Synthesis of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-YL)-1-(propan-2-YL)-1h-benzimidazol-6-YL]pyrimidin-2-YL}amino)-2,3-dideoxy-d-threo-pentitol

Abstract

This disclosure relates novel methods to prepare 1,5-anhydro-3-({5-chloro-4-[4- fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2- yl}amino)-2,3-dideoxy-D-threo-pentitol, and hydrates and stereoisomers thereof, as well as intermediates, including solid forms of the intermediates, useful for the preparation of such compounds and the synthesis of said intermediates.

Description

[0001] PC073049A SYNTHESIS OF 1,5-ANHYDRO-3-({5-CHLORO-4-[4-FLUORO-2-(2- HYDROXYPROPAN-2-YL)-1-(PROPAN-2-YL)-1H-BENZIMIDAZOL-6-YL]PYRIMIDIN- 2-YL}AMINO)-2,3-DIDEOXY-D-THREO-PENTITOL 5 FIELD OF INVENTION The present disclosure relates to novel processes to prepare 1,5-anhydro-3-({5- chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6- yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol. In some embodiments, the disclosure provides processes to prepare 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-0 hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3- dideoxy-D-threo-pentitol monohydrate Form 2. The disclosure also provides intermediates used for the preparation of such compounds. BACKGROUND OF THE INVENTION 5 Cyclin-dependent kinases (CDKs) are important cellular enzymes that perform essential functions in regulating eukaryotic cell division and proliferation. CDK inhibitors may be useful for the treatment of proliferative disorders, including cancer. 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)- 1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol useful as a0 CDK4 are disclosed in U.S. Patent Nos. 10,766,884 and 11,220,494 and International Publication No. WO 2019 / 207463. The preparation of solid forms of 1,5-anhydro-3-({5- chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6- yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol is disclosed in International Publication No. WO 2022 / 058871. The contents of each of the foregoing are incorporated5 herein by reference in their entirety. The synthetic routes described in the above-cited application were not designed for large scale synthesis or commercial scale-up. Therefore, alternative routes for the preparation of such compounds that are cost-efficient, scaleable and productive are highly desirable. 0 SUMMARY OF THE INVENTION The present invention provides improved processes for the preparation of Compound A and intermediates useful for the preparation of Compound A. Compound A refers to 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan- 2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo- pentitol, which has the following chemical structure, including hydrates (such as, monohydrate), salts and polymorphs thereof: Compound A. In one 3-({5-chloro-4-[4-fluoro-2-(2- hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3- dideoxy-D-threo-pentitol monohydrate. In one embodiment, Compound A is 1,5- anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H- benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol monohydrate (Form 2). Compound A can be prepared from amino alcohols of Formula (V), and the compound of Formula (VIII), 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)propan-2-ol. The amino alcohols of Formula (IV) can be prepared from the potassium sulfonate of Formula (I), and alternately can be prepared from the compound of Formula (II), 3-(benzyloxy)tetrahydro-4H-pyran-4-one. The compound of Formula (VII) can be prepared from compound of Formula (VI), 2-(6-bromo-4-fluoro-1- isopropyl-1H-benzo[d]imidazol-2-yl)propan-2-ol. A retrosynthetic scheme of the improved routes is provided in Scheme 1 below.

[0002] Scheme 1 A: comprising: (a) providing a compound Formula (VIII) ; (b) (VIII) with a compound of Formula (V) wherein Xˉ in the presence of a base and a suitable solvent to produce Compound A. In one aspect, the disclosure provides a process for preparing a compound of Formula (V) ), wherein Xˉ is OTsˉ or H2PO4ˉ, comprising: (a) providing a co pou o Formula (II) OOHO SO K; (b) Formula (II) to a compound of Formula (III) ; (c) of Formula (III) with an acid selected from p- toluenesulfonic acid or phosphoric acid to produce a compound of Formula (IV) , wherein Xˉ is OTsˉ or H2PO4ˉ; and (d) debenzylating the compound of Formula (IV) to provide the compound of Formula (V) . In other provides crystalline forms of the following compounds of Formulae (IVa), (IVb), (Va), and (Vb) having the following structures: . In one aspect, the disclosure provides a process for preparing 2-[6-(2,5- dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol, Formula (VIII) ; comprising: (a) a (VI) with bis(neopentyl glycolato)diboron in the presence of a potassium salt of an organic acid, a suitable organic solvent and an organopalladium catalyst to produce a compound of Formula (VII)

[0003] (b) contacting the compound of Formula (VII) with 2,4,5-trichloropyrimidine in the presence of a base to produce the compound of Formula (VIII). In another aspect, the disclosure provides a crystalline form of a compound of Formula (VII) having the structure: . FIG.1. PXRD pattern of crystalline tosylate salt Formula (IVa) (Form 1). FIG.2. PXRD pattern of crystalline tosylate salt Formula (IVa) (Form 2). FIG.3. PXRD pattern of crystalline phosphate salt Formula (IVb) (Form 1). FIG.4. PXRD pattern of crystalline tosylate salt Formula (Va) (Form 1). FIG.5. PXRD pattern of crystalline phosphate salt Formula (Vb) (Form 1). FIG.6. PXRD pattern of crystalline Formula (VII) (Form 1). FIG.7. PXRD pattern of crystalline Formula (VIII) (Form 3). FIG.8. PXRD pattern of crystalline Formula (VIII) (Form 1). DETAILED DESCRIPTION OF THE INVENTION The present invention may be understood more readily by reference to the following detailed description of the preferred embodiments of the invention and the Examples included herein. It is to be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting. It is further to be understood that unless specifically defined herein, the terminology used herein is to be given its traditional meaning as known in the relevant art. The singular form "a", "an", and "the," as used herein, include plural references unless indicated otherwise. For example, "a" suitable solvent may include one or more suitable solvents (i.e., a suitable solvent mixture). The term "about" means having a value falling within an accepted standard of error of the mean, when considered by one of ordinary skill in the art, e.g., within plus or minus (±) 10% of the stated value. The term "alkyl," as used herein, refers to a saturated, monovalent straight or branched chain hydrocarbon having from one to six carbons (C1-C6alkyl), sometimes from one to five carbons (C1-C5 alkyl), and preferably from one to four carbons (C1-C4 alkyl). Representative examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, and the like. The term “OTs” as used herein refers to p-toluenesulfonate or tosylate (i.e., 4- CH3C6H4SO3) moiety. The term "protecting group," as used herein, refers to selectively introducible and removable groups which protect functional groups against undesirable side reactions during synthetic procedures. Examples of suitable protecting groups for various functional groups and relevant reaction conditions are provided in Wuts, Peter G.M. Greene’s Protective Groups in Organic Synthesis (5thed.). New York: Wiley, 2007.The invention described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein. Thus, for example, in each instance herein any of the terms "comprising", "consisting essentially of", and "consisting of" may be replaced with either of the other two terms. “Compound A” refers to the compound 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2- hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3- dideoxy-D-threo-pentitol, and all of the existing crystalline forms, which includes the monohydrate form 2. One of ordinary skill in the art will also appreciate that Compound A include deuterium substitutes where they may be formed. “Deuterium enrichment factor” as used herein means the ratio between the deuterium abundance and the natural abundance of deuterium, each relative to hydrogen abundance. An atomic position designated as having deuterium typically has a deuterium enrichment factor of, in particular embodiments, at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). The term “water activity” refers to the measure of the free water in a system that can participate in chemical reactions and support microbial growth. It is expressed as a ratio of the vapor pressure of water in a substance to the vapor pressure of pure water under the same conditions. For reference, water has a water activity of 1.0. The present disclosure provides more efficient process to synthesize Compound A as demonstrated in Scheme 2. Scheme 2 The process involves coupling (or contacting) 2-[6-(2,5- dichloropyrimidin-4-yl)-4- fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol, Formula (VIII), with a salt of 4- aminotetrahydro-2H-pyran-3-ol, for example, a compound of Formula (V). In one embodiment, the compound of Formula (V) is (3S, 4R)-3-hydroxytetrahydro-2H-pyran- 4-aminium tosylate salt, Formula (Va), wherein X is OTs. In one embodiment, the compound of Formula (V) is (4R)-3-hydroxytetrahydro-2H-pyran-4-aminium dihydrogen phosphate salt, Formula (Vb), wherein X is H2PO4. The inventors of this disclosure discovered that the formation and isolation of the salt Formula (IV) and thus salt Formula (V) are significant in enhancing efficiency in the synthesis of Compound A. Scale-up synthesis of Compound A via salts Formula (IV) and (V) provide more options for isolation and confer greater stability on the isolated intermediates. In some embodiments, the process of coupling 2-[6-(2,5- dichloropyrimidin-4-yl)- 4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol, Formula (VIII), with a compound of Formula (V) is conducted in the presence of a base and a suitable solvent to produce Compound A. In some embodiments, the process of coupling 2-[6-(2,5- dichloropyrimidin-4-yl)- 4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol, Formula (VIII) with a compound of Formula (V) is conducted at a temperature of from about 80 to about 110°C, from about 80 to about 100°C, or from about 80 to about 95°C. Preferred solvents suitable for such coupling reaction includes a polar solvent, such as, 1-propanol, 2-propanol, 2-butanol, t-amyl alcohol, acetonitrile, sulfolane, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethylformamide (DMF), dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO) and mixtures thereof. In one embodiment, the polar solvent is acetonitrile. In a particularly preferred embodiment, the polar solvent is sulfolane. Suitable bases for such coupling reaction includes trialkylamines (such as, N,N- diisopropylethylamine (DIPEA), triethylamine, tri-n-butyl, tri-n-octyl, etc.); alkaline earth carbonate or bicarbonates (such as, sodium bicarbonate, potassium carbonate, cesium carbonate, etc.); alkaline earth carboxylates (such as, potassium propionate etc.); alkaline earth phosphate bases (such as, mono-, di-, tri-potassium phosphate, etc.); and other inorganic bases (such as, barium hydroxide, calcium hydroxide, sodium hydroxide, potassium hydroxide, etc.); and mixtures thereof. In some embodiments, the base is a buffered carbonate mixture, such as, a mixture of potassium carbonate and sodium bicarbonate. In some embodiments, the base includes an organic and an inorganic bases, such as, a mixture of a trialkylamine and an alkaline earth phosphate base (e.g., mixture of DIPEA and K3PO4). The stoichiometry of the base to 2-[6-(2,5- dichloropyrimidin-4-yl)-4-fluoro-1- (propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol, Formula (VIII) ranges from about 1.0 to about 4.5 molar equivalents, from about 1.5 to about 4.0 molar equivalents, or from about 1.5 to about 3.5 molar equivalents. In some embodiments, the coupling reaction comprises about 2.0 or about 3.0 molar equivalent base and about 1.0 of 2-[6-(2,5- dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol, Formula (VIII). Scheme 3 illustrates the preparation of the compounds of Formulae (Va) and (Vb) from the benzyl protected compounds of Formula (I) or (II). Scheme 3: In one aspect, the disclosure provides a process for preparing a compound of Formula (V) , wherein Xˉ is or Xˉ is H2PO4ˉ (Formula Vb). The process for preparing the compound of Formula (V) comprising (a) providing a compound of Formula (II); (b) converting the compound of Formula (II) to a compound of Formula (III); (c) contacting the compound of Formula (III) with an acid selected from p- toluenesulfonic acid or phosphoric acid to produce a compound of Formula (IV) ), wherein Xˉ is Xˉ is H2PO4ˉ (Formula IVb); and (d) debenzylating the compound of Formula (IV) to provide the compound of Formula (V). Alternatively, the compound of Formula (V) can be prepared from a compound of Formula (I). In some embodiments, the process for preparing the compound of Formula (V) comprising (a) providing a compound of Formula (I); (b) converting the compound of Formula (I) to a compound of Formula (III); (c) contacting the compound of Formula (III) with an acid selected from p-toluenesulfonic acid or phosphoric acid to produce a compound of Formula (IV) described above; and (d) debenzylating the compound of Formula (IV) to provide the compound of Formula (V). In some embodiments, the step (b) of converting the compound of Formula (II) to a compound of Formula (III) or the step (b) of converting the compound of Formula (I) to a compound of Formula (III) is conducted at a pH ranging from about 8 to about 12, from about 9 to about 12, or from about 10 to about 12. In some embodiments, the step (b) is conducted at a temperature ranging from about 35 to about 55°C, from about 35 to about 50°C, or from about 40 to about 50°C. In some embodiments, the step (b) is conducted in the presence of an enzyme, such as an engineered transaminase enzyme, for example ATA-303 enzyme sold by Codexis, Inc., described in U.S. Patent 8,293,507 and WO 2010 / 099501, the disclosures of which are incorporated herein by reference in their entireties. In some embodiments, the step (b) is conducted in the presence of a donor amine, such as, isopropylamine, and α-methylbenzylamine. Referring to Scheme 2, the disclosure provides a process for preparing 2-[6-(2,5- dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol, Formula (VIII). The process comprising (a) contacting a compound of Formula (VI) with bis(neopentyl glycolato)diboron in the presence of a potassium salt of an organic acid, a suitable organic solvent and an organopalladium catalyst to provide a compound of Formula (VII); and (b) contacting the compound of Formula (VII) with 2,4,5- trichloropyrimidine in the presence of a base to produce the compound of Formula (VIII). In some embodiments, the potassium salt of an organic acid in step (a) is selected from the group consisting of potassium pivalate, potassium 2-ethylhexanoate, potassium acetate, and mixtures thereof. In some embodiments, the organic solvent used in step (a) comprises a tertiary alcohol, or a tertiary ether, or an optionally substituted tetrahydrofuran or tetrahydropyran. Preferred organic solvents used in step (a) include tert-butanol, tert- amyl alcohol, methyl tert-butyl ether, cyclopentyl methyl ether (CPME), tert-amyl-methyl ether (TAME), tetrahydropyran, tetrahydrofuran, 2-methyltetrahydrofuran (2-MeTHF), 3- methyltetrahydrofuran (3-MeTHF), or mixture thereof. In some embodiments, the organopalladium catalyst used in step (a) is selected from the group consisting of bis(triphenylphosphine)palladium(II) dichloride (PdCl2(PPh3)2), allylpalladium(II) chloride dimer ([Pd(allyl)Cl]2), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), bis(triphenylphosphine)palladium(II) diacetate (Pd(OAc)2(PPh3)2), 1,4- bis(diphenylphosphino)butane-palladium(II) chloride (PdCl2(dppb)), 1,1’- bis(diphenylphosphino)ferrocene palladium(II) dichloride (PdCl2(dppf)), and [9,9- dimethyl-4,5-bis(diphenylphosphino)xanthene] palladium(II) dichloride (PdCl2(xantphos)). In one embodiment, the organopalladium catalyst is bis(triphenylphosphine)palladium(II) dichloride (PdCl2(PPh3)2). In some embodiments, the base used in step (b) is an alkali metal hydroxide or carbonate base, or an alkaline earth hydroxide or carbonate base. Preferably, the base is sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, cesium carbonate, and mixture thereof. In yet other aspects, the disclosure provides intermediates and their crystalline forms useful in the synthesis of Compound A. In certain embodiments, the disclosure provides a compound and a crystalline form of Formula (IVa) (Form 1) having the structure:

