Process for the preparation of 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)-pyrrolidin-2-yl]imidazo[1,5-a]-pyrazin-1-yl}N-(pyridin-2-yl)-benzamide

Abstract

Provided are intermediates for preparing acalabrutinib. [Solution] A crystalline form of a compound having the structure of the following formula, characterized by a reflection X-ray powder diffraction pattern selected from a reflection X-ray powder diffraction pattern containing at least three peaks selected from the group consisting of 9.9±0.2°2θ, 11.1±0.2°2θ, etc., and a reflection X-ray powder diffraction pattern containing at least three peaks selected from the group consisting of 7.4±0.2°2θ, 11.7±0.2°2θ, etc. JPEG2026021364000206.jpg58160

Description

[Technical Field]

[0001] The present disclosure relates generally to processes for the preparation of 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)-benzamide, and in particular to improvements in large-scale processes for making 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide and / or intermediates utilized in such processes. [Background technology]

[0002] 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide (also known by the International Nonproprietary Name acalabrutinib) is the active pharmaceutical ingredient in the drug product CALQUENCE®. In 2017, the U.S. Food and Drug Administration granted marketing approval for CALQUENCE® for the treatment of mantle cell lymphoma in adult patients who have received at least one prior therapy. Clinical trials evaluating the use of CALQUENCE® to treat additional indications, including chronic lymphocytic leukemia and Waldenström's macroglobulinemia, are ongoing.

[0003] Example 6 of Patent Document 1 discloses acalabrutinib and reports the synthesis shown in Scheme 1 below: Scheme 1 [ka]

[0004] Non-Patent Document 1 (digitally published October 6, 2016) reports the synthesis of acalabrutinib, as shown in Scheme 2 below: Scheme 2 [ka]

[0005] However, previously reported synthetic methods are not suitable for large-scale, particularly commercial-scale, production of acalabrutinib. The present disclosure provides an improved process that can be operated on a large scale and offers one or more advantages over previously reported synthetic methods, such as improved compound purity, improved compound isolation (e.g., filterability), shorter cycle times, less stringent process control requirements, higher yields, reduced costs, and improved compliance with regulatory requirements for pharmaceutical starting materials, intermediates, and products. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] U.S. Patent No. 9,290,504 [Non-patent literature]

[0007] [Non-Patent Document 1] Research Disclosure Database Number 631028 Summary of the Invention [Means for solving the problem]

[0008] As noted above, the present disclosure relates to improvements in large-scale processes for preparing acalabrutinib and / or intermediates utilized in preparing acalabrutinib.

[0009] In one aspect, the present disclosure provides a compound having the structure of formula (VIII): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (VII): [ka] or a salt thereof, with 2-butynoic acid, or a salt thereof, in the presence of 1-propylphosphonic anhydride and a base in a reaction medium to form a reaction mixture comprising a compound of formula (VIII), or a salt thereof, and one or more reaction by-products; and Selective isolation of the compound of formula (VIII), or a salt thereof, from the reaction mixture relative to one or more reaction by-products.

[0010] In another aspect, the present disclosure provides a compound having the structure of formula (VII): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (V): [ka] or a salt thereof, with a compound having the structure of formula (VI): [ka] or a salt thereof in an aqueous reaction medium comprising an organic solvent in the presence of a base and a palladium catalyst to form a reaction mixture comprising a compound of formula (VII), or a salt thereof; reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising a compound of formula (VII), or a salt thereof; and and isolating the compound of formula (VII), or a salt thereof, from the substantially anhydrous mixture.

[0011] In another aspect, the present disclosure provides a compound having the structure of formula (VI): [ka] or a salt thereof, the process comprising: Compounds of formula (IV): [ka] or a salt thereof, with an acidic medium under conditions sufficient to deprotect the compound of formula (IV) and form a reaction mixture comprising a compound of formula (VI), or a salt thereof, and a benzyl halide by-product; and and isolating the compound of formula (VI), or a salt thereof, from the reaction mixture under conditions sufficient to substantially avoid the formation of the aminal impurity.

[0012] In another aspect, the present disclosure provides a compound having the structure of formula (V): [ka] or a salt thereof, the process comprising contacting 4-carboxyphenylboronic acid, or a salt thereof, with thionyl chloride and a catalyst in a reaction medium comprising an organic solvent to form an acyl chloride intermediate, followed by in situ contact with 2-aminopyridine to form a reaction mixture comprising a compound of formula (V), or a salt thereof.

[0013] In another aspect, the present disclosure provides a compound having the structure of formula (IV): [ka] The process for preparing a sulfate salt of A compound having the structure of formula (III): [ka] or a salt thereof, with an aminating agent in a reaction medium to form a reaction mixture comprising a compound of formula (IV); forming a sulfate salt of a compound of formula (IV); and and isolating the sulfate salt.

[0014] In another aspect, the present disclosure provides a compound having the structure of formula (III): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (I): [ka] or a salt thereof is contacted with a cyclizing agent in the presence of a catalyst in a reaction medium to produce a compound of formula (II): [ka] or forming a salt thereof; and The compound of formula (II) or a salt thereof is brominated with a brominating agent to obtain a compound having the structure of formula (III): [ka] or a salt thereof; The temperature of the reaction medium is controlled during the contacting step in a manner sufficient to maintain at least about 80% chiral purity with respect to the compound of formula (II), or a salt thereof.

[0015] In another aspect, the present disclosure provides a compound having the structure of formula (II): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (I): [ka] or a salt thereof, with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound of formula (II), or a salt thereof; The temperature of the reaction medium is controlled during the contacting step in a manner sufficient to maintain at least about 80% chiral purity with respect to the compound of formula (II), or a salt thereof.

[0016] In another aspect, the present disclosure provides a compound having the structure of formula (VII): [ka] With respect to the crystalline form of The crystalline form is a reflection X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 9.9±0.2 degrees two-theta, 11.1±0.2 degrees two-theta, 12.8±0.2 degrees two-theta, 14.1±0.2 degrees two-theta, and 19.0±0.2 degrees two-theta; and The compound is characterized by a reflection X-ray powder diffraction pattern selected from reflection X-ray powder diffraction patterns comprising at least three peaks selected from the group consisting of 7.4±0.2°2θ, 11.7±0.2°2θ, 12.5±0.2°2θ, 22.3±0.2°2θ, and 21.6±0.2°2θ.

[0017] In another aspect, the present disclosure provides a compound having the structure of formula (VII): [ka] With respect to the crystalline form of The crystalline form is characterized by a reflection X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 9.9±0.2 degrees 2θ, 11.1±0.2 degrees 2θ, 12.8±0.2 degrees 2θ, 14.1±0.2 degrees 2θ, and 19.0±0.2 degrees 2θ.

[0018] In one aspect, the present disclosure provides a compound having the structure of formula (IV): [ka] This relates to the crystalline sulfate salt of [Brief explanation of the drawings]

[0019] [Figure 1] FIG. 1 shows an X-ray powder diffraction (PXRD) pattern measured in reflectance mode from a sample of the crystalline sulfate salt of benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate, having a stoichiometric ratio of approximately one sulfate molecule and one hydrogen sulfate molecule for all three free base molecules. [Figure 2]1 shows an X-ray powder diffraction (PXRD) pattern measured in reflectance mode from a sample of the Form 2 crystalline form of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]-imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide. [Figure 3] 1 shows an X-ray powder diffraction (PXRD) pattern measured in reflectance mode from a sample of the Form 3 crystalline form of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]-imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide. [Figure 4] 1 shows an X-ray powder diffraction (PXRD) pattern measured in reflectance mode from a sample of the Form C crystalline form of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]-imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide. DETAILED DESCRIPTION OF THE INVENTION

[0020] This written description uses examples to disclose the invention and will enable any person skilled in the art to make and use the disclosed salts, substances, or compositions, and to practice the invention, including performing any of the disclosed methods or processes. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have elements that do not differ from the literal wording of the claims, or if they contain equivalent elements that have insubstantial differences from the literal wording of the claims.

[0021] I. Definition The section headings and the overall disclosure as used in this section are not intended to be limiting.

[0022] When a range of numbers is recited, each number within the range is expressly contemplated to the same degree of precision. For example, for the range 6 to 9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0 to 7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are expressly contemplated. Similarly, all recited ratios also include all subratios falling within the broader ratio.

[0023] The singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise.

[0024] The term "about" generally refers to a range of numbers that one of ordinary skill in the art would consider equivalent to the recited value (i.e., having the same function or result). In many instances, the term "about" may include numbers that are rounded to the nearest significant figure.

[0025] Unless the context otherwise requires, the words "comprise," "comprises," and "comprising" are used with the express understanding that they are to be interpreted inclusively and not exclusively, and that applicant intends each of these words to be so interpreted in interpreting this patent, including the claims that follow.

[0026] The term "sulfate (2:3)" refers to a sulfate salt having a stoichiometric ratio of sulfate to free base of about 2:3, including sulfate salts having one sulfate molecule and one hydrogen sulfate molecule for every three free base molecules.

[0027] The term "crystalline purity," when used in reference to a crystalline form of a compound, refers to the percentage of the crystalline form relative to other crystalline or amorphous forms of the compound in the referenced composition.

[0028] Abbreviations used throughout this disclosure have the meanings set out in Table 1 below.

[0029] [Table 1]

[0030] For clarity, Table 2 below summarizes the compound identifiers, chemical names, and structures used interchangeably throughout this application for each compound disclosed.

[0031] [Table 2]

[0032] [Table 3]

[0033] [Table 4]

[0034] The present disclosure also discusses crystalline forms of certain compounds listed in Table 2 and includes X-ray powder diffraction patterns characterizing such crystalline forms. It is known in the art that measurement conditions (such as the instrument, sample preparation, or machine used) can result in X-ray powder diffraction patterns with one or more measurement errors. In particular, it is generally known that the intensities in X-ray powder diffraction patterns can vary depending on the measurement conditions and sample preparation. For example, those skilled in the art of X-ray powder diffraction will understand that the relative intensities of peaks can vary depending on the orientation of the sample being tested and the type and settings of the instrument being used. Those skilled in the art will also understand that the position of reflections can be affected by the exact height at which the sample is positioned within the diffractometer and the zero calibration of the diffractometer. The surface planarity of the sample may also have some effect. As such, one of ordinary skill in the art will recognize that the diffraction pattern data presented herein should not be construed as absolute, and that any crystalline form that gives a powder diffraction pattern substantially identical to that disclosed herein is within the scope of the present disclosure (for further information, see Jenkins, R & Snyder, R.L., "Introduction to X-Ray Powder Diffractometry," John Wiley & Sons, 1996).

[0035] II. Synthesis of U.S. Patent No. 9,290,504 As previously mentioned, the synthesis reported in Example 6 of U.S. Patent No. 9,290,504 is not suitable for large-scale production of acalabrutinib. Among other limitations, the reported process does not provide information on the chiral or achiral purity of the intermediates, utilizes chromatography to isolate intermediates at various points during the process, and produces milligram quantities of the final product. The overall yield of acalabrutinib from this bench-scale synthesis starting from Compound I was approximately 5%.

[0036] III. Clinical Trial Supply Process Scheme 3 below shows the process that was subsequently developed to manufacture supplies of acalabrutinib for clinical trials. The individual steps in Scheme 3 are discussed in more detail throughout this disclosure. Scheme 3 [ka]

[0037] This process was used to produce approximately 100-150 kilograms of acalabrutinib for use in clinical trials, but the process lacked robustness, was difficult to operate, and had a very long cycle time. As a result, the process was deemed unsuitable for large-scale production of acalabrutinib.

[0038] More specifically, the process of Scheme 3 has several limitations, including the following: (1) Racemization of the chiral center during the process to produce compound (II) was difficult to control and caused the failure of some batches. (2) Some environmentally undesirable solvents are utilized in some steps. (3) One of the more problematic solvents utilized is dichloromethane. In addition to environmental concerns, the use of dichloromethane in processes involving amines has the additional drawback of producing aminal impurities from the reaction of the amine with dichloromethane, potentially even leading to batch failure. During the process to produce compound (VI), for example, methylene-bridged dimers may be formed. Furthermore, the acid-based liquid chromatography analytical method used in connection with the process to produce compound (VI) failed to detect the aminal impurity. (4) The use of the combination of N,N-dimethylformamide and thionyl chloride used to produce compound (V) can potentially result in the formation of toxic dimethylcarbamoyl chloride. (5) The coupling reaction in the step to produce compound (VII) is prone to stalling. Adding more palladium catalyst increases the burden on the removal step in the final step to produce acalabrutinib, which already requires excessive repeated cycles with silica-based scavengers. (6) Isolation of compound (VII) by filtration is difficult and unsuitable for large-scale production. For a 50 kg scale, the use of two pressure filters and multiple manual discharges of the product as a wet paste were required, with significant time penalties. (7) Multiple batch failures occurred through a variety of different failure modes for the acylation to produce acalabrutinib. (8) Isolation of acalabrutinib using distillation precipitation does not allow control over the particle characteristics of the isolated product.

[0039] IV. Large-scale processes In view of the limitations associated with the clinical trial supply process, an improved process was developed that overcomes these limitations and is suitable for large-scale manufacturing of acalabrutinib. Scheme 4 below shows one representative embodiment of this large-scale process for manufacturing acalabrutinib. The individual steps of Scheme 4 are discussed in more detail throughout this disclosure. Scheme 4 [ka]

[0040] V. Preparation of (2S)-2-(8-chloro-imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate benzyl (Compound II) The present disclosure relates, in part, to a process for preparing benzyl (2S)-2-(8-chloro-imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (compound II), or a salt thereof, from benzyl (2S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl]pyrrolidine-1-carboxylate (compound I), or a salt thereof. Scheme 5 below shows the general process: Scheme 5 [ka]

[0041] Cyclization of compound (I) to form the imidazole ring present in compound (II) is advantageous because it provides stability to the chiral center of subsequent intermediates utilized in the manufacture of acalabrutinib. However, the clinical trial delivery process is problematic because uncyclized compound (I) readily racemizes under the acidic conditions of the cyclization reaction. Unwanted racemization is difficult to control and has resulted in multiple batch failures. The use of a nitrogen sweep to remove generated hydrochloric acid somewhat limits the chiral reduction that occurs, but the extent of chiral reduction remains highly variable.

[0042] The clinical trial supply process utilized a reaction temperature of approximately 80°C with an N,N-dimethylformamide catalyst loading of approximately 0.2 molar equivalents. It has now been discovered that increasing the N,N-dimethylformamide loading (e.g., to approximately 0.6 molar equivalents) and decreasing the reaction temperature (e.g., to approximately 40°C) limits the observed chiral degradation and consistently results in the production of chirally pure Compound (II). The lower N,N-dimethylformamide catalyst loading utilized in the clinical trial supply process results in a reaction rate that requires higher temperatures for completion of the reaction, subsequently resulting in the observed chiral degradation. In contrast, the increased N,N-dimethylformamide catalyst loading of the improved process results in a faster reaction rate and allows the reaction to be carried out at a lower temperature, which suppresses racemization. Chiral degradation is reduced, chiral integrity is maintained, and yields are therefore improved.

[0043] Thus, in one embodiment, the present disclosure provides a compound having the structure of formula (II): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (I): [ka] or a salt thereof, with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound of formula (II), or a salt thereof; The temperature of the reaction medium is controlled during the contacting step in a manner sufficient to maintain at least about 80% chiral purity with respect to the compound of formula (II), or a salt thereof.

[0044] As noted above, proper control of the reaction temperature during the cyclization reaction is important to maintain a suitable chiral purity of the product. Generally, the temperature of the reaction medium is controlled during the cyclization reaction in a manner sufficient to maintain at least about 85% chiral purity for the compound of Formula (II), or a salt thereof. In one embodiment, the temperature of the reaction medium is controlled during the contacting step in a manner sufficient to maintain at least about 90% chiral purity for the compound of Formula (II), or a salt thereof. In another embodiment, the temperature of the reaction medium is controlled during the contacting step in a manner sufficient to maintain at least about 95% chiral purity for the compound of Formula (II), or a salt thereof. In another embodiment, the temperature of the reaction medium is controlled during the contacting step in a manner sufficient to maintain at least about 99% chiral purity for the compound of Formula (II), or a salt thereof.

[0045] Maintaining the reaction medium at a temperature of less than about 80°C during the contacting step generally improves the chiral purity of the compound of Formula (II), or a salt thereof. In one embodiment, the reaction medium is maintained at a temperature of less than about 70°C during the contacting step. In another embodiment, the reaction medium is maintained at a temperature of less than about 60°C during the contacting step. In another embodiment, the reaction medium is maintained at a temperature of less than about 50°C during the contacting step. In another embodiment, the reaction medium is maintained at a temperature of about 30°C to about 50°C during the contacting step. In another embodiment, the reaction medium is maintained at a temperature of about 40°C during the contacting step.

[0046] The catalyst may comprise any suitable catalyst, particularly a catalyst selected from the group consisting of N,N-dimethylformamide and N-methylformanilide. In one embodiment, the catalyst comprises N,N-dimethylformamide. In another embodiment, the catalyst comprises N-methylformanilide. As noted above, the amount of catalyst charged to the reaction medium can also affect the chiral purity of the product. At least about 0.1 molar equivalent of catalyst relative to the compound of Formula (I), or a salt thereof, is generally charged to the reaction medium. In one embodiment, at least about 0.4 molar equivalent of catalyst relative to the compound of Formula (I), or a salt thereof, is charged to the reaction medium. In a further embodiment, at least about 0.6 molar equivalent of catalyst relative to the compound of Formula (I), or a salt thereof, is charged to the reaction medium. In a further embodiment, about 0.1 to about 1.0 molar equivalent of catalyst relative to the compound of Formula (I), or a salt thereof, is charged to the reaction medium. In a further embodiment, the catalyst is charged to the reaction medium in an amount of about 0.4 to about 1.0 molar equivalents relative to the compound of Formula (I), or a salt thereof. In a further embodiment, the catalyst comprises N,N-dimethylformamide, and the catalyst is charged to the reaction medium in an amount of about 0.1 to about 1.0 molar equivalents relative to the compound of Formula (I), or a salt thereof. In a further embodiment, the catalyst comprises N,N-dimethylformamide, and the catalyst is charged to the reaction medium in an amount of about 0.4 to about 1.0 molar equivalents relative to the compound of Formula (I), or a salt thereof. In a further embodiment, the catalyst comprises N,N-dimethylformamide, and the catalyst is charged to the reaction medium in an amount of about 0.6 molar equivalents relative to the compound of Formula (I), or a salt thereof.

[0047] The cyclizing agent can be any suitable cyclizing agent, particularly phosphorus oxychloride. The compound of formula (I), or a salt thereof, is generally contacted with about 0.7 to about 10 molar equivalents of the cyclizing agent relative to the compound of formula (I), or a salt thereof. In one embodiment, the compound of formula (I), or a salt thereof, is contacted with about 1.5 to about 2.5 molar equivalents of the cyclizing agent relative to the compound of formula (I), or a salt thereof. In another embodiment, the compound of formula (I), or a salt thereof, is contacted with about 2.0 molar equivalents of the cyclizing agent relative to the compound of formula (I), or a salt thereof.

[0048] The reaction medium can be any suitable reaction medium, particularly one comprising at least one solvent selected from the group consisting of aromatic hydrocarbons, chlorinated hydrocarbons, ethers, and nitriles. In one embodiment, the reaction medium comprises at least one compound selected from the group consisting of acetonitrile, butyronitrile, dichloromethane, toluene, anisole, tetrahydrofuran, and 2-methyltetrahydrofuran. In another embodiment, the reaction medium comprises acetonitrile. The volume of the reaction medium is generally from about 2 liters to about 20 liters per kilogram of the compound of Formula (I), or a salt thereof, charged to the reaction medium. In one embodiment, the volume of the reaction medium is from about 3 liters to about 10 liters per kilogram of the compound of Formula (I), or a salt thereof, charged to the reaction medium.

[0049] The contacting step is generally carried out as a batch reaction, particularly when at least about 50 kilograms of the compound of Formula (I), or a salt thereof, is charged to the batch reaction. In one embodiment, at least about 100 kilograms of the compound of Formula (I), or a salt thereof, is charged to the batch reaction. In another embodiment, at least about 200 kilograms of the compound of Formula (I), or a salt thereof, is charged to the batch reaction. In another embodiment, at least about 300 kilograms of the compound of Formula (I), or a salt thereof, is charged to the batch reaction.

[0050] The process generally provides a stoichiometric process yield of at least about 50% of the compound of formula (II), or a salt thereof. In one embodiment, the stoichiometric process yield of the compound of formula (II), or a salt thereof, is at least about 65%. In another embodiment, the stoichiometric process yield of the compound of formula (II), or a salt thereof, is at least about 80%. In another embodiment, the stoichiometric process yield of the compound of formula (II), or a salt thereof, is at least about 90%. In fact, the improved process has been able to output high-quality material at a yield of approximately 95% at a scale exceeding 300 kg (input).

[0051] In another exemplary embodiment, the present disclosure provides a compound having the structure of formula (II): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (I): [ka] or a salt thereof with phosphorus oxychloride in the presence of a catalyst in a reaction medium to form a compound of formula (II), or a salt thereof; the reaction medium is maintained at a temperature of less than about 80°C during the contacting step; At least about 0.4 molar equivalents of catalyst relative to the compound of formula (I), or salt thereof, is charged to the reaction medium; The compound of formula (II), or a salt thereof, has a chiral purity of at least about 80%.

[0052] In one embodiment, the reaction medium is maintained at a temperature of less than about 70°C during the contacting step; at least about 0.4 to about 1.0 molar equivalents of catalyst relative to the compound of Formula (I), or a salt thereof, is charged to the reaction medium; and the chiral purity of the compound of Formula (II), or a salt thereof, is at least about 85%. In another embodiment, the reaction medium is maintained at a temperature of less than about 60°C during the contacting step; at least about 0.4 to about 1.0 molar equivalents of catalyst relative to the compound of Formula (I), or a salt thereof, is charged to the reaction medium; and the chiral purity of the compound of Formula (II), or a salt thereof, is at least about 90%. In another embodiment, the reaction medium is maintained at a temperature of about 30°C to about 50°C during the contacting step; at least about 0.4 to about 1.0 molar equivalents of catalyst relative to the compound of Formula (I), or a salt thereof, is charged to the reaction medium; and the chiral purity of the compound of Formula (II), or a salt thereof, is at least about 90%. In another embodiment, the reaction medium is maintained at a temperature of about 40° C. during the contacting step; about 0.6 molar equivalents of catalyst relative to the compound of Formula (I), or a salt thereof, is charged to the reaction medium; and the chiral purity of the compound of Formula (II), or a salt thereof, is at least about 90%. In a further embodiment, the catalyst comprises N,N-dimethylformamide.

[0053] Scheme 6 below corresponds to the process described in Example 3 and illustrates one representative embodiment of an improved process for preparing compound (II). Scheme 6 [ka]

[0054] VI. Preparation of (2S)-2-(1-bromo-8-chloro-imidazo[1,5-a]pyrazin-3-yl)-pyrrolidine-1-carboxylate benzyl (compound III) The present disclosure relates, in part, to a process for preparing benzyl (2S)-2-(1-bromo-8-chloro-imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Compound III), or a salt thereof, from benzyl (2S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl]pyrrolidine-1-carboxylate (Compound I), or a salt thereof. Compound (II), or a salt thereof, is prepared from Compound (I), or a salt thereof, as previously described, and subsequently brominated to produce Compound (III), or a salt thereof. Scheme 7 below illustrates the general process: Scheme 7 [ka]

[0055] Thus, in one embodiment, the present disclosure provides a compound having the structure of formula (III): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (I): [ka] or a salt thereof is contacted with a cyclizing agent in the presence of a catalyst in a reaction medium to produce a compound of formula (II): [ka] or forming a salt thereof; and The compound of formula (II) or a salt thereof is brominated with a brominating agent to obtain a compound having the structure of formula (III): [ka] or a salt thereof; The temperature of the reaction medium is controlled during the contacting step in a manner sufficient to maintain at least about 80% chiral purity with respect to the compound of formula (II), or a salt thereof.

[0056] The brominating agent may be any suitable brominating agent, in particular N-bromosuccinimide. The compound of formula (III), or a salt thereof, may be prepared from the compound of formula (II), or a salt thereof, without first isolating the compound of formula (II), or a salt thereof, from the reaction mixture (i.e., in situ bromination, which may include a solvent exchange step), or the compound of formula (II), or a salt thereof, may be isolated from the reaction medium and subsequently brominated to provide the compound of formula (III), or a salt thereof. In one embodiment, the compound of formula (III), or a salt thereof, is prepared from the compound of formula (II), or a salt thereof, without first isolating the compound of formula (II), or a salt thereof, from the reaction mixture (i.e., in situ bromination). In another embodiment, the compound of formula (II), or a salt thereof, is isolated from the reaction medium (e.g., a solvent exchange process including isolation of an oil containing the compound of formula (II), or a salt thereof), and subsequently brominated to provide the compound of formula (III), or a salt thereof.

