution containing HBr to the third mixture to adjust the pH to between 3 and 9; m) adding an antisolvent to the third mixture to obtain a resulting slurry containingCompound 4A, wherein the antisolvent is aqueous NaBr or a mixture of acetonitrile / water; and n) isolating Compound 4A.

[0020] In a further embodiment of the fifth embodiment, the first slurry is heated to about 40°C to about 70 °C for about 18 to about 36 hours before filtering the first slurry.

[0021] In a further embodiment of the fifth embodiment, the resulting mixture of step c) is heated to above about 40°C before the third solvent is added to the resulting mixture. In a further embodiment of the fifth embodiment, the resulting mixture of step c) is heated to above about 50°C before the third solvent is added to the resulting mixture.

[0022] In a sixth embodiment, the instant invention is directed to a process for preparingCompound 2Acomprising the steps of: a) combining MeOH and acetyl bromide to obtain a solution of HBr; b) adding Compound 1A and heating the resulting mixture to between about 40°C and about 200°C; c) cooling the resulting mixture to about 20 °C; d) adding 2-MeTHF and distilling to obtain a slurry; e) filtering the slurry to obtain a filtrate containing Compound 2*, or a solvate and / or hydrate thereof; f mixing p-toluenesulfonic acid hydrate and 2-MeTHF to obtain a first solution; g) adding the first solution of step e to filtrate of step d to obtain a crystalline slurry containing Compound 2A, or a solvate and / or hydrate thereof; h) adding MTBE to the crystalline slurry and cooling to between about -20 °C and about 15 °C; and i) filtering the crystalline slurry to obtain Compound 2A.

[0023] In a further embodiment of the sixth embodiment, the resulting mixture in step b) is heated above about 0°C.

[0024] In a seventh embodiment, the instant invention is directed to a process for preparingCompound 4A,or a solvate and / or hydrate thereof, comprising the steps of: a) mixing NMP and sodium teH-but oxide to obtain a first solution; b) adding Compound 3 to the first solution to create a first mixture; c) adding Compound 2A to the first mixture to obtain a second mixture; d) adding HBr and adjusting the pH of the second mixture to between pH 4 and 9; e) cooling between about -20°C and about 20°C to produce a slurry containing Compound 4A; f) adding aqueous NaBr or a mixture of acetonitrile and water to obtain a third mixture containing Compound 4A;g) heating the third mixture to between about 20°C to about 60 °C for about 1 to about 16 hours; and h) cooling to between about -20°C and about 20°C and filtering the resulting slum- to obtain Compound 4A.

[0025] In a further embodiment of the seventh embodiment, water is added to the first mixture and the temperature is adjusted to between about -20°C and about 90 °C for between about 0.1 to about 1.5 hours, before Compound 2A is added to the first mixture.

[0026] In an embodiment, the present invention is directed to Compound 2*or a solvate or hydrate thereof, wherein A is selected from bromide, chloride, tosylate or phosphate.

[0027] In an embodiment, the present invention is directed to the tosylate salt of Compound 2*, as shown by the structure of Compound 2A

[0028] In an embodiment, the present invention is directed to a compound of Formula Ior a salt, solvate and / or hydrate thereof. The present invention is directed to a salt of a compound of Formula I, which may also be in a hydrate or solvate form, such as Compound 4A below.

[0029] In an embodiment, the present invention is directed to Compound 4or solvate thereof, wherein A is selected from bromide, chloride, tosylate or phosphate.