[0004] In one embodiment, the crystalline form of Formula (IVa) (Form 1) characterized by a powder X-ray diffraction (PXRD) pattern. In one embodiment, the crystalline form of Formula (IVa) has a PXRD pattern comprising peaks at 2θ values of: 5.1, 12.4, 16.8, and 22.5 °2θ ± 0.2 °2θ. In one embodiment, the crystalline form of Formula (IVa) (Form 1) has a PXRD pattern comprising: (a) one, two, three, four, five, or more than five peaks selected from the group consisting of the peaks in Table 1 in °2θ ± 0.2 °2θ; or (b) peaks at 2θ values essentially the same as in FIG.1. In one embodiment, the crystalline form of Formula (IVa) is anhydrous (Form 1). In certain embodiments, the disclosure provides a compound and a crystalline form of Formula (IVa) (Form 2) having the structure: (IVa). In one embodiment, the crystalline form of Formula (IVa) (Form 2) characterized by a powder X-ray diffraction (PXRD) pattern. In one embodiment, the crystalline form of Formula (IVa) has a PXRD pattern comprising peaks at 2θ values of: 5.5, 8.5, 21.2, and 23.4 °2θ ± 0.2 °2θ. In one embodiment, the crystalline form of Formula (IVa) (Form 2) has a PXRD pattern comprising: (a) one, two, three, four, five, or more than five peaks selected from the group consisting of the peaks in Table 2 in °2θ ± 0.2 °2θ; or (b) peaks at 2θ values essentially the same as in FIG.2. In one embodiment, the crystalline form of Formula (IVa) is hemi-hydrate (Form 2). In certain embodiments, the disclosure provides a compound and a crystalline form of Formula (IVb) having the structure: . In one embodiment, the crystalline form of Formula (IVb) (Form 1) characterized by a powder X-ray diffraction (PXRD) pattern. In one embodiment, the crystalline form of Formula (IVb) has a PXRD pattern comprising peaks at 2θ values of: 5.0, 18.3, 21.5, 22.7 and 23.7 °2θ ± 0.2 °2θ. In one embodiment, the crystalline form of Formula (IVb) (Form 1) has a PXRD pattern comprising: (a) one, two, three, four, five, or more than five peaks selected from the group consisting of the peaks in Table 3 in °2θ ± 0.2 °2θ; or (b) peaks at 2θ values essentially the same as in FIG.3. In one embodiment, the crystalline form of Formula (IVb) is anhydrous (Form 1). In certain embodiments, the disclosure provides a compound and a crystalline form of Formula (Va) (Form 1) having the structure: . In one crystalline form of Formula (Va) (Form 1) characterized by a powder X-ray diffraction (PXRD) pattern. In one embodiment, the crystalline form of Formula (Va) has a PXRD pattern comprising peaks at 2θ values of: 6.5, 17.0, 19.5, 21.4, and 22.6 °2θ ± 0.2 °2θ. In one embodiment, the crystalline form of Formula (Va) (Form 1) has a PXRD pattern comprising: (a) one, two, three, four, five, or more than five peaks selected from the group consisting of the peaks in Table 4 in °2θ ± 0.2 °2θ; or (b) peaks at 2θ values essentially the same as in FIG.4. In one embodiment, the crystalline form of Formula (Va) is anhydrous (Form 1). In certain embodiments, the disclosure provides a compound and a crystalline form of Formula (Vb) (Form 1) having the structure: . In one embodiment, the crystalline form of Formula (Vb) (Form 1) characterized by a powder X-ray diffraction (PXRD) pattern. In one embodiment, the crystalline form of Formula (Vb) has a PXRD pattern comprising peaks at 2θ values of: 10.7, 15.9,17.3, 21.0, and 21.4 °2θ ± 0.2 °2θ. In one embodiment, the crystalline form of Formula (Vb) (Form 1) has a PXRD pattern comprising: (a) one, two, three, four, five, or more than five peaks selected from the group consisting of the peaks in Table 5 in °2θ ± 0.2 °2θ; or (b) peaks at 2θ values essentially the same as in FIG.5. In one embodiment, the crystalline form of Formula (Vb) is anhydrous (Form 1). In one aspect, the disclosure provides a crystalline form of Formula (VII) (Form 1) having the structure: . form of Formula (VII) (Form 1) characterized by a powder X-ray diffraction (PXRD) pattern. In one embodiment, the crystalline form of Formula (VII) has a PXRD pattern comprising peaks at 2θ values of: 10.0, 12.4, 14.6, 18.6, and 23.7 °2θ ± 0.2 °2θ. In one embodiment, the crystalline form of Formula (VII) (Form 1) has a PXRD pattern comprising: (a) one, two, three, four, five, or more than five peaks selected from the group consisting of the peaks in Table 6 in °2θ ± 0.2 °2θ; or (b) peaks at 2θ values essentially the same as in FIG.6. In one embodiment, the crystalline form of Formula (VII) is anhydrous (Form 1). In one aspect, the disclosure provides a crystalline form of Formula (VIII) (Form 3) having the structure: . In one embodiment, the crystalline form of Formula (VIII) (Form 3) characterized by a powder X-ray diffraction (PXRD) pattern. In one embodiment, the crystalline form of Formula (VIII) has a PXRD pattern comprising peaks at 2θ values of: 5.1, 10.7, 14.1, and 17.3 °2θ ± 0.2 °2θ. In one embodiment, the crystalline form of Formula (VIII) (Form 3) has a PXRD pattern comprising: (a) one, two, three, four, five, or more than five peaks selected from the group consisting of the peaks in Table 7 in °2θ ± 0.2 °2θ; or (b) peaks at 2θ values essentially the same as in FIG.7. In one embodiment, the crystalline form of Formula (VIII) is anhydrous (Form 3). In one aspect, the disclosure provides a crystalline form of Formula (VIII) (Form 1) having the structure: . form of Formula (VIII) (Form 1) characterized by a powder X-ray diffraction (PXRD) pattern. In one embodiment, the crystalline form of Formula (VIII) has a PXRD pattern comprising peaks at 2θ values of: 9.4, 12.8, 14.5, and 16.4 °2θ ± 0.2 °2θ. In one embodiment, the crystalline form of Formula (VIII) (Form 1) has a PXRD pattern comprising: (a) one, two, three, four, five, or more than five peaks selected from the group consisting of the peaks in Table 8 in °2θ ± 0.2 °2θ; or (b) peaks at 2θ values essentially the same as in FIG.8. In one embodiment, the crystalline form of Formula (VIII) is monohydrate (Form 1). Examples All reactions were performed under a nitrogen atmosphere. All reagents purchased from vendors were used as received unless specified otherwise. 1H Nuclear Magnetic Resonance (NMR) spectra were recorded on Bruker XWIN- NMR (400 or 700 MHz) spectrometer.1H resonances are reported in parts per million (ppm) downfield from tetramethylsilane.1H NMR data are reported as multiplicity (e.g., s, singlet; d, doublet; t, triplet; q, quartet; quint, quintuplet; dd, doublet of doublets; dt, doublet of triplets; br s, broad singlet; m, multiplet). For spectra obtained in CDCl3, DMSO- d6, and CD3OD, the residual protons (7.27, 2.50, and 3.31 ppm, respectively) were used as the internal reference. All observed coupling constants, J, are reported in Hertz (Hz). “δ” means chemical shift. Exchangeable protons are not always observed. The mass spectra (m / z) were recorded using either electrospray ionisation (ESI), atmospheric pressure chemical ionisation (APCI), or flame ionization detector (FID). The nomenclature is written as described by IUPAC (International Union of Pure and Applied Chemistry generated within Perkin Elmers Chemdraw 20.1.1.125. The naming convention provided with Perkin Elmers Chemdraw 20.1.1.125 is well known by those skilled in the art and it is believed that the naming convention provided with Perkin Elmers Chemdraw 20.1.1.125 generally comports with the IUPAC (International Union for Pure and Applied Chemistry) recommendations on Nomenclature of Organic Chemistry and the CAS Index rules. General PXRD method 1 The PXRD patterns were collected with a PANalytical X’Pert PRO MPD diffractometer using an incident beam of Cu radiation produced using a long, fine-focus source. The tube voltage and amperage were set to 45 kV to 40 mA, respectively. An elliptically graded multilayer mirror was used to focus Cu Kα X-rays through the specimen and onto the detector. Prior to the analysis, a silicon specimen (NIST SRM 640f) was analyzed to verify the observed position of the Si 111 peak is consistent with the NIST- certified position. A specimen of the sample was sandwiched between 3-μm-thick films and analyzed in transmission geometry and rotated at 1 revolution per second. Diffracted radiation was detected using an X’Celerator Scientific RTMS X-ray detector. A beam- stop, short antiscatter extension, and antiscatter knife edge were used to minimize the background generated by air. Soller slits for the incident and diffracted beams were used to minimize broadening and asymmetry from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X’Celerator) located 240 mm from the specimen and Data Colelctor sofrware v. 5.5. Data were collected from 1 to 40 degrees 2-theta (°2θ) using a step size of 0.0167 °2θ and a counting time of 36.83 s. Peaks with a relative intensity greater than or equal to 2 were chosen for inclusion in the table. General PXRD method 2 The powder X-ray diffraction pattern was generated using a Bruker AXS D8 Endeavor diffractometer equipped with a Cu radiation source. The tube voltage and amperage were set to 40 kV and 40 mA, respectively. The motorized divergence slits were set at constant illumination of 11 mm. Diffracted radiation was detected using a LYNXEYE XE-T energy dispersive X-ray detector, with the position sensitive detector (PSD) opening set at 4.00°. Data were collected on the theta-theta goniometer at the Cu wavelength from 2.0 to 55.0 degrees 2-theta (°2θ) using a step size of 0.019 °2θ) and a time per step of 0.2 seconds. Samples were prepared for analysis by placing them in a silicon low background cavity holder and rotated at 15 rpm during data collection. Data were analyzed in DIFFRAC.EVA V5.0 software. The collected powder pattern was aligned with the simulated powder pattern from the crystal structure for Form 1. Peak lists were prepared using reflections with a relative intensity ≥ 5 % of the most intense band in each respective diffraction pattern. A typical error of ± 0.2 °2θ in peak positions (USP-941) applies to this data. The minor error associated with this measurement can occur because of a variety of factors including: (a) sample preparation (e.g., sample height), (b) instrument characteristics, (c) instrument calibration, (d) operator input (e.g. in determining the peak locations), and (e) the nature of the material (e.g. preferred orientation and transparency effects). Abbreviations Ambient temperature is generally between 20 and 25 °C. ACN is acetonitrile. aq is aqueous. CDCl3is deuterochloroform. DMSO-d6 is fully deuterated dimethyl sulfoxide. DIPEA is N,N-diisopropylethyl amine. ca. is circa. psiq is pounds per square inch gauge EtOH is ethanol. Et3N is triethylamine. eq. is molar equivalent. IPA is isopropyl alcohol. KOAc is potassium acetate. Me is methyl (-CH3). MeOH is methanol. mL is milliliter. mmol is millimole. PXRD is powder X-ray diffraction THF is tetrahydrofuran. Example 1 Preparation of potassium 3-(benzyloxy)-4-hydroxytetrahydro-2H-pyran-4- sulfonate, Formula : The compound of to Scheme 4 below. Scheme 4: 2H-pyran-3-ol Potassium hydroxide (93.3 g, 1.5 mol, 2.4 eq.) was combined with MeOH (700 mL, 11.2 mL / g) and stirred to give a solution with cooling to 3-5°C. Compound 1 (62.4 g, 623 mmol, 1 eq., obtained from Sigma-Aldrich) was added over 12 minutes maintaining temperature <5°C. The reaction was stirred for 45 minutes at ~3°C. Separately, a solution of iodine (158.9 g, 623 mmol, 1 eq.) in MeOH (1.4 L, 22.4 mL / g) was prepared with the exclusion of light. The solution of iodine was added to the reaction over 3 hours maintaining temperature <5°C and excluding light. Following addition, the reaction was heated to 20°C and stirred for 30 minutes. The mixture was concentrated under reduced pressure at 40°C to leave a slurry. Dichloromethane (410 mL, 6.6 mL / g) was added to the residue and the slurry was filtered. The filtrate was concentrated under reduced pressure at 40°C to leave an oil. n-Heptane (104 mL, 1.7 mL / g) was added and the mixture concentrated under reduced pressure at 40°C to leave an oil. Dichloromethane (210 mL, 3.4 mL / g) and methyl tert-butyl ether (410 mL, 6.6 mL / g) were added and the resultant solution was washed with water (52 mL, 0.8 mL / g). The aqueous phase was extracted with dichloromethane (130 mL, 2.1 mL / g). The combined organics were dried over Na2SO4, filtered, and concentrated to leave Compound 2 (80.01 g, 493 mmol, 79% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 1.73-1.77 (m, 1H), 1.89-1.97 (m, 1H), 3.24 (s, 3H), 3.26 (s, 3H), 3.44-3.50 (m, 1H), 3.65-3.69 (m, 2H), 3.76-3.83 (m, 2H).13C NMR (101 MHz, CDCl3) δ ppm 29.0, 47.5, 48.4, 64.6, 67.6, 69.4, 98.3. Step 2: Compound 3: 3-(benzyloxy)-4,4-dimethoxytetrahydro-2H-pyran Compound 2 (73.6 g, 454 mmol, 1 eq.) was combined with toluene (390 mL, 5.3 mL / g) and the mixture was concentrated under vacuum to leave an oil to which tetrahydrofuran (390 mL, 5.3 mL / g) was added. In a separate vessel, sodium tert- butoxide (48.34 g, 498 mmol, 1.1 eq.) was combined with tetrabutylammonium iodide (34.09 g, 90.5 mmol, 0.2 eq.) and tetrahydrofuran (390 mL, 5.3 mL / g) and the resultant mixture was stirred and cooled to 15°C. The solution of Compound 2 was added to this mixture over 45 minutes maintaining temperature <20°C. Benzyl bromide (54.3 mL, 454 mmol, 1.0 eq.) was added over 8 minutes maintaining the temperature <20°C. The resultant mixture was heated to 35°C and stirred for 24 hours then was cooled to 20°C. Water (780 mL, 10.6 mL / g) was added and the phases separated. The aqueous phase was extracted three time with methyl tert-butyl ether (3 x 780 mL, 3 x 10.6 mL / g). The combined organic phases were concentrated under reduced pressure to leave an oil. The oil was purified by flash chromatography on silica gel (10 to 100% iso-propyl acetate in n-heptane) to leave Compound 3 (82.75 g, 328 mmol, 72% yield) as a yellow oil.1H NMR (300 MHz, DMSO-d6) δ ppm 1.72-1.76 (m, 1H), 1.77-1.81 (m, 1H), 3.11 (s, 3H), 3.14 (s, 3H), 3.31-3.39 (m, 1H), 3.43-3.48 (m, 2H), 3.61-3.70 (m, 1H), 4.49-4.54 (m, 1H), 4.63- 4.67 m, 1H), 7.20-7.37 (m, 5H). Step 3: Compound 4: 3-(benzyloxy)tetrahydro-4H-pyran-4-one mmol, 1 eq.) was with water (450 mL, 6 mL / g) and toluene (900 mL, 12 mL / g) and the mixture was stirred at 20°C. Formic acid (450 mL, 6 mL / g) was added over 11 minutes and the reaction stirred for 20 hours at 20°C. The reaction was cooled to 5°C and a solution of sodium hydroxide in water (10 M, 1.21 L, 16 mL / g) was added over 3 hours maintaining temperature <12°C. The phases were separated and the aqueous layer extracted with toluene (225 mL, 3 mL / g). The combined organic phases were washed with a saturated solution of ammonium chloride in water (225 mL, 3 mL / g). The organic phase was dried over Na2SO4, filtered, and concentrated at reduced pressure to leave an oil. Methyl tert-butyl ether (300 mL, 4 mL / g) was added and the mixture was filtered. The filtrate is concentrated under reduced pressure to leave Compound 4 (60.06 g, 291 mmol, 98% yield) as an oil.1H NMR (300 MHz, DMSO-d6) δ ppm 2.35-2.41 (m, 1H), 2.60-2.72 (m, 1H), 3.42-3.49 (m, 1H), 3.58- 3.67 (m, 1H), 4.03-4.20 (m, 3H), 4.50-4.54 (m, 1H), 4.72-4.76 (m, 1H), 7.30-7.37 (m, 5H). Step 4: Formula (II): potassium 3-(benzyloxy)-4-hydroxytetrahydro-2H-pyran-4- sulfonate A soluti , , 250 mL, 10 mL / g) was cooled to 10°C and a solution of potassium metabisulfite (17 g, 73 mmol, 0.6 eq.) in water (25 mL, 1 mL / g) was added over ~30 minutes. The reaction was stirred at 10°C for 2 hours then filtered and the filter cake rinsed with toluene (75 mL, 3 mL / g). The filter cake was combined with ethanol (300 mL, 12 mL / g) and the slurry stirred at 25-30°C for 30 minutes. The slurry was collected by filtration, rinsed with ethanol (25 mL, 1 mL / g), and dried at 55-60°C to leave Formula (I) (28 g, 86 mmol, 71% yield) as a crystalline white solid.1H NMR (300 MHz, DMSO-d6) δ ppm 1.79-1.83 (m, 2H), 3.10-3.17 (m, 1H), 3.40-3.50 (m, 2H), 3.60-3.70 (m, 1H), 3.85-3.90 (m, 1H), 4.31 (s, 1H), 4.56-4.59 (m, 1H), 4.78-4.82 (m, 1H), 7.23-7.39 (m, 5H). Example 2 Preparation of salts Formula V : A buffer was prepared from boric acid (0.50 g, 8.1 mmol), isopropylamine (6.8 mL, 79 mmol) and water (25 mL), and adjusted to pH 11.5 using concentrated HCl. Further water was added to give a total volume of 40 mL. To a vessel was charged pyridoxal phosphate (22.5 mg, 0.75% w / w), ATA-303 (105 mg, 3.5% w / w; obtained from Codexis, Inc.) and the prepared buffer (19.5 mL, 6.5 mL / g). The mixture was stirred at 40°C for 15 minutes and a slurry of the compound of Formula (II) (3.0 g, 9.2 mmol, 1.0 eq.) in the prepared buffer (6.0 mL, 2 mL / g) was added. The reaction was stirred for 22 hours, and methyl ethyl ketone (30 mL, 10 mL / g) was added. The biphasic mixture was filtered to remove insoluble matter and the filtrate separated into two phases. The aqueous phase was extracted with methyl ethyl ketone (15 mL, 5 mL / g) and the organics combined. n- Heptane (2.5 mL, 0.83 mL / g) was added to the organic phase and any aqueous phase was separated. The organics were washed with saturated brine (15 mL, 5 mL / g) and concentrated to dryness to leave a yellow oil. The oil was taken up in 2- methyltetrahydrofuran (7.5 mL, 2.5 mL / g) and concentrated to dryness to leave the compound of Formula (III) (1.80 g, 8.7 mmol, >99%ee, >90:10 dr, 95% yield) as a pale yellow oil.1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 - 1.36 (m, 1 H) 1.74 (ddt, J=13.26, 4.74, 2.50, 2.50 Hz, 1 H) 2.67 (ddd, J=10.64, 8.02, 4.59 Hz, 1H) 2.94 - 3.08 (m, 2 H) 3.27 (td, J=11.44, 2.50 Hz, 1 H) 3.68 - 3.81 (m, 1 H) 3.88 - 4.02 (m, 1 H) 4.49 - 4.67 (m, 2 H) 7.22 - 7.42 (m, 5 H).13C NMR (101 MHz, DMSO-d6) δ ppm 33.35 (s, 1 C) 52.49 (s, 1 C) 65.66 (s, 1 C) 67.53 (s, 1 C) 71.12 (s, 1 C) 80.34 (s, 1 C) 127.33 (s, 1 C) 127.54 (s, 1 C) 128.14 (s, 1 C) 138.90 (s, 1 C). Step 1 (Alternate): (3S,4R)-3-(benzyloxy)tetrahydro-2H-pyran-4-amine, Formula (III): Alternately, the compound of Formula (III) can be prepared from 3- (benzyloxy)tetrahydro-4H-pyran-4-one, Formula (I). A buffer was prepared from boric acid (9.9 g), isopropylamine (68 mL) and water (500 mL), and adjusted to pH 11.5 using 4M HCl. Further, water was added to give a total volume of 800 mL (final borate concentration of 0.2M and isopropylamine concentration of 1M). To a vessel was charged pyridoxal phosphate (401 mg, 2% w / w) and the borate buffer solution (320 mL, 18 mL / g). A fluorescent yellow solution formed on stirring. ATA- 303 (4 g, 20% w / w) was added and the mixture heated to 40°C and stirred for 45 minutes to give a thin slurry. A solution of 3-(benzyloxy)tetrahydro-4H-pyran-4-one, 4 (20 g, 97.0 mmol, 1 eq.) in DMSO (40 mL, 2 mL / g) was added in ten equal portions over the course of 10 hours at 40°C. Following complete addition, the reaction was stirred for a further 14 hours at 40°C. The reaction mixture was filtered to remove any solids, then the filtrate extracted three time with MeTHF / heptane (4:1 v:v, 1.0 L, 50 mL / g). The combined organic phase was washed with 10%wt. aq. Na2SO4 (200 mL, 10 mL / g) then clarified by filtration through a pad of Celite (30 g, 150%wt.). The filter cake was washed with MeTHF (60 mL, 3 mL / g). The combined filtrate and wash were concentrated under reduced pressure to leave a clear yellow oil (19.3 g, 93.1 mmol, 96%) as a 95.3:4.7 trans:cis mixture of diastereomers. The assay yield of the compound of Formula (III) was 87% (17.6 g). The oil was dissolved in MeTHF (200 mL, 10.4 mL / g) and the resultant solution is stored at −20°C. Step 2a: (3S, 4R)-3-(benzyloxy)tetrahydro-2H-pyran-4-aminium tosylate salt, Formula (IVa): A solution of (3S,4R)-3-(benzyloxy)tetrahydro-2H-pyran-4-amine, Formula (III) (26.63 g, 129 mmol, 1 eq.) in 2-MeTHF (270 mL, 10 mL / g) was charged to a vessel. In a separate vessel, para-toluenesulfonic acid monohydrate (25.36 g, 133 mmol, 1.03 eq.) was dissolved in 2-MeTHF (130 mL, 5 mL / g). The acid solution was charged to the solution of Formula (III) over 15 minutes at 22°C with overhead stirring. Around third of the way into the addition some cloudiness began to appear and shortly afterwards a thick white precipitate forms. Following complete addition the white slurry was aged for an additional 2 hours the collected by vacuum filtration, washing with 2:1 v:v mixture of 2- MeTHF / n-heptane (60 mL, 2.3 mL / g). Tosylate salt Formula (IVa) was isolated as a low density white solid (42.49 g, 112 mmol, 87%) after drying for 6 hours at 50°C.1H NMR (400 MHz, DMSO-d6) δ ppm 1.60 (qd, J=12.32, 4.89 Hz, 1 H) 1.91-2.01 (m, 1 H) 2.29 (s, 3 H) 3.03 (dd, J=10.91, 10.19 Hz, 1 H) 3.18 (ddd, J=11.77, 9.69, 4.65 Hz, 1 H) 3.32 (td, J=11.89, 2.09 Hz, 1 H) 3.46 (td, J=9.83, 4.77 Hz, 1 H) 3.81 (dd, J=11.62, 4.11 Hz, 1 H) 4.07 (dd, J=11.03, 4.71 Hz, 1 H) 4.54 - 4.65 (m, 2 H) 7.07 - 7.18 (m, 2 H) 7.26 - 7.43 (m, 5 H) 7.45 - 7.58 (m, 2 H) 8.03 (s, 3 H).13C NMR (101 MHz, DMSO-d6) δ ppm 20.72 (s, 1 C) 29.40 (s, 1 C) 51.50 (s, 1 C) 64.92 (s, 1 C) 67.48 (s, 1 C) 71.06 (s, 1 C) 74.85 (s, 1 C) 125.45 (s, 1 C) 127.66 (s, 1 C) 127.86 (s, 1 C) 128.04 (s, 1 C) 128.17 (s, 1 C) 137.70 (s, 1 C) 137.96 (s, 1 C) 145.50 (s, 1 C). Step 2b: (3S, 4R)-3-(benzyloxy)tetrahydro-2H-pyran-4-aminium dihydrogen phosphate salt, Formula (IVb): A - pyran- Formula (III) (32.4 g, 156 mmol, 1 eq.) in IPA (500 mL, 15.4 mL / g) was treated with a solution of 85% H3PO4 (18 g, 156 mmol, 1 eq.) in IPA (130 mL, 4 mL / g). The resulting slurry was aged at 20°C for 1 hour, then collected by filtration. The vessel and cake were washed twice with IPA (150 mL, 4.6 mL / g) and pulled dry on the filter for 1 hour. Dihydrogen phosphate salt Formula (IVb) was isolated as a white solid (42.4 g, 139 mmol, 89%) after drying overnight at 50°C.1H NMR (400 MHz, deuterium oxide) δ ppm 1.79 (qd, J=12.48, 4.89 Hz, 1 H) 2.05 – 2.22 (m, 1 H) 3.22 (t, J=10.73 Hz, 1 H) 3.29 – 3.40 (m, 1 H) 3.49 (t, J=12.10 Hz, 1 H) 3.64 (td, J=9.95, 4.89 Hz, 1 H) 4.00 (dd, J=11.92, 4.29 Hz, 1 H) 4.22 (dd, J=11.32, 4.89 Hz, 1 H) 4.63 – 4.73 (m, 2 H) 7.38 -7.57 (m, 5 H).13C NMR (101 MHz, deuterium oxide) δ ppm 28.92 (s, 1 C) 52.00 (s, 1 C) 65.60 (s, 1 C) 67.64 (s, 1 C) 72.11 (s, 1 C) 74.36 (s, 1 C) 128.75 (s, 1 C) 128.78 (s, 1 C) 128.94 (s, 1 C) 136.95 (s, 1 C).31P NMR (162 MHz, deuterium oxide) δ ppm 0.06 (s, 1 P). Step 3a: (3S, 4R)-3-hydroxytetrahydro-2H-pyran-4-aminium tosylate salt, Formula Tosylate salt Formula (IVa) obtained from step 2a (30.4 g, 80.1 mmol) and 10% Pd / C (7.52 g, 25 wt%, obtained from Johnson Matthey) were charged to an autoclave. MeOH (600 mL, 20 mL / g) was charged and the vessel placed under a hydrogen atmosphere (2.8 bar). The resulting reaction mixture was stirred at room temperature for 16 hours. Following reaction completion, the vessel was vented to atmospheric pressure and purged with nitrogen. The reaction mixture was filtered through celite (ensuring the filter pad remained wet) and the cake washed with MeOH (300 mL, 10 mL / g). The combined filtrate and the wash was concentrated under partial vacuum to 5 mL / g, diluted with 2-MeTHF (450 mL, 15 mL / g) and concentrated under partial vacuum to 10 mL / g. A further portion of 2-MeTHF (300 mL, 10 mL / g) was added and the mixture concentrated to 10 mL / g giving a slurry. A further portion of 2-MeTHF (300 mL, 10 mL / g) was charged and the slurry was concentrated under partial vacuum to 10 mL / g. The resulting slurry was collected by vacuum filtration and the cake washed with 2-MeTHF (2 x 60 mL, 2 x 2 mL / g). The resulting wet cake was dried at ambient temperature to yield the tosylate salt Formula (Va) as a white solid (21.0 g, 72.6 mmol, 91%).1H NMR (400 MHz, deuterium oxide) δ ppm 1.69 - 1.89 (m, 1 H) 2.12 (br dd, J=13.23, 2.15 Hz, 1 H) 2.41 (s, 3 H) 3.17 - 3.34 (m, 2 H) 3.49 (br t, J=12.16 Hz, 1 H) 3.65 - 3.77 (m, 1 H) 3.94 - 4.12 (m, 2 H) 7.34 - 7.44 (m, 2 H) 7.67 - 7.77 (m, 2 H).13C NMR (101 MHz, deuterium oxide) δ ppm 20.51 (s, 1 C) 28.84 (s, 1 C) 53.38 (s, 1 C) 65.63 (s, 1 C) 67.10 (s, 1 C) 69.86 (s, 1 C) 125.40 (s, 1 C) 129.48 (s, 1 C) 139.50 (s, 1 C) 142.51 (s, 1 C). Step 3b: (3S, 4R)-3-hydroxytetrahydro-2H-pyran-4-aminium dihydrogen phosphate salt, Formula (Vb):