[0057] When the compound of formula (II), or a salt thereof, is isolated from the reaction mixture and subsequently contacted with a brominating agent in a bromination medium, the bromination medium can be any suitable bromination medium, particularly one comprising at least one solvent selected from the group consisting of chlorinated hydrocarbons and polar aprotic solvents. In one embodiment, the bromination medium comprises at least one solvent selected from the group consisting of N,N-dimethylformamide, N-methylpyrrolidinone, N-butylpyrrolidinone, dimethylsulfoxide, dimethylacetamide, and dichloromethane. In another embodiment, the bromination medium comprises N,N-dimethylformamide. In another embodiment, the bromination medium comprises N-methylpyrrolidinone.

[0058] The compound of formula (II), or a salt thereof, is contacted with an effective amount of brominating agent, for example, about 0.8 to about 1.2 molar equivalents of brominating agent relative to the compound of formula (II), or a salt thereof. To avoid over-reaction, it may be advantageous to "titrate in" the brominating agent, control the temperature of the reaction medium / bromination medium during the addition of the brominating agent, and / or perform repeated in-process control measurements during the addition of the brominating agent. In one embodiment, the reaction medium / bromination medium is maintained at a temperature of about 5°C to about 40°C during the bromination step. In another embodiment, the reaction medium / bromination medium is maintained at a temperature of about 20°C during the bromination step. In another embodiment, the brominating agent is titrated into the reaction medium / bromination medium.

[0059] The process may further include isolating the compound of Formula (III), or a salt thereof, from the final reaction mixture. In one embodiment, an aqueous solution is added to the final reaction mixture to precipitate the compound of Formula (III), or a salt thereof. In another embodiment, an aqueous solution having a basic pH is added to the final reaction mixture to precipitate the compound of Formula (III), or a salt thereof. In another embodiment, an aqueous sodium bicarbonate solution is added to the final reaction mixture to precipitate the compound of Formula (III), or a salt thereof. In another embodiment, the sodium bicarbonate solution is about 1% to 10% sodium bicarbonate by weight. In another embodiment, the sodium bicarbonate solution is about 2% sodium bicarbonate by weight.

[0060] When compound (II), or a salt thereof, is isolated from the reaction mixture and subsequently brominated, the bromination is generally carried out as a batch reaction, particularly when at least about 50 kilograms of the compound of formula (II), or a salt thereof, is charged to the batch reaction. In one embodiment, at least about 100 kilograms of the compound of formula (II), or a salt thereof, is charged to the batch reaction. In another embodiment, at least about 200 kilograms of the compound of formula (II), or a salt thereof, is charged to the batch reaction. In another embodiment, at least about 300 kilograms of the compound of formula (II), or a salt thereof, is charged to the batch reaction.

[0061] Compound (II), or a salt thereof, is brominated in situ; the in situ reaction is generally carried out as a batch reaction, particularly where at least about 50 kilograms of the compound of formula (I), or a salt thereof, is initially charged to the reaction. In one embodiment, at least about 100 kilograms of the compound of formula (I), or a salt thereof, is initially charged to the reaction. In another embodiment, at least about 200 kilograms of the compound of formula (I), or a salt thereof, is initially charged to the reaction. In another embodiment, at least about 300 kilograms of the compound of formula (I), or a salt thereof, is initially charged to the reaction.

[0062] Reacting compound (II), or a salt thereof, with a brominating agent (e.g., N-bromosuccinimide) to produce compound (III), or a salt thereof, generally works well, outputting high-quality material in high yield. The process generally provides a stoichiometric process yield of at least about 50% of the compound of formula (III), or a salt thereof. In one embodiment, the stoichiometric process yield of the compound of formula (III), or a salt thereof, is at least about 65%. In another embodiment, the stoichiometric process yield of the compound of formula (III), or a salt thereof, is at least about 80%. In another embodiment, the stoichiometric process yield of the compound of formula (III), or a salt thereof, is at least about 90%. In practice, the improved process has been able to output high-quality material in approximately 95% yield at a scale exceeding 300 kg (input).

[0063] In another exemplary embodiment, the present disclosure provides a compound having the structure of formula (III): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (I): [ka] or a salt thereof is contacted with phosphorus oxychloride in the presence of a catalyst in a reaction medium to produce a compound of formula (II): [ka] or forming a salt thereof; and The compound of formula (II) or a salt thereof is brominated with N-bromosuccinimide to give a compound having the structure of formula (III): [ka] or a salt thereof; the reaction medium is maintained at a temperature of less than about 80°C during the contacting step; At least about 0.4 molar equivalents of catalyst relative to the compound of formula (I), or salt thereof, is charged to the reaction medium; The compound of formula (II), or a salt thereof, has a chiral purity of at least about 80%.

[0064] In one embodiment, the reaction medium is maintained at a temperature of less than about 70°C during the contacting step; at least about 0.4 to about 1.0 molar equivalents of catalyst relative to the compound of Formula (I), or a salt thereof, is charged to the reaction medium; and the chiral purity of the compound of Formula (II), or a salt thereof, is at least about 85%. In another embodiment, the reaction medium is maintained at a temperature of less than about 60°C during the contacting step; at least about 0.4 to about 1.0 molar equivalents of catalyst relative to the compound of Formula (I), or a salt thereof, is charged to the reaction medium; and the chiral purity of the compound of Formula (II), or a salt thereof, is at least about 90%. In another embodiment, the reaction medium is maintained at a temperature of about 30°C to about 50°C during the contacting step; at least about 0.4 to about 1.0 molar equivalents of catalyst relative to the compound of Formula (I), or a salt thereof, is charged to the reaction medium; and the chiral purity of the compound of Formula (II), or a salt thereof, is at least about 90%. In another embodiment, the reaction medium is maintained at a temperature of about 40° C. during the contacting step; at least about 0.6 molar equivalents of catalyst relative to the compound of Formula (I), or a salt thereof, is charged to the reaction medium; and the chiral purity of the compound of Formula (II), or a salt thereof, is at least about 90%. In a further embodiment, the catalyst comprises N,N-dimethylformamide.

[0065] Scheme 8 below corresponds to the process described in Example 3 and illustrates one representative embodiment of an improved process for preparing compound (III), or a salt thereof. Scheme 8 [ka]

[0066] VII. Preparation of (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidine benzyl carboxylate (compound IV) and the corresponding sulfate (2:3) The present disclosure relates, in part, to a process for preparing benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (compound IV), or a salt thereof, from benzyl (2S)-2-(1-bromo-8-chloro-imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (compound III), or a salt thereof. Scheme 9 below shows the general process: Scheme 9 [ka]

[0067] As reflected in Scheme 9 above, compound (III), or a salt thereof, is aminated with an aminating agent (e.g., ammonia, ammonium hydroxide, etc.) to obtain compound (IV), which can optionally be converted to a salt, particularly the sulfate salt of compound (IV), as discussed further below. Because the amination reaction can result in the presence of residual ammonia, it can be advantageous to reduce the amount of residual ammonia present (e.g., via distillation of the crude compound (IV) product) prior to forming the salt of compound (IV), particularly if the sulfate salt of compound (IV) is desired. If the residual ammonia present with compound (IV) is sufficiently removed when the sulfate salt is produced, for example, inorganic ammonium sulfate will be produced in addition to the sulfate salt of compound (IV), which can pose difficulties in determining the exact stoichiometry of the sulfate salt produced. From a regulatory perspective, understanding the exact stoichiometry of the sulfate salt produced may be required (e.g., when the sulfate salt is a registered starting material for regulatory purposes).

[0068] Thus, in one embodiment, the present disclosure provides a compound having the structure of formula (IV): [ka] The process for preparing a sulfate salt of A compound having the structure of formula (III): [ka] or a salt thereof, with an aminating agent in a reaction medium to form a reaction mixture comprising a compound of formula (IV); forming a sulfate salt of a compound of formula (IV); and and isolating the sulfate salt.

[0069] Generally, the sulfate salt of the compound having the structure of Formula (IV) has a stoichiometric ratio of one sulfate molecule and one hydrogen sulfate molecule to three free base molecules. In one embodiment, the sulfate salt is a crystalline salt. In another embodiment, the crystalline sulfate salt is characterized by a reflection X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 7.7±0.2°2θ, 10.6±0.2°2θ, 11.1±0.2°2θ, 12.6±0.2°2θ, and 13.5±0.2°2θ. In another aspect, the crystalline Sulfate Salt is characterized by a reflection X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 7.7±0.2 degrees two-theta, 10.6±0.2 degrees two-theta, 11.1±0.2 degrees two-theta, 12.6±0.2 degrees two-theta, 13.5±0.2 degrees two-theta, 17.4±0.2 degrees two-theta, 18.0±0.2 degrees two-theta, 18.9±0.2 degrees two-theta, 19.2±0.2 degrees two-theta, and 21.9±0.2 degrees two-theta.

[0070] The isolated crystalline sulfate salt generally has a crystalline purity of at least 50%. In one embodiment, the isolated crystalline sulfate salt has a crystalline purity of at least 60%. In another embodiment, the isolated crystalline sulfate salt has a crystalline purity of at least 70%. In another embodiment, the isolated crystalline sulfate salt has a crystalline purity of at least 80%. In another embodiment, the isolated crystalline sulfate salt has a crystalline purity of at least 90%. In another embodiment, the isolated crystalline sulfate salt has a crystalline purity of at least 95%. In another embodiment, the isolated crystalline sulfate salt has a crystalline purity of at least 96%. In another embodiment, the isolated crystalline sulfate salt has a crystalline purity of at least 97%. In another embodiment, the isolated crystalline sulfate salt has a crystalline purity of at least 98%. In another embodiment, the isolated crystalline sulfate salt has a crystalline purity of at least 99%. In another embodiment, the isolated crystalline sulfate salt is substantially phase pure.

[0071] The aminating agent can be any suitable aminating agent, particularly ammonia or ammonium hydroxide. In one embodiment, the aminating agent is gaseous ammonia. In another embodiment, the aminating agent is ammonium hydroxide. The compound of formula (III), or a salt thereof, is generally contacted with an effective amount of aminating agent, for example, about 5 to about 20 molar equivalents of the aminating agent relative to the compound of formula (III), or a salt thereof.

[0072] The reaction medium can be any suitable reaction medium, particularly one containing at least one solvent selected from the group consisting of alkyl hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons, aromatic heterocycles, alcohols, ethers, and dipolar aprotic solvents. In one embodiment, the reaction medium contains at least one compound selected from the group consisting of methanol, ethanol, propanol, butanol, pentanol, N-methylpyrrolidinone, and N,N-dimethylformamide. In another embodiment, the reaction medium contains an aliphatic alcohol. In another embodiment, the reaction medium contains butanol. In another embodiment, the reaction medium contains 2-butanol. The volume of the reaction medium is generally from about 1.5 liters to about 40 liters per kilogram of the compound of Formula (III), or a salt thereof, charged to the reaction medium. In one embodiment, the volume of the reaction medium is from about 2.0 liters to about 30 liters per kilogram of the compound of Formula (III), or a salt thereof, charged to the reaction medium.

[0073] During the contacting step, the reaction medium is generally maintained at a temperature greater than 70°C. In one embodiment, the reaction medium is maintained at a temperature greater than 90°C during the contacting step. In another embodiment, the reaction medium is maintained at a temperature of from about 50°C to about 100°C during the contacting step. In another embodiment, the reaction medium is maintained at a temperature of from about 60°C to about 95°C during the contacting step.

[0074] The contacting step is generally carried out as a batch reaction, particularly when at least about 50 kilograms of the compound of formula (III), or a salt thereof, is charged to the batch reaction. In one embodiment, at least about 100 kilograms of the compound of formula (III), or a salt thereof, is charged to the batch reaction. In another embodiment, at least about 200 kilograms of the compound of formula (II), or a salt thereof, is charged to the batch reaction. In another embodiment, at least about 300 kilograms of the compound of formula (III), or a salt thereof, is charged to the batch reaction.

[0075] When the sulfate salt of compound (IV) is desired, the forming step generally comprises contacting the compound of formula (IV) with sulfuric acid to form a sulfate mixture containing the sulfate salt. In one embodiment, the compound of formula (IV) is contacted with at least about 0.8 molar equivalents of sulfuric acid relative to the compound of formula (III). In another embodiment, the compound of formula (IV) is contacted with about 1.25 to about 1.75 molar equivalents of sulfuric acid relative to the compound of formula (III).

[0076] The process optionally includes isolating the compound of Formula (IV) from the reaction mixture as a free base prior to the formation step. Isolating the free base prior to salt conversion can be advantageous in reducing the amount of residual ammonia present and avoiding potential problems associated with the presence of residual ammonia. In one aspect, the process includes isolating the compound of Formula (IV) from the reaction medium as a free base; contacting the free base with sulfuric acid to form a sulfate salt; and isolating the sulfate salt. In one aspect, the process includes washing the reaction mixture to reduce the amount of ammonia present in the reaction mixture; isolating the compound of Formula (IV) from the washed reaction medium as a free base; contacting the free base with sulfuric acid to form a sulfate salt; and isolating the sulfate salt. In another aspect, the process includes washing the reaction mixture with an aqueous salt solution; distilling the washed reaction mixture to reduce the amount of ammonia present in the washed reaction mixture; isolating the compound of Formula (IV) from the distilled reaction medium as a free base; contacting the free base with sulfuric acid to form a sulfate salt; and isolating the sulfate salt. In another aspect, the sulfate salt is isolated by filtration.

[0077] The process generally provides a stoichiometric process yield of at least about 50% of the sulfate salt of formula (IV). In one embodiment, the stoichiometric process yield of the compound of formula (IV) sulfate is at least about 65%. In another embodiment, the stoichiometric process yield of the compound of formula (IV) sulfate is at least about 75%. In fact, the improved process has been shown to produce high-quality material at approximately 85% yield at scales exceeding 300 kg (input).

[0078] In another exemplary embodiment, the present disclosure provides a compound having the structure of formula (IV): [ka] The process for preparing a sulfate salt of A compound having the structure of formula (III): [ka] or a salt thereof, with an aminating agent in a reaction medium to form a reaction mixture comprising a compound of formula (IV); isolating the compound of formula (IV) from the reaction mixture as a free base; contacting the free base with sulfuric acid to form the sulfate salt of the compound of formula (IV); and isolating the sulfate salt; The sulfate salt has a stoichiometric ratio of one sulfate molecule and one hydrogen sulfate molecule to three free base molecules.

[0079] In one embodiment, the Sulfate Salt is a crystalline salt. In another embodiment, the crystalline Sulfate Salt is characterized by a reflection X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 7.7±0.2 degrees 2θ, 10.6±0.2 degrees 2θ, 11.1±0.2 degrees 2θ, 12.6±0.2 degrees 2θ, and 13.5±0.2 degrees 2θ. In another aspect, the crystalline Sulfate Salt is characterized by a reflection X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 7.7±0.2°2Θ, 10.6±0.2°2Θ, 11.1±0.2°2Θ, 12.6±0.2°2Θ, 13.5±0.2°2Θ, 17.4±0.2°2Θ, 18.0±0.2°2Θ, 18.9±0.2°2Θ, 19.2±0.2°2Θ, and 21.9±0.2°2Θ. In another aspect, the crystalline Sulfate Salt is characterized by a reflection X-ray powder diffraction pattern comprising at least five peaks selected from the group of peaks.

[0080] Scheme 10 below corresponds to the process described in Example 5 and illustrates one representative embodiment of an improved process for preparing compound (II). Scheme 10 [ka]

[0081] VIII. Preparation of 4-(2-pyridylcarbamoyl)phenyl]boronic acid (compound V) This disclosure relates, in part, to a process for preparing 4-(2-pyridylcarbamoyl)phenyl]boronic acid (Compound V), or a salt thereof, from 4-carboxyphenylboronic acid, or a salt thereof, and 2-aminopyridine. Scheme 11 below shows the general process: Scheme 11 [ka]

[0082] The clinical trial supply process reacts 4-carboxyphenylboronic acid with 2-aminopyridine to produce compound (V). This coupling reaction is carried out in the presence of thionyl chloride and N,N-dimethylformamide. However, thionyl chloride and N,N-dimethylformamide can potentially react to produce toxic dimethylcarbamoyl chloride. To circumvent this issue, the improved process replaces N,N-dimethylformamide with a compound (e.g., tetrabutylammonium chloride) that does not produce this toxic by-product, providing improved safety during this step.

[0083] Thus, in one embodiment, the present disclosure provides a compound having the structure of formula (V): [ka] or a salt thereof, the process comprising contacting 4-carboxyphenylboronic acid, or a salt thereof, with thionyl chloride and a catalyst in a reaction medium comprising an organic solvent to form an acyl chloride intermediate, followed by in situ contact with 2-aminopyridine to form a reaction mixture comprising the compound of Formula (V), or a salt thereof. In one embodiment, the process further comprises isolating the compound of Formula (V), or a salt thereof, from the reaction mixture.

[0084] A molar excess of 2-aminopyridine relative to 4-carboxyphenylboronic acid or a salt thereof is typically charged to the reaction medium. In one embodiment, about 1.5 to about 5 molar equivalents of 2-aminopyridine relative to 4-carboxyphenylboronic acid or a salt thereof are charged to the reaction medium. In another embodiment, about 1.5 to about 3.5 molar equivalents of 2-aminopyridine relative to 4-carboxyphenylboronic acid or a salt thereof are charged to the reaction medium. In another embodiment, about 2 molar equivalents of 2-aminopyridine relative to 4-carboxyphenylboronic acid or a salt thereof are charged to the reaction medium.

[0085] A molar excess of thionyl chloride relative to 4-carboxyphenylboronic acid or a salt thereof is generally charged to the reaction medium. In one embodiment, 4-carboxyphenylboronic acid or a salt thereof is contacted with about 2 to about 5 molar equivalents of thionyl chloride relative to 4-carboxyphenylboronic acid or a salt thereof. In another embodiment, 4-carboxyphenylboronic acid or a salt thereof is contacted with about 2 to about 3.5 molar equivalents of thionyl chloride relative to 4-carboxyphenylboronic acid or a salt thereof. In another embodiment, 4-carboxyphenylboronic acid or a salt thereof is contacted with about 2.75 molar equivalents of thionyl chloride relative to 4-carboxyphenylboronic acid or a salt thereof.

[0086] The catalyst can include any suitable catalyst, particularly a catalyst selected from the group consisting of tetrabutylammonium chloride and N-methylformanilide. In one embodiment, the catalyst includes tetrabutylammonium chloride. In another embodiment, the catalyst includes N-methylformanilide. In another embodiment, the catalyst does not include N,N-dimethylformamide. About 0.01 to about 0.1 molar equivalents of catalyst relative to 4-carboxyphenylboronic acid or a salt thereof is typically charged to the reaction medium.

[0087] The reaction medium can be any suitable reaction medium, particularly one containing at least one solvent selected from the group consisting of aromatic hydrocarbons, aromatic heterocycles, and nitriles. In one embodiment, the reaction medium contains a compound selected from the group consisting of toluene, acetonitrile, and pyridine. In another embodiment, the reaction medium contains toluene. In another embodiment, the reaction medium does not contain N,N-dimethylformamide. In another embodiment, neither the reaction medium nor the catalyst contains N,N-dimethylformamide. The volume of the reaction medium is generally from about 3 liters to about 30 liters of reaction medium per kilogram of 4-carboxyphenylboronic acid or a salt thereof charged to the reaction medium. In one embodiment, the volume of the reaction medium is from about 5 liters to about 15 liters of reaction medium per kilogram of 4-carboxyphenylboronic acid or a salt thereof charged to the reaction medium.

[0088] The reaction medium is generally maintained at a temperature of from about 50° C. to about 90° C. during the contacting step. In one aspect, the reaction medium is maintained at a temperature of from about 60° C. to about 80° C. during the contacting step.

[0089] The contacting step is generally carried out as a batch reaction, particularly when at least about 50 kilograms of 4-carboxyphenylboronic acid, or a salt thereof, is charged to the batch reaction. In one embodiment, at least about 100 kilograms of 4-carboxyphenylboronic acid, or a salt thereof, is charged to the batch reaction.

[0090] The process generally provides a stoichiometric process yield of at least about 50% of the compound of formula (V), or a salt thereof. In one embodiment, the stoichiometric process yield of the compound of formula (V), or a salt thereof, is at least about 60%. In another embodiment, the stoichiometric process yield of the compound of formula (V), or a salt thereof, is at least about 65%. In another embodiment, the stoichiometric process yield of the compound of formula (V), or a salt thereof, is at least about 70%.

[0091] In another exemplary embodiment, the present disclosure provides a compound having the structure of formula (V): [ka] or a salt thereof, the process comprising contacting 4-carboxyphenylboronic acid, or a salt thereof, with thionyl chloride and a catalyst in a reaction medium comprising an organic solvent to form an acyl chloride intermediate, followed by in situ contact with 2-aminopyridine to form a reaction mixture comprising a compound of formula (V), or a salt thereof; neither the reaction medium nor the catalyst comprises N,N-dimethylformamide.

[0092] In one embodiment, the catalyst comprises a catalyst selected from the group consisting of tetrabutylammonium chloride and N-methylformanilide. In one embodiment, the catalyst comprises tetrabutylammonium chloride. In another embodiment, the catalyst comprises N-methylformanilide. In another embodiment, the reaction medium is maintained at a temperature of from about 50° C. to about 90° C. during the contacting step. In another embodiment, the process further comprises isolating the compound of Formula (V), or a salt thereof, from the reaction mixture.

[0093] Scheme 12 below corresponds to the process described in Example 11 and illustrates one representative embodiment of an improved process for preparing compound (V). Scheme 12 [ka]

[0094] IX. Preparation of 1-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (Compound VI) This disclosure relates, in part, to a process for preparing 1-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (Compound VI), or a salt thereof, from benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (Compound IV), or a salt thereof. Scheme 13 below shows the general process: Scheme 13 [ka]

[0095] Initial development efforts to avoid aggressive acidic conditions by utilizing hydrogenation to deprotect compound (IV), or a salt thereof, and provide compound (VI), or a salt thereof, were unsuccessful due to the presence of an unstable bromide on the imidazole ring. Further development efforts faced challenges, including the generation and / or removal of several impurities.

[0096] First, the deprotection reaction generates a benzyl halide (e.g., benzyl chloride) which can potentially further react with compound (VI), or a salt thereof, to give compound (IX): [ka] This produces an N-benzyl impurity having the structure:

[0097] Second, the use of dichloromethane in the deprotection reaction affords compound (X): [ka] This can produce an aminal impurity having the structure:

[0098] Third, an oxidation impurity having the structure of compound (XI) below was observed in some batches for this process step: [ka]

[0099] The improved process addresses N-benzyl impurities by removing benzyl halides from the reaction mixture containing the crude Compound (VI) product (e.g., by extraction with heptane) prior to isolating Compound (VI), or a salt thereof, from the reaction mixture. The improved process addresses aminal impurities by selecting a solvent that does not produce aminal impurities (e.g., replacing dichloromethane with 2-methyltetrahydrofuran). The improved process addresses oxidative impurities through proper control of oxygen levels in the reaction vessel during processing. Proper control of the inerting regime (e.g., nitrogen sweep) and materials of vessel construction significantly prevents product discoloration and the formation of oxidative impurities observed in conventional campaigns, improving product quality by eliminating the need for prior carbon treatment.

[0100] Thus, in one embodiment, the present disclosure provides a compound having the structure of formula (VI): [ka] or a salt thereof, the process comprising: Compounds of formula (IV): [ka] or a salt thereof, with an acidic medium under conditions sufficient to deprotect the compound of formula (IV), or a salt thereof, and to form a reaction mixture comprising a compound of formula (VI), or a salt thereof, and a benzyl halide by-product; removing at least a portion of the benzyl halide by-product from the reaction mixture; and and isolating the compound of formula (VI), or a salt thereof, from the reaction mixture under conditions sufficient to substantially avoid the formation of the aminal impurity.

[0101] In one embodiment, the sulfate salt of the compound of formula (IV) is contacted with an acidic medium.

[0102] Aminal impurities generally include compounds having the structure of formula (X): [ka] or a salt thereof. In one embodiment, the isolated compound of formula (VI), or a salt thereof, contains less than 5% by weight of aminal impurities. In another embodiment, the isolated compound of formula (VI), or a salt thereof, contains less than 3% by weight of aminal impurities. In another embodiment, the isolated compound of formula (VI), or a salt thereof, contains less than 1% by weight of aminal impurities.

[0103] In one embodiment, the acidic medium is an aqueous acidic medium. The aqueous acidic medium generally comprises a mineral acid, particularly hydrochloric acid, and at least about 10 molar equivalents of acid relative to the compound of Formula (IV) or a salt thereof. In one embodiment, the aqueous acidic medium comprises about 10 to about 40 molar equivalents of acid relative to the compound of Formula (IV) or a salt thereof. In another embodiment, the aqueous acidic medium comprises about 10 to about 25 molar equivalents of acid relative to the compound of Formula (IV) or a salt thereof. The volume of the aqueous reaction medium is generally about 2 liters to about 10 liters of aqueous reaction medium per kilogram of the compound of Formula (IV) or a salt thereof charged to the acidic medium. In one embodiment, the volume of the aqueous reaction medium is about 3 liters to about 4 liters of aqueous reaction medium per kilogram of the compound of Formula (IV) or a salt thereof charged to the aqueous reaction medium. During the contacting step, the aqueous reaction medium is generally maintained at a temperature of about 25°C to about 70°C. In one embodiment, the aqueous reaction medium is maintained at a temperature of about 40° C. to about 50° C. during the contacting step.