[0030] In an embodiment, the present invention is directed to Compound 4A

[0031] In an embodiment, the present invention is directed to Compound 4B

[0032] In an embodiment, the present disclosure is directed to a cry stalline form of a compound of Formula I. The crystalline form can be obtained via seeding or in the absence of seeding. In a further embodiment, the present disclosure is directed to a crystalline form of Compound 4A, (1S)-2-Amino-3-(l-(6-aminohexyl)-5-fluoro-17 / -indol-3-yl)propanoic acid hydrobromide hydrate. In a further embodiment, the present disclosure is directed to a crystalline form of Compound 4B. (S)-2 -Amino-3-(l-(6-aminohexyl)-5-fluoro-17 / -indol-3-yl)propanoic acid hydrobromide. In an embodiment, the present disclosure is directed to a hemi-solvate crystalline form of the compound (5)-2-Amino-3-(l-(6-aminohexyl)-5-fluoro-17 / -indol-3-yl)propanoic acid or a saltand / or hydrate thereof. In an embodiment, the present disclosure is directed to a solvate crystalline form of the compound (1S)-2-Amino-3-(l-(6-aminohexyl)-5-fluoro-177-indol-3- yl)propanoic acid or a salt and / or hydrate thereof.

[0033] In an embodiment, the present disclosure is directed to an isolated crystalline form of the compound (S)-2-Amino-3-(l-(6-aminohexyl)-5-fluoro-17f-indol-3-yl)propanoic acid or a salt and / or hydrate thereof. In an embodiment, the present disclosure is directed to an isolated hemisolvate crystalline form of the compound (5)-2-Amino-3-(l-(6-aminohexyl)-5-fluoro-177-indol-3- yl)propanoic acid or a salt and / or hydrate thereof. In an embodiment, the present disclosure is directed to an isolated solvate crystalline form of the compound ((S)-2-Amino-3-(l-(6- aminohexyl)-5-fluoro-17f-indol-3-yl)propanoic acid or a salt and / or hydrate thereof.

[0034] In an embodiment, the present disclosure is directed to an anhydrous crystalline form of the compound (S)-2-Amino-3-(l-(6-aminohexyl)-5-fluoro-1 7-indol-3-yl)propanoic acid or salt thereof. In an embodiment, the present disclosure is directed to an anhydrous hemi-solvate crystalline form of the compound (<S)-2-Amino-3-(l-(6-aminohexyl)-5-fluoro-l / f-indol-3- yl)propanoic acid or salt thereof. In an embodiment, the present disclosure is directed to an anhydrous solvate crystalline form of the compound (S)-2-Amino-3-(l-(6-aminohexyl)-5-fluoro- I / / -indol-3-yl)propanoic acid or salt thereof.

[0035] In the embodiments of the instant invention, the processes of the disclosure may be conducted in a single vessel, as a “one-pot” process, or the steps may be conducted sequentially. For clarity, it should be noted that 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. It should also be noted that when a term is used more than once, such as third solvent, the definition at each instance is independent of a prior selection. For example, the same, or a different, third solvent may be chosen for each step of the process independently of a previous selection.

[0036] By achieving selective alkylation without the use of protecting groups, the disclosed invention not only simplifies the synthetic pathway but also reduces the overall cost of production. This breakthrough is particularly advantageous for industrial-scale manufacturing of tryptophan analogues and related compounds.

[0037] The innovation involves a carefully designed reaction sequence that allows for the direct and selective alkylation of the indole nitrogen of tryptophan analogues. This process is not only efficient but also demonstrates a high degree of regioselectivity, ensuring that the desired alkylated products are obtained with only minimal amounts of unwanted side reactions. Thedisclosed method is versatile and compatible with a wide range of tryptophan analogues, expanding its applicability to various derivatives and bioactive molecules.Definitions

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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).

[0043] 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 varybetween 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.

[0044] 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.

[0045] In embodiments of the invention, the dihalogenated hexane is selected from 1,6- dibromohexane, 1,6-dichlorohexane, 1,6-diiodohexane, 1 -bromo-6-chlorohexane, l-chloro-6- iodohexane or l-bromo-6-iodohexane. In a further embodiment, the dihalogenated hexane is 1,6- dibromohexane.

[0046] In embodiments of the invention, the halide is independently selected from bromide, chloride or iodide. In a further embodiment, the halide is bromide or chloride. In another embodiment, the halide is bromide.

[0047] In embodiments of the invention, the first solvent is selected from a non-alcohol, organic solvent. In a further embodiment, the first solvent is selected from acetone, tetrahydrofuran (THF), or dimethylcarbonate. In a further embodiment, the first solvent is tetrahydrofuran. In a further embodiment, the first solvent is dimethylcarbonate.