[0005] To a suitable pressure vessel was charged the dihydrogen phosphate salt Formula (IVb) obtained from step 2b (4.0 g, 13.1 mmol, 1 eq.), water (8.0 mL, 2 mL / g), 85% H3PO4 (0.4 g, 10%w / w) and activated charcoal (0.4 g, 10%w / w). The resulting slurry was stirred at 40°C for 1 hour.10% Pd / C (80 mg, 2%w / w) was charged and the reactor purged with hydrogen to 50 psig. The reaction was stirred and heated to 60°C for 22 hours. The reaction was cooled to 20°C and vented. The slurry was filtered over Celite to remove catalyst and the cake washed twice with water (4 mL, 1 mL / g). The combined filtrate and washes was concentrated to dryness then EtOH (32 mL, 8 mL / g) was added. The slurry was heated to reflux with stirring, then cooled to room temperature and filtered. The cake was washed twice with cold EtOH (4 mL, 1 mL / g) and the solids dried under vacuum. Dihydrogen phosphate salt Formula (Vb) was isolated as an off-white solid (2.44 g, 11.3 mmol, 87%).1H NMR (400 MHz, deuterium oxide) δ ppm 1.71 - 1.90 (m, 1 H) 2.13 (br dd, J=13.11, 1.91 Hz, 1 H) 3.15 - 3.36 (m, 2 H) 3.50 (br t, J=12.16 Hz, 1 H) 3.61 - 3.80 (m, 1 H) 3.94 - 4.15 (m, 2H).13C NMR (101 MHz, deuterium oxide) δ ppm 28.82 (s, 1 C) 53.35 (s, 1 C) 65.63 (s, 1 C) 67.07 (s, 1 C) 69.85 (s, 1 C).31P NMR (162 MHz, deuterium oxide) δ ppm 0.06 (s, 1 P). Example 3 Preparation of 2-(6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)propan-2-ol, Formula (VIII) Cl N