[0104] In another embodiment, the process includes removing at least a portion of the benzyl halide by-product from the reaction mixture; raising the pH of the resulting reaction mixture to a basic pH to form a basic reaction medium comprising a compound of formula (VI), or a salt thereof; and isolating the compound of formula (VI), or a salt thereof, from the basic reaction mixture.

[0105] In another embodiment, the process includes removing at least a portion of the benzyl halide by-product from the reaction mixture by selectively extracting the benzyl halide by-product from the reaction mixture prior to isolating the compound of Formula (VI), or a salt thereof. In one aspect, the benzyl halide by-product from the reaction mixture is selectively extracted into a waste organic phase relative to the compound of Formula (VI), or a salt thereof. In another aspect, at least about 80% by weight of the benzyl halide by-product present in the reaction mixture is extracted into a waste organic phase. In another aspect, less than about 20% by weight of the compound of Formula (VI), or a salt thereof, present in the reaction mixture is extracted into a waste organic phase. In another aspect, at least about 80% by weight of the benzyl halide by-product present in the reaction mixture and less than about 20% by weight of the compound of Formula (VI), or a salt thereof, present in the reaction mixture are extracted into a waste organic phase. In another embodiment, at least about 90% by weight of the benzyl halide by-products present in the reaction mixture and less than about 10% by weight of the compound of Formula (VI), or a salt thereof, present in the reaction mixture is extracted into a discarded organic phase. In another embodiment, at least about 95% by weight of the benzyl halide by-products present in the reaction mixture and less than about 5% by weight of the compound of Formula (VI), or a salt thereof, present in the reaction mixture is extracted into a discarded organic phase.

[0106] The discarded organic phase generally comprises at least one solvent selected from the group consisting of alkyl hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons, and ethers. In another embodiment, the discarded organic phase comprises at least one compound selected from the group consisting of pentane, hexane, heptane, octane, nonane, toluene, dichloromethane, methyl tert-butyl ether, and 2-methyltetrahydrofuran. In another embodiment, the discarded organic phase comprises heptane.

[0107] In a further embodiment, the process includes increasing the pH of the reaction mixture after extraction of the benzyl halide by-product to form a basic reaction medium containing the compound of Formula (VI), or a salt thereof; and extracting the compound of Formula (VI), or a salt thereof, from the basic reaction medium into a product organic phase. In one aspect, the process includes extracting at least a portion of the benzyl halide by-product from the reaction mixture into a waste organic phase; increasing the pH of the resulting reaction mixture to a basic pH (e.g., via the addition of sodium hydroxide) to form a basic reaction medium containing the compound of Formula (VI), or a salt thereof; extracting the compound of Formula (VI), or a salt thereof, from the basic reaction medium into a product organic phase; and isolating the compound of Formula (VI), or a salt thereof, from the product organic phase. The pH of the basic reaction mixture is generally increased to at least about 8.0. In one aspect, the pH of the basic reaction mixture is increased to at least about 10.0.

[0108] The product organic phase generally comprises at least one solvent selected from the group consisting of alkyl hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons, and ethers. In one embodiment, the product organic phase comprises at least one compound selected from the group consisting of 2-methyltetrahydrofuran and anisole. In another embodiment, the product organic phase comprises 2-methyltetrahydrofuran. In another embodiment, the product organic phase does not comprise dichloromethane.

[0109] It may be advantageous to wash the product organic phase (e.g., with water) before isolating the compound of Formula (VI), or a salt thereof. It may also be advantageous to distill the product organic phase under conditions sufficient to reduce the amount of water present in the product organic phase before isolating the compound of Formula (VI), or a salt thereof. In one embodiment, the process comprises washing the product organic phase with water and distilling the product organic phase under conditions sufficient to reduce the amount of water present in the product organic phase. In another embodiment, the product organic phase is distilled under atmospheric pressure. In another embodiment, the product organic phase comprises 2-methyltetrahydrofuran, and additional 2-methyltetrahydrofuran is charged to the product organic phase during the distillation step.

[0110] The compound of formula (VI) or a salt thereof can be isolated from the reaction mixture by any suitable means, particularly by crystallizing the compound of formula (VI) or a salt thereof from the reaction mixture. In one embodiment, the isolating step comprises seeding the reaction mixture with a crystalline form of the compound of formula (VI) or a salt thereof to promote crystallization. In another embodiment, the isolating step comprises seeding the reaction mixture with at least about 0.005 relative weight of the crystalline form of the compound of formula (VI) or a salt thereof to promote crystallization. In another embodiment, the isolating step comprises seeding the reaction mixture with at least about 0.01 relative weight of the crystalline form of the compound of formula (VI) or a salt thereof to promote crystallization. In another embodiment, the isolating step comprises seeding the reaction mixture with at least about 0.005 to about 0.02 relative weight of the crystalline form of the compound of formula (VI) or a salt thereof to promote crystallization. It may also be advantageous to charge the reaction mixture with an anti-solvent to promote crystallization. In one embodiment, the anti-solvent is heptane.

[0111] The contacting step is generally carried out as a batch reaction, particularly where at least about 50 kilograms of the compound of formula (IV), or a salt thereof, is initially charged to the reaction. In one embodiment, at least about 100 kilograms of the compound of formula (IV), or a salt thereof, is initially charged to the reaction. In another embodiment, at least about 200 kilograms of the compound of formula (IV), or a salt thereof, is initially charged to the reaction. In another embodiment, at least about 300 kilograms of the compound of formula (IV), or a salt thereof, is initially charged to the reaction.

[0112] The process generally provides a stoichiometric process yield of at least about 50% of the compound of formula (VI), or a salt thereof. In one embodiment, the stoichiometric process yield of the compound of formula (VI), or a salt thereof, is at least about 65%. In another embodiment, the stoichiometric process yield of the compound of formula (VI), or a salt thereof, is at least about 75%. In another embodiment, the stoichiometric process yield of the compound of formula (VI), or a salt thereof, is at least about 80%. In fact, the improved process has been able to output high-quality material at a yield of approximately 85% at a scale exceeding 300 kg (input).

[0113] In another exemplary embodiment, the present disclosure provides a compound having the structure of formula (VI): [ka] or a salt thereof, the process comprising: Compounds of formula (IV): [ka] or a salt thereof, with an acidic medium under conditions sufficient to deprotect the compound of formula (IV), or a salt thereof, and to form a reaction mixture comprising a compound of formula (VI), or a salt thereof, and a benzyl halide by-product; selectively extracting at least a portion of the benzyl halide by-product from the reaction mixture into an organic phase which is discarded relative to the compound of formula (VI), or a salt thereof; raising the pH of the resulting reaction mixture to a pH greater than about 7.0 to form a basic reaction mixture; Selectively extracting at least a portion of the compound of formula (VI), or a salt thereof, from the basic reaction mixture into a product organic phase; and distilling the product organic phase under conditions sufficient to reduce the amount of water present in the product organic phase to form a distilled organic phase comprising the compound of formula (VI), or a salt thereof.

[0114] In one embodiment, the discarded organic phase comprises heptane. In another embodiment, the product organic phase comprises 2-methyltetrahydrofuran. In another embodiment, the discarded organic phase comprises heptane and the product organic phase comprises 2-methyltetrahydrofuran. In another embodiment, the process further comprises crystallizing the compound of formula (VI), or a salt thereof, from the distilled organic phase.

[0115] Scheme 14 below corresponds to the process described in Example 9 and illustrates one representative embodiment of an improved process for preparing compound (VI). Scheme 14 [ka]

[0116] X. Preparation of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]-imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (Compound VII) The present disclosure relates, in part, to a process for preparing 4-{8-amino-3-[(2S)-2-pyrrolidinyl]-imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (Compound VII), or a salt thereof, from [4-(2-pyridylcarbamoyl)phenyl]boronic acid (Compound V), or a salt thereof, and 1-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (Compound VI), or a salt thereof. Scheme 15 below shows the general process: Scheme 15 [ka]

[0117] The process utilizes the Suzuki reaction to couple Compound (V) with Compound (VI) to produce Compound (VII). The clinical trial supply process carried out the Suzuki coupling in aqueous 2-butanol medium. Crude Compound (VII) was crystallized from the aqueous 2-butanol medium in a crystalline form (subsequently identified as Form 2 crystalline form of Compound (VII)), which was extremely difficult to filter from the medium even at a 50 kg scale. Form 2 crystalline form of Compound (VII) was isolated as a viscous, clay-like product, which required oven drying to remove the large amount of water that clung to the wet paste upon discharge from the filter.

[0118] Attempts to improve the filterability of crystallized Compound (VII) have led to the discovery of two additional crystalline forms of Compound (VII), designated Crystal Form 3 and Crystal Form C. Crystal Form 2 has an ultrafine needle-like morphology and is believed to be a hemi-butanol solvate-hydrate. Crystal Form 3 has a needle-like morphology and is believed to be a butanol solvate. Crystal Form C is an anhydrate with improved morphology resulting in larger crystals. It has been found that crystallization of Compound (VII) from non-aqueous (generally less than 5% water by weight) media can produce Crystal Form 3 and / or Crystal Form C. While both crystalline forms permeate faster than Crystal Form 2, Crystal Form C also permeates faster than Crystal Form 3. Therefore, further efforts have focused on reducing or substantially removing (e.g., by distillation) any water present prior to the initial isolation of Compound (VII) in order to reproducibly isolate Compound (VII) as Crystal Form C.

[0119] Removal of water prior to isolation of Compound (VII) typically resulted in the Type C crystalline form, although occasional batches still crystallized with a variable amount of the Type 3 crystalline form present. Further investigation determined that the Type C crystalline form is the thermodynamic form at temperatures above approximately 75°C. At this temperature, any Type 3 crystalline form present generally converts to the Type C crystalline form within a relatively short period of time. By incorporating temperature cycling prior to isolation of Compound (VII), the Type C crystalline form can always be produced as the thermodynamic form. Conversion of the Type C crystalline form to the Type 3 crystalline form can occur upon cooling below 75°C (especially in the presence of residual water), but this conversion is slow enough to allow cooling and filtration without significant conversion to the Type 3 crystalline form.

[0120] Furthermore, it has been found to be advantageous to move the silica scavenger treatment from the final step in producing acalabrutinib from compound (VII) (as utilized in the clinical trial supply process) to this step in producing compound (VII). This change in the sequencing of the silica scavenger treatment results in a better balance of efficient palladium removal against loss of product yield (to the scavenger).

[0121] Furthermore, it was found that prolonged heating during the Suzuki reaction on a scale for this process (e.g., work-up at 80°C and atmospheric distillation at 80-100°C) resulted in the formation of two impurities, compound (XII) and compound (XIII), having the structures shown below: [ka] However, by utilizing lower temperatures (eg, work-up below 60° C. and atmospheric distillation), the formation of these impurities can be suppressed.

[0122] Thus, in one embodiment, the present disclosure provides a compound having the structure of formula (VII): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (V): [ka] or a salt thereof, with a compound having the structure of formula (VI): [ka] or a salt thereof in an aqueous reaction medium comprising an organic solvent in the presence of a base and a palladium catalyst to form a reaction mixture comprising a compound of formula (VII); reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising a compound of formula (VII), or a salt thereof; and and isolating the compound of formula (VII), or a salt thereof, from the substantially anhydrous mixture.

[0123] The compound of formula (VII), or a salt thereof, is isolated from the substantially anhydrous mixture as a substantially crystalline form of the compound of formula (VII), or a salt thereof. In one embodiment, the substantially crystalline form of the compound of formula (VII) is characterized by a reflection X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 9.9±0.2°2θ, 11.1±0.2°2θ, 12.8±0.2°2θ, 14.1±0.2°2θ, and 19.0±0.2°2θ. In another embodiment, the substantially crystalline form of the compound of formula (VII) is characterized by a reflection X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 7.4±0.2°2θ, 8.9±0.2°2θ, 9.9±0.2°2θ, 11.1±0.2°2θ, 12.8±0.2°2θ, 14.1±0.2°2θ, 14.8±0.2°2θ, 19.0±0.2°2θ, and 21.6±0.2°2θ. In another embodiment, the substantially crystalline form of the compound of formula (VII) is characterized by a reflection X-ray powder diffraction pattern comprising at least five peaks selected from the group of peaks. In another embodiment, the substantially crystalline form is a substantially anhydrous crystalline form of the compound of formula (VII).

[0124] A substantially crystalline form of the compound of Formula (VII) isolated from a substantially anhydrous mixture generally has a Form C crystalline purity of at least 50%. In one embodiment, the isolated substantially crystalline form has a Form C crystalline purity of at least 60%. In another embodiment, the isolated substantially crystalline form has a Form C crystalline purity of at least 70%. In another embodiment, the isolated substantially crystalline form has a Form C crystalline purity of at least 80%. In another embodiment, the isolated substantially crystalline form has a Form C crystalline purity of at least 90%. In another embodiment, the isolated substantially crystalline form has a Form C crystalline purity of at least 95%. In another embodiment, the isolated substantially crystalline form has a Form C crystalline purity of at least 96%. In another embodiment, the isolated substantially crystalline form has a Form C crystalline purity of at least 97%. In another embodiment, the isolated substantially crystalline form has a Form C crystalline purity of at least 98%. In another embodiment, the isolated substantially crystalline form has a Form C crystalline purity of at least 99%. In another embodiment, the isolated substantially crystalline form is a substantially phase-pure Form C crystalline form.

[0125] In another embodiment, the aqueous reaction medium further comprises an alkali metal halide. In one aspect, the aqueous reaction medium comprises an alkali metal iodide. In another aspect, the aqueous reaction medium comprises potassium iodide. At least about 0.1 molar equivalent of the alkali metal halide relative to the compound of Formula (VI), or a salt thereof, is typically charged to the aqueous reaction medium. In one aspect, about 0.1 to about 1.0 molar equivalent of the alkali metal halide relative to the compound of Formula (VI), or a salt thereof, is typically charged to the aqueous reaction medium. In one aspect, about 0.1 to about 1.0 molar equivalent of potassium iodide relative to the compound of Formula (VI), or a salt thereof, is charged to the aqueous reaction medium. In another aspect, about 0.2 to about 0.4 molar equivalent of potassium iodide relative to the compound of Formula (VI), or a salt thereof, is charged to the aqueous reaction medium.

[0126] The compound of formula (VI) or a salt thereof is generally contacted with about 0.5 to about 1.5 molar equivalents of the compound of formula (V) or a salt thereof relative to the compound of formula (VI). In one embodiment, the compound of formula (VI) or a salt thereof is contacted with about 0.8 to about 1.2 molar equivalents of the compound of formula (V) or a salt thereof relative to the compound of formula (VI). In another embodiment, the compound of formula (VI) or a salt thereof is contacted with about 0.9 to about 1.1 molar equivalents of the compound of formula (V) or a salt thereof relative to the compound of formula (VI).

[0127] The base can be any suitable base, particularly a base comprising at least one compound selected from the group consisting of triethylamine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, tripropylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, methyldicyclohexylamine, and potassium phosphate. In one embodiment, the base comprises triethylamine. In another embodiment, the base comprises potassium carbonate. In another embodiment, the base comprises triethylamine and potassium carbonate. The aqueous reaction medium is generally charged with about 0.5 to about 10 molar equivalents of the base relative to the compound of Formula (VI), or a salt thereof. In one embodiment, the base comprises triethylamine, and the aqueous reaction medium is charged with about 0.5 to about 10 molar equivalents of triethylamine relative to the compound of Formula (VI), or a salt thereof. In another embodiment, the base comprises triethylamine, and about 1.0 to about 2.0 molar equivalents of triethylamine relative to the compound of Formula (VI) or a salt thereof are charged to the aqueous reaction medium. In another embodiment, the base comprises potassium carbonate, and about 0.5 to about 10.0 molar equivalents of potassium carbonate relative to the compound of Formula (VI) or a salt thereof are charged to the aqueous reaction medium. In another embodiment, the base comprises potassium carbonate, and about 2.0 to about 3.0 molar equivalents of potassium carbonate relative to the compound of Formula (VI) or a salt thereof are charged to the aqueous reaction medium. In another embodiment, the base comprises potassium carbonate, and about 2.3 to about 2.7 molar equivalents of potassium carbonate relative to the compound of Formula (VI) or a salt thereof are charged to the aqueous reaction medium.

[0128] The palladium catalyst can be any suitable palladium catalyst, particularly bis(tert-butyldicyclohexylphosphine)dichloropalladium(II). The aqueous reaction medium is typically charged with about 0.002 to about 0.05 molar equivalents of the palladium catalyst relative to the compound of formula (VI), or a salt thereof. In one embodiment, the aqueous reaction medium is charged with about 0.007 to about 0.013 molar equivalents of the palladium catalyst relative to the compound of formula (VI), or a salt thereof.

[0129] The organic solvent can be any suitable solvent, particularly one selected from the group consisting of aromatic hydrocarbons, alcohols, ketones, ethers, esters, and nitriles. In one embodiment, the organic solvent comprises at least one solvent selected from the group consisting of methanol, ethanol, propanol, butanol, pentanol, dioxane, toluene, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, ethyl acetate, isopropyl acetate, n-butyl acetate, and ethyl lactate. In another embodiment, the organic solvent comprises 2-butanol.

[0130] The volume of the aqueous reaction medium is generally about 10 liters to about 20 liters per kilogram of the compound of Formula (VI) or a salt thereof charged to the aqueous reaction medium. In one embodiment, the volume ratio of water to organic solvent for the aqueous reaction medium is about 1:3 to about 3:1. During the contacting step, the aqueous reaction medium is generally maintained at a temperature of about 50°C to about 100°C. In one embodiment, the aqueous reaction medium is maintained at a temperature of about 70°C to about 90°C during the contacting step.

[0131] In one embodiment, the reducing step comprises separating the reaction mixture into an aqueous waste phase and an organic phase comprising the compound of Formula (VII). In one aspect, the reducing step further comprises distilling the organic phase under conditions sufficient to reduce the amount of water present in the organic phase, resulting in a substantially anhydrous mixture. In another aspect, the process further comprises washing the organic phase with water prior to distillation.

[0132] In a further embodiment, the organic phase is treated with a silica scavenger prior to distillation. In one aspect, the organic phase is treated with the silica scavenger prior to distillation for at least 2 hours. The silica scavenger generally comprises propanethiol-functionalized silica. In one aspect, the silica scavenger comprises QuadraSil™ MP. The process may further comprise removing the silica scavenger from the organic phase prior to distillation. In one aspect, the silica scavenger is removed from the organic phase by filtration prior to distillation. In another aspect, the process further comprises washing the organic phase with an aqueous salt solution after removing the catalyst and prior to distillation.

[0133] In another embodiment, the reducing step comprises separating the reaction mixture into an aqueous waste phase and an organic phase comprising the compound of Formula (VII), or a salt thereof; washing the organic phase with water; treating the organic phase with a silica scavenger; removing the silica scavenger from the organic phase; washing the organic phase with an aqueous salt solution; and distilling the organic phase under conditions sufficient to reduce the amount of water present in the organic phase.

[0134] Distillation of the organic phase can be carried out under suitable conditions, particularly distillation of the organic phase by vacuum distillation. In one embodiment, the organic phase is distilled by continuous level vacuum distillation. In another embodiment, the organic phase is distilled at a temperature not exceeding about 60°C. In another embodiment, the organic phase is distilled at a temperature of about 50°C to about 60°C. In another embodiment, the organic phase comprises an alcohol. In another embodiment, the organic phase is replenished with an alcohol during the distillation process. In another embodiment, the organic phase comprises 2-butanol. In another embodiment, the organic phase is replenished with 2-butanol during the distillation process.

[0135] A substantially anhydrous mixture generally contains less than about 5% water by weight. In one embodiment, a substantially anhydrous mixture contains less than about 3% water by weight. In another embodiment, a substantially anhydrous mixture contains less than about 1% water by weight.

[0136] The isolation step generally involves crystallizing the compound of Formula (VII) as the Type C crystalline form from the substantially anhydrous mixture. To ensure that the product crystallizes as the Type C crystalline form, the substantially anhydrous mixture is heated to a temperature of at least about 70°C (e.g., at least about 75°C) and then cooled to crystallize the compound of Formula (VII). The period for which the substantially anhydrous mixture is maintained at a temperature (or temperature range) of at least about 70°C before cooling begins will depend on the temperature (or temperature range) selected. At higher temperatures, a shorter holding period is generally required to convert any non-Type C crystalline form present to the Type C crystalline form. However, the selected temperature should not result in decomposition of the compound of Formula (VII) or exceed the boiling point of the substantially anhydrous mixture. Furthermore, stirring the substantially anhydrous mixture during the holding period and / or seeding the substantially anhydrous mixture with the Type C crystalline form may be advantageous in further reducing the duration of any required holding period. Thus, in various embodiments, the substantially anhydrous mixture is maintained at a selected temperature (or range of temperatures) for a period of time after initiation of crystallization and before initiation of cooling, the temperature (or range of temperatures) and selected period of time being sufficient to obtain substantially Form C crystalline form of the compound of Formula (VII) upon cooling of the substantially anhydrous mixture.

[0137] In one embodiment, the substantially anhydrous mixture is heated to a temperature of at least about 80°C. In another embodiment, the temperature is at least about 85°C. In another embodiment, the temperature is at least about 90°C. In another embodiment, the temperature is at least about 95°C. In another embodiment, the temperature is from about 70°C to about 105°C. In another embodiment, the temperature is from about 75°C to about 105°C. In another embodiment, the temperature is from about 80°C to about 105°C. In another embodiment, the temperature is from about 85°C to about 105°C. In another embodiment, the temperature is from about 90°C to about 105°C.

[0138] In another embodiment, the temperature selected is high enough so that an additional holding period is not required before cooling begins. In another embodiment, the holding period before cooling is at least about 15 minutes. In another embodiment, the holding period before cooling is at least about 30 minutes. In another embodiment, the holding period before cooling is at least about 1 hour. In another embodiment, the holding period before cooling is at least about 1.5 hours. In another embodiment, the holding period before cooling is at least about 2 hours.

[0139] In one embodiment, the temperature is at least about 75°C and the holding period before cooling is at least about 2 hours. In another embodiment, the temperature is at least about 80°C and the holding period is at least about 1.5 hours. In another embodiment, the temperature is at least about 85°C and the holding period is at least about 1 hour. In another embodiment, the temperature is at least about 90°C and the holding period is at least about 15 minutes. In another embodiment, the temperature is at least about 90°C and no holding period is required. In another embodiment, the temperature is about 75°C to about 105°C and the holding period is about 15 minutes to about 3 hours. In another embodiment, the temperature is about 80°C to about 105°C and the holding period is about 15 minutes to about 3 hours. In another embodiment, the temperature is about 85°C to about 105°C and the holding period is about 15 minutes to about 3 hours. In another embodiment, the temperature is about 90°C to about 105°C and the holding period is about 5 minutes to about 2 hours. In another embodiment, the temperature is from about 90° C. to about 105° C. and no additional holding period is required before cooling.

[0140] In each of the above embodiments, the substantially anhydrous mixture can be seeded with the Type C crystalline form of the compound of Formula (VII) to further promote crystallization of the desired crystalline form. For example, the substantially anhydrous mixture can be seeded with the Type C crystalline form and maintained at a temperature of about 85°C to about 105°C for a holding period of about 5 minutes to about 3 hours, followed by cooling to crystallize the compound of Formula (VII).

[0141] The contacting step is generally carried out as a batch reaction, particularly where at least about 25 kilograms of the compound of formula (VI), or a salt thereof, is initially charged to the reaction. In one embodiment, at least about 50 kilograms of the compound of formula (VI), or a salt thereof, is initially charged to the reaction. In another embodiment, at least about 75 kilograms of the compound of formula (VI), or a salt thereof, is initially charged to the reaction. In another embodiment, at least about 100 kilograms of the compound of formula (VI), or a salt thereof, is initially charged to the reaction.

[0142] The process generally provides a stoichiometric process yield of at least about 50% of the compound of formula (VII) or a salt thereof. In one embodiment, the stoichiometric process yield of the compound of formula (VII) or a salt thereof is at least about 65%. In another embodiment, the stoichiometric process yield of the compound of formula (VII) or a salt thereof is at least about 75%. In fact, the improved process has been able to output high-quality material at a yield of approximately 80% at a scale exceeding 100 kg (input). Furthermore, the improved process has a faster filtration time, significantly reducing the cycle time for this process to less than one week.

[0143] In another exemplary embodiment, the present disclosure provides a compound having the structure of formula (VII): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (V): [ka] or a salt thereof, with a compound having the structure of formula (VI): [ka] or a salt thereof in an aqueous reaction medium comprising an organic solvent in the presence of a base and a palladium catalyst to form a reaction mixture comprising a compound of formula (VII); separating the reaction mixture into an aqueous waste phase and an organic phase comprising the compound of formula (VII), or a salt thereof; treating the organic phase with a silica scavenger; removing the silica scavenger from the organic phase; distilling the organic phase under conditions sufficient to reduce the amount of water present in the organic phase and to form a substantially anhydrous mixture comprising a compound of formula (VII), or a salt thereof; and crystallizing a compound of formula (VII) from the substantially anhydrous mixture; The compound of formula (VII) crystallizes as Type C crystalline form.