[0048] In embodiments of the invention, the second solvent is selected from an alcohol. In a further embodiment, the second solvent is selected from methanol, ethanol, propanol, isopropanol, butanol and the like. In a further embodiment, the second solvent is methanol.

[0049] In embodiments of the invention, the third solvent is selected from acetonitrile or 2- methyltetrahydrofuran. In a further embodiment, the third solvent is 2-methyltetrahydrofuran.

[0050] In embodiments of the invention, the polar solvent is selected from A-methyl pyrrolidine, tetrahydrofuran, Ar. A-di methyl acetamide, l,3-Dimethyl-2-imidazolidinone, N,N'- Dimethylpropyleneurea, Hexamethylphosphoramide, Tripyrrolidinophosphine oxide or mixtures thereof. In a further embodiment, the polar solvent is A-methyl pyrrolidine.

[0051] In embodiments of the invention, the additive is selected from hydrogen bromide or acetyl bromide. In a further embodiment, the additive is acety l bromide.

[0052] In embodiments of the invention, the acid is independently selected from hydrobromic acid, phosphoric acid, p-toluenesulfonic acid, or hydrochloric acid. In a further embodiment, the acid used to adjust the pH is hydrobromic acid. In another embodiment, wherein the acid is mixed with a third solvent, the acid is p-toluenesulfonic acid.

[0053] In embodiments of the invention, the base is selected from sodium / -buloxide. lithium / c / 7-buloxide. potassium / c / v-butoxide. sodium tert-pentoxide, lithium tert-pentoxide, potassium tert-pentoxide, sodium hexamethyldisilazide, lithium hexamethyldisilazide, or potassium hexamethyldisilazide. In a further embodiment, the base is sodium tert-butoxide.

[0054] As used herein, an antisolvent refers to a solvent that reduces the solubility of the solute. In embodiments of this invention, the antisolvent is independently selected from MTBE, acetonitrile, THF, NaBr, nPrOH, water and mixtures thereof. In an embodiment, the antisolvent is independently selected from MTBE, aqueous NaBr, a mixture of THF / water, a mixture of acetonitrile / water, or a mixture of nPrOH / water. In a further embodiment, the antisolvent is aqueous NaBr. In a further embodiment, the antisolvent is a mixture of acetonitrile / water.

[0055] The compounds of the present invention 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 invention. The present invention 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 invention 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.

[0056] 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, racemicmixtures 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 diastereomeric 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 w ell 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.

[0057] The compounds of the present disclosure w hich contain olefinic double bounds, unless specified otherwise, are meant to include both E and Z geometric isomers.

[0058] 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 w ell as mixtures thereof are encompassed by the compounds of the present disclosure.

[0059] 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.

[0060] 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-enrichedcompounds 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.

[0061] 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, ,V. W-dibenzylethylcnc-diaminc. diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine. A'-ethylpipendine. glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0062] When the compound of the present invention 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 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. For use in medicine, the salts of the compounds described herein may be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds or their pharmaceuticallyacceptable salts, according to the invention. When the compound of the present invention is acidic, suitable “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Examples of inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and similar salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic 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'-dibenzylethylenediamine. 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.

[0063] When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic 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. Additional examples of such acids include aryl sulfonic acids, such as but not limited to / Mol uenesul Tonic 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, phenyl acetic acid, trimethylacetic acid, tetrafluoroboric acid, tetraphenylboric acid, maleic acid, fumaric acid, oxalic acid, or camphorsulfonic acid. Specific examples are citric, hydrobromic, p- toluenesulfonic, benzenesulfonic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. Preferred are p-toluenesulfonic, hydrobromic, phosphoric, and hydrochloric acids. The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described by Berg et al., “Pharmaceutical Salts,” J. Pharm. Set., 1977:66: 1-19.

[0064] As used herein, “anion” refers to an anion suitable for forming a salt. Accordingly, the anion corresponding to the salts described herein could be A', according to the present disclosure.