[0006] Compound 6: 1-((4-bromo-2,6-difluorophenyl)amino)-2-methyl-1-oxopropan-2-yl acetate Compound 5 (30.0 g, 144.2 mmol, 1 eq., obtained from Sigma Aldrich) was combined with acetonitrile (135 mL, 4.5 mL / g) and pyridine (17.1 g, 216.3 mmol, 1.5 eq.). The mixture was cooled to 0°C and 1-chloro-2-methyl-1-oxopropan-2-yl acetate (95%wt., 30.0 g, 173 mmol, 1.2 eq.) was added slowly over 15 minutes maintaining reaction temperature <10°C, followed by a rinse of acetonitrile (15 mL, 0.5 mL / g). The reaction was stirred for 15 minutes and then heated to 25°C for 30 minutes to give a solution of intermediate compound 6 that was used directly in the next step. Compound 7: N-(4-bromo-2,6-difluorophenyl)-2-hydroxy-2-methylpropanamide A solution of sodium hydroxide (2M, 389.4 g, 721.2 mmol, 5 eq.) was added to the solution of compound 6 and the reaction stirred at 25°C for 18 hours. Methyl tert-butyl ether (300 mL, 10 mL / g) was added and the phases separated. The aqueous phase was extracted with methyl tert-butyl ether (150 mL, 5 mL / g). The combined organic phases were washed with water (150 mL, 5 mL / g). The organic phase was combined with toluene (300 mL, 10 mL / g) and the mixture was concentrated at atmospheric pressure to ca.120 mL (ca.4 mL / g). The mixture was cooled to 70°C and n-heptane (720 mL, 24 mL / g) was added over ca.20 minutes. The resultant slurry was stirred at 70°C for 30 minutes, then cooled to 10°C. The slurry was collected by filtration, washed with cold n-heptane (2 x 60 mL, 2 x 2 mL / g), and dried at 40°C to leave compound 7 as a white solid (35.71 g, 121.4 mmol, 84.2% yield).1H NMR (400 MHz, CDCl3) δ ppm 1.56 (s, 6H), 2.43 (bs, 1H), 7.15 (d, J = 7.0 Hz, 2H), 8.14 (bs, 1H).13C NMR (101 MHz, CDCl3) δ ppm 28.0, 74.7, 113.4 (t, J = 16.5 Hz), 115.7-116.2 (m), 119.6 (t, J = 11.6 Hz), 157.8 (dd, J = 254.7, 5.8 Hz), 174.9. Step 3: Compound 8: 2-(6-bromo-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2- yl)propan-2-ol