[0144] In one embodiment, the process further comprises washing the organic phase with water prior to the treating step. In another embodiment, the process further comprises washing the organic phase with an aqueous salt solution after the removing step and prior to the distilling step. In another embodiment, the organic phase is distilled by vacuum distillation, during which dry butanol is added to the organic phase and serves to remove any water present. In another embodiment, the substantially anhydrous mixture is held at a temperature greater than 75°C until any crystalline liquid present is substantially converted to the Type C crystalline form prior to isolating the compound of Formula (VII) from the substantially anhydrous mixture.

[0145] Scheme 16 below corresponds to the process described in Example 14 and illustrates one representative embodiment of an improved process for preparing compound (VII). Scheme 16 [ka]

[0146] XII. Preparation of Acalabrutinib (Compound VIII) The present disclosure relates, in part, to a process for preparing acalabrutinib, or a salt thereof, from 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)-benzamide (Compound VII) and 2-butynoic acid, or a salt thereof. Scheme 17 below shows the general process: Scheme 17 [ka]

[0147] Compound (VII) reacts with 2-butynoic acid in the presence of a coupling agent to produce acalabrutinib. This coupling step is difficult to manipulate in clinical trial supply chains. Adding a small excess of 2-butynoic acid to compound (VII) in dichloromethane produced a relatively viscous mixture containing the tetrol salt of compound (VII), which was difficult to stir. Subsequent addition of triethylamine to the viscous mixture did not significantly improve the viscosity. However, adding triethylamine before the 2-butynoic acid avoided the formation of the tetrol salt of compound (VII) and resulted in a relatively thin, stirrable slurry. However, the subsequent addition of a coupling agent (e.g., 1-propylphosphonic anhydride) to the resulting slurry was difficult to control, resulting in a narrow control window in the process to meet the quality standards for the acalabrutinib product. Adding too little 1-propylphosphonic anhydride will not consume all of the starting material (i.e., compound (VII)), while adding too much will produce an impurity with the structure of compound (XIV): [ka] This caused the formation of

[0148] Both unreacted Compound (VII) and Compound (XIV) impurities were difficult to remove in the subsequent isolation of the acalabrutinib product and were responsible for the failure of several batches for the clinical trial supply process.

[0149] It has been discovered that the obstacles associated with the removal of the two impurities can be overcome using a sequential extraction approach. Calquence is selectively extracted from the reaction mixture relative to the compound (XIV) impurity into an aqueous phase having a first acidic pH (e.g., pH 1.8-2.2), and the reaction mixture containing the compound (XIV) impurity is discarded. The pH of the aqueous phase containing acalabrutinib is then adjusted to a second pH (e.g., pH 4.5-5.0), and acalabrutinib is selectively extracted from the aqueous phase relative to the compound (VII) impurity into an organic phase, and the aqueous phase containing the compound (VII) impurity is discarded. Because the sequential extraction approach results in efficient removal of the unwanted impurities from the final product, the addition of 1-propylphosphonic anhydride does not require the same strict control as in the clinical trial supply process, and the addition of 1-propylphosphonic anhydride is more robust.

[0150] Another issue encountered in the clinical trial supply process involved the solvent exchange from dichloromethane to ethanol, which utilized multiple "put-and-take" distillation cycles. The acalabrutinib product consistently became oily or gummy before ultimately crystallizing. The kinetics of acalabrutinib crystallization from ethanol were found to be significantly slow. The point at which the oil crystallized could not be controlled, and the crystallized acalabrutinib carried unwanted amounts of the crystallization solvent. As a result, inclusion of dichloromethane in the acalabrutinib crystal lattice was a concern for the clinical trial supply process. A more controlled procedure is currently being developed that utilizes continuous levels of vacuum distillation (e.g., 18-20 rel.vol., 50°C) to maintain acalabrutinib in solution throughout the distillation (even upon complete replacement of the dichloromethane solvent with ethanol) and avoid the oiling issue. Once distillation is complete, seeding with crystalline acalabrutinib and holding the seeded solution at a suitable temperature (e.g., 50°C) results in controlled crystallization from which the acalabrutinib product can be isolated with consistent particle characteristics. Crystallization further purifies the acalabrutinib product, particularly relative to any over-acylated by-products present.

[0151] Thus, in one embodiment, the present disclosure provides a compound having the structure of formula (VIII): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (VII): [ka] or a salt thereof, with 2-butynoic acid, or a salt thereof, in the presence of 1-propylphosphonic anhydride and a base in a reaction medium to form a reaction mixture comprising a compound of formula (VIII) and one or more reaction by-products; and Selective isolation of the compound of formula (VIII), or a salt thereof, from the reaction mixture relative to one or more by-products.

[0152] As mentioned above, the order of addition with respect to the process may have an effect. Generally, the contacting step includes adding a compound of formula (VII), or a salt thereof, and a base to a reaction medium; adding 2-butynoic acid, or a salt thereof, to a reaction medium containing a compound of formula (VII), or a salt thereof, and a base; and adding 1-propylphosphonic anhydride to a reaction medium containing a compound of formula (VII), or a salt thereof, 2-butynoic acid, or a salt thereof, and a base.

[0153] In another embodiment, the present disclosure provides a compound having the structure of formula (VIII): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (VII): [ka] or a salt thereof, with 2-butynoic acid, or a salt thereof, in the presence of 1-propylphosphonic anhydride and a base in a reaction medium to form a reaction mixture comprising a compound of formula (VIII), or a salt thereof; an unreacted compound of formula (VII), or a salt thereof; and a reaction by-product, the reaction by-product being a compound having the structure of formula (XIV): [ka] or salts thereof); and Selectively isolating the compound of formula (VIII), or a salt thereof, from the reaction mixture relative to the compound of formula (VII), or a salt thereof, and the compound of formula (XIV), or a salt thereof.

[0154] In one embodiment, the selectively isolated compound of Formula (VIII), or a salt thereof, contains less than about 1.0% by weight of the compound of Formula (VII), or a salt thereof. In another embodiment, the selectively isolated compound of Formula (VIII), or a salt thereof, contains less than about 0.8% by weight of the compound of Formula (VII), or a salt thereof. In another embodiment, the selectively isolated compound of Formula (VIII), or a salt thereof, contains less than about 0.6% by weight of the compound of Formula (VII), or a salt thereof. In another embodiment, the selectively isolated compound of Formula (VIII), or a salt thereof, contains less than about 0.4% by weight of the compound of Formula (VII), or a salt thereof. In another embodiment, the selectively isolated compound of Formula (VIII), or a salt thereof, contains less than about 0.3% by weight of the compound of Formula (VII), or a salt thereof. In another embodiment, the selectively isolated compound of Formula (VIII), or a salt thereof, contains less than about 1.0% by weight of the compound of Formula (XIV), or a salt thereof. In another embodiment, the selectively isolated compound of Formula (VIII), or a salt thereof, contains less than about 0.8% by weight of the compound of Formula (XIV), or a salt thereof. In another embodiment, the selectively isolated compound of Formula (VIII), or a salt thereof, contains less than about 0.6% by weight of the compound of Formula (XIV), or a salt thereof. In another embodiment, the selectively isolated compound of Formula (VIII), or a salt thereof, contains less than about 0.4% by weight of the compound of Formula (XIV), or a salt thereof. In another embodiment, the selectively isolated compound of Formula (VIII), or a salt thereof, contains less than about 0.3% by weight of the compound of Formula (XIV), or a salt thereof. In another embodiment, the selectively isolated compound of Formula (VIII), or a salt thereof, contains less than about 1.0% by weight of the compound of Formula (VII), or a salt thereof, and less than about 1.0% by weight of the compound of Formula (XIV), or a salt thereof. In another embodiment, the selectively isolated compound of Formula (VIII), or a salt thereof, contains less than about 0.8% by weight of the compound of Formula (VII), or a salt thereof, and less than about 0.8% by weight of the compound of Formula (XIV), or a salt thereof. In another embodiment, the selectively isolated compound of Formula (VIII), or a salt thereof, contains less than about 0.6% by weight of the compound of Formula (VII), or a salt thereof, and less than about 0.6% by weight of the compound of Formula (XIV), or a salt thereof.In another embodiment, the selectively isolated compound of formula (VIII), or a salt thereof, contains less than about 0.4% by weight of the compound of formula (VII), or a salt thereof, and less than about 0.4% by weight of the compound of formula (XIV), or a salt thereof. In another embodiment, the selectively isolated compound of formula (VIII), or a salt thereof, contains less than about 0.3% by weight of the compound of formula (VII), or a salt thereof, and less than about 0.3% by weight of the compound of formula (XIV), or a salt thereof.

[0155] In another embodiment, the present disclosure provides a compound having the structure of formula (VIII): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (VII): [ka] or a salt thereof, with 2-butynoic acid, or a salt thereof, in the presence of 1-propylphosphonic anhydride and a base in a reaction medium to form a reaction mixture comprising a compound of formula (VIII), or a salt thereof; an unreacted compound of formula (VII), or a salt thereof; and a reaction by-product, the reaction by-product being a compound having the structure of formula (XIV): [ka] or its salts); extracting at least a portion of the compound of formula (VIII), or a salt thereof, from the reaction mixture into an aqueous phase (the compound of formula (VIII), or a salt thereof, is selectively extracted into the aqueous phase relative to the compound of formula (XIV), or a salt thereof); adjusting the pH of the aqueous phase; and Extracting at least a portion of the compound of formula (VIII), or a salt thereof, from the aqueous phase into an organic phase, wherein the compound of formula (VIII), or a salt thereof, is selectively extracted into the organic phase relative to the compound of formula (VII), or a salt thereof.

[0156] In one embodiment, the contacting step includes adding a compound of Formula (VII) and a base to a reaction medium; adding 2-butynoic acid to the reaction medium containing the compound of Formula (VII) and the base; and adding 1-propylphosphonic anhydride to the reaction medium containing the compound of Formula (VII), 2-butynoic acid, and the base. In another embodiment, the reaction mixture is washed with water, and the washed reaction mixture is separated into an aqueous phase and a waste phase, and the compound of Formula (VIII) is selectively extracted into the aqueous phase. In another embodiment, the process further includes isolating the compound of Formula (VIII) from the organic phase into which the compound of Formula (VIII) has been selectively extracted.

[0157] The compound of formula (VII) is generally contacted with at least about 0.5 molar equivalents of 2-butynoic acid relative to the compound of formula (VII). In one embodiment, the compound of formula (VII) is contacted with about 0.5 to about 5.0 molar equivalents of 2-butynoic acid relative to the compound of formula (VII). In another embodiment, the compound of formula (VII) is contacted with about 1.0 to about 1.3 molar equivalents of 2-butynoic acid relative to the compound of formula (VII). In another embodiment, the compound of formula (VII) is contacted with about 1.2 molar equivalents of 2-butynoic acid relative to the compound of formula (VII).

[0158] Typically, at least about 0.3 molar equivalents of 1-propylphosphonic anhydride relative to the compound of formula (VII) are typically charged to the reaction medium. In one embodiment, at least about 0.5 molar equivalents of 1-propylphosphonic anhydride relative to the compound of formula (VII) are typically charged to the reaction medium. In another embodiment, at least about 1.0 molar equivalents of 1-propylphosphonic anhydride relative to the compound of formula (VII) are typically charged to the reaction medium. In another embodiment, about 0.3 to about 3.0 molar equivalents of 1-propylphosphonic anhydride relative to the compound of formula (VII) are typically charged to the reaction medium. In another embodiment, about 0.5 to about 2.0 molar equivalents of 1-propylphosphonic anhydride relative to the compound of formula (VII) are typically charged to the reaction medium. In another embodiment, about 0.7 to about 1.5 molar equivalents of 1-propylphosphonic anhydride relative to the compound of formula (VII) are typically charged to the reaction medium. In another embodiment, about 1.0 to about 1.2 molar equivalents of 1-propylphosphonic anhydride relative to the compound of formula (VII) is charged to the reaction medium.

[0159] The base can be any suitable base, particularly a base comprising at least one compound selected from the group consisting of triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate. In one embodiment, the base comprises triethylamine. Generally, about 1.0 to about 10.0 molar equivalents of base relative to the compound of formula (VII) are charged to the reaction medium. In one embodiment, about 2.0 to about 5.0 molar equivalents of base relative to the compound of formula (VII) are charged to the reaction medium. In another embodiment, about 2.4 to about 3.0 molar equivalents of base relative to the compound of formula (VII) are charged to the reaction medium.

[0160] The reaction medium can be any suitable reaction medium, particularly a reaction medium comprising at least one solvent selected from the group consisting of alkyl hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ketones, ethers, esters, nitriles, and polar aprotic solvents. In one embodiment, the reaction medium comprises at least one solvent selected from the group consisting of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, tert-amyl alcohol, acetone, methyl isobutyl ketone, 2-butanol, methyl ethyl ketone, acetonitrile, and ethyl acetate. In another embodiment, the reaction medium comprises dichloromethane. The volume of the reaction medium is generally from about 5 liters to about 20 liters per kilogram of compound of Formula (VII) charged to the reaction medium. During the contacting step, the reaction medium is generally maintained at a temperature of from about 10°C to about 30°C.

[0161] Typically, the aqueous phase comprises greater than about 75 area % of the compound of formula (VIII) and less than about 2.0 area % of the compound of formula (XIV) as measured by high performance liquid chromatography ("HPLC") at the completion of the aqueous phase extraction. In one embodiment, the aqueous phase comprises greater than about 80 area % of the compound of formula (VIII) as measured by HPLC at the completion of the aqueous phase extraction. In another embodiment, the aqueous phase comprises greater than about 85 area % of the compound of formula (VIII) as measured by HPLC at the completion of the aqueous phase extraction. In another embodiment, the aqueous phase comprises greater than about 90 area % of the compound of formula (VIII) as measured by HPLC at the completion of the aqueous phase extraction. In another embodiment, the aqueous phase comprises less than about 1.0 area % of the compound of formula (XIV) as measured by HPLC at the completion of the aqueous phase extraction. In another embodiment, the aqueous phase comprises less than about 0.8 area % of the compound of formula (XIV) as measured by HPLC at the completion of the aqueous phase extraction. In another embodiment, the aqueous phase comprises less than about 0.5 area% of the compound of formula (XIV) as measured by HPLC at the completion of the aqueous phase extraction. In another embodiment, the aqueous phase comprises less than about 0.2 area% of the compound of formula (XIV) as measured by HPLC at the completion of the aqueous phase extraction. In another embodiment, the aqueous phase comprises less than about 0.1 area% of the compound of formula (XIV) as measured by HPLC at the completion of the aqueous phase extraction. In another embodiment, the aqueous phase comprises more than about 80 area% of the compound of formula (VIII) and less than about 1.0 area% of the compound of formula (XIV) as measured by HPLC at the completion of the aqueous phase extraction. In another embodiment, the aqueous phase comprises more than about 85 area% of the compound of formula (VIII) and less than about 0.8 area% of the compound of formula (XIV) as measured by HPLC at the completion of the aqueous phase extraction. In another embodiment, the aqueous phase comprises greater than about 85 area % of the compound of formula (VIII) and less than about 0.5 area % of the compound of formula (XIV) as measured by HPLC upon completion of the aqueous phase extraction. In another embodiment, the aqueous phase comprises greater than about 85 area % of the compound of formula (VIII) and less than about 0.2 area % of the compound of formula (XIV) as measured by HPLC upon completion of the aqueous phase extraction.In another embodiment, the aqueous phase comprises greater than about 90 area % of the compound of Formula (VIII) and less than about 0.1 area % of the compound of Formula (XIV), as measured by HPLC upon completion of the aqueous phase extraction. During the aqueous phase extraction step, the aqueous phase generally has a pH of less than about 2.5. In one embodiment, the aqueous phase has a pH of about 1.8 to about 2.2 during the aqueous phase extraction step.

[0162] Typically, the organic phase comprises greater than about 75 area % of the compound of formula (VIII) and less than about 2.0 area % of the compound of formula (VII) as measured by HPLC upon completion of the organic phase extraction. In one embodiment, the organic phase comprises greater than about 80 area % of the compound of formula (VIII) as measured by HPLC upon completion of the organic phase extraction. In another embodiment, the organic phase comprises greater than about 85 area % of the compound of formula (VIII) as measured by HPLC upon completion of the organic phase extraction. In another embodiment, the organic phase comprises greater than about 90 area % of the compound of formula (VIII) as measured by HPLC upon completion of the organic phase extraction. In another embodiment, the organic phase comprises less than about 1.0 area % of the compound of formula (VII) as measured by HPLC upon completion of the organic phase extraction. In another embodiment, the organic phase comprises less than about 0.8 area % of the compound of formula (VII) as measured by HPLC upon completion of the organic phase extraction. In another embodiment, the organic phase comprises less than about 0.6 area% of the compound of Formula (VII) as measured by HPLC at the completion of the organic phase extraction. In another embodiment, the organic phase comprises less than about 0.4 area% of the compound of Formula (VII) as measured by HPLC at the completion of the organic phase extraction. In another embodiment, the organic phase comprises less than about 0.3 area% of the compound of Formula (VII) as measured by HPLC at the completion of the organic phase extraction. In another embodiment, the organic phase comprises greater than about 80 area% of the compound of Formula (VIII) and less than about 1.0 area% of the compound of Formula (VII) as measured by HPLC at the completion of the organic phase extraction. In another embodiment, the organic phase comprises greater than about 85 area% of the compound of Formula (VIII) and less than about 0.8 area% of the compound of Formula (VII) as measured by HPLC at the completion of the organic phase extraction. In another embodiment, the organic phase comprises greater than about 85 area % of the compound of formula (VIII) and less than about 0.6 area % of the compound of formula (VII) as measured by HPLC upon completion of the organic phase extraction. In another embodiment, the organic phase comprises greater than about 85 area % of the compound of formula (VIII) and less than about 0.4 area % of the compound of formula (VII) as measured by HPLC upon completion of the organic phase extraction.In another embodiment, the organic phase comprises greater than about 90 area % of the compound of Formula (VIII) and less than about 0.3 area % of the compound of Formula (VII), as measured by HPLC upon completion of the organic phase extraction. During the organic phase extraction step, the aqueous phase generally has a pH greater than about 4.0. In one embodiment, the aqueous phase has a pH of about 4.5 to about 5.0 during the organic phase extraction step.

[0163] The organic phase can comprise any suitable solvent, particularly at least one solvent selected from alkyl hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ketones, ethers, esters, and nitriles. In one embodiment, the organic phase comprises dichloromethane and at least one compound selected from the group consisting of 2-methyltetrahydrofuran, tert-amyl alcohol, methyl isobutyl ketone, 2-butanol, methyl ethyl ketone, ethyl acetate, isopropyl acetate, N-butyl acetate, butyronitrile, toluene, xylene, heptane, hexane, isohexane, and chloroform. In another embodiment, the organic phase comprises dichloromethane.

[0164] The compound of formula (VIII) can be isolated from the organic phase by any suitable means, particularly by crystallizing the compound of formula (VIII) from the organic phase. In one embodiment, the organic phase comprises an organic phase solvent, and the process further comprises exchanging the organic phase solvent with a replacement solvent to form a crystallization mixture comprising the compound of formula (VIII). In another embodiment, the compound of formula (VIII) is crystallized from the crystallization mixture. In another embodiment, the crystallization mixture is seeded with a crystalline form of the compound of formula (VIII). In another embodiment, the crystallization mixture is seeded with at least about 0.01 relative weight of the crystalline form. In another embodiment, the crystallization mixture is seeded with at least about 0.02 relative weight of the crystalline form. In another embodiment, the crystallization mixture is seeded with at least about 0.03 relative weight of the crystalline form. In another embodiment, the crystalline form is an anhydrous crystalline form.

[0165] The organic phase solvent may comprise any suitable solvent, particularly a polar solvent. In one embodiment, the organic phase solvent comprises at least one solvent selected from the group consisting of chlorinated hydrocarbons and ethers. In another embodiment, the organic phase solvent comprises at least one compound selected from the group consisting of dichloromethane and 2-methyltetrahydrofuran. In another embodiment, the organic phase solvent comprises dichloromethane.

[0166] The displacement solvent may comprise any suitable solvent. In one embodiment, the displacement solvent comprises an alcohol. In another embodiment, the displacement solvent comprises ethanol. In another embodiment, the organic phase solvent has a boiling point lower than that of the displacement solvent. In another embodiment, the boiling point of the organic phase solvent is at least about 20° C. lower than that of the displacement solvent. In another embodiment, the organic phase solvent comprises a polar solvent, and the displacement solvent comprises an alcohol. In another embodiment, the organic phase solvent comprises dichloromethane, and the displacement solvent comprises ethanol.

[0167] In one embodiment, the organic phase solvent is exchanged for a replacement solvent by continuous level distillation. In one aspect, the continuous level distillation is carried out under conditions sufficient to maintain the compound of Formula (VIII) in solution during the continuous distillation. In another aspect, the continuous level distillation is a continuous level vacuum distillation. In another aspect, the replacement solvent is charged in an amount sufficient to maintain at least about 15 relative volumes of total solvent per kilogram of the compound of Formula (VIII) during the distillation. In another aspect, the replacement solvent is charged in an amount sufficient to maintain at least about 18 relative volumes of total solvent per kilogram of the compound of Formula (VIII) during the distillation. In another aspect, the continuous level vacuum distillation is carried out at a temperature not exceeding about 60°C.

[0168] It may generally be advantageous to maintain the crystallization mixture at a temperature above about 40° C. for a period after the initiation of crystallization (e.g., after seeding). In one embodiment, the crystallization mixture is maintained at a temperature above about 40° C. for at least about 1 hour after the initiation of crystallization. In another embodiment, the crystallization mixture is maintained at a temperature above about 40° C. for at least about 2 hours after the initiation of crystallization. In another embodiment, the crystallization mixture is maintained at a temperature above about 40° C. for at least about 3 hours after the initiation of crystallization. In another embodiment, the crystallization mixture is maintained at a temperature above about 40° C. for at least about 4 hours after the initiation of crystallization. In another embodiment, the crystallization mixture is maintained at a temperature above about 40° C. for at least about 5 hours after the initiation of crystallization. In another embodiment, the crystallization mixture is seeded with a crystalline form of the compound of Formula (VIII). In another embodiment, the crystallization mixture is cooled to a temperature of about 20° C. over a period of at least 5 hours before isolating the compound of Formula (VIII). In another embodiment, the crystallization mixture is seeded with a crystalline form of the compound of formula (VIII), maintained at a temperature above about 40° C. for at least about 5 hours, and then cooled to a temperature of about 20° C. over at least 5 hours before isolating the compound of formula (VIII).

[0169] The contacting step is generally carried out as a batch reaction, particularly where at least about 25 kilograms of the compound of formula (VII), or a salt thereof, is initially charged to the reaction. In one embodiment, at least about 50 kilograms of the compound of formula (VII), or a salt thereof, is initially charged to the reaction. In another embodiment, at least about 75 kilograms of the compound of formula (VII), or a salt thereof, is initially charged to the reaction. In another embodiment, at least about 100 kilograms of the compound of formula (VII), or a salt thereof, is initially charged to the reaction.

[0170] The process generally provides a stoichiometric process yield of at least about 50% of the compound of formula (VIII), or a salt thereof. In one embodiment, the stoichiometric process yield of the compound of formula (VIII), or a salt thereof, is at least about 60%. In another embodiment, the stoichiometric process yield of the compound of formula (VIII), or a salt thereof, is at least about 65%. In another embodiment, the stoichiometric process yield of the compound of formula (VIII), or a salt thereof, is at least about 70%. In practice, the improved process has been able to output high-quality material at a yield of approximately 75% at a scale exceeding 100 kg (input).

[0171] In another exemplary embodiment, the present disclosure provides a compound having the structure of formula (VIII): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (VII): [ka] or a salt thereof, with 2-butynoic acid, or a salt thereof, in the presence of 1-propylphosphonic anhydride and a base in a reaction medium to form a reaction mixture comprising a compound of formula (VIII), unreacted compound of formula (VII), and a reaction by-product, the reaction by-product being a compound having the structure of formula (XIV): [ka] or its salts); extracting at least a portion of the compound of formula (VIII), or a salt thereof, from the reaction mixture into an aqueous phase having a pH of about 1.8 to about 2.2, wherein the compound of formula (VIII) is selectively extracted into the aqueous phase relative to the compound of formula (XIV); adjusting the pH of the aqueous phase to about 4.5 to about 5.0; and Extracting at least a portion of the compound of formula (VIII), or a salt thereof, from the aqueous phase into an organic phase, wherein the compound of formula (VIII) is selectively extracted into the organic phase relative to the compound of formula (VII).