[0065] Further examples of acceptable salts, and their corresponding anions, that may be used with the present disclosure include, but are not limited to, bromide, chloride, tosylate or phosphate.

[0066] One or more compounds herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents, such as water, ethanol, and the like, and this disclosure is intended to embrace both solvated and unsolvated forms. '‘Solvate” means a physical association of a compound with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances of this aspect, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solutionphase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate in which the solvent molecule is H2O.

[0067] The present disclosure further includes compounds and synthetic intennediates in all their isolated forms. For example, the identified compounds are intended to encompass all forms of the compounds such as, any solvates, hydrates, stereoisomers, and tautomers thereof.

[0068] 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.

[0069] Those skilled in the art will recognize that certain compounds, and in particular compounds containing certain heteroatoms and double or triple bonds, can be tautomers, structural isomers that readily interconvert. Common tautomeric pairs are: ketone-enol, amidenitrile, lactam-lactim, amide-imidic acid tautomerism in heterocyclic rings (e.g., in nucleobases such as guanine, thymine and cytosine), amine-enamine and enamine-imine.

[0070] Those skilled in the art will recognize that chiral compounds, such as the compounds presented herein, can be drawn in a number of different ways that are equivalent.

[0071] 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 tobe limiting. The transaminase enzymes were used as lyophilized cell-free lysate powders. Unless otherwise indicated, solvents and reagents were commercially available and were used as received.ABBREVIATIONSMEASUREMENTS: g Grams h hour(s)L liter mg MilligramMHz Megahertz min minutes ml. mL milliliter mM millimolar, ImM is a concentration of one thousandth of a mole per literMmol millimole, a thousandth of a mole (the amount of any chemical substance that equals the number of atoms in 12 grams of carbon- 12). mp Melting pointN Normality’, the gram equivalent weight of a solution in a solution, which is its molar concentration divided by an equivalence factor. rpm Revolutions per minute ul, uL, [il, |iL microliterDMSO dimethyl sulfoxideEtOH ethanolHMTA HexamethylenetetramineHRMS High Resolution Mass SpectrometryI-PrOH isopropanol1-PrOH 1 -propanolMeCN acetonitrileMeOH methanolMTBE methyl tert-butyl etherNa-Ot-Bu sodium tert-butoxideNMP N-methyl 2-pyrrolidoneNMR Nuclear Magnetic Resonance Spectrometry2-MeTHF 2-methyltetrahydrofuranTHF tetrahydrofuranTsO 4-methylbenzene sulfonateAdditional abbreviations may be defined throughout this disclosure.EXAMPLES

[0072] 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 1Preparation of l-(6-Bromohexyl)-1.3,5.7-tetraazaadamantan-l-ium bromide (Compound 1A)

[0073] To a 2 L jacketed flask equipped with a mechanical stirrer and temperature probe was added 355 ml of THF, followed by 312g (1.28 mol) of 1,6-dibromohexane. The mixture was heated to 55 °C. Hexamethylenetetramine (71.0 g, 1.26 mol) was added portion-wise, about 8.8 to 9.0 grams per hour) over 8 hours, followed by rinsing with 35.5 ml of THF after each addition. The reaction mixture was aged 14 hours at 55 °C. The resulting slurry was cooled to room temperature, aged for 4 hours, and filtered. The wet cake was washed with 213 ml THF and dried at 40 °C for 18-20 hours to provide Compound 1A (96%): 1H NMR DMSO-d6, 500 MHz) d 5.07 (s. 6 H). 4.60 (d, 3H, J = 12.5 Hz), 4.46 (d, 3H, J = 12.5 Hz), 3.55 (t, 2H, J = 6.6 Hz), 2.82- 2.68 (m, 2H), 1.83 (m. 2H), 1.64 (m, 2H), 1.44 (m, 2H), 1.28 (m, 2H); 13C NMR (DMSO-d6, 125 MHz) d 78.6, 70.8, 56.5, 36.1, 32.8, 27.9, 26.4, 20.0.EXAMPLE 2APreparation of 6-Bromohexan-l-aminium 4-methylbenzenesulfonate (Compound 2A)O5. Filter tosylate salt