[0007] Compound 7 (75.0 g, 255.0 mmol, 1 eq.), isopropylamine (220 mL, 2.50 mol, 10 eq.) and NMP (375 mL, 5 mL / g) were combined in a pressure vessel and the mixture heated to 113°C for 24 hours. The mixture was cooled to 25°C and water (1.13 L, 15 mL / g) was added over 2.5 hours. The resultant slurry was cooled to 2°C and stirred for 2 hours. The slurry was collected by filtration, washed with a mixture of NMP and water (1:3 v:v, 150 mL, 2 mL / g) then water (150 mL, 2 mL / g), and dried at 40°C to leave Compound 8 as an off white solid (69.8 g, 209.5 mmol, 82.2% yield).1H NMR (400 MHz, CDCl3) δ ppm 1.22 (d, J = 6.3 Hz, 6H), 1.57 (s, 6H), 2.46 (bs, 1H), 3.56 (septet, J = 6.3 Hz, 1 H), 6.60-6.65 (m, 2H), 8.14 (bs, 1H).13C NMR (101 MHz, CDCl3) δ ppm 22.7, 28.2, 44.8, 74.6, 107.6 (d, J = 24.2 Hz), 110.0 (d, J = 15.3 Hz), 111.5, 121.3 (d, J = 12.9 Hz), 145.1, 157.8 (d, J = 247.7), 175.9. Step 4: Formula (VI): 2-(6-bromo-4-fluoro-1-isopropyl-1H-benzo[d]imidazol-2- 2-ol (250 mL, 5 mL / g) at 21°C, and methanesulfonic acid (9.75 mL, 150.1 mmol, 1 eq.) was added over ca.1 hour. The reaction was heated to 100°C for 18 hours then cooled to 22°C. Water (100 mL, 2 vol) was added over 30 minutes, then a solution of NaOH (6.5 g, 162.5 mmol, 1.08 eq.) in water (275 mL, 5.5 mL / g) was added over 2 hours. The resultant slurry was stirred at 23°C for 16 hours. The slurry was collected by filtration, washed with a mixture of NMP and water (3:7 v:v, 100 mL, 2 mL / g) then water (100 mL, 2 mL / g), and dried at 40°C to leave the compound of Formula (VI) as a beige solid (44.1 g, 139.9 mmol, 93.2% yield).1H NMR (400 MHz, CDCl3) δ ppm 1.63 (d, J = 7.0 Hz, 6H), 1.78 (s, 6H), 2.92 (bs, 1H), 5.46 (septet, J = 7.0 Hz, 1H), 7.08 (d, J = 9.7 Hz, 1H), 7.49 (s, 1H).13C NMR (101 MHz, CDCl3) δ ppm 21.0, 30.0, 49.2, 71.1, 111.5 (d, J = 21.0 Hz), 111.9 (d, J = 4.3 Hz), 114.6 (d, J = 8.9 Hz), 130.2 (d, J = 16.3Hz), 137.9 (d, J = 9.2 Hz), 153.9 (d, J = 257.0 Hz), 158.7. Step 5: 2-(6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-fluoro-1-isopropyl-1H- benzo[d]imidazol-2-yl)propan-2-ol, Formula (VII): The compound of Formula (VI) (5.00 g, 15.86 mmol, 1 eq.) was combined with bis(neopentyl glycolato)diboron (4.12 g, 18.25, 1.15 eq.), potassium pivalate (2.50 g, 17.45 mmol, 1.10 eq.), potassium 2-ethylhexanoate (1.18 g, 6.34 mmol, 0.4 eq.) and bis(triphenylphosphine)palladium(II) dichloride (0.114 g, 0.159 mmol, 0.01 eq.). Methyl tert-butyl ether (30 mL, 6 mL / g) was added and the mixture degassed using vacuum / nitrogen cycles. The reaction was heated to 50°C for 3 hrs to give a slurry of Formula (VII). The slurry of Formula (VII) was maintained at >40°C and used directly in the next step. A sample of the compound of Formula (VII) for analysis was isolated as follows. The above slurry of the compound of Formula (VII) from a 9.0 g scale reaction (Formula (VI)) was cooled to 25°C and the solids collected by filtration. The cake was washed with methyl tert-butyl ether (45 mL, 5 mL / g) and water (23 mL, 2.5 mL / g) and dried to give a pale colored solid (2.03 g). The methyl tert-butyl ether filtrate was concentrated to dryness, dissolved in ethyl acetate (90 mL, 10 mL / g) and washed twice with water (45 mL, 5 mL / g). The organics were dried over MgSO4, filtered and concentrated and dried to give a brown solid. The brown solid was redissolved in ethyl acetate (90 mL) and treated with activated charcoal (1 g) at 50°C for 1 hr. The slurry was filtered on a pad of Arbocel and the filtrate cooled to 25°C resulting in precipitation of solids. Heptane (23 mL) was added, and the slurry cooled to 0°C. The solids were collected by filtration and dried to give a colorless solid (4.13 g). The two solid lots (~6.2 g) were combined and suspended in ethyl acetate (160 mL) at 70°C. The thin slurry was filtered to remove insolubles, then cooled to 25°C and heptane (25 mL) was added. The slurry was cooled further to 0°C then filtered and dried to leave compound of Formula (VII) as a pale pink solid (4.2 g).1H NMR (400 MHz, DMSO-d6) δ ppm 0.97 (s, 6 H) 1.58 (d, J=7.03 Hz, 6 H) 1.65 (s, 6 H) 3.78 (s, 4 H) 5.66 - 5.83 (m, 2 H) 7.17 (d, J=11.32 Hz, 1 H) 7.75 (s, 1 H).13C NMR (101 MHz, DMSOd6) δ ppm 20.51 (s, 1 C) 21.29 (s, 1 C) 29.95 (s, 1 C) 31.43 (s, 1 C) 48.08 (s, 1 C) 69.75 (s, 1 C) 71.46 (s, 1 C) 110.27 (d, J=15.59 Hz, 1 C) 114.04 (d, J=2.87 Hz, 1 C) 125.01 - 127.17 (m, 1 C) 132.71 (d, J=17.23 Hz, 1 C) 136.92 (d, J=8.20 Hz, 1 C) 153.20 (d, J=250.21 Hz, 1 C) 159.34 (s, 1 C). Step 6: 2-[6-(2,5- dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2- yl]propan-2-ol, Formula (VIII): The slurry of the compound of Formula (VII) from step 5 was stirred at 50°C and to it was charged a degassed solution of sodium hydroxide in water (2M, 11.9 mL, 1.5 eq.). The biphasic mixture was stirred for 1 hr at 50°C and a pH probe was added. The pH of the mixture was adjusted to ca.10 using additional degassed sodium hydroxide in water (2M, ca. 8 mL, ca. 1 eq.). A solution of 2,4,5-trichloropyrimidine (3.78 g, 20.62 mmol, 1.3 eq., obtained from Sigma Aldrich) in methyl tertbutyl ether (20 mL, 4 mL / g) was degassed and added to the reaction mixture. The reaction was stirred at 50°C for 18 hrs while the pH was maintained at ca.10 through addition of degassed sodium hydroxide was water (2M, ca.11.9 mL, ca.1.5 eq.). The reaction was quenched with concentrated aqueous hydrochloric acid to a pH of 0-1 (12.2M, 5.0-6.2, 3.8-4.8 eq.) at 40-45°C. Sodium chloride (7.5 g, 1.5 g / g (i.e., weight equivalent: 1.5 grams of NaCl per 1 gram of starting material Formula (VI)) was added and the mixture stirred for 0.5-1 hr. The reaction mixture was filtered on a pad of Arbocel to remove insoluble matter. The filter cake was washed with methyl tert-butyl ether at 40-45°C (3 x 15 mL, 9 mL / g total). The phases were allowed to separate and the aqueous extracted with methyl tert-butyl ether at 40- 45°C (25 mL, 5 mL / g). The organics were combined are washed at 40-45°C with sodium hydroxide in water (1M, 30 mL, 6 mL / g) then with sodium chloride in water (23.5%w / w, 35 mL, 7 mL / g). The organic phase was treated with silica thiol (2.5 g, 0.5 g / g) at 40-45°C for 18 hours, then the slurry filtered on a pad of Arbocel. The filter cake was washed with methyl tert-butyl ether at 40-45°C (3 x 15 mL, 9 mL / g total). The filtrate was concentrated to ca.15 mL (ca.3 mL / g) and n-heptane (50 mL, 10 mL / g) was added at 40-45°C to give a mobile slurry. The slurry was cooled to 0°C and the solids isolated by filtration. The cake was washed with cold n-heptane (10 mL, 2 mL / g) and dried to leave the compound of Formula (VIII) in 86-98% uncorrected yield (5.2-6.0 g). The compound of Formula (VIII) was recrystallized from ethanol / water as follows. Crude compound of Formula (VIII) (12.5 g) was suspended in ethanol (125 mL, 10 mL / g) and heated to 50°C to give a solution. The solution was filtered to remove insoluble matter, then concentrated to ca.25 mL (ca.2 mL / g). The mixture was stirred at 50°C to give a slurry, then a mixture of ethanol (10 mL, 0.8 mL / g) and water (10 mL, 0.8 mL / g) was added. The slurry was cooled to 0°C and the solids isolated by filtration. The cake was washed twice with a cooled mixture of ethanol (12.5 mL, 1 mL / g) and water (3.75 mL, 0.3 mL / g), and dried to leave the compound of Formula (VIII) as an off-white to brown solid (7.94 g, 64% yield). Example 4a Preparation of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1- (propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo- pentitol monohydrate (Form 2), Compound A 2-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2- yl]propan-2-ol, Formula (VIII) (7.05 g, 18.4 mmol, 1 eq.) and tosylate salt Formula (Va) (7.59 g, 25.7 mmol, 1.4 eq.) were charged to a vessel and purged with nitrogen. Acetonitrile (40 mL, 5 mL / g) is added followed by N,N-diisopropyl ethyl amine (11.2 mL, 64.3 mmol, 3.5 eq.). The reaction mixture was heated to gentle reflux (jacket temperature 85°C) for 43 hrs. Water (40 mL, 5 mL / g) was added over 15 mins and the reaction mixture was cooled to 22°C to give a slurry. The slurry was collected by filtration and the cake washed with a mixture of acetonitrile (40 mL, 5 mL / g) and water (40 mL, 5 mL / g), and dried to leave Compound A as a white solid (7.23 g, 15 mmol, 82% yield). Example 4b Alternately, Compound A was prepared using hydrogen phosphate salt Formula (Vb) 2- - - 2- yl]propan-2-ol, Formula (VIII) (40.0 g, 104 mmol, 1 eq.), dihydrogen phosphate salt Formula (Vb) (24.7 g, 115 mmol, 1.1 eq.) and dipotassium hydrogen phosphate (54.4 g, 312 mmol, 3 eq.) were charged to a vessel and purged with nitrogen. Sulfolane (3% wet, 124 mL, 3.1 mL / g) and water (40 mL, 1 mL / g) were added and the reaction mixture was heated to 92-98°C for 41 hrs. The mixture was cooled to 90°C and water (76 mL, 1.9 mL / g) is added. The mixture was aged at 90°C for 20 minutes then 2-propanol (40 mL, 1 mL / g) was added). The mixture was aged for 20 minutes, then cooled to ca.65°C over 1 hour and seeded with Compound A. The resultant slurry was cooled to 0°C over 30 minutes and stirred at 0°C for 1.5 hours. The slurry was collected by filtration and the cake was further washed with water (2 x 240 mL, 2 x 6 mL / g) and dried to leave Compound A as a white solid (43.24 g, 89.7 mmol, 86% yield). Example 5a Evaluation of reaction conditions for the formation of Compound A step described in Example 4a Several combinations of base and solvent were explored for the coupling step of 2-[6-(2,5- dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan- 2-ol, Formula (VIII) with the tosylate salt Formula (Va). Compound A was synthesized according to the procedure described in Example 4a above except that the reaction conditions (i.e., base, solvent, water) were altered. Tables 1 and 2 summarize the reaction yields of Compound A obtained from different combinations of base and solvent with or without the presence of water respectively. Table 1: Base / solvent combinations for the coupling step of 2-[6-(2,5- dichloropyrimidin-4-yl)-4- fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol, Formula (VIII) with the tosylate salt Formula (Va) with the presence of water Solvent 2-butanol t-amyl 2- 1-propanol ACN anisole sulfolane 2- Base alcohol propanol MeTHF (3.0 eq.) DIPEA 49.40 43.90 67.53 60.76 67.13 10.78 84.93 19.34 K2HPO456.51 44.89 58.64 57.04 61.31 5.86 79.19 26.70 Et2N 62.25 51.60 62.81 65.13 60.86 6.19 68.64 29.01 Calcium 21.42 21.48 26.06 24.18 n.d. 2.52 31.86 9.03 propionate Ba(OH)2H2O n.d. 18.89 11.14 n.d. n.d. 22.41 17.14 n.d. KOAc 21.00 14.58 19.54 24.89 n.d. 0.93 39.42 6.02 n.d. = no Compound A detected Table 2: Base / solvent combinations for the coupling step of 2-[6-(2,5- dichloropyrimidin-4-yl)-4- fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol, Formula (VIII) with the tosylate salt Formula (Va) without the presence of water Solvent 2-butanol t-amyl 2- 1- ACN anisole sulfolane 2- Base alcohol propanol propanol MeTHF (2.0 eq.) DIPEA 61.35 55.17 66.96 71.34 67.09 13.08 91.24 39.24 K2HPO449.03 50.10 55.50 68.75 50.63 1.82 77.32 n.d. Et2N 66.67 64.37 67.96 72.40 74.20 12.42 82.98 48.07 Calcium 42.21 36.85 37.99 35.77 33.01 1.90 36.51 31.16 propionate Ba(OH)2 H2O 24.33 37.68 43.44 25.23 38.20 2.25 55.08 35.24 KOAc 47.29 40.24 53.42 46.87 58.71 3.05 71.60 48.97 Base (3.0 eq.) DIPEA 65.71 51.10 63.82 77.61 78.93 3.61 88.71 0.56 K2HPO4 0.14 0.09 0.14 0.19 0.16 n.d. 0.30 0.05 Et2N 69.93 73.00 73.39 72.07 73.70 14.55 85.05 54.60 Calcium 37.36 39.89 33.48 32.87 29.29 2.66 36.60 n.d. propionate Ba(OH)2 H2O 20.53 20.27 38.93 17.20 28.97 1.05 11.06 10.35 KOAc 55.55 46.43 57.81 55.08 54.58 6.86 89.17 50.48 n.d. = no Compound A detected Example 5b Evaluation of reaction conditions for the formation of Compound A step described in Example 4b Several combinations of base and solvent were explored for the coupling step of 2-[6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan- 2-ol, Formula (VIII) with the dihydrogen phosphate salt Formula (Vb). Compound A was synthesized according to the procedure described in Example 4a above except that the reaction conditions (i.e., base, solvent, water) were altered. Tables 3 and 4 summarized the reaction yields of Compound A obtained from different combinations of base and solvent with or without the presence of water respectively. Table 3: Base / solvent combinations for the coupling step of 2-[6-(2,5- dichloropyrimidin-4-yl)-4- fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol, Formula (VIII) with the dihydrogen phosphate salt Formula (Vb) with the presence of water Solvent 2-butanol t-amyl 2- 1-propanol ACN anisole sulfolane 2- Base alcohol propanol MeTHF (3.0 eq.) DIPEA 54.81 40.77 75.69 80.33 81.22 15.78 85.55 24.43 K2HPO4 43.26 29.51 56.58 58.96 53.04 5.57 85.33 23.48 Et2N 66.21 52.42 77.96 79.57 80.74 10.73 85.58 34.98 Calcium 19.82 14.79 17.41 24.25 24.95 n.d. 39.99 9.03 propionate Ba(OH)2 H2O 57.18 66.45 59.60 62.58 66.31 36.28 67.11 54.36 KOAc 14.43 