[0172] In one embodiment, the contacting step includes adding a compound of Formula (VII) and a base to a reaction medium; adding 2-butynoic acid to the reaction medium containing the compound of Formula (VII) and the base; and adding 1-propylphosphonic anhydride to the reaction medium containing the compound of Formula (VII), 2-butynoic acid, and the base. In another embodiment, the reaction mixture is washed with water, and the washed reaction mixture is separated into an aqueous phase and a waste phase, and the compound of Formula (VIII) is selectively extracted into the aqueous phase. In another embodiment, the organic phase includes an organic phase solvent, and the process further includes exchanging the organic phase solvent with a displacement solvent to form a crystallization mixture containing the compound of Formula (VIII). In another embodiment, the process further includes isolating the compound of Formula (VIII) from the crystallization mixture. In another embodiment, the crystallization mixture is seeded with a crystalline form of the compound of Formula (VIII) and maintained at a temperature greater than about 40° C. for at least about 5 hours after the initiation of crystallization.

[0173] Scheme 18 below corresponds to the process described in Example 17 and illustrates one representative embodiment of an improved process for preparing compound (VI). Scheme 18 [ka]

[0174] XIII. Additional Embodiments Various embodiments of the individual processes described above can be combined to provide further embodiments of the overall process for preparing acalabrutinib. The following embodiments are representative embodiments that further describe the overall process. They are intended to illustrate the overall process and are not limiting.

[0175] In one embodiment, a compound having the structure of formula (VIII): [ka] or a salt thereof, A compound having the structure of formula (VII): [ka] or a salt thereof, with 2-butynoic acid, or a salt thereof, in the presence of 1-propylphosphonic anhydride and a base in a reaction medium to form a reaction mixture comprising a compound of formula (VIII) and one or more reaction by-products; and prepared by a process comprising selectively isolating a compound of formula (VIII), or a salt thereof, from a reaction mixture relative to one or more by-products; The compound having the structure of formula (VII) or a salt thereof is A compound having the structure of formula (V): [ka] or a salt thereof, with a compound having the structure of formula (VI): [ka] or a salt thereof in an aqueous reaction medium comprising an organic solvent in the presence of a base and a palladium catalyst to form a reaction mixture comprising a compound of formula (VII); reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising a compound of formula (VII), or a salt thereof; and It is prepared by a process comprising isolating a compound of formula (VII), or a salt thereof, from a substantially anhydrous mixture.

[0176] In another embodiment, a compound having the structure of Formula (VIII): [ka] or a salt thereof, A compound having the structure of formula (VII): [ka] or a salt thereof, with 2-butynoic acid, or a salt thereof, in the presence of a coupling agent and a base in a reaction medium to form a reaction mixture comprising a compound of formula (VIII), or a salt thereof; an unreacted compound of formula (VII), or a salt thereof; and a reaction by-product, the reaction by-product being a compound having the structure of formula (XIV): [ka] or its salts); extracting at least a portion of the compound of formula (VIII), or a salt thereof, from the reaction mixture into an aqueous phase (the compound of formula (VIII), or a salt thereof, is selectively extracted into the aqueous phase relative to the compound of formula (XIV), or a salt thereof); adjusting the pH of the aqueous phase; and is prepared by a process comprising extracting at least a portion of the compound of formula (VIII), or a salt thereof, from an aqueous phase into an organic phase, wherein the compound of formula (VIII), or a salt thereof, is selectively extracted into the organic phase relative to the compound of formula (VII), or a salt thereof; The compound having the structure of formula (VII) or a salt thereof is A compound having the structure of formula (V): [ka] or a salt thereof, with a compound having the structure of formula (VI): [ka] or a salt thereof in an aqueous reaction medium comprising an organic solvent in the presence of a base and a palladium catalyst to form a reaction mixture comprising a compound of formula (VII), or a salt thereof; reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising a compound of formula (VII), or a salt thereof; and It is prepared by a process comprising isolating a compound of formula (VII), or a salt thereof, from a substantially anhydrous mixture.

[0177] In another embodiment, the process further comprises: Compounds of formula (IV): [ka] or a salt thereof, with an acidic medium under conditions sufficient to deprotect the compound of formula (IV), or a salt thereof, and to form a reaction mixture comprising a compound of formula (VI), or a salt thereof, and a benzyl halide by-product; removing at least a portion of the benzyl halide by-product from the reaction mixture; and preparing a compound having the structure of formula (VI), or a salt thereof, by a process comprising isolating the compound of formula (VI), or a salt thereof, from a reaction mixture under conditions sufficient to substantially avoid the formation of an aminal impurity.

[0178] In another embodiment, the process further comprises preparing a compound having the structure of Formula (V), or a salt thereof, by a process comprising contacting 4-carboxyphenylboronic acid, or a salt thereof, with thionyl chloride and a catalyst in a reaction medium comprising an organic solvent to form an acyl chloride intermediate, followed by in situ contacting with 2-aminopyridine to form a reaction mixture comprising the compound of Formula (V), or a salt thereof.

[0179] In another embodiment, the process further comprises providing a compound having the structure of formula (III): [ka] or a salt thereof, with an aminating agent in a reaction medium to form a reaction mixture comprising a compound of formula (IV); forming a sulfate salt of a compound of formula (IV); and The present invention includes preparing a compound having the structure of formula (IV), or a salt thereof, by a process which includes isolating the sulfate salt.

[0180] In another embodiment, the process further comprises providing a compound having the structure of formula (I): [ka] or a salt thereof is contacted with a cyclizing agent in the presence of a catalyst in a reaction medium to produce a compound of formula (II): [ka] or forming a salt thereof; and The compound of formula (II) or a salt thereof is brominated with a brominating agent to obtain a compound having the structure of formula (III): [ka] or a salt thereof; The temperature of the reaction medium is controlled during the contacting step in a manner sufficient to maintain at least about 80% chiral purity with respect to the compound of formula (II), or a salt thereof.

[0181] In another embodiment, the present disclosure provides a compound having the structure of formula (VIII): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (V): [ka] or a salt thereof, with a compound having the structure of formula (VI): [ka] or a salt thereof in an aqueous reaction medium containing an organic solvent in the presence of a base and a palladium catalyst to produce a compound having a structure of formula (VII): [ka] or a salt thereof; reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising a compound of formula (VII), or a salt thereof; isolating the compound of formula (VII), or a salt thereof, from the substantially anhydrous mixture; and The method comprises converting a compound of formula (VII), or a salt thereof, into a compound of formula (VIII), or a salt thereof.

[0182] In another embodiment, the present disclosure provides a compound having the structure of formula (VIII): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (IV): [ka] or a salt thereof, is deprotected to obtain a compound of formula (IV) or a salt thereof, and the compound has the structure of formula (VI): [ka] or a salt thereof, and a benzyl halide by-product; removing at least a portion of the benzyl halide by-product from the reaction mixture; isolating the compound of formula (VI), or a salt thereof, from the reaction mixture under conditions sufficient to substantially avoid the formation of an aminal impurity; and The method comprises converting a compound of formula (VI), or a salt thereof, into a compound of formula (VIII), or a salt thereof.

[0183] In another embodiment, the present disclosure provides a compound having the structure of formula (VIII): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (III): [ka] or a salt thereof is contacted with an aminating agent in a reaction medium to produce a compound having the structure of formula (IV): [ka] forming a reaction mixture comprising: forming a sulfate salt of the compound of formula (IV); isolating the sulfate salt; and The method comprises converting the sulfate salt to a compound of formula (VIII), or a salt thereof.

[0184] In another embodiment, the present disclosure provides a compound having the structure of formula (VIII): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (I): [ka] or a salt thereof is contacted with a cyclizing agent in the presence of a catalyst in a reaction medium to produce a compound of formula (II): [ka] or forming a salt thereof; The compound of formula (II) or a salt thereof is brominated with a brominating agent to obtain a compound having the structure of formula (III): [ka] or a salt thereof; and converting a compound of formula (III), or a salt thereof, into a compound of formula (VIII), or a salt thereof; The temperature of the reaction medium is controlled during the contacting step in a manner sufficient to maintain at least about 80% chiral purity with respect to the compound of formula (II), or a salt thereof.

[0185] In another embodiment, the present disclosure provides a compound having the structure of formula (VIII): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (I): [ka] or a salt thereof is contacted with a cyclizing agent in the presence of a catalyst in a reaction medium to produce a compound having the structure of formula (II): [ka] or forming a salt thereof; and converting a compound of formula (II), or a salt thereof, into a compound of formula (VIII), or a salt thereof; The temperature of the reaction medium is controlled during the contacting step in a manner sufficient to maintain at least about 80% chiral purity with respect to the compound of formula (II), or a salt thereof.

[0186] Overall, the improved large-scale process results in high quality acalabrutinib that can be consistently produced from Compound (I) on a large scale with a reduction in batch failures and with yields of greater than 32%. [Example]

[0187] XIV. Examples Example 1: Preparation of (2S)-2-(1-bromo-8-chloro-imidazo[1,5-a]-pyrazin-3-yl)pyrrolidine-1-carboxylate benzyl (compound (III)) [ka] Benzyl (2S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl]pyrrolidine-1-carboxylate (Compound (I); 179.4 kg, 1.00 mol.eq.) was mixed with acetonitrile (809.6 kg, 4.5 rel.wt.) and N,N-dimethylformamide (6.8 kg, 0.1 mol.eq.), and phosphorus oxychloride (140.2 kg, 1.9 mol.eq.) was added slowly while maintaining the temperature below 25°C. The reaction mixture was heated at 72-82°C under a nitrogen sweep to remove evolved hydrochloric acid until the reaction was complete. The mixture was cooled to 35-45°C and subsequently concentrated to approximately 3.6 rel.vol. while maintaining the temperature below 45°C. Acetonitrile (350.2 kg, 1.95 rel.wt.) was added and the mixture concentrated to approximately 3.6 rel.vol. while maintaining the temperature below 45°C, this operation was repeated once more. The mixture was cooled to 15-25°C and then slowly transferred to a cooled solution of sodium bicarbonate (136.6 kg, 8.0 mol.eq.), water (1139 L, 6.3 rel.vol.), and ice (375.8 kg, 2.1 rel.wt.).

[0188] The product was then extracted from the mixture twice with dichloromethane (905 kg, 5.0 rel. wt.). The combined organic extracts were then washed with a solution of sodium bicarbonate (114.4 kg) in water (1139 L), followed by a solution of sodium chloride (75 kg) in water (376 L), filtered through Celite (18 kg), and then filtered through silica (40 kg), washing the silica cake twice with dichloromethane (909 kg). The solvent was removed by vacuum distillation, maintaining a temperature below 40°C, to approximately 1.0 rel. vol. N-methylpyrrolidone (819 kg, 4.6 rel. wt.) was added to dissolve the mixture, after which N-bromosuccinimide (77.3 kg, approximately 1.1 mol. eq.) was added slowly, stirring at 20°C to 30°C after each change until the reaction was deemed complete. The mixture was then added to a solution of sodium bicarbonate (21.8 kg) in water (1092 L), and the product was subsequently extracted with dichloromethane (1500 kg, 8.4 rel.wt.) followed by dichloromethane (907 kg, 5.1 rel.wt.). The organic phases were combined and washed three times with water (682 L) and eight times with water (382 L). The organic solution was concentrated to approximately 1.0 rel.vol. and concentrated from heptane (191 kg, 1.1 rel.vol.), followed by crystallization by the addition of heptane (191 kg, 1.1 rel.vol.). Filtration and drying yielded solid benzyl (2S)-2-(1-bromo-8-chloro-imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Compound (III), 152.2 kg, 75.6%). Enantiomeric excess = 97.8%.

[0189] However, the above process conditions often resulted in batches with reduced chiral purity and yield, and in some cases even caused batch failure. The generated hydrochloric acid created acidic conditions that caused racemization of the benzyl (2S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl]-pyrrolidine-1-carboxylate starting material. The use of a nitrogen sweep to remove the generated hydrochloric acid reduced the degree of racemization, but control over the degree of chiral reduction was still highly variable.

[0190] Example 2: Preparation of (2S)-2-(8-chloro-imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate benzyl (compound (II)) [ka] For the conditions of Example 1, the effect of decreasing the reaction temperature and increasing the N,N-dimethylformamide loading on the chiral purity of benzyl (2S)-2-(8-chloro-imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate was evaluated. As shown below, increasing the amount of N,N-dimethylformamide catalyst to at least 0.6 mol eq. increased the reaction rate and allowed the reaction to be carried out at a lower temperature. These changes in process conditions increased the yield and provided improved control over the chiral purity of the product.

[0191] In four vials equipped with magnetic stir bars, benzyl (2S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl]pyrrolidine-1-carboxylate (Compound (I), 1.00 g) was combined with acetonitrile (5 ml) and N,N-dimethylformamide (0.08, 0.12, 0.16, and 0.20 g; 0.4, 0.6, and 1.0 mol eq.) was added. Phosphorus oxychloride (0.82 g, 2.0 mol eq.) was added to each vial, and the contents were stirred for 15 minutes and placed in a heat block preheated to 42 °C with stirring. The internal temperature of the vials reached 41 °C. 0.50 ml samples were withdrawn from each vial at 1, 3, 5, and 21 hours. The samples were quenched into 10 ml of saturated sodium bicarbonate solution and extracted into 5 ml of methyl tert-butyl ether. The organic layer was separated and dried over magnesium sulfate. The extract was analyzed by HPLC for purity and chirality, and the results are shown in Table 3 below.

[0192] [Table 5]

[0193] Example 3: Preparation of (2S)-2-(1-bromo-8-chloro-imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate benzyl (compound (III)) [ka] The synthesis described in Example 1 was modified in light of the results of Example 2, and the modified process was carried out on a large scale. The modified process resulted in improved yields and largely avoided the racemization problems previously encountered during crystallization.

[0194] Benzyl (2S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl]pyrrolidine-1-carboxylate (Compound (I), 337.5 kg, 1.00 mol.eq.) was mixed with acetonitrile (1688 L, 5.0 rel.vol.) and N,N-dimethylformamide (39.5 kg, 0.6 mol.eq.), and phosphorus oxychloride (276.1 kg, 2.0 mol.eq.) was added slowly while maintaining the temperature below 30°C. The reaction mixture was heated at 40°C for 3 hours. The mixture was cooled and then slowly transferred to a cooled solution of sodium bicarbonate (605.1 kg, 8.0 mol.eq.) and water (3375 L, 10.0 rel.vol.). The product was then extracted from the mixture three times with methyl tert-butyl ether (1013 L, 3.0 rel.vol.). The combined organic extracts were then washed with a solution of sodium bicarbonate (151.3 kg, 2.0 mol eq.) in water (2025 L, 6.0 rel.vol.), followed by 25% w / w aqueous brine solution (675 kg, 2.0 rel.wt.), and then circulated through a bag filter containing magnesium sulfate. The solvent was removed by vacuum distillation (jacket temperature 30°C) to yield a dark red oil. N,N-dimethylformamide (1350 L, 4.0 rel.vol.) was added to dissolve the oil, followed by the addition of N-bromosuccinimide (160.3 kg, 1.0 mol eq.) in small increments, stirring at 20°C after each change. After the reaction was deemed complete, the mixture was cooled to 5°C, and a solution of 2% w / w aqueous sodium bicarbonate (2531 L, 7.5 rel.vol.) was slowly added to precipitate the product, maintaining the temperature below 10°C. The mixture was filtered and washed with a premixed solution of water (675 L, 2.0 rel.vol.) and N,N-dimethylformamide (338 L, 1.0 rel.vol.), followed by two washes with water (675 L, 2.0 rel.vol.). The resulting solid was returned to the reactor and reslurried in water (1688 L, 5.0 rel.vol.).The product was isolated, washed twice with water (675 L, 2.0 rel.vol.), and dried under vacuum at 45°C to give solid (2S)-benzyl 2-(1-bromo-8-chloro-imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (compound (III), 353.6 kg, 90.1%). Enantiomeric excess = >99.8%.

[0195] The compound exists as a mixture of conformers in solution, and resonances are quoted only for the major conformer. 1H NMR(500MHz,DMSO-d6)δ 1.86-1.94(m,1H),2.02-2.09(m,1H),2.10-2.18(m,1H),2.27-2.34(m,1H),3.49-3.54(m,1H),3.55-3.61(m,1H),4.59(d,J=12.3Hz,1H) ,4.99(d,J=12.3Hz,1H),5.41(dd,J=7.7,4.6Hz,1H),6.67-6.71(m,2H),7.08-7.13(m,2H),7.16-7.22(m,2H),8.28(d,J=5.0Hz,1H).13C NMR(126MHz,DMSO-d6)δ 23.5, 32.3, 46.9, 51.5, 65.9, 109.6, 115.4, 119.3, 126.7, 127.1, 127.7, 128.0, 136.0, 142.8, 143.0, 153.3.

[0196] Example 4: Preparation of benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate sulfate (sulfate of compound (IV)) [ka] Benzyl (2S)-2-(1-bromo-8-chloro-imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Compound (III), 90.0 kg, 1.00 mol eq.) was mixed with isopropanol (351 kg, 3.0 rel.wt.) and N-methylpyrrolidone (180 kg, 2.0 rel.wt.) in a sealed autoclave. Ammonia (451 kg, 5.0 rel.wt.) was injected into the mixture, which was then heated to 90-95°C until the reaction was complete. The reaction mixture was cooled to 50-60°C and water (900 kg, 10.0 rel.vol.) was added. The mixture was cooled to 20-30°C and extracted with dichloromethane (957 kg, 10.6 rel.wt.) followed by dichloromethane (360 kg, 4.0 rel.wt.). The organic phases were combined, washed with water, and then concentrated to approximately 2.5 rel.vol. Ethanol (574 kg, 6.4 rel.wt.) was added to the mixture, followed by the slow addition of concentrated sulfuric acid (30.4 kg, 1.5 mol.eq.) while maintaining the temperature below 25°C. The resulting slurry was cooled to 0-5°C, filtered, and dried under vacuum at 40°C to yield an off-white crystalline solid, which was the sulfate salt of benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (Compound (IV), 89.2 kg, 83.5%, assuming the monosulfate salt).

[0197] Example 5: Preparation of sulfate salt (2:3) of benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (compound (IV)) [ka] The synthesis described in Example 4 assumed that the final product would have a 1:1 ratio of free base to salt, but the assay and mass balance did not correspond. Therefore, the synthesis was further modified as described below to obtain a final product with a defined stoichiometry that could meet regulatory requirements for the characterization of intermediates used in the preparation of registered drug substances. The presence of inorganic ammonium sulfate in the product of Example 4 posed a challenge in accurately determining the sulfate stoichiometry. The modified process below removes residual ammonia prior to sulfate generation, essentially eliminating this issue.

[0198] Benzyl (2S)-2-(1-bromo-8-chloro-imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Compound (III), 336.5 kg, 1.00 mol. eq.) was mixed with 2-butanol (1683 L, 5.0 rel. vol.) and 30% w / w ammonium hydroxide (841 kg, 2.5 rel. wt.) in a sealed autoclave and heated to 90-95°C for 32 hours. The reaction mixture was cooled to 20°C and the lower aqueous phase was removed. The organic phase was washed twice with 50:50 brine:water solution (337 L, 1.0 rel. vol.) and subsequently distilled under vacuum at approximately 40°C to approximately one-third volume. 2-Butanol (1346 L, 4.0 rel.vol.) and water (841 L, 2.5 rel.vol.) were added to dissolve the oil, and the lower aqueous phase was removed and discarded. The organic phase was filtered to remove interfacial material, followed by the slow addition of 93% sulfuric acid (122.2 kg, 1.5 mol.eq.) while maintaining the temperature below 25°C. The resulting slurry was cooled to 0-5°C, filtered, washed with 10% v / v aqueous 2-butanol (673 L, 2.0 rel.vol.), and then dried under vacuum at 40°C to yield an off-white crystalline solid, the sulfate salt of benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidine-carboxylate (Compound (IV), 324.4 kg, 87.2%, calculated as the sulfate salt (2:3)).

[0199] The compound exists as a mixture of conformers in solution, and resonances are quoted only for the major conformer. 1H NMR (500MHz, DMSO-d6 with 10% TFA)δ 1.84-1.94(m,1H),1.98-2.05(m,1H),2.07-2.17(m,2H),2.25-2.34(m,1H),3.47-3.60(m,2H),4.57(d,J=12.1Hz,1H),5 .02(d,J=12.1Hz,1H),5.30(dd,J=7.6,5.3Hz,1H),6.79-6.84(m,3H),7.12-7.22(m,3H),7.73(d,J=6.0Hz,1H),9.48(br s,2H).13C NMR (126MHz, DMSO-d6 with 10% TFA)δ 23.8, 32.7, 47.2, 51.6, 66.4, 108.8, 112.9, 116.1, 117.1, 127.9, 128.2, 128.3, 136.4, 147.3, 148.7, 153.5. X-ray powder diffraction of the solid gave a diffractogram consistent with that in Figure 1.

[0200] Example 6: Analysis of benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate sulfate (sulfate of compound (IV)) A. Checking salt stoichiometry In four vials equipped with magnetic stir bars, purified benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (Compound (IV) free base, 500 mg) was combined with ethanol (8 ml) and concentrated sulfuric acid was added (0.25, 0.50, 0.75, and 1.0 mol eq.). After holding for 1 hour and subsequently cooling to 0°C for 1 hour, the mixture was filtered and dried under vacuum. The results are shown in Table 4 below and demonstrate that the stoichiometry is not consistent with the previously assumed 1:1 salt ratio, but is consistent with a 2:3 ratio.

[0201] [Table 6]

[0202] B. Single-crystal X-ray diffraction analysis Single crystals of the sulfate salt of (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate benzyl (compound (IV)) were grown by slow evaporation from dimethyl sulfoxide. Suitable crystals for single X-ray diffraction were identified and analyzed by single crystal diffraction. Crystal data details: 3(C 18 H 19 BrN5O2) . SO4 . HSO4 . H2O., M r =1463.02, trigonal, R3(No.146), a=15.89896(17)Å, b=15.89896(17)Å, c=20.9836(3)Å, α=90°, β=90°, γ=120°, V=4593.54(12)Å 3 , T = 100(2) K, Z = 3, Z' = 0.33333, μ(CuKα) = 3.748, 30561 measured reflections, 3873 independent (R int = 0.0306), which were used in all calculations. The final wR2 was 0.0791 (all data) and R1 was 0.0292 (I > 2(I)). Flack parameter = -0.023(5).

[0203] The stoichiometry was confirmed to be three molecules of benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate, one sulfate, and one hydrogen sulfate. Analysis of the crystal structure also identified one molecule of water per three molecules of benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate, although further diffraction studies and thermal analysis indicate that this can be varied without substantially affecting the overall structure and salt stoichiometry.

[0204] CX-ray powder diffraction analysis X-ray powder diffraction data were collected by mounting sulfate powder of benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (Compound (IV)) on a silicon wafer mount and analyzing the sample using a Bruker D4 Endeavour diffractometer (λ = 1.5418 Å). The sample was measured in reflection geometry in the θ-2θ scan mode configuration over a scan range of 2° to 40° 2θ with an exposure time of 0.12 seconds per 0.02° increment. X-rays were generated by a copper long fine-focus tube operated at 40 kV and 40 mA. The resulting X-ray diffraction pattern is shown in Figure 1, with selected peaks and relative intensities reported in Table 5 below.

[0205] [Table 7]

[0206] Characteristic peaks for this crystalline form include those at 7.7, 10.6, 11.1, 12.6, 13.5, 17.4, 18.0, 18.9, 19.2, and 21.9±0.2 degrees 2θ, particularly those at 7.7, 10.6, 11.1, 12.6, and 13.5±0.2 degrees 2θ.

[0207] Example 7: Preparation of 1-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (compound (VI)) [ka] The sulfate salt (2:3) of benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (Compound (IV), 261 kg, 1.0 mol eq.) and concentrated aqueous hydrochloric acid (996 L, 3.8 rel.wt.) were mixed and heated to 40-50°C under an inert atmosphere for at least 2 hours. The batch was cooled and washed four times with methyl tert-butyl ether (192 kg, 4 x 0.73 rel.wt.). Aqueous sodium hydroxide was added slowly with cooling to reach a pH greater than 12. The product was extracted with dichloromethane (3632 kg, 13.9 rel.wt.), clarified with Celite, and subsequently decolorized with charcoal (13 kg, 0.05 rel.wt.). The organic extract was concentrated at atmospheric pressure to approximately 0.86 rel.vol. Methyl tert-butyl ether (519 L, 1.99 rel.wt.) was added, the mixture was cooled to 20°C, and the resulting slurry was filtered, washed with a mixture of methyl tert-butyl ether, and then dried under vacuum at 40°C to give solid 1-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (compound (VI), 119 kg, 78% yield).

[0208] Example 8: Preparation of 1-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (compound (VI)) [ka] The sulfate salt (2:3) of benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (compound (IV), 370 kg) and concentrated aqueous hydrochloric acid were mixed and heated to 50° C. for at least 6 hours. The batch was cooled and washed with methyl tert-butyl ether followed by heptane. Aqueous sodium hydroxide was added slowly with cooling to reach a pH greater than 12. The product was extracted with dichloromethane and methanol was added. The solution was clarified through Celite and subsequently decolorized with charcoal. The organic extract was concentrated at atmospheric pressure and exchanged into methyl tert-butyl ether. The resulting mixture was cooled, and the resulting slurry was filtered, washed with a mixture of methyl tert-butyl ether, and then dried under vacuum to give solid 1-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (Compound (VI), 188.8 kg). The product required further purification to remove the aminal impurity by slurrying the product in ethyl acetate, filtering, and washing the filter cake with ethyl acetate.