[0074] In a 100 mL Easymax vessel, equipped with mechanical stirrer and temperature probe, was added 125 mL of MeOH. The solution was cooled to -5 °C and 23.7 mL (318 mmol) of acetyl bromide was added dropwise to give a solution of HBr. The solution was warmed to 20 °C and aged for 3 hours. To the solution was added 25.0 g (62.3 mmol) of l-(6-Bromohexyl)- 1,3,5,7-tetraazaadamantan-l-ium bromide (Compound 1A) and the mixture was heated to 50 °C and aged for 22 h. The mixture was concentrated to approximately 75 mL and distilled while maintaining a constant volume of 75 mL by adding 2-MeTHF continuously during distillation. The final volume was adjusted to 125 mL, after distillation with 2-MeTHF. The mixture was aged for 10 hours at 20 °C and the resulting slurry was filtered through celite to remove ammonium bromide and the wet cake was washed with 2-MeTHF. The filtrate (Solution 1) was then transferred into a 100 mL Easymax vessel equipped with mechanical stirrer and temperature probe. To a separate vessel 18.97 g (50 mmol) of p-toluenesulfonic acid monohydrate and 25 mL of 2-MeTHF was added, and this mixture was stirred until fully homogeneous (Solution 2). The filtrate (Solution 1) was warmed to 40 °C and Solution 2 was then added to Solution 1 and aged at 40 °C for 6 h. The mixture is then cooled to 20 °C and aged 4 hours. To the mixture. 325 mL of MTBE was added over 3.5 hours. The mixture was aged for 1 hour then cooled to 5 °C and aged for 4-24 hours. The cry stalline slurry' was filtered and the wet cake washed with 50 mL of 1:3 2-MeTHF / MTBE twice then dried under vacuum at 40 °C for 18-20 h to afford Compound 2A: 1H NMR (DMSO-d6, 500 MHz) d 7.65 (s, 3H), 7.51 (d, 2H, J = 8.0 Hz), 7.13 (d, 2H, J = 8.0 Hz), 3.53 (t, 2H, J = 6.7 Hz), 2.86-2.68 (m, 2H), 2.30 (s, 3H), 1.79 (q, 2H, J = 6.8 Hz), 1.52 (q, 2H, J = 7.5 Hz), 1.46-1.20 (m, 4H); 13C NMR (DMSO-d6, 125 MHz) d 145.7, 139.1, 129.2, 126.4, 39.7, 32.9, 27.9, 27.6, 25.8, 21.7.EXAMPLE 2BPreparation of 6-Bromohexan-l-aminium bromide (Compound 2B)2. Solvent switch to MTBE3. Filter salt

[0075] To a 250 mL round-bottom flask with a stir bar was added 50.0 mL of EtOH. The flask was cooled to 0 °C and 4.82 mL of acetyl bromide (65.1 mmol) was added. The resulting mixture was warmed to room temperature (~21 °C) and 3.06 mL of tert-buty l (6-bromohexyl)carbamate (13.02 mmol) was added. The reaction mixture was warmed to 60 °C and aged for 18 hours. The reaction mixture was concentrated until solids started to precipitate then 50.0 mL of MTBE was added to the flask. The resulting slurry was cooled to 0 °C and aged for 2 hours. The slurry was then filtered, and the solids were washed with MTBE and dried under vacuum / N2 sweep for 18 h to give Compound 2B.EXAMPLE 3APreparation of (S)-2-Amino-3-(l-(6-aminohexyl)-5-fluoro-17f-indol-3-yl)propanoic acid hvdrobromide hydrate (Compound 4A)