7.87 16.08 25.62 24.62 n.d. 37.10 n.d. n.d. = no Compound A detected Table 4: Base / solvent combinations for the coupling step of 2-[6-(2,5- dichloropyrimidin-4-yl)-4- fluoro-1-(propan-2-yl)-1H-benzimidazol-2-yl]propan-2-ol, Formula (VIII) with the dihydrogen phosphate salt Formula (Vb) without the presence of water Solvent 2-butanol t-amyl 2-propanol 1-propanol ACN anisole sulfolane 2- Base alcohol MeTHF (2.0 eq.) DIPEA 4.62 n.d. 5.37 11.78 n.d. n.d. 30.95 n.d. K2HPO4 54.92 70.68 76.20 83.27 85.24 43.01 91.21 58.35 Et2N 5.82 n.d. 10.86 18.56 n.d. n.d. 38.0 n.d. Calcium 48.06 46.02 49.10 54.97 52.17 21.76 71.92 56.29 propionate Ba(OH)2H2O 11.70 1305 3.93 5.90 n.d. n.d. 76.89 7.91 KOAc 78.02 67.15 80.22 79.23 84.67 15.38 87.67 64.31 n.d. = no Compound A detected Example 6 Two solid forms were observed for the tosylate salt Formula (IVa). Characterization of the tosylate salt Formula (IVa) (Form 1): Form 1 (anhydrous form) was prepared according to the procedure described in Example 2 Step 2a, was characterized as follows: FIG.1 shows PXRD data for the tosylate salt Formula (IVa) (Form 1), collected according to general PXRD method 1. A list of PXRD peaks at diffraction angles 2-theta ° (°2θ) ± 0.2 °2θ and their relative intensities is provided in Table 5. Table 5: PXRD Peak list for the tosylate salt Formula (IVa) (Form 1) (2θ°) Angle (2-theta °) Relative Intensity Angle (2-theta °) ± Relative Intensity ± 0.2 °2θ (%) 0.2 °2θ (%) 5.1 10 25.5 8 12.4 61 25.8 5 15.2 2 26.3 4 16.0 9 26.9 6 16.8 31 27.3 8 17.5 14 27.7 4 17.6 12 27.9 7 19.0 2 29.3 3 19.6 11 30.2 3 19.7 36 34.3 3 22.5 100 35.4 2 23.1 48 37.9 4 24.8 5 38.3 6 25.0 2 Characterization of the tosylate salt Formula (IVa) (Form 2): Form 2 (hemi-hydrate) was prepared by exposing Form 1 to water and was characterized as follows: FIG.2 shows PXRD data for the tosylate salt Formula (IVa) (Form 2), collected according to General PXRD method 1. A list of PXRD peaks at diffraction angles 2-theta ° (°2θ) ± 0.2 °2θ and their relative intensities is provided in Table 6. Table 6: PXRD Peak list for the tosylate salt Formula (IVa) (Form 2) (2θ°) Angle (2-theta °) Relative Intensity Angle (2-theta °) Relative Intensity ± 0.2 °2θ (%) ± 0.2 °2θ (%) 5.5 100 22.0 5 8.5 73 23.4 74 9.9 17 23.8 30 10.2 4 24.3 6 10.9 14 24.7 10 13.7 3 24.9 12 14.1 14 26.2 17 15.7 32 27.2 24 16.5 10 27.3 26 17.0 10 27.6 11 17.5 99 27.9 4 17.7 18 29.3 9 18.1 14 29.5 7 18.3 3 30.1 4 18.8 5 30.6 2 19.8 79 31.3 8 20.7 36 31.8 7 21.2 88 32.2 7 21.5 8 33.2 5 Example 7 Polymorph screening on the phosphate salt of Formula (IVb) indicated that Form 1 was the only form observed and is likely to be the most thermodynamically stable form under the tested conditions. Characterization of the phosphate salt Formula (IVb) (Form 1): The phosphate salt of Formula (IVb) (Form 1) prepared according to the procedure described in Example 2 Step 2b, was characterized as follows: FIG.3 shows PXRD data for the phosphate salt Formula (IVb) (Form 1), collected according to General PXRD method 1. A list of PXRD peaks at diffraction angles 2-Theta ° (°2θ) ± 0.2 °2θ and their relative intensities is provided in Table 7. Table 7: PXRD Peak list for the tosylate salt Formula (IVa) (Form 1) (2θ°) Angle (2-theta °) Relative Intensity Angle (2-theta °) Relative Intensity ± 0.2 °2θ (%) ± 0.2 °2θ (%) 5.0 73 26.0 4 10.3 7 26.4 4 11.2 10 27.1 5 12.6 17 27.7 13 14.3 6 28.2 10 15.3 4 28.8 15 16.2 17 29.6 13 18.3 53 30.0 2 19.0 4 30.6 20 19.5 3 30.9 5 20.2 35 31.4 12 20.3 45 32.0 5 20.8 3 32.8 2 21.5 67 33.2 4 22.0 20 34.2 2 22.7 100 34.7 3 23.7 93 34.9 2 24.3 16 35.7 2 24.9 4 36.1 6 25.4 3 36.4 4 Example 8 Form 1 was observed for the tosylate salt of Formula (Va). Characterization of the tosylate salt Formula (Va) (Form 1): The tosylate salt of Formula (Va) (Form 1) prepared according to the procedure described in Example 2 Step 3a, was characterized as follows: FIG.4 shows PXRD data for the tosylate salt Formula (Va) (Form 1), collected according to General PXRD method 1. A list of PXRD peaks at diffraction angles 2-Theta ° (°2θ) ± 0.2 °2θ and their relative intensities is provided in Table 8. Table 8: PXRD Peak list for the tosylate salt Formula (Va) (Form 1) (2θ°) Angle (2-theta °) Relative Intensity Angle (2-theta °) Relative Intensity ± 0.2 °2θ (%) ± 0.2 °2θ (%) 6.5 49 24.3 15 10.1 24 24.8 4 10.6 21 25.4 28 12.0 9 26.0 3 13.1 5 26.2 4 14.1 4 26.4 3 14.8 10 26.9 13 15.2 25 27.2 10 16.2 34 27.6 9 16.6 8 27.8 6 16.7 5 28.4 3 17.0 53 28.8 11 18.0 11 30.0 3 19.2 16 30.2 4 19.5 100 30.4 3 19.7 9 30.8 9 19.9 6 30.9 10 20.3 31 31.4 4 20.6 15 31.9 4 21.4 81 32.1 2 21.6 11 32.9 2 22.2 5 33.1 7 22.6 43 33.7 5 23.3 14 33.8 6 23.6 7 34.6 5 Example 9 Polymorph screening on the phosphate salt of Formula (Vb) indicated that Form 1 was the only form observed and is likely to be the most thermodynamically stable form under the tested conditions. Characterization of the phosphate salt Formula (Vb) (Form 1): The phosphate salt of Formula (Vb) (Form 1) prepared according to the procedure described in Example 2 Step 3b, was characterized as follows: FIG.5 shows PXRD data for the phosphate salt Formula (Vb) (Form 1), collected according to General PXRD method 1. A list of PXRD peaks at diffraction angles 2-Theta ° (°2θ) ± 0.2 °2θ and their relative intensities is provided in Table 9. Table 9: PXRD Peak list for the phosphate salt Formula (Vb) (Form 1) (2θ°) Angle (2-theta °) Relative Intensity Angle (2-theta °) ± Relative Intensity ± 0.2 °2θ (%) 0.2 °2θ (%) 10.7 24 26.0 8 13.6 9 26.4 22 15.1 2 27.3 4 15.9 18 28.1 11 16.5 4 28.5 21 17.3 55 29.3 8 17.9 3 29.4 7 19.2 6 29.8 6 21.0 100 31.7 9 21.4 78 31.8 10 22.1 4 32.2 9 22.5 11 32.5 4 24.6 9 32.8 8 25.5 7 34.3 2 25.9 26 35.5 6 Example 10 Solid Form of the Compound of Formula (VII): Polymorph screening revealed that Form 1 was the only form of the compound of Formula (VII) observed and is the most thermodynamically stable form under the tested conditions. Another PXRD pattern observed during screening was determined to be a product of degradation. Characterization of the Compound of Formula (VII) (Form 1): The Compound of Formula (VII) (Form 1) prepared according to the procedure described in Example 3 Step 5, was characterized as follows: PXRD data: FIG.6 shows PXRD data for the compound of Formula (VII) (Form 1), collected according to General PXRD method 2. A list of PXRD peaks at diffraction angles 2-theta ° (°2θ) ± 0.2 °2θ and their relative intensities is provided in Table 10. Table 10: PXRD Peak list for the compound of Formula (VII) (Form 1) (2θ°) Angle (2-theta °) Relative Intensity Angle (2-theta °) ± Relative Intensity ± 0.2 °2θ (%) 0.2 °2θ (%) 10.0 100.0 20.6 5.5 12.4 12.0 21.1 5.7 13.2 13.5 23.7 41.9 14.6 12.6 24.9 13.6 16.4 11.1 25.1 6.7 17.4 20.1 25.4 5.3 18.2 25.1 27.7 6.5 18.6 68.9 29.3 9.5 19.4 11.6 29.4 8.8 20.0 16.3 30.2 10.1 20.4 14.6 31.6 14.0 Example 11 A polymorph screen was performed on the compound of Formula (VIII), involving over 150 solvent and non-solvent based screening experiments. Form 1 (monohydrate) and Form 3 (anhydrous) were observed along with several solvates. The solvates have shown to be unstable at ambient conditions, drying to either an anhydrous or monohydrate form. Both Form 1 and Form 3 have been isolated during synthesis dependent on the water activity of the isolation solvents and the extent of drying, and both forms have been successfully used in the next step (i.e., Example 4a or 4b). Compound of Formula (VIII) Form 3 (anhydrous): Form 3 was prepared according to the procedure described in Example 3 Step 6. Alternately, Form 3 can be prepared from several evaporation experiments, or Form 3 can be prepared through dehydration of Form 1. It was observed that several solvated forms convert to Form 3 upon drying. Form 3 was physically stable under ambient and 40°C / 75% RH conditions. Characterization of the Compound of Formula (VIII) (Form 3): The Compound of Formula (VIII) (Form 3) was characterized as follows: PXRD data: FIG.7 shows PXRD data for the compound of Formula (VIII) (Form 3), collected according to General PXRD method. A list of PXRD peaks at diffraction angles 2-Theta ° (°2θ) ± 0.2 °2θ and their relative intensities is provided in Table 11. Table 11: PXRD Peak list for the compound of Formula (VIII) (Form 3) (2θ°) Angle (2-theta °) Relative Intensity Angle (2-theta °) Relative Intensity ± 0.2 °2θ (%) ± 0.2 °2θ (%) 5.1 48.7 21.5 13.1 10.3 55.5 22.7 15.5 10.7 88.8 22.8 30.6 11.3 10.9 24.3 11.0 14.0 40.3 25.0 10.7 14.1 59.7 25.2 19.5 14.8 27.2 25.6 10.6 15.4 12.6 25.7 26.6 17.3 79.2 25.9 38.6 17.6 100.0 26.2 27.7 18.0 84.8 26.8 62.4 19.8 79.6 28.3 14.7 20.8 30.3 29.1 21.8 21.0 12.3 29.9 10.9 21.1 14.2 Compound of Formula (VIII) Form 1 (monohydrate): Form 1 can be prepared by slurring the Compound of Formula (VIII) in a solvent system containing water. For example, in the present disclosure, form 1 was prepared from evaporation of acetone / water (90:10 v / v) and dioxane / water (82:18 v / v). Form 1 is a stable physical form at a water activity (a.w) greater than 0.543. The sample analyzed in this experiment was prepared on a ~700 mg scale by slurring Form 3 in acetone / water 1:5 v / v for 88 hours. Form 1 was physically stable under ambient and 40°C / 75% RH conditions. Characterization of the Compound of Formula (VIII) (Form 1): The Compound of Formula (VIII) (Form 1) was characterized as follows: PXRD data: FIG.8 shows PXRD data for the compound of Formula (VIII) (Form 1), collected according to General PXRD method. A list of PXRD peaks at diffraction angles 2-theta ° (°2θ) ± 0.2 °2θ and their relative intensities is provided in Table 12. Table 12: PXRD Peak list for the compound of Formula (VIII) (Form 1) (2θ°) Angle (2-theta °) Relative Intensity Angle (2-theta °) Relative Intensity ± 0.2 °2θ (%) ± 0.2 °2θ (%) 9.4 44.3 22.3 11.9 10.4 50.0 22.8 16.6 12.8 28.8 23.4 100.0 14.5 77.8 25.4 21.3 15.3 14.0 25.6 24.1 16.1 56.0 26.7 10.6 16.4 35.9 27.9 12.8 18.9 16.2 28.3 89.9 19.1 18.0 28.4 41.0 19.8 21.9 29.3 13.0 21.5 25.6 32.1 16.6 Example 12 The compounds shown in Table 13 are prophetic deuterated analogs (PDA) of Compound A. The PDAs are predicted based on the metabolic profile of Compound A predicted using MetaSite 6.0.5 x64 (Molecular Discovery Ltd.) Examples: Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14Y15Y16Y17Compound A - PDA D1 D D D H H H H H H H H H H H H H HD2 H H H D D D H H H H H H H H H H HD3 H H H H H H D H H H H H H H H H HD4 H H H H H H H D H H H H H H H H HD5 H H H H H H H H D H H H H H H H H D6 H H H H H H H H H D H H H H H H H D7 H H H H H H H H H H D D H H H H H D8 H H H H H H H H H H H H D D H H H D9 H H H H H H H H H H H H H H D D H D10 H H H H H H H H H H H H H H H H D D11 H H H H H H H H H H D D D D H H H D12 H H H H H H H H D H D D H H H H H D13 H H H H H H D H H H D D H H H H H D14 H H H H H H H H D H H H D D H H HD15 H H H H H H D H H H H H D D H H HD16 H H H H H H D H D H H H H H H H HD17 H H H H H H D H H H D D D D H H HGeneral methods / reviews of obtaining metabolite profile and identifying metabolites of a compound are described in: Dalvie, et al., “Assessment of Three Human in Vitro Systems in the Generation of Major Human Excretory and Circulating Metabolites,” Chemical Research in Toxicology, 2009, 22, 2, 357-368, tx8004357 (acs.org); King, R., “Biotransformations in Drug Metabolism,” Ch.3, Drug Metabolism Handbook Introduction, https: / / doi.org / 10.1002 / 9781119851042.ch3; Wu, Y., et al, “Metabolite Identification in the Preclinical and Clinical Phase of Drug Development,” Current Drug Metabolish, 2021, 22, 11, 838-857, 10.2174 / 1389200222666211006104502; Godzien, J., et al, “Chapter Fifteen - Metabolite Annotation and Identification”. Numerous publicly available and commercially available software tools are available to aid in the predictions of metabolic pathways and metabolites of compounds. Examples of such tools include, BioTransformer 3.0 (biotransformer.ca / new) which predicts the metabolic biotransformations of small molecules using a database of known metabolic reactions; MetaSite (moldiscovery.com / software / metasite / ) which predicts metabolic transformations related to cytochrome P450 and flavin-containing monooxygenase mediated reactions in phase I metabolism; and Lhasa Meteor Nexus (lhasalimited.org / products / meteor-nexus.htm) offers prediction of metabolic pathways and metabolite structures using a range of machine learning models, which covers phase I and phase II biotransformations of small molecules. Example D1-D17 in Table 13 may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements, reduced CYP450 inhibition (competitive or time dependent), or an improvement in therapeutic index or tolerability. A person with ordinary skill may make additional deuterated analogs of Example D1-D17 with different combinations of Y1-Y17as provided in Table 13. Such additional deuterated analogs may provide similar therapeutic advantages that may be achieved by the deuterated analogs.