[0209] Example 9: Preparation of 1-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (compound (VI)) [ka] The syntheses exemplified in Examples 7 and 8 sometimes resulted in increased impurities (e.g., aminal impurities when dichloromethane was used as the extraction solvent) and poor operability. Therefore, the following process was developed to improve the purity of the final product.

[0210] The sulfate salt (2:3) of benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (compound (IV), 343 kg, 1.0 mol.eq.) and 37% w / w aqueous hydrochloric acid (1142 L, 3.33 rel.vol.) were mixed and heated to 40°C under an inert atmosphere for 14 hours. The batch was cooled and washed twice with heptane (1715 L, 5.0 rel.vol.). 30% w / w aqueous sodium hydroxide (104.4 kg, 1.10 mol.eq.) was added slowly with cooling to reach a pH of >10. The product was extracted twice with 2-methyltetrahydrofuran (2401 L, 7.0 rel.vol.), and the combined extracts were washed with water (343 L, 1.0 rel.vol.) before being concentrated at atmospheric pressure to a volume of 3.5 rel.vol. 2-Methyltetrahydrofuran (1029 L, 3.0 rel.vol.) was added, and the mixture was concentrated at atmospheric pressure to a volume of 1200 L, 3.5 rel.vol. The mixture was cooled to 70°C, and crystalline 1-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (Compound (VI), 0.34 kg, 0.001 rel.wt.) was added, seeding the mixture. The mixture was cooled to 20°C, and heptane (686 L, 2.0 rel.vol.) was added. The resulting slurry was filtered, washed with a mixture of 2-methyltetrahydrofuran (309 L, 0.90 rel.vol.) and heptane (206 L, 0.60 rel.vol.), and then dried under vacuum at 40°C to give a tan crystalline solid, 1-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (Compound (VI), 168 kg, 84% yield). 1H NMR(500MHz,DMSO-d6)δ 1.65-1.75(m,1H),1.77-1.86(m,1H),1.98-2.06(m,1H),2.09-2.17(m,1H),2.75-3.06(m,3H),4.44(dd,J=7.6,6.7Hz,1H),6.61(br s,2H),6.96(d,J=5.0Hz,1H),7.70(d,J=5.0Hz,1H).13C NMR(126MHz,DMSO-d6)δ 25.7,29.4,46.5,54.0,105.1,107.5,115.3,128.1,142.8,150.8.

[0211] Example 10: Preparation of [4-(2-pyridylcarbamoyl)phenyl]boronic acid (compound (V)) [ka] 4-Carboxyphenylboronic acid (116.0 kg, 1.0 mol.eq.) was mixed with toluene (696 kg, 6.0 rel.vol.) and N,N-dimethylformamide (2.0 kg, 0.04 mol.eq.) at 50°C. Thionyl chloride (249.5 kg, 3.0 mol.eq.) was slowly charged to the slurry. The reaction was heated to 60°C, stirred for 8 hours, and then cooled. The mixture was then concentrated under vacuum to remove 348 L (3.0 rel.vol.) of solvent, followed by the addition of toluene (348 L, 3.0 rel.vol.). This was repeated three more times to remove excess thionyl chloride. The mixture was then concentrated under vacuum to remove 348 L (3.0 rel.vol.) of solvent, followed by the addition of pyridine (348 L, 3.0 rel.vol.). This was repeated once to remove toluene. Pyridine (580 L, 5.0 rel.vol.) was added to the slurry, and the mixture was cooled to -5°C. A solution of 2-aminopyridine (131.6 kg, 2.0 mol.eq.) in pyridine (232.0 L, 2.0 rel.vol.) was added as quickly as possible while maintaining the temperature below 20°C. The reaction was slowly heated to 65-70°C and stirred for 8 hours. The mixture was then concentrated under vacuum to remove 812 L (7.0 rel.vol.) of solvent. The reaction mixture was adjusted to a temperature of 65-70°C, water (116 L, 1.0 rel.vol.) was added, and the mixture was stirred at 65-70°C for 12 hours. Toluene (232 L, 2.0 rel.vol.) was charged, followed by water (928 L, 8.0 rel.vol.), at a temperature of 65-70°C. The mixture was then cooled to 20°C and filtered. The filter cake was washed four times with water (464 L, 4.0 rel.vol.) and dried at 50°C to give a white crystalline solid [4-(2-pyridylcarbamoyl)phenyl]-boronic acid (compound (V), 141.8 kg, 83.8% theory).

[0212] Example 11: Preparation of [4-(2-pyridylcarbamoyl)phenyl]boronic acid (compound (V)) [ka] The synthesis described in Example 10 was further modified to identify a suitable replacement solvent for N,N-dimethylformamide that would, among other things, reduce the potential formation of unwanted by-products, especially dimethylcarbamoyl chloride.

[0213] 4-Carboxyphenylboronic acid (7.0 g, 1.0 mol.eq.) was mixed with toluene (66.5 mL, 9.5 rel.vol.) and tetrabutylammonium chloride (0.59 g, 0.05 mol.eq.) at 50°C. Thionyl chloride (13.8 g, 2.75 mol.eq.) was slowly charged to the slurry, followed by a line wash of toluene (3.5 mL, 0.5 rel.vol.). The reaction was heated to 70°C and stirred for at least 6 hours before cooling. The mixture was then concentrated under vacuum to approximately 4.0 rel.vol., followed by the addition of pyridine (56 mL, 8.0 rel.vol.). The mixture was then concentrated under vacuum to approximately 4.0 rel.vol. and subsequently added to a solution of 2-aminopyridine (7.94 g, 2.0 mol.eq.) in pyridine (35 ml, 5.0 rel.vol.), followed by a pyridine (7 ml, 1.0 rel.vol.) line wash. The reaction was slowly heated to 70°C and stirred for at least 18 hours. The mixture was then concentrated under vacuum to approximately 3.0 rel.vol. Water (7 ml, 1.0 rel.vol.) was added and the mixture was stirred at 70°C for at least 1 hour. Water (56 ml, 8.0 rel.vol.) was charged at 70°C. The mixture was then cooled to 20°C and filtered. The filter cake was washed four times with water (28 ml, 4.0 rel.vol.) and dried at 50°C to give a white crystalline solid [4-(2-pyridylcarbamoyl)phenyl]-boronic acid (compound (V), 8.79 kg, 85% theory).

[0214] The compound exists as a mixture of conformers in solution, and resonances are quoted only for the major conformer. 1H NMR(500MHz,DMSO-d6)δ 7.16(ddd,J=7.2,4.9,0.9Hz,1H),7.83(ddd,J=8.3,7.2,1.9Hz,1H),7.87-7.90(m,2H),7.95-7.99(m,2H),8.17-8.20(m,1H),8.24(br s,2H),8.38(ddd,J=4.9,1.9,0.8Hz,1H),10.74(s,1H).13C NMR(126MHz,DMSO-d6)δ 114.7,119.8,126.8,134.0,135.3,138.1,138.3,147.9,152.2,166.1.

[0215] Example 12: Preparation of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]-imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (compound (VII)) [ka] 1-Bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (Compound (VI), 49.7 kg, 1.00 mol eq.) and [4-(2-pyridylcarbamoyl)phenyl]boronic acid (Compound (V), 44.7 kg, 1.05 mol eq.) were mixed with bis(tert-butyldicyclohexylphosphine)dichloropalladium(II) (0.61 kg, 0.005 mol eq.), potassium iodide (9.0 kg, 0.30 rel.vol.), and triethylamine (54 kg, 3.0 mol eq.) in water (422 L, 8.45 rel.vol.) and 2-butanol (184 L, 4.55 rel.vol.). The reaction mixture was then heated to 82°C under nitrogen for at least 24 hours. The reaction mixture was slowly cooled to approximately 23°C and then thermocycled by warming to about 42°C, cooling to about 23°C, and warming to about 42°C.

[0216] Water (727 L, 15 rel. vol.) was then slowly added, and the mixture was cooled to approximately 20°C before being filtered and washed with water. The filtration and washing cycle was very slow. Two filters and multiple releases were required during the process, which typically took 3–4 days to complete. X-ray powder diffraction of the material isolated during this filtration step yielded a diffractogram consistent with that shown in Figure 2 (i.e., Form 2). The water-wet product was further dried by refluxing in heptane (964 L) under Dean-Stark conditions for 29 hours, followed by filtration and drying under vacuum at 45°C to yield a yellow crystalline solid, 4-{8-amino-3-[(2S)-2-pyrrolidinyl]-imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (Compound (VII), 61.6 kg, 81.5%).

[0217] Example 13: Preparation of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]-imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (compound (VII)) [ka] The synthesis described in Example 12 was further modified to, among other things, improve filtration of the crude product and reduce the cycle time of the synthesis.

[0218] 1-Bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (compound (VI), 26.5 kg, 1.00 mol eq.) and [4-(2-pyridylcarbamoyl)phenyl]boronic acid (compound (V), 25 kg, 1.10 mol eq.) were mixed with bis(tert-butyldicyclohexylphosphine)dichloropalladium(II) (0.64 kg, 0.01 mol eq.), potassium iodide (4.7 kg, 0.30 rel.vol.), and triethylamine (28.9 kg, 1.50 mol eq.) in water (224 L, 8.45 rel.vol.) and 2-butanol (120 L, 4.55 rel.vol.). The reaction mixture was then heated to 82°C for 15 hours. The reaction mixture was diluted with 2-butanol (149 L, 5.6 rel.vol.), water (11 L, 0.4 rel.vol.), and 3 M aqueous potassium carbonate (53 L, 2.0 rel.vol.) at 75°C to 82°C, and the aqueous layer was removed and discarded. The organic layer was treated with QuadraSil MP (5.3 kg, 0.20 rel.wt.) at 80°C for 18 hours. The scavenger was removed by filtration at 80°C and washed with 2-butanol (27 L, 1.0 rel.vol.). The organic mixture was washed with a solution of water (56 L, 2.1 rel.vol.) and 3 M aqueous potassium carbonate (9 L, 0.33 rel.vol.) at a temperature of 75°C to 82°C, followed by a wash with water (55 L, 2.0 rel.vol.) at a temperature of 75°C to 82°C. 2-Butanol was added to adjust the volume of the solution to 16 rel.vol., and the mixture was distilled at atmospheric pressure, maintaining a constant volume of about 16 rel.vol. in the vessel by the addition of further 2-butanol, until the mixture reached a temperature above 97° C. The mixture was seeded with crystalline 4-{8-amino-3-[(2S)-2-pyrrolidinyl]-imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (Compound (VII), 0.13 kg, 0.005 rel.wt.) and further distilled at atmospheric pressure to reduce the volume to about 10 rel.vol.The mixture was slowly cooled to 20°C, then filtered, washed with 2-butanol (106 L, 4.0 rel.vol.), followed by 2-butanol (53 L, 2.0 rel.vol.), then heptane (53 L, 2.0 rel.vol.), and dried under vacuum at 45°C to give a yellow crystalline solid: 4-{8-amino-3-[(2S)-2-pyrrolidinyl]-imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (Compound (VII), 26.8 kg, 75%). The filtration and washing cycle was accomplished in less than 24 hours using a single discharge onto one filter.

[0219] Solid 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (compound (VII), 40.6 kg, 1.0 mol.eq.) was purified by slurrying in 1 M aqueous potassium carbonate (162.4 L, 4.0 rel.vol.) to remove the impure 4-[8-amino-3-[(2S)-pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl] After removal of [1,5-a]pyrazin-1-yl]benzoic acid (compound (XII)), the mixture was filtered and washed with water (81.2 L, 2.0 rel.vol.) followed by heptane (81.2 L, 2.0 rel.vol.) to give yellow crystalline 4-{8-amino-3-[(2S)-2-pyrrolidinyl]-imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (compound (VII), 39.7 kg, 98%). In addition to the 4-[8-amino-3-[(2S)-pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]benzoic acid (compound (XII)) impurity, another impurity, 4-[8-amino-3-[(2S)-1-[4-[8-amino-3-[(2S)-pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]benzoyl]pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]-N-(2-pyridyl)benzamide (compound (XIII)), was observed and was not removed by this rework.

[0220] Example 14: Preparation of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]-imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (compound (VII)) [ka] Although the process described in Example 13 resulted in improvements in filtration and cycle time, two unwanted impurities were formed due to prolonged heating under process conditions. Therefore, the process was further modified to, among other things, reduce the formation of these impurities and improve the purity of the final product.

[0221] 1-Bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (Compound (VI), 115.0 kg, 1.00 mol eq.) and [4-(2-pyridylcarbamoyl)phenyl]boronic acid (Compound (V), 96.7 kg, 0.98 mol eq.) were mixed with bis(tert-butyldicyclohexylphosphine)dichloropalladium(II) (2.8 kg, 0.01 mol eq.), potassium iodide (20.3 kg, 0.30 mol eq.), and triethylamine (135.2 kg, 2.40 mol eq.) in water (920 L, 8.0 rel.vol.) and 2-butanol (978 L, 8.5 rel.vol.). The reaction mixture was then heated to 80°C for 16 hours. The layers were separated, and the aqueous layer was discarded. The organic layer was diluted with 2-butanol (460 L, 4.0 rel.vol.) and washed with water (575 L, 5.0 rel.vol.) followed by water (460 L, 4.0 rel.vol.) at 60°C, followed by treatment with QuadraSil MP (23 kg, 0.20 rel.wt.) at 60°C for 9 hours. The scavenger was removed by filtration at 60°C and washed with 2-butanol (173 L, 1.5 rel.vol.). The resulting mixture was washed with a solution of sodium chloride (46 kg, 0.40 rel.wt.) in water (230 L, 2.0 rel.vol.) at 60°C. The mixture was seeded with crystalline 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)-benzamide (Compound (VII), 1.15 kg, 0.01 rel.wt.) and then distilled under vacuum (0.2 bar) while maintaining a constant volume of 1840 L (16 rel.vol.) in the vessel by adding additional 2-butanol (1610 L, 14.0 rel.vol.) and maintaining a temperature below 60°C. The mixture was then distilled (0.2 bar) to a volume of 1380 L (12.0 rel.vol.) while maintaining a temperature below 60°C. Heating to 80°C for 2 hours was followed by cooling to 20°C and filtering.The product was washed with 2-butanol (460 L, 4.0 rel.vol.), followed by 2-butanol (230 L, 2.0 rel.vol.) and then heptane (230 L, 2.0 rel.vol.) and dried under vacuum at 45°C to give a yellow crystalline solid, 4-{8-amino-3-[(2S)-2-pyrrolidinyl]-imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (Compound VII, 131.7 kg, 80.4%). The filtration and washing cycle was accomplished in less than 24 hours using a single discharge and a single filter.

[0222] 1H NMR(500MHz,DMSO-d6)δ 1.71-1.80(m,1H),1.83-1.92(m,1H),2.06-2.14(m,1H),2.22-2.30(m,1H),2.89(t,J=6.8Hz,2H),4.55(t,J=7.2Hz,1H),6.11(br s,2H),7.07(d,J=5.0Hz,1H),7.17(ddd,J=7.4,4.9,0.9Hz,1H),7.72-7.75(m,2H),7.77(d,J=5.0Hz,1H),7.85 (ddd,J=8.4,7.4,2.0Hz,1H),8.13-8.16(m,2H),8.20-8.23(m,1H),8.39(ddd,J=4.9,2.0,0.9Hz,1H),10.82(br s,1H).13C NMR(126MHz,DMSO-d6)δ 25.8, 29.5, 46.6, 54.2, 107.4, 114.6, 114.7, 119.8, 127.5, 128.3, 129.0, 132.3, 132.6, 138.1, 138.1, 142.8, 148.0, 151.5, 152.2, 165.7. X-ray powder diffraction of the resulting crystalline solid gave a diffractogram consistent with that in Figure 4 (i.e., Form C).

[0223] Example 15: X-ray powder diffraction analysis of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (compound (VII)) A. Analysis Protocol Crystalline samples of Forms 2, 3, and C of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]-imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (Compound (VII)) were analyzed by X-ray powder diffraction. Samples were mounted on silicon wafer mounts and analyzed using a PANalytical CubiX PRO diffractometer (λ = 1.5418 Å). Samples were measured in reflection geometry in the θ-θ configuration over a scan range of 2° to 40° 2θ with a nominal exposure of 25 seconds per 0.02° increment. X-rays were generated by a copper long fine-focus tube operated at 45 kV and 40 mA. Results for Forms 2, 3, and C crystals are reported below in subsections A, B, and C, respectively.

[0224] Analysis of B.2 Crystal Form A sample of Form 2 crystalline 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (Compound (VII)) was analyzed by X-ray powder diffraction. The resulting X-ray diffraction pattern is shown in Figure 2, with selected peaks and relative intensities reported in Table 6 below.

[0225] [Table 8]

[0226] The Form 2 crystalline form exhibits characteristic peaks at 5.0, 5.7, 7.2, 9.0, 9.9, 11.2, 12.7, 14.1, and 14.9±0.2 degrees 2θ, particularly peaks at 5.0, 5.7, 7.2, 9.9, and / or 11.2±0.2 degrees 2θ. As previously mentioned, the product isolated from the initial filtration of Example 12 corresponds to the Form 2 crystalline form.

[0227] Analysis of C.3 crystal form A sample of Form 3 crystalline 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (Compound (VII)), produced by slurrying Form 2 in pure butanol at ambient conditions for 7 days, was analyzed by X-ray powder diffraction. The resulting X-ray diffraction pattern is shown in Figure 3, with selected peaks and relative intensities reported in Table 7 below.

[0228] [Table 9]

[0229] The Form 3 crystalline form exhibits characteristic peaks at 4.8, 7.4, 7.7, 9.6, 11.7, 12.5, 12.8, 15.3, 22.3, and / or 21.6±0.2 degrees 2θ, in particular peaks at 7.4, 11.7, 12.5, 22.3, and / or 21.6±0.2 degrees 2θ.

[0230] Analysis of DC-type crystals A sample of Form C crystalline 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (Compound (VII)) was analyzed by X-ray powder diffraction. The resulting X-ray diffraction pattern is shown in Figure 4, with selected peaks and relative intensities reported in Table 8 below.

[0231] [Table 10]

[0232] The Type C crystalline form exhibits characteristic peaks at 7.4, 8.9, 9.9, 11.1, 12.8, 14.1, 14.8, 19.0, and / or 21.6±0.2 degrees 2θ, in particular peaks at 9.9, 11.1, 12.8, 14.1, and 19.0±0.2 degrees 2θ. As previously mentioned, the product isolated from the filtration of Example 14 corresponds to the Type C crystalline form.

[0233] Example 16: Preparation of 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide (compound (VIII)) [ka] 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)-benzamide (Compound (VII), 70 kg, 1.0 mol eq.) and 2-butynoic acid (17.5 kg, 1.2 mol eq.) were mixed in dichloromethane (1537 kg, 22 rel.vol.) to give a viscous slurry. Triethylamine (44.5 kg, 2.5 mol eq.) was added, followed by 1-propylphosphonic anhydride (T3P) (approximately 111.4 kg, 1.0 mol eq.). (Further aliquots of T3P were added in small portions until the reaction was deemed complete.) The resulting organic solution of the product was washed twice with water (525 kg, 7.5 rel.vol.) and then concentrated to approximately 2-3 rel.vol. Water (700 kg, 10.0 rel.vol.) was added, and the mixture was then acidified using 6 M aqueous hydrochloric acid to reach approximately pH 2, after which the organic phase was separated and discarded. The aqueous layer (containing the product) was washed three times with 2-methyltetrahydrofuran (478 kg, 8.0 rel.vol.), followed by two more washes with 2-methyltetrahydrofuran (180 kg, 3.0 rel.vol.). Dichloromethane (742 kg, 8.0 rel.vol.) was added to the aqueous phase, and the mixture was adjusted to a pH of 7.0-8.5 with triethylamine (variable amount), and the product was extracted into the organic phase. The organic phase was separated and washed twice with water (350 kg, 5.0 rel.vol.), then filtered through carbon, followed by repeated treatment with Quadrasil-MP (17.5 kg, 0.25 rel.wt.), washing the spent scavenger mass with methanol each time until the palladium specification was met. The filtrate was concentrated to 5 rel.vol. Ethanol (276 kg, 5 rel.vol.) was added and concentrated to 5 rel.vol., and this operation was repeated two more times. The mixture was then heated to 50°C, cooled to 20°C, and filtered. The product was washed twice with ethanol (55 kg, 1.0 rel.vol.), then the wet mass was returned to the vessel and dissolved in methanol (831 kg, 15 rel.vol.) at 60°C. The filtrate was concentrated to 5 rel.vol. Ethanol (276 kg, 5 rel.vol.) was added and concentrated to 5 rel.vol., and repeated once.The mixture was then heated to 50°C, cooled to 20°C and filtered. The product was washed twice with ethanol (55 kg, 1.0 rel.vol.) and then dried under vacuum at 50°C to give acalabrutinib (Compound VIII, 52.2 kg, 64%) as a white crystalline solid.

[0234] Example 17: Preparation of 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide (compound (VIII)) [ka] The synthesis described in Example 16 was further modified to, among other things, allow for greater flexibility in operating conditions while still resulting in a product of adequate purity. Among other advantages, the modified synthesis provides improvements in the removal of certain impurities.

[0235] 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)-benzamide (Compound (VII), 131.7 kg, 1.0 mol eq.) was slurried in dichloromethane (955 L, 7.25 rel.vol.) and triethylamine (90.1 kg, 2.7 mol eq.). 2-Butynoic acid (33.3 kg, 1.2 mol eq.) in dichloromethane (263.4 L, 2.0 rel.vol.) was added, followed by 1-propylphosphonic anhydride (T3P) (50% w / w solution in dichloromethane, 209.8 kg, 1.0 mol eq.). The resulting organic solution of the product was washed twice with water (658.5 L, 5.0 rel.vol.), followed by the addition of water (1317 L, 10.0 rel.vol.). The mixture was then acidified to approximately pH 2.2 using 6 M aqueous hydrochloric acid, followed by the addition of 2 M aqueous hydrochloric acid to reach a pH of 1.8-2.2. The organic phase was then separated and discarded. Dichloromethane (1317 L, 10.0 rel.vol.) was added to the aqueous phase, and the mixture was adjusted to a pH of 4.5-5.0 with triethylamine. The organic phase was separated, and the aqueous phase was re-extracted with dichloromethane (527 L, 4.0 rel.vol.). The combined dichloromethane extracts were screened, and the organic phase was concentrated to approximately 5.0 rel.vol. Ethanol (1712 L, 13.0 rel.vol.) was added and the mixture was distilled (approximately 360 mbar) while maintaining a constant volume (18.0 rel.vol.) by the addition of ethanol (1580 L, 12.0 rel.vol.). A portion of crystalline 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide (compound (VIII), 1.32 kg, 0.01 rel.wt.) was added as seed, and the solution was held at 50°C for 10 hours to crystallize the product. The mixture was then cooled over 7 hours and filtered. The product was washed twice with ethanol (527 L, 4.0 rel.vol.) and then dried under vacuum at 50°C to give acalabrutinib (Compound VIII, 113.6 kg, 74%) as a white crystalline solid.

[0236] This compound exists as a mixture of stereoisomers in solution, and resonances are quoted only for the major stereoisomer. 1H NMR (500 MHz, DMSO-d6) δ 1.95-2.02 (m, 4H), 2.09-2.15 (m, 1H), 2.23-2.38 (m, 2H), 3.81 (t, J = 6.7 Hz, 2H), 5.47 (dd, J = 7.6, 4.3 Hz, 1H), 6.13 (br s,2H),7.11(d,J=5.1Hz,1H),7.17(ddd,J=7.4,4.8,0.8Hz,1H),7.70-7.73(m,2H),7.78(d,J=5.1Hz,1H),7 .82-7.87(m,1H),8.13-8.16(m,2H),8.20-8.23(m,1H),8.39(ddd,J=4.8,1.9,0.8Hz,1H),10.83(s,1H).13C NMR(126MHz,DMSO-d6)δ 3.3, 23.9, 31.2, 48.2, 51.3, 74.3, 88.3, ​​107.0, 113.8, 114.7, 119.8, 127.9, 128.3, 129.0, 132.7, 133.2, 137.9, 138.1, 141.0, 148.0, 151.4, 151.8, 152.2, 165.7.

[0237] Example 18: Preparation of (2S)-2-[(3-chloropyrazin-2-yl)methyl-carbamoyl]pyrrolidine-1-carboxylate benzyl (compound (I)) [ka] A. Preparation of Compound (7) To a solution of (2S)-1-benzyloxycarbonylpyrrolidine-2-carboxylic acid (1.039 kg, 1.0 mol.Eq.) and toluene (6.3 L, 6.0 rel.vol.), thionyl chloride (0.75 kg, 1.5 mol.Eq.) was added, and the mixture was stirred at 30°C for 7 hours. The reaction mixture was concentrated under vacuum at 35-45°C (to approximately 4.5 rel.vol.). Toluene (2.1 L, 2.0 rel.vol.) was added, and the reaction mixture was concentrated under vacuum at 35-45°C (to approximately 4.5 rel.vol.). The product (compound (7)) solution was assayed (5.6 kg @ 18.3% w / w = 1.03 kg, 91.8% yield).