[0076] In a 250 mL 3-neck flask equipped with a mechanical stirrer and temperature probe was added 15 mL of NMP and 5.20 g (54.0 mmol) of solid sodium tert-butoxide. To this solution was added 3.00 g (13.5 mmol) of solid 5 -fluorotryptophan (Compound 3) and the sides of the flask rinsed with 6 mL of NMP. To the mixture w as added 0.073 mL of water and the mixture w as warmed to 45 °C for 1.5 h. In a separate flask was added 5.2 g (14.2 mmol) of 6-Bromohexan-l- aminium 4-methylbenzenesulfonate (Compound 2A) and 10 mL of NMP and the mixture was warmed to 45 °C to give a homogeneous solution which was added to the above mixture. The mixture is aged for 1 h, and then at this point and the pH of the mixture w as adjusted to betw een4-9 by the addition of 48% aqueous HBr solution. The mixture is then cooled to below 5 °C to allow for crystal growth of Compound 4A. The temperature is returned to 20 °C and then is diluted with 30 mL of ! saturated aqueous NaBr which was prepared by dissolving 49.0 g of NaBr in 100 mL of w ater. The temperature of the reaction mixture was raised between 50-55 °C, and the resulting slurry was aged at 50 °C overnight, and then cooled to 5 °C over a period of 5 h. The slurry was filtered and washed with 8: 1 1-PrOH / water and dried under vacuum at 55 °C overnight to give Compound 4A: mp 246 °C (DSC);rH NMR (DMSO-< <?, 500 MHz) 5 7.87 (br s, 5H), 7.41 (dd, 1H, J = 8.9 and 4.4 Hz), 7.37 (dd, 1H, J= 10.1 and 2.5 Hz), 7.28 (s, 1H), 6.94 (td. 1H, J= 9.2 and 2.5 Hz), 4.12 (t, 2H. J= 6.4 Hz), 3.55 (t, 2H, J= 5.5 Hz), 3.30 (br s, 2H), 3.10 (qd, 2H, J= 15.0 and 5.5 Hz), 2.71 (m, 2H), 1.73 (m, 2H), 1.49 (m, 2H), 1.37-1.21 (m, 2H), 1.13 (m, 2H);13C NMR (DMSO- 125 MHz) 5 171.5, 156.9 (d, J= 231.0 Hz), 132.7, 129.7, 128.1 (d, J= 9.8 Hz), 110.6 (d, J= 10.0 Hz), 109.0 (d, J = 26.4 Hz), 108.5 (d, J = 4.8 Hz), 103.7 (d, J= 22.0 Hz), 54.5, 45.4, 38.5, 29.4, 26.8, 26.6, 25.6. 25.3;19F NMR (DMSO- 471 MHz) 5 -125.6. HRMS Cacld. For C17H15FNO2: 322.1931 [M + H], Found: 322.1925 [M + H], EXAMPLE 3BPreparation of -2-Amino-3-(l-(6-aminohexyl)-5-fluoro-177-indol-3-yl)propanoic acidhydrobromide hydrate (Compound 4A)

[0077] In a 100 mL Easy Max vessel equipped ith a mechanical stirrer and temperature probe was added 32 mL of NMP and 8.65 g (90.0 mmol) of solid sodium / -butoxide. To this solution was added 5.00 g (22.5 mmol) of solid 5 -fluorotryptophan (Compound 3) and the sides of the vessel rinsed with 5 mL of NMP. To the mixture was added 0. 122 mL of water and the mixture was warmed to 45 °C for 2 h. To the mixture 8.33 g (22.5 mmol) of 6-Bromohexan-l-aminium 4- methylbenzenesulfonate (Compound 2A) was charged in four portions and the vessel rinsed with 3 mL of NMP and the mixture was aged for 10 minutes at 45 °C. To the mixture post aging was added 15 mL of 6:1 MeCN / w ater and the pH of the mixture was adjusted to between 4-9 by the addition of 48% aqueous HBr solution. The mixture is then cooled to 30 °C and seeded with Compound 4A. The temperature is raised to 50 °C and aged for 1 h at that temperature. To themixture was added 45 mL of 6: 1 MeCN / water over 5 h. The mixture is then cooled to 25 °C over 4 h, aged for 2 h, then cooled to 4 °C over 4 h. The resulting slurry was filtered and washed with 8: 1 1-PrOH / water and dried under vacuum at 45 °C overnight to give Compound 4A: mp 246 °C (DSC); ’H NMR (DMSO-rfe, 500 MHz) 5 7.87 (br s, 5H). 7.41 (dd, 1H, J = 8.9 and 4.4 Hz), 7.37 (dd, 1H, J= 10.1 and 2.5 Hz), 7.28 (s. 1H), 6.94 (td, 1H, J= 9.2 and 2.5 Hz). 4.12 (t. 2H, J= 6.4 Hz), 3.55 (t, 2H, J= 5.5 Hz), 3.30 (br s, 2H), 3.10 (qd, 2H, J= 15.0 and 5.5 Hz), 2.71 (m, 2H), 1.73 (m, 2H), 1.49 (m, 2H), 1.37-1.21 (m, 2H), 1.13 (m, 2H);1?C NMR (DMSO- 125 MHz) 6 171.5, 156.9 (d, J = 231.0 Hz), 132.7, 129.7, 128.1 (d, J= 9.8 Hz), 110.6 (d, J= 10.0 Hz), 109.0 (d, J= 26.4 Hz), 108.5 (d, J= 4.8 Hz), 103.7 (d. J= 22.0 Hz), 54.5. 45.4. 38.5, 29.4, 26.8, 26.6, 25.6, 25.3;19F NMR (DMSO- 471 MHz) 5 -125.6. HRMS Cacld. For C17H15FNO2: 322.1931 [M + H] . Found: 322.1925 [M + H] .