Claims

CLAIMS What is claimed:

1. A process for preparing a compound of Compound A: Compound A comprising:(a) providing a compound Formula (VIII) ; (b) (VIII) with a compound of Formula (V),, wherein X is OTs or H2PO4, in the presence ofsolvent to produce Compound A.

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

3. The process of claim 1, wherein X is H2PO4.

4. The process of any one of claims 1-3, wherein the solvent is a polar solvent.

5. The process of any one of claims 1-4, wherein the polar solvent comprises 1- propanol, 2-propanol, 2-butanol, t-amyl alcohol, acetonitrile, sulfolane, or 2-methyl tetrahydrofuran, 2-methyl tetrahydrofuran, dimethylformamide (DMF),dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP), or dimethyl sulfoxide (DMSO).

6. The process of any one of claims 1-5, wherein the solvent comprises acetonitrile.

7. The process of any one of claims 1-5, wherein the solvent comprises sulfolane.

8. The process of any one of claims 1-7, wherein the base is selected from the group consisting of a trialkylamine, an alkaline earth carbonate, an alkaline earth bicarbonate, an alkaline earth phosphate, an inorganic base, and mixtures thereof.

9. The process of any one of claims 1-8, wherein the base is selected from the group consisting of N,N-diisopropylethylamine (DIPEA), triethylamine, tri-n-butyl, tri-n-octyl, sodium bicarbonate, potassium carbonate, cesium carbonate, potassium propionate, mono-potassium phosphate, di-potassium phosphate, tri-potassium phosphate, barium hydroxide, calcium hydroxide, sodium hydroxide, potassium hydroxide, and mixtures thereof.

10. The process of any one of claims 1-9, wherein the contacting step (b) is conducted at a temperature of from about 80°C to about 110°C.

11. The process of any one of claims 1-8, wherein the compound of Formula (V) is prepared according to claim 13.

12. The process of any one of claims 1-8, wherein the compound of Formula (VIII) is prepared according to claim 14.

13. A process for preparing a compound of Formula (V) , wherein Xˉ is OTsˉ or H2PO4ˉ, comprising:(a) providing a compound of Formula (II) OOHO SO K; (b)Formula (II) to a compound of Formula (III); ; (c)of Formula (III) with an acid selected from p- toluenesulfonic acid or phosphoric acid to produce a compound of Formula (IV) , wherein Xˉ is OTsˉ or H2PO4ˉ; and(d) of Formula (IV) to provide the compound of Formula (V) .

14. A process for preparing a compound of Formula (VIII)I); comprising: (a) conac ng a compoun o ormula (VI) with bisin the presence of a potassium salt of an organic acid, a suitable organic solvent and an organopalladium catalyst to provide a compound of Formula (VII)(b) contacting the compound of Formula (VII) with 2,4,5-trichloropyrimidine in the presence of a base to produce the compound of Formula (VIII).

15. The process of claim 14, wherein the potassium salt of an organic acid used in step (a) is selected from the group consisting of potassium pivalate, potassium 2- ethylhexanoate, potassium acetate, and mixtures thereof.

16. The process of any one of claims 14-15, wherein the organic solvent used in step (a) comprises a tertiary alcohol, a tertiary ether, or an optionally substituted tetrahydrofuran or tetrahyropyran.

17. The process of any one of claims 14-16, wherein the organic solvent used in step (a) is selected from the group consisting of tert-butanol, tert-amyl alcohol, methyl tert- butyl ether, cyclopentyl methyl ether (CPME), tert-amyl-methyl ether (TAME), tetrahydropyran, tetrahydrofuran, 2-methyltetrahydrofuran, 3-methyltetrahydrofuran, or mixture thereof.

18. The process of any one of claims 14-17, wherein the organopalladium catalyst used in step (a) is selected from the group consisting of bis(triphenylphosphine)palladium(II) dichloride (PdCl2(PPh3)2), allylpalladium(II) chloride dimer ([Pd(allyl)Cl]2), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), bis(triphenylphosphine)palladium(II) diacetate (Pd(OAc)2(PPh3)2), 1,4- bis(diphenylphosphino)butane-palladium(II) chloride (PdCl2(dppb)), 1,1’- bis(diphenylphosphino)ferrocene palladium(II) dichloride (PdCl2(dppf)), and [9,9- dimethyl-4,5-bis(diphenylphosphino)xanthene] palladium(II) dichloride (PdCl2(xantphos)).

19. The process of any one of claims 14-18, wherein the base used in step (b) is an alkali metal hydroxide or carbonate base, or an alkaline earth hydroxide or carbonate base.

20. The process of any one of claims 14-19, wherein the base used in step (b) is sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, cesium carbonate, and mixture thereof.

21. A crystalline form of Formula (IVa) (Form 1) having the structure:having a powder X-ray diffraction (PXRD) pattern comprising peaks at 2θ values of: 5.1, 12.4, 16.8, and 22.5 °2θ ± 0.2 °2θ.

22. A crystalline form of Formula (IVa) (Form 2) having the structure:a) having s at 2θ values of: 5.5, 8.5, 21.2, and 23.4 °2θ ± 0.2 °2θ.

23. A crystalline form of Formula (IVb) (Form 1) having the structure: having aat 2θ values of: 5.0, 18.3, 21.5, 22.7 and 23.7 °2θ ± 0.2 °2θ.

24. A crystalline form of Formula (Va) (Form 1) having the structure:having a PXRD pattern comprising peaks at 2θ values of: 6.5, 17.0, 19.5, 21.4, and 22.6 °2θ ± 0.2 °2θ.

25. A crystalline form of Formula (Vb) (Form 1) having the structure:having a PXRD pattern comprising peaks at 2θ values of: 10.7, 15.9,17.3, 21.0, and 21.4 °2θ ± 0.2 °2θ.

26. A crystalline form of Formula (VII) (Form 1) having the structure:peaks at 2θ values of: 10.0, 12.4, 14.6, 18.6, and 23.7 °2θ ± 0.2 °2θ.

27. A crystalline form of Formula (VIII) (Form 1) having the structure:a peaks at 2θ values of: 9.4, 12.8, 14.5, and 16.4 °2θ ± 0.2 °2θ.

28. A crystalline form of Formula (VIII) (Form 3) having the structure:having a PXRD pattern comprising peaks at 2θ values of: 5.1, 10.7, 14.1, and 17.3 °2θ ± 0.2 °2θ.

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