[0238] B. Preparation of (2S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl]-pyrrolidine-1-carboxylate (benzyl compound (I)) Step 1: Diphenylmethanimine (compound (1), 1.44 kg, 1.0 mol.eq.) and glycine methyl ester hydrochloride (compound (2), 1.099 kg, 1.1 mol.eq.) were mixed in acetonitrile (7.2 L, 5.0 rel.vol.) at 35-40°C for 3 hours. The mixture was cooled to 20-25°C, filtered, and the cake was washed twice with acetonitrile (2.88 L, 2.0 rel.vol.). The assay of the product (compound (3)) solution was determined (10.05 kg @ 18.9% w / w = 1.9 kg, 94.4% yield).

[0239] Step 2: 2,3-Dipyrazine (compound (4), 0.911 kg, 1.0 mol eq.) and cesium carbonate (2.39 kg, 1.2 mol eq.) were added to the filtrate solution (10.05 kg @ 18.9% w / w = 1.9 kg, 1.2 mol eq.), and the mixture was heated to 80-85°C for 13 hours. After cooling to 20-25°C and filtering, the cake was washed twice with acetonitrile (1.8 L, 2.0 rel.vol.). The product (compound (5),) solution was assayed (14.7 kg @ 13.3% w / w = 1.96 kg, 89.0% yield).

[0240] Step 3: Water (3.6 kg, 2.0 rel.vol.) was added to a solution of compound (5) (13.5 kg @ 13.3% w / w = 1.8 kg) in acetonitrile, and the mixture was distilled under vacuum to 2.5 rel.vol. Additional water (3.6 kg, 2.0 rel.vol.) was added, and the mixture was distilled under vacuum to 3.5 rel.vol. Concentrated hydrochloric acid (1.8 L, 1.0 rel.vol. relative to the amount of compound (5)) was added and heated to 80-85°C for 7 hours. After cooling to 20°C, the aqueous phase was washed with a mixture of toluene (5.4 L, 3.0 rel.vol.) and acetonitrile (3.6 L, 2.0 rel.vol.), followed by an additional wash with toluene (5.4 L, 3.0 rel.vol.). The analysis of the aqueous phase containing compound (6) was determined (10.25 kg @ 5.9% w / w = 0.605 kg, 85.8% yield).

[0241] Step 4: To a solution of compound 6 (6.1 kg @ 5.9% w / w = 0.36 kg, 1.0 mol eq.), 25% aqueous NaOH was added (to approximately pH = 8-9). Toluene (1.8 L, 5.0 rel vol.) and a solution of compound 7 (4.4 kg @ 18.3% w / w = 0.805 kg, 1.2 mol eq.) in toluene were added at 10-15 °C (while 25% aqueous sodium hydroxide was charged to the reaction mixture to maintain a pH of 8-9). The mixture was stirred for 3 hours and extracted with a mixture of toluene (1.8 L, 5.0 rel vol.) and acetonitrile (1.44 L, 4.0 rel vol.), followed by separation and extraction of the aqueous phase with a mixture of toluene (1.8 L, 5.0 rel vol.) and acetonitrile (0.72 L, 2.0 rel vol.). The organic phases were combined and washed with brine (1.8 L, 5.0 rel.vol.) followed by water (1.8 L, 5.0 rel.vol.).

[0242] The organic phase was concentrated under vacuum at 40-45°C (to approximately 5.0 rel.vol.), and the mixture was heated to 60°C. After stirring for 15 minutes to obtain a solution, the mixture was cooled to 50°C. Methyl tert-butyl ether (1.6 L, 4.4 rel.vol.) was added dropwise to the mixture until a suspension was observed. The mixture was cooled to 5-10°C over 3 hours and stirred for 12 hours. After filtration and drying of the wet cake (at 45°C), the product (Compound (I), 920.0 g, 96.3%) (72% yield from 2,3-dipyrazine) was isolated. This compound exists as a mixture of stereoisomers in solution, and resonances are quoted only for the major stereoisomer. 1 H NMR (500 MHz, DMSO-d6) δ 1.75-1.85(m,2H),1.87-1.93(m,1H),2.12-2.21(m,1H),3.34-3.40(m,1H),3. 42-3.48(m,1H),4.29(dd,J=8.6,3.5Hz,1H),4.43(dd,J=16.2,5.4Hz,1H),4.49 (dd,J=16.2,5.4Hz,1H),4.98(d,J=13.0Hz,1H),5.04(d,J=13.0Hz,1H),7.24-7 .31(m,5H),8.39(d,J=2.4Hz,1H),8.49(t,J=5.4Hz,1H),8.53(d,J=2.4Hz,1H). 13 C NMR(126MHz,DMSO-d6)δ 23.0,31.2,41.4,47.1,59.5,65.7,126.9,127.5,128.1,137.0,142.6,142.7,147.1,151.5,153.8,172.3.

[0243] XV. SELECTED EMBODIMENTS Embodiment 1. A compound having the structure of Formula (VIII): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (VII): [ka] or a salt thereof, with 2-butynoic acid, or a salt thereof, in the presence of 1-propylphosphonic anhydride and a base in a reaction medium to form a reaction mixture comprising a compound of formula (VIII), or a salt thereof, and one or more reaction by-products; and Selective isolation of the compound of formula (VIII), or a salt thereof, from the reaction mixture relative to one or more reaction by-products.

[0244] Embodiment 2. The contacting step comprises: adding a compound of formula (VII), or a salt thereof, and a base to a reaction medium; adding 2-butynoic acid, or a salt thereof, to a reaction medium containing a compound of formula (VII), or a salt thereof, and a base; and 2. The process of embodiment 1, comprising adding 1-propylphosphonic anhydride to a reaction medium comprising a compound of formula (VII), or a salt thereof; 2-butynoic acid, or a salt thereof; and a base.

[0245] Embodiment 3. The process comprises: A compound having the structure of formula (VII): [ka] or a salt thereof, with 2-butynoic acid, or a salt thereof, in the presence of 1-propylphosphonic anhydride and a base in a reaction medium to form a reaction mixture comprising a compound of formula (VIII), or a salt thereof; an unreacted compound of formula (VII), or a salt thereof; and a reaction by-product, the reaction by-product being a compound having the structure of formula (XIV): [ka] or salts thereof); and 3. The process of embodiment 1 or 2, comprising selectively isolating the compound of formula (VIII), or a salt thereof, from the reaction mixture relative to the compound of formula (VII), or a salt thereof, and the compound of formula (XIV), or a salt thereof.

[0246] Embodiment 4. The process comprises: A compound having the structure of formula (VII): [ka] or a salt thereof, with 2-butynoic acid, or a salt thereof, in the presence of 1-propylphosphonic anhydride and a base in a reaction medium to form a reaction mixture comprising a compound of formula (VIII), or a salt thereof; an unreacted compound of formula (VII), or a salt thereof; and a reaction by-product, the reaction by-product being a compound having the structure of formula (XIV): [ka] or its salts); extracting at least a portion of the compound of formula (VIII), or a salt thereof, from the reaction mixture into an aqueous phase (the compound of formula (VIII), or a salt thereof, is selectively extracted into the aqueous phase relative to the compound of formula (XIV), or a salt thereof); adjusting the pH of the aqueous phase; and 3. The process of embodiment 1 or 2, comprising extracting at least a portion of the compound of formula (VIII), or a salt thereof, from the aqueous phase into an organic phase, wherein the compound of formula (VIII), or a salt thereof, is selectively extracted into the organic phase relative to the compound of formula (VII), or a salt thereof.

[0247] Embodiment 5. The process of embodiment 3 or 4, wherein the selectively isolated compound of formula (VIII), or salt thereof, comprises less than about 1.0% by weight of the compound of formula (VII), or salt thereof.

[0248] Embodiment 6. The process of embodiment 3 or 4, wherein the selectively isolated compound of formula (VIII), or salt thereof, comprises less than about 1.0% by weight of the compound of formula (XIV), or salt thereof.

[0249] Embodiment 7. The process of embodiment 3 or 4, wherein the selectively isolated compound of formula (VIII), or a salt thereof, comprises less than about 1.0% by weight of a compound of formula (VII), or a salt thereof, and less than about 1.0% by weight of a compound of formula (XIV), or a salt thereof.

[0250] Embodiment 8. The process of any of embodiments 4-7, wherein the reaction mixture is washed with water, the washed reaction mixture is separated into an aqueous phase and a waste phase, and the compound of formula (VIII) is selectively extracted into the aqueous phase.

[0251] Embodiment 9. The process of any of embodiments 4-8, wherein the process further comprises isolating the compound of formula (VIII) from the organic phase into which the compound of formula (VIII) has been selectively extracted.

[0252] Embodiment 10. The process of any of embodiments 4-9, wherein the aqueous phase comprises greater than about 75 area % of the compound of Formula (VIII) as measured by high performance liquid chromatography upon completion of the aqueous phase extraction.

[0253] Embodiment 11. The process of any of embodiments 4-9, wherein the aqueous phase comprises less than about 2.0 area % of the compound of Formula (XIV) as measured by high performance liquid chromatography upon completion of the aqueous phase extraction.

[0254] Embodiment 12. The process of any of embodiments 4-9, wherein the aqueous phase comprises greater than about 75 area % of the compound of Formula (VIII) and less than about 2.0 area % of the compound of Formula (XIV), as measured by high performance liquid chromatography upon completion of the aqueous phase extraction.

[0255] Embodiment 13. The process of any of embodiments 4-12, wherein the organic phase comprises at least about 75 area % of the compound of Formula (VIII) as measured by high performance liquid chromatography upon completion of the organic phase extraction.

[0256] Embodiment 14. The process of any of embodiments 4-12, wherein the organic phase comprises less than about 2.0 area % of the compound of Formula (VII) as measured by high performance liquid chromatography upon completion of the organic phase extraction.

[0257] Embodiment 15. The process of any of embodiments 4-12, wherein the organic phase comprises at least about 75 area % of the compound of Formula (VIII) and less than about 2.0 area % of the compound of Formula (VII), as measured by high performance liquid chromatography upon completion of the organic phase extraction.

[0258] Embodiment 16. The process of any of embodiments 4 to 15, wherein the aqueous phase has a pH of less than about 2.5 during the aqueous phase extraction step.

[0259] Embodiment 17. The process of any of embodiments 4 to 15, wherein the aqueous phase has a pH of about 1.8 to about 2.2 during the aqueous phase extraction step.

[0260] Embodiment 18. The process of any of embodiments 4-15, wherein the aqueous phase has a pH greater than about 4.0 during the organic phase extraction step.

[0261] Embodiment 19. The process of any of embodiments 4 to 15, wherein the aqueous phase has a pH of about 4.5 to about 5.0 during the organic phase extraction step.

[0262] Embodiment 20. The process of any of embodiments 4-19, wherein the reaction medium comprises at least one solvent selected from the group consisting of alkyl hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ketones, ethers, esters, nitriles, and polar aprotic solvents.

[0263] Embodiment 21. The process of any of embodiments 4-19, wherein the reaction medium comprises at least one solvent selected from the group consisting of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, tert-amyl alcohol, acetone, methyl iso-butyl ketone, 2-butanol, methyl ethyl ketone, acetonitrile, and ethyl acetate.

[0264] Embodiment 22. The process of any of embodiments 4 to 19, wherein the reaction medium comprises dichloromethane.

[0265] Embodiment 23. The process of any of embodiments 4-22, wherein the base comprises at least one compound selected from the group consisting of triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.

[0266] Embodiment 24 The process of any of embodiments 4 to 22, wherein the base comprises triethylamine.

[0267] Embodiment 25. The process of any of embodiments 4-24, wherein the organic phase comprises at least one solvent selected from alkyl hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ketones, ethers, esters, and nitriles.

[0268] Embodiment 26. The process of any of embodiments 4-24, wherein the organic phase comprises at least one compound selected from the group consisting of dichloromethane, methyltetrahydrofuran, and 2-methyltetrahydrofuran, tert-amyl alcohol, methyl iso-butyl ketone, 2-butanol, methyl ethyl ketone, ethyl acetate, isopropyl acetate, N-butyl acetate, butyronitrile, toluene, xylene, heptane, hexane, isohexane, and chloroform.

[0269] Embodiment 27. The process of any of embodiments 4 to 24, wherein the organic phase comprises dichloromethane.

[0270] Embodiment 28 The process of any of Embodiments 4 to 27, wherein the compound of Formula (VII) is contacted with about 0.5 to about 5.0 molar equivalents of 2-butynoic acid relative to the compound of Formula (VII).

[0271] Embodiment 29. The process of any of embodiments 4 to 27, wherein the compound of Formula (VII) is contacted with about 1.0 to about 1.3 molar equivalents of 2-butynoic acid relative to the compound of Formula (VII).

[0272] Embodiment 30. The process of any of embodiments 4 to 27, wherein the compound of Formula (VII) is contacted with about 1.2 molar equivalents of 2-butynoic acid relative to the compound of Formula (VII).

[0273] Embodiment 31. The process of any of embodiments 4 to 30, wherein about 0.3 to about 3.0 molar equivalents of 1-propylphosphonic anhydride relative to the compound of Formula (VII) is charged to the reaction medium.

[0274] Embodiment 32. The process of any of embodiments 4 to 30, wherein about 0.5 to about 2.0 molar equivalents of 1-propylphosphonic anhydride relative to the compound of Formula (VII) is charged to the reaction medium.

[0275] Embodiment 33. The process of any of embodiments 4 to 30, wherein about 0.7 to about 1.5 molar equivalents of 1-propylphosphonic anhydride relative to the compound of Formula (VII) is charged to the reaction medium.

[0276] Embodiment 34. The process of any of embodiments 4 to 30, wherein about 1.0 to about 1.2 molar equivalents of 1-propylphosphonic anhydride relative to the compound of Formula (VII) is charged to the reaction medium.

[0277] Embodiment 35. The process of any of embodiments 4 to 34, wherein about 1.0 to about 10.0 molar equivalents of base relative to the compound of Formula (VII) is charged to the reaction medium.

[0278] Embodiment 36. The process of any of embodiments 4 to 34, wherein about 2.0 to about 5.0 molar equivalents of base relative to the compound of Formula (VII) are charged to the reaction medium.

[0279] Embodiment 37. The process of any of embodiments 4 to 34, wherein about 2.4 to about 3.0 molar equivalents of base relative to the compound of Formula (VII) are charged to the reaction medium.

[0280] Embodiment 38. The process of any one of embodiments 4 to 37, wherein the reaction medium is maintained at a temperature of from about 10°C to about 30°C during the contacting step.

[0281] Embodiment 39. The process of any of embodiments 4 to 38, wherein the volume of the reaction medium is from about 5 liters to about 20 liters of reaction medium per kilogram of compound of Formula (VII) charged to the reaction medium.

[0282] Embodiment 40. The process of any of embodiments 4 to 39, wherein the contacting step is carried out as a batch reaction.

[0283] Embodiment 41 The process of embodiment 40, wherein at least about 25 kilograms of the compound of formula (VII) is charged to the batch reaction.

[0284] Embodiment 42 The process of embodiment 40, wherein at least about 50 kilograms of the compound of formula (VII) is charged to the batch reaction.

[0285] Embodiment 43 The process of embodiment 40, wherein at least about 75 kilograms of the compound of formula (VII) is charged to the batch reaction.

[0286] Embodiment 44 The process of embodiment 40, wherein at least about 100 kilograms of the compound of formula (VII) is charged to the batch reaction.

[0287] Embodiment 45. The process of any of embodiments 4 to 44, wherein the compound of Formula (VIII) is isolated from the organic phase by crystallization.

[0288] Embodiment 46. The process of any of embodiments 4-44, wherein the organic phase comprises an organic phase solvent, and the process further comprises exchanging the organic phase solvent with a displacement solvent to form a crystallization mixture comprising the compound of Formula (VIII).

[0289] Embodiment 47. The process of embodiment 46, wherein the process further comprises crystallizing the compound of formula (VIII) from the crystallization mixture.

[0290] Embodiment 48 The process of embodiment 47, wherein the crystallization mixture is seeded with a crystalline form of the compound of formula (VIII).

[0291] Embodiment 49. The process of embodiment 48, wherein the crystallization mixture is seeded with at least about 0.01 relative weight of crystalline form.

[0292] Embodiment 50. The process of embodiment 49, wherein the crystallization mixture is seeded with at least about 0.03 relative weight of crystalline form.

[0293] Embodiment 51. The process of any of embodiments 48-50, wherein the crystalline form is an anhydrous crystalline form.

[0294] Embodiment 52. The process of any of embodiments 46-51, wherein the organic phase solvent comprises a polar solvent.

[0295] Embodiment 53 The process of any of embodiments 46-51, wherein the organic phase solvent comprises at least one solvent selected from the group consisting of chlorinated hydrocarbons and ethers.

[0296] Embodiment 54. The process of any of Embodiments 46-51, wherein the organic phase solvent comprises at least one compound selected from the group consisting of dichloromethane and 2-methyltetrahydrofuran.

[0297] Embodiment 55. The process of any of embodiments 46-51, wherein the organic phase solvent comprises dichloromethane.

[0298] Embodiment 56 The process of any of embodiments 46-55, wherein the displacement solvent comprises an alcohol.

[0299] Embodiment 57. The process of any of embodiments 46-55, wherein the displacement solvent comprises ethanol.

[0300] Embodiment 58 The process of any of embodiments 46-51, wherein the organic phase solvent comprises a polar solvent and the displacement solvent comprises an alcohol.

[0301] Embodiment 59. The process of any of embodiments 46-51, wherein the organic phase solvent comprises dichloromethane and the displacement solvent comprises ethanol.

[0302] Embodiment 60. The process of any of embodiments 46-51, wherein the organic phase solvent has a boiling point lower than the boiling point of the displacement solvent.

[0303] Embodiment 61. The process of embodiment 60, wherein the boiling point of the organic phase solvent is at least about 20° C. lower than the boiling point of the displacement solvent.

[0304] Embodiment 62. The process of any of embodiments 46-61, wherein the organic phase solvent is exchanged with a replacement solvent by continuous levels of distillation.

[0305] Embodiment 63. The process of embodiment 62, wherein the continuous level of distillation is carried out under conditions sufficient to maintain the compound of formula (VIII) in solution during the continuous distillation.

[0306] Embodiment 64. The process of embodiment 62 or 63, wherein the continuous level distillation is a continuous level vacuum distillation.

[0307] Embodiment 65. The process of any of embodiments 62-64, wherein the displacement solvent is charged in an amount sufficient to maintain at least about 15 relative volumes of total solvent per kilogram of compound of Formula (VIII) during distillation.

[0308] Embodiment 66. The process of any of embodiments 62-64, wherein the displacement solvent is charged in an amount sufficient to maintain at least about 18 relative volumes of total solvent per kilogram of compound of Formula (VIII) during distillation.

[0309] Embodiment 67. The process of any of embodiments 62-66, wherein the continuous level vacuum distillation is carried out at a temperature not exceeding about 60°C.

[0310] Embodiment 68. The process of any of embodiments 46-67, wherein the crystallization mixture is seeded with a crystalline form of the compound of formula (VIII) and maintained at a temperature above about 40° C. for at least about 5 hours after seeding.

[0311] Embodiment 69. The process of any of embodiments 46-68, wherein the crystallization mixture is cooled to a temperature of about 20° C. over a period of at least 5 hours before isolating the compound of Formula (VIII).

[0312] Embodiment 70. The process of any of embodiments 1-69, wherein the stoichiometric process yield of the compound of Formula (VIII) is at least about 50%.

[0313] Embodiment 71. The process of any of embodiments 1-69, wherein the stoichiometric process yield of the compound of Formula (VIII) is at least about 60%.

[0314] Embodiment 72. A compound having the structure of Formula (VII): [ka] A crystalline form of 1. A crystalline form, wherein the crystalline form is characterized by a reflection X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 9.9±0.2 degrees 2θ, 11.1±0.2 degrees 2θ, 12.8±0.2 degrees 2θ, 14.1±0.2 degrees 2θ, and 19.0±0.2 degrees 2θ.

[0315] Embodiment 73. A compound having the structure of Formula (VII): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (V): [ka] or a salt thereof, with a compound having the structure of formula (VI): [ka] or a salt thereof in an aqueous reaction medium comprising an organic solvent in the presence of a base and a palladium catalyst to form a reaction mixture comprising a compound of formula (VII), or a salt thereof; reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising a compound of formula (VII), or a salt thereof; and isolating the compound of formula (VII), or a salt thereof, from the substantially anhydrous mixture.

[0316] Embodiment 74. The process of embodiment 73, wherein the isolating step comprises filtering the substantially anhydrous mixture.

[0317] Embodiment 75. The process of embodiment 73 or 74, wherein the aqueous reaction medium further comprises an alkali metal halide.

[0318] Embodiment 76 The process of embodiment 73 or 74, wherein the aqueous reaction medium further comprises an alkali metal iodide.

[0319] Embodiment 77 The process of embodiment 73 or 74, wherein the aqueous reaction medium further comprises potassium iodide.

[0320] Embodiment 78. The process of any of embodiments 73-77, wherein the organic solvent comprises at least one solvent selected from the group consisting of aromatic hydrocarbons, alcohols, ketones, ethers, esters, and nitriles.

[0321] Embodiment 79. The process of any of embodiments 73-77, wherein the organic solvent comprises at least one solvent selected from the group consisting of methanol, ethanol, propanol, butanol, pentanol, dioxane, toluene, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, ethyl acetate, isopropyl acetate, n-butyl acetate, and ethyl lactate.

[0322] Embodiment 80. The process of any of embodiments 73 to 77, wherein the organic solvent comprises 2-butanol.

[0323] Embodiment 81. The process of any of embodiments 73-80, wherein the base comprises at least one compound selected from the group consisting of triethylamine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, tripropylamine, tributylamine, diiso-propylethylamine, N-methylmorpholine, N-methylpyrrolidine, methyldicyclohexylamine, and potassium phosphate.

[0324] Embodiment 82. The process of any of embodiments 73 to 80, wherein the base comprises triethylamine.

[0325] Embodiment 83 The process of any of embodiments 73 to 80, wherein the base comprises potassium carbonate.

[0326] Embodiment 84. The process of any of embodiments 73 to 80, wherein the base comprises triethylamine and potassium carbonate.

[0327] Embodiment 85. The process of any of embodiments 73-84, wherein the palladium catalyst comprises bis(tert-butyldicyclohexylphosphine)dichloropalladium(II).

[0328] Embodiment 86 The process of any of embodiments 73-85, wherein the compound of Formula (VI) is contacted with about 0.5 to about 1.5 molar equivalents of the compound of Formula (V) relative to the compound of Formula (VI).

[0329] Embodiment 87. The process of any of embodiments 73-85, wherein the compound of Formula (VI) is contacted with about 0.8 to about 1.2 molar equivalents of the compound of Formula (V) relative to the compound of Formula (VI).

[0330] Embodiment 88 The process of any of embodiments 73-85, wherein the compound of Formula (VI) is contacted with about 0.9 to about 1.1 molar equivalents of the compound of Formula (V) relative to the compound of Formula (VI).

[0331] Embodiment 89. The process of any of Embodiments 77-88, wherein about 0.1 to about 1.0 molar equivalents of potassium iodide relative to the compound of Formula (VI) is charged to the aqueous reaction medium.

[0332] Embodiment 90. The process of any of Embodiments 77-88, wherein about 0.2 to about 0.4 molar equivalents of potassium iodide relative to the compound of Formula (VI) is charged to the aqueous reaction medium.

[0333] Embodiment 91. The process of any of embodiments 73-90, wherein about 0.5 to about 10 molar equivalents of base relative to the compound of Formula (VI) is charged to the aqueous reaction medium.

[0334] Embodiment 92. The process of any of embodiments 73-90, wherein the base comprises triethylamine, and about 0.5 to about 10 molar equivalents of triethylamine relative to the compound of Formula (VI) are charged to the aqueous reaction medium.

[0335] Embodiment 93. The process of any of embodiments 73-90, wherein the base comprises triethylamine, and about 1.0 to about 2.0 molar equivalents of triethylamine relative to the compound of Formula (VI) are charged to the aqueous reaction medium.

[0336] Embodiment 94. The process of any of embodiments 73-90, wherein the base comprises potassium carbonate, and about 0.5 to about 10.0 molar equivalents of potassium carbonate relative to the compound of Formula (VI) are charged to the aqueous reaction medium.

[0337] Embodiment 95. The process of any of embodiments 73-90, wherein the base comprises potassium carbonate, and about 2.0 to about 3.0 molar equivalents of potassium carbonate relative to the compound of Formula (VI) are charged to the aqueous reaction medium.

[0338] Embodiment 96. The process of any of embodiments 73-90, wherein the base comprises potassium carbonate, and about 2.3 to about 2.7 molar equivalents of potassium carbonate relative to the compound of Formula (VI) are charged to the aqueous reaction medium.

[0339] Embodiment 97. The process of any of Embodiments 73 to 96, wherein about 0.002 to about 0.05 molar equivalents of the palladium catalyst relative to the compound of Formula (VI) is charged to the aqueous reaction medium.