[0078] It will be appreciated that various of the above-discussed and other features and functions, or alternatives thereof, may be desirably combined into many other different systems or applications. It will also be appreciated that various presently unforeseen or unanticipated alternatives, modifications, variations or improvements therein may be subsequently made by those skilled in the art which are also intended to be encompassed by the following claims.

[0079] The disclosed subject matter is not to be limited in scope by the specific embodiments and 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.

[0080] All 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 same 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

WHAT IS CLAIMED IS:

1. A process for preparing a compound of Formula I:or a salt, solvate and / or hydrate thereof, comprising the steps of: a) combining Compound 3, or a salt, solvate, and / or hydrate thereof,and Compound 2, or a salt, solvate, and / or hydrate thereof,2 in the presence of a base, wherein X is selected from a halide; and b) isolating a compound of Formula I, or a salt, solvate and / or hydrate thereof.

2. The process of Claim 1, wherein one or more solvents is present when combining Compound 3, or a salt, solvate, and / or hydrate thereof, with Compound 2, or a salt, solvate, and / or hydrate thereof.

3. The process for preparing a compound of Formula 1. or a salt, solvate and / or hydrate thereof, further comprising the steps of preparing Compound 2or a salt, solvate and / or hydrate thereof wherein X is selected from a halide, by: a) mixing hexamethylenetetramine, a first solvent and a dihalogenated hexane to obtain Compound 1, or salt, solvate and / or hydrate thereof,wherein X and Y are independently selected from a halide; and b) reacting Compound 1, or solvate and / or hydrate thereof, with a second solvent and an additive selected from hydrogen bromide or acetyl bromide to obtain Compound 2, or a salt, solvate or hydrate thereof.

4. The process of Claim 2, further comprising the steps of: a) mixing a polar solvent, a base, and Compound 3, or salt, solvate and / or hydrate thereof,to obtain a mixture: combining Compound 2’, or salt, solvate or hydrate thereof.with the mixture to produce a reaction mixture; c) adding an acid to adjust the pH of the reaction mixture to 3 to 9; and d) adding an antisolvent to the reaction mixture to obtain a compound of Formula I or a salt, solvate and / or hydrate thereof.

5. The process of Claim 4, further comprising the steps of preparing Compound 2’or a salt, solvate or hydrate thereof comprises the steps of: a) mixing hexamethylenetetramine, a first solvent and 1 ,6-dibromohexane to obtain Compound 1A, or solvate and / or hydrate thereof,b) reacting Compound 1 A, or a solvate and / or hydrate thereof, with a second solvent and an additive selected from hydrogen bromide or acetyl bromide to produce a resulting mixture containing Compound 2’, or a salt, solvate and / or hydrate thereof; and c) adding a third solvent to the resulting mixture to obtain a Compound 2’, or a salt, solvate and / or hydrate thereof.

6. The process of Claim 5, wherein the resulting mixture from step b is cooled to obtain a compound of Formula I, or a salt, solvate and / or hydrate thereof.

7. The process of Claim 2 comprising the steps of: a) mixing hexamethylenetetramine, 1,6-dibromohexane and a first solvent to create a first slurry'; b) heating the first slurry' to above about 20°C to obtain Compound 1Ac) adding Compound 1 A to a mixture containing a second solvent and an additive selected from hydrogen bromide or acetyl bromide; d) adding a third solvent to obtain a first mixture containing Compound 2*or a solvate and / or hydrate thereof, wherein A is selected from an anion; e) mixing an acid and a third solvent to obtain a first solution; f) combining the first mixture containing Compound 2* with the first solution to obtain a second slurry' containing Compound 2*, or a solvate and / or hydrate thereof; g) filtering the slurry' containing Compound 2*, or a solvate or hydrate thereof, to obtain crystalline Compound 2*; h) mixing a polar solvent, a base, and Compound 3 to obtain a second mixture; i) adding crystalline Compound 2*, or a solvate and / or hydrate thereof, to the second mixture to produce a third mixture; j) adding an acid to adjust the pH to between 3 and 9 of the third mixture; k) adding an antisolvent to the third mixture to obtain a resulting slurry containing a compound of Formula I, or a salt, solvate and / or hydrate thereof; and l) isolating a compound of Formula I, or a salt, solvate or hydrate thereof, from the resulting slurry.

8. A process for preparing Compound 4A:comprising the steps of: a) mixing hexamethylenetetramine, 1 ,6-dibromohexane and a first solvent to create a first slurry, wherein the first solvent is selected from THF, acetone, or dimethylcarbonate; b) filtering the first slurry to obtain Compound I A: c) adding Compound 1 A to a mixture containing a methanol and acetyl bromide to obtain a resulting mixture; d) adding a third solvent to the resulting mixture to obtain a first mixture containing Compound 2*or a solvate and / or hydrate thereof, wherein A is selected from an anion and the third solvent is selected from MeCN or 2-MeTHF; e) distilling the first mixture to obtain a second slurry containing Compound 2* or a solvate and / or hydrate thereof; f) filtering the second slurry' to obtain the filtrate containing Compound 2* or a solvate and / or hydrate thereof; g) mixing p-toluenesulfonic acid hydrate and a third solvent to obtain a first solution, wherein the third solvent is MeCN, 2-MeTHF or a mixture of MeCN / tri ethylamine; h) combining the filtrate containing Compound 2*, or a solvate and / or hydrate thereof, with the first solution to obtain a third slurry, which contains Compound 2Ai) filtering the third slurry containing Compound 2A to obtain Compound 2A; j) mixing NMP, a base, and Compound 3 to obtain a second mixture; k) adding Compound 2A from step i with the second mixture of step j to produce a third mixture; l) adding a solution containing HBr to the third mixture to adjust the pH to between 3 and 9; m) adding an antisolvent to the third mixture to obtain a resulting slurry containing Compound 4A, wherein the antisolvent is aqueous NaBr or a mixture of acetonitrile / water; and n) isolating Compound 4A.

9. The process of Claim 8 wherein the first slurry is heated to about 40°C to about 70 °C for about 18 to about 36 hours before filtering the first slurry.

10. The process of Claim 8 or 9 wherein the resulting mixture is heated to above about 50°C before the third solvent is added to the resulting mixture.

11. A compound of Formula I:or a salt, solvate and / or hydrate thereof.

12. The compound of Claim 11 wherein the compound of Formula I is crystalline.

13. The compound of Claim 11 or 12 having the structure of Compound 4or solvate thereof, wherein A is selected from bromide, chloride, tosylate or phosphate.

14. The compound of Claim 11 or 12 having the structure of Compound 4A15. The compound of Claim 11 or 12 having the structure of Compound 4B

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