[0340] Embodiment 98. The process of any of embodiments 73 to 96, wherein about 0.007 to about 0.013 molar equivalents of the palladium catalyst relative to the compound of Formula (VI) is charged to the aqueous reaction medium.

[0341] Embodiment 99. The process of any of embodiments 73-98, wherein the aqueous reaction medium is maintained at a temperature of from about 50°C to about 100°C during the contacting step.

[0342] Embodiment 100. The process of any of embodiments 73-98, wherein the aqueous reaction medium is maintained at a temperature of from about 70°C to about 90°C during the contacting step.

[0343] Embodiment 101. The process of any of embodiments 73-100, wherein the volume of the aqueous reaction medium is from about 10 liters to about 20 liters of aqueous reaction medium per kilogram of compound of Formula (VI) charged to the aqueous reaction medium.

[0344] Embodiment 102. The process of any of embodiments 73 to 101, wherein the volume ratio of water to organic solvent for the aqueous reaction medium is from about 1:3 to about 3:1.

[0345] Embodiment 103. The process of any of embodiments 73 to 101, wherein the contacting step is carried out as a batch reaction.

[0346] Embodiment 104 The process of embodiment 103, wherein at least about 25 kilograms of the compound of formula (VI) is charged to the batch reaction.

[0347] Embodiment 105 The process of embodiment 103, wherein at least about 50 kilograms of the compound of formula (VI) is charged to the batch reaction.

[0348] Embodiment 106 The process of embodiment 103, wherein at least about 75 kilograms of the compound of formula (VI) is charged to the batch reaction.

[0349] Embodiment 107 The process of embodiment 103, wherein at least about 100 kilograms of the compound of formula (VI) is charged to the batch reaction.

[0350] Embodiment 108. The process of any of embodiments 73 to 107, wherein the reducing step comprises separating the reaction mixture into an aqueous waste phase and an organic phase comprising the compound of formula (VII).

[0351] Embodiment 109. The process of embodiment 108, wherein the reducing step further comprises distilling the organic phase under conditions sufficient to reduce the amount of water present in the organic phase, resulting in a substantially anhydrous mixture.

[0352] Embodiment 110. The process of embodiment 109, wherein the process further comprises washing the organic phase with water before distillation.

[0353] Embodiment 111. The process of any of embodiments 109 or 110, wherein the organic phase is treated with a silica scavenger prior to distillation.

[0354] Embodiment 112. The process of any of embodiments 109-111, wherein the organic phase is treated with a silica scavenger prior to distillation for at least 2 hours.

[0355] Embodiment 113. The process of embodiment 111 or 112, wherein the silica scavenger comprises propanethiol-functionalized silica.

[0356] Embodiment 114. The process of embodiment 111 or 112, wherein the silica scavenger comprises QuadraSil™ MP.

[0357] Embodiment 115. The process of any of embodiments 111-114, wherein the process further comprises removing the silica scavenger from the organic phase prior to distillation.

[0358] Embodiment 116. The process of any of embodiments 111-114, wherein the process further comprises removing the silica scavenger from the organic phase by filtration prior to distillation.

[0359] Embodiment 117. The process of embodiment 115 or 116, wherein the process further comprises washing the organic phase with an aqueous salt solution after removing the catalyst and before distillation.

[0360] Embodiment 118. The reducing step comprises: separating the reaction mixture into an aqueous waste phase and an organic phase comprising the compound of formula (VII); washing the organic phase with water; treating the organic phase with a silica scavenger; removing the silica scavenger from the organic phase; washing the organic phase with an aqueous brine solution; and 118. The process of any of embodiments 109-117, comprising distilling the organic phase under conditions sufficient to reduce the amount of water present in the organic phase.

[0361] Embodiment 119. The process of any of embodiments 109-118, wherein the organic phase is distilled by vacuum distillation.

[0362] Embodiment 120. The process of any of embodiments 109-118, wherein the organic phase is distilled by continuous level vacuum distillation.

[0363] Embodiment 121. The process of any of embodiments 109-120, wherein the organic phase is distilled at a temperature not exceeding about 60°C.

[0364] Embodiment 122. The process of any of embodiments 109-120, wherein the organic phase is distilled at a temperature of about 50°C to about 60°C.

[0365] Embodiment 123. The process of any of embodiments 109 to 122, wherein the organic phase comprises an alcohol.

[0366] Embodiment 124. The process of embodiment 123, wherein the organic phase is replenished with alcohol during the distillation step.

[0367] Embodiment 125. The process of any of embodiments 109 to 122, wherein the organic phase comprises 2-butanol.

[0368] Embodiment 126. The process of embodiment 125, wherein the organic phase is replenished with 2-butanol during the distillation step.

[0369] Embodiment 127. The process of any of embodiments 73-126, wherein the substantially anhydrous mixture comprises less than about 5% water by weight.

[0370] Embodiment 128. The process of any of embodiments 73-126, wherein the substantially anhydrous mixture contains less than about 3% water by weight.

[0371] Embodiment 129. The process of any of embodiments 73-128, wherein the isolating step comprises crystallizing the compound of Formula (VII) from the substantially anhydrous mixture.

[0372] Embodiment 130. The process of embodiment 129, wherein the substantially anhydrous mixture is seeded with a crystalline form of the compound of formula (VII).

[0373] Embodiment 131. The process of embodiment 129 or 130, wherein the substantially anhydrous mixture is maintained at a temperature of at least about 70° C. for at least 2 hours after initiating crystallization.

[0374] Embodiment 132. The process of embodiment 129 or 130, wherein the substantially anhydrous mixture is maintained at a temperature of at least about 70° C. for at least 2 hours after initiating crystallization, and then cooled to crystallize the compound of formula (VII).

[0375] Embodiment 133. The process of any of embodiments 73-132, wherein the stoichiometric process yield of the compound of formula (VII) is at least about 50%.

[0376] Embodiment 134. The process of any of embodiments 73-132, wherein the stoichiometric process yield of the compound of formula (VII) is at least about 65%.

[0377] Embodiment 135. The process of any of embodiments 73-132, wherein the stoichiometric process yield of the compound of formula (VII) is at least about 75%.

[0378] Embodiment 136. A compound having the structure of Formula (VI): [ka] or a salt thereof, the process comprising: Compounds of formula (IV): [ka] or a salt thereof, with an acidic medium under conditions sufficient to deprotect the compound of formula (IV) and form a reaction mixture comprising a compound of formula (VI), or a salt thereof, and a benzyl halide by-product; removing at least a portion of the benzyl halide by-product from the reaction mixture; and isolating the compound of formula (VI), or a salt thereof, from the reaction mixture under conditions sufficient to substantially avoid the formation of an aminal impurity.

[0379] Embodiment 137. The isolation step comprises: removing at least a portion of the benzyl halide by-product from the reaction mixture; raising the pH of the resulting reaction mixture to a basic pH to form a basic reaction medium containing a compound of formula (VI), or a salt thereof; and 137. The process of embodiment 136, comprising isolating the compound of formula (VI), or a salt thereof, from the basic reaction mixture.

[0380] Embodiment 138. The isolation step comprises: extracting at least a portion of the benzyl halide by-product from the reaction mixture into a discarded organic phase; raising the pH of the resulting reaction mixture to a basic pH to form a basic reaction medium comprising a compound of formula (VI), or a salt thereof; Extracting the compound of formula (VI), or a salt thereof, from the basic reaction medium into a product organic phase; and 137. The process of embodiment 136, comprising isolating the compound of formula (VI), or a salt thereof, from the product organic phase.

[0381] Embodiment 139. The process of any of embodiments 136 to 138, wherein the acidic medium is an aqueous acidic medium.

[0382] Embodiment 140. The process of any of embodiments 136-139, wherein the sulfate salt of the compound of Formula (IV) is contacted with an acidic medium.

[0383] Embodiment 141. The process of any of embodiments 136 to 140, wherein the acidic medium comprises a mineral acid.

[0384] Embodiment 142. The process of any of embodiments 136 to 140, wherein the acidic medium comprises hydrochloric acid.

[0385] Embodiment 143. The process of any of embodiments 136-142, wherein the acidic medium comprises at least about 10 molar equivalents of acid relative to the compound of formula (IV), or salt thereof.

[0386] Embodiment 144. The process of any of embodiments 136-142, wherein the acidic medium comprises about 10 to about 40 molar equivalents of acid relative to the compound of formula (IV), or salt thereof.

[0387] Embodiment 145. The process of any of embodiments 136-142, wherein the acidic medium comprises about 10 to about 25 molar equivalents of acid relative to the compound of formula (IV), or salt thereof.

[0388] Embodiment 146. The process of any of embodiments 136-145, wherein the volume of the acidic medium is from about 2 liters to about 10 liters of acidic medium per kilogram of the compound of formula (IV), or a salt thereof, charged to the acidic medium.

[0389] Embodiment 147. The process of any of embodiments 136-145, wherein the volume of the acidic medium is from about 3 liters to about 4 liters of acidic medium per kilogram of the compound of formula (IV), or a salt thereof, charged to the acidic medium.

[0390] Embodiment 148. The process of any of embodiments 136-147, wherein the acidic medium is maintained at a temperature of from about 25°C to about 70°C during the contacting step.

[0391] Embodiment 149. The process of any of embodiments 136-147, wherein the acidic medium is maintained at a temperature of about 40°C to about 50°C during the contacting step.

[0392] Embodiment 150. The process of any of embodiments 136 to 149, wherein the contacting step is carried out as a batch reaction.

[0393] Embodiment 151 The process of embodiment 150, wherein at least about 50 kilograms of the compound of formula (IV) is charged to the batch reaction.

[0394] Embodiment 152 The process of embodiment 150, wherein at least about 100 kilograms of the compound of formula (IV) is charged to the batch reaction.

[0395] Embodiment 153 The process of embodiment 150, wherein at least about 200 kilograms of the compound of formula (IV) is charged to the batch reaction.

[0396] Embodiment 154. The process of embodiment 150, wherein at least about 300 kilograms of the compound of formula (IV) is charged to the batch reaction.

[0397] Embodiment 155. The process of any of embodiments 136-154, wherein the process comprises selectively extracting at least a portion of the benzyl halide by-product from the reaction mixture to a waste organic phase relative to the compound of Formula (VI) prior to the isolation step.

[0398] Embodiment 156. The process of embodiment 155, wherein at least about 80% by weight of the benzyl halide by-product compounds present in the reaction mixture are extracted into a discarded organic phase.

[0399] Embodiment 157. The process of embodiment 155, wherein less than about 20% by weight of the compound of formula (VI) present in the reaction mixture is extracted into a discarded organic phase.

[0400] Embodiment 158. The process of embodiment 155, wherein at least about 80% by weight of the benzyl halide by-product compounds present in the reaction mixture and less than about 20% by weight of the compound of formula (VI) present in the reaction mixture is extracted into a discarded organic phase.

[0401] Embodiment 159. The process of embodiment 155, wherein at least about 90% by weight of the benzyl halide by-product compounds present in the reaction mixture and less than about 10% by weight of the compound of formula (VI) present in the reaction mixture is extracted into a discarded organic phase.

[0402] Embodiment 160. The process of embodiment 155, wherein at least about 95% by weight of the benzyl halide by-product compounds present in the reaction mixture and less than about 5% by weight of the compound of formula (VI) present in the reaction mixture is extracted into a discarded organic phase.

[0403] Embodiment 161. The process of any of embodiments 155-160, wherein the discarded organic phase comprises at least one solvent selected from the group consisting of alkyl hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons, and ethers.

[0404] Embodiment 162. The process of any of embodiments 155-160, wherein the discarded organic phase comprises at least one compound selected from the group consisting of pentane, hexane, heptane, octane, nonane, toluene, dichloromethane, methyl tert-butyl ether, and 2-methyltetrahydrofuran.

[0405] Embodiment 163. The process of any of embodiments 155 to 160, wherein the discarded organic phase comprises heptane.

[0406] Embodiment 164. The process further comprises: increasing the pH of the reaction mixture after benzyl halide by-product extraction to form a basic reaction medium containing a compound of formula (VI), or a salt thereof; and The process of any of embodiments 155 to 163, comprising extracting the compound of formula (VI), or a salt thereof, from the basic reaction medium into a product organic phase.

[0407] Embodiment 165. The process of embodiment 164, wherein the pH of the basic reaction mixture is at least about 8.0.

[0408] Embodiment 166. The process of embodiment 164, wherein the pH of the basic reaction mixture is at least about 10.0.

[0409] Embodiment 167. The process of any of embodiments 164-166, wherein the product organic phase comprises at least one solvent selected from the group consisting of alkyl hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons, and ethers.

[0410] Embodiment 168. The process of any of embodiments 164-166, wherein the product organic phase comprises at least one compound selected from the group consisting of dichloromethane, 2-methyltetrahydrofuran, and anisole.

[0411] Embodiment 169. The process of any of embodiments 164 to 166, wherein the product organic phase comprises 2-methyltetrahydrofuran.

[0412] Embodiment 170. The process of any of embodiments 164 to 169, wherein the process further comprises washing the product organic phase with water.

[0413] Embodiment 171. The process of any of embodiments 164-170, wherein the process further comprises distilling the product organic phase under conditions sufficient to reduce the amount of water present in the product organic phase.

[0414] Embodiment 172. The process of embodiment 171, wherein the product organic phase comprises 2-methyltetrahydrofuran, and additional 2-methyltetrahydrofuran is charged to the product organic phase during the distillation step.

[0415] Embodiment 173. The process of embodiment 171 or 172, wherein the product organic phase is distilled under atmospheric pressure.

[0416] Embodiment 174. The process of any of embodiments 136 to 173, wherein the isolating step comprises crystallizing the compound of formula (VI).

[0417] Embodiment 175. The process of embodiment 174, wherein the isolating step further comprises seeding with a crystalline form of the compound of formula (VI) to promote crystallization.

[0418] Embodiment 176. The process of embodiment 174, wherein the isolating step comprises seeding with at least about 0.0005 relative weight of the crystalline form of the compound of formula (VI) to promote crystallization.

[0419] Embodiment 177. The process of embodiment 174, wherein the isolating step comprises seeding with at least about 0.001 relative weight of a crystalline form of the compound of formula (VI) to promote crystallization.

[0420] Embodiment 178. The process of any of embodiments 175-177, wherein the process further comprises charging an anti-solvent to promote crystallization.

[0421] Embodiment 179. The process of embodiment 178, wherein the anti-solvent is heptane.

[0422] Embodiment 180. The isolation step comprises: selectively extracting at least a portion of the benzyl halide by-product from the reaction mixture into an organic phase that is discarded relative to the compound of formula (VI); raising the pH of the resulting reaction mixture to a pH greater than about 7.0 to form a basic reaction mixture; Selectively extracting at least a portion of the compound of formula (VI) from the basic reaction mixture into a product organic phase; and 137. The process of embodiment 136, comprising distilling the product organic phase under conditions sufficient to reduce the amount of water present in the product organic phase to form a distilled organic phase comprising the compound of formula (VI).

[0423] Embodiment 181. The process of embodiment 180, wherein the process further comprises crystallizing the compound of formula (VI) from the distilled organic phase.

[0424] Embodiment 182. A compound wherein the aminal impurity has the structure of formula (X): [ka] 182. The process of any of embodiments 136-181, comprising:

[0425] Embodiment 183. The process of any of embodiments 136-182, wherein the isolated compound of Formula (VI), or a salt thereof, contains less than 5% by weight of an aminal impurity.

[0426] Embodiment 184. The process of any of embodiments 136-182, wherein the isolated compound of Formula (VI), or a salt thereof, contains less than 3% by weight of an aminal impurity.

[0427] Embodiment 185. The process of any of embodiments 136-182, wherein the isolated compound of Formula (VI), or a salt thereof, contains less than 1% by weight of an aminal impurity.

[0428] Embodiment 186. The process of any of embodiments 136-185, wherein the stoichiometric process yield of the compound of formula (VI) is at least about 50%.

[0429] Embodiment 187. The process of any of embodiments 136-185, wherein the stoichiometric process yield of the compound of formula (VI) is at least about 65%.

[0430] Embodiment 188. The process of any of embodiments 136-185, wherein the stoichiometric process yield of the compound of formula (VI) is at least about 80%.

[0431] Embodiment 189. A compound having the structure of Formula (V): [ka] or a salt thereof, the process comprising contacting 4-carboxyphenylboronic acid, or a salt thereof, with thionyl chloride and a catalyst in a reaction medium comprising an organic solvent to form an acyl chloride intermediate, followed by in situ contact with 2-aminopyridine to form a reaction mixture comprising a compound of formula (V), or a salt thereof.

[0432] Embodiment 190. The process of embodiment 189, wherein the process further comprises isolating the compound of formula (V), or a salt thereof, from the reaction mixture.

[0433] Embodiment 191. The process of embodiment 189 or 190, wherein the catalyst comprises tetrabutylammonium chloride.

[0434] Embodiment 192. The process of embodiment 189 or 190, wherein the catalyst comprises N-methylformanilide.

[0435] Embodiment 193. The process of embodiment 189 or 190, wherein the catalyst does not comprise N,N-dimethylformamide.

[0436] Embodiment 194. The process of any of embodiments 189 to 193, wherein the reaction medium does not comprise N,N-dimethylformamide.

[0437] Embodiment 195. The process of any of embodiments 189-194, wherein the organic solvent comprises at least one solvent selected from the group consisting of aromatic hydrocarbons, aromatic heterocycles, and nitriles.

[0438] Embodiment 196. The process of any of embodiments 189-194, wherein the organic solvent comprises a compound selected from the group consisting of toluene, acetonitrile, and pyridine.

[0439] Embodiment 197. The process of any of embodiments 189 to 194, wherein the organic solvent comprises toluene.

[0440] Embodiment 198. The process of any of embodiments 189-197, wherein the volume of the reaction medium is from about 3 liters to about 30 liters of reaction medium per kilogram of 4-carboxyphenyl-boronic acid, or a salt thereof, charged to the reaction medium.

[0441] Embodiment 199. The process of any of embodiments 189-197, wherein the volume of the reaction medium is from about 5 liters to about 15 liters of reaction medium per kilogram of 4-carboxyphenyl-boronic acid, or a salt thereof, charged to the reaction medium.

[0442] Embodiment 200. The process of any of embodiments 189-199, wherein the reaction medium is maintained at a temperature of from about 50°C to about 90°C during the contacting step.

[0443] Embodiment 201. The process of any of embodiments 189-199, wherein the reaction medium is maintained at a temperature of from about 60°C to about 80°C during the contacting step.

[0444] Embodiment 202. The process of any of embodiments 189-201, wherein the contacting step is carried out as a batch reaction.

[0445] Embodiment 203. The process of any of Embodiments 189-202 wherein the 4-carboxyphenylboronic acid, or salt thereof, is contacted with about 2 to about 5 molar equivalents of thionyl chloride relative to the 4-carboxyphenylboronic acid, or salt thereof.

[0446] Embodiment 204. The process of any of Embodiments 189-202 wherein the 4-carboxyphenylboronic acid, or salt thereof, is contacted with about 2 to about 3.5 molar equivalents of thionyl chloride relative to the 4-carboxyphenylboronic acid, or salt thereof.

[0447] Embodiment 205. The process of any of Embodiments 189-202 wherein the 4-carboxyphenylboronic acid, or salt thereof, is contacted with about 2.75 molar equivalents of thionyl chloride relative to the 4-carboxyphenylboronic acid, or salt thereof.

[0448] Embodiment 206. The process of any of Embodiments 189 to 205, wherein about 1.5 to 5 molar equivalents of 2-aminopyridine relative to the 4-carboxyphenylboronic acid, or salt thereof, is charged to the reaction medium.

[0449] Embodiment 207. The process of any of Embodiments 189 to 205, wherein about 1.5 to 3.5 molar equivalents of 2-aminopyridine relative to the 4-carboxyphenylboronic acid, or salt thereof, is charged to the reaction medium.

[0450] Embodiment 208. The process of any of Embodiments 189-205, wherein about 2 molar equivalents of 2-aminopyridine relative to the 4-carboxyphenylboronic acid, or salt thereof, is charged to the reaction medium.

[0451] Embodiment 209. The process of any of embodiments 189-208, wherein the stoichiometric process yield of the compound of Formula (V) is at least about 50%.

[0452] Embodiment 210. The process of any of embodiments 189-208, wherein the stoichiometric process yield of the compound of Formula (V) is at least about 70%.

[0453] Embodiment 211. A compound having the structure of formula (IV): [ka] Crystalline sulfate of.

[0454] Embodiment 212. The crystalline sulfate salt of embodiment 211, wherein the crystalline sulfate salt has a stoichiometric ratio of one sulfate molecule and one hydrogen sulfate molecule to three free base molecules.

[0455] Embodiment 213. The crystalline sulfate salt of embodiment 211 or 212, wherein the crystalline sulfate salt is characterized by a reflection X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 7.7±0.2°2θ, 10.6±0.2°2θ, 11.1±0.2°2θ, 12.6±0.2°2θ, and 13.5±0.2°2θ.

[0456] Embodiment 214. A compound having the structure of formula (IV): [ka] 1. A process for preparing a sulfate salt of A compound having the structure of formula (III): [ka] or a salt thereof, with an aminating agent in a reaction medium to form a reaction mixture comprising a compound of formula (IV); forming a sulfate salt of a compound of formula (IV); and isolating the sulfate salt.

[0457] Embodiment 215. The process of embodiment 214, wherein the sulfate salt has a stoichiometric ratio of one sulfate molecule and one hydrogen sulfate molecule to three free base molecules.

[0458] Embodiment 216. The process of embodiment 214 or 215, wherein the process comprises isolating the compound of formula (IV) as a free base from the reaction mixture prior to the forming step.

[0459] Embodiment 217. The process comprises: isolating the compound of formula (IV) as a free base from the reaction medium; contacting the free base with sulfuric acid to form the sulfate salt; and 216. The process of embodiment 214 or 215, comprising isolating the sulfate salt.

[0460] Embodiment 218. The process comprises: washing the reaction mixture to reduce the amount of ammonia present in the reaction mixture; isolating the compound of formula (IV) from the washed reaction medium as the free base; contacting the free base with sulfuric acid to form the sulfate salt; and 216. The process of embodiment 214 or 215, comprising isolating the sulfate salt.

[0461] Embodiment 219. The process comprises: washing the reaction mixture with a brine solution; distilling the washed reaction mixture to reduce the amount of ammonia present in the washed reaction mixture; isolating the compound of formula (IV) from the reaction medium distilled as a free base; contacting the free base with sulfuric acid to form the sulfate salt; and 216. The process of embodiment 214 or 215, comprising isolating the sulfate salt.

[0462] Embodiment 220. The process of any of embodiments 214-219, wherein the process further comprises isolating the sulfate salt by filtration.

[0463] Embodiment 221. The process of any of embodiments 214 to 220, wherein the aminating agent is ammonia.

[0464] Embodiment 222. The process of any of embodiments 214 to 220, wherein the aminating agent is ammonium hydroxide.

[0465] Embodiment 223. The process of any of embodiments 214-221, wherein the reaction medium comprises at least one solvent selected from the group consisting of alkyl hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons, aromatic heterocycles, alcohols, ethers, and dipolar aprotic solvents.

[0466] Embodiment 224. The process of any of embodiments 214-221, wherein the reaction medium comprises at least one compound selected from the group consisting of methanol, ethanol, propanol, butanol, pentanol, N-methylpyrrolidinone, and N,N-dimethylformamide.

[0467] Embodiment 225. The process of any of embodiments 214-221, wherein the reaction medium comprises an aliphatic alcohol.

[0468] Embodiment 226. The process of any of embodiments 214 to 221, wherein the reaction medium comprises butanol.

[0469] Embodiment 227. The process of any of embodiments 214 to 221, wherein the reaction medium comprises 2-butanol.

[0470] Embodiment 228. The process of any of embodiments 214 to 227, wherein the reaction medium is maintained at a temperature greater than 70°C during the contacting step.

[0471] Embodiment 229. The process of any of embodiments 214 to 227, wherein the reaction medium is maintained at a temperature greater than 90°C during the contacting step.

[0472] Embodiment 230. The process of any of Embodiments 214-227, wherein the reaction medium is maintained at a temperature of from about 50°C to about 100°C during the contacting step.

[0473] Embodiment 231. The process of any of embodiments 214-227, wherein the reaction medium is maintained at a temperature of from about 60°C to about 95°C during the contacting step.

[0474] Embodiment 232. The process of any of Embodiments 214-231, wherein the volume of the reaction medium is from about 1.5 liters to about 40 liters of reaction medium per kilogram of the compound of Formula (III), or a salt thereof, charged to the reaction medium.

[0475] Embodiment 233. The process of any of Embodiments 214 to 231, wherein the volume of the reaction medium is from about 2.0 liters to about 30 liters of reaction medium per kilogram of the compound of Formula (III), or a salt thereof, charged to the reaction medium.

[0476] Embodiment 234. The process of any of embodiments 214 to 233, wherein the contacting step is carried out as a batch reaction.

[0477] Embodiment 235. The process of embodiment 234, wherein at least about 50 kilograms of the compound of formula (III) is charged to the batch reaction.

[0478] Embodiment 236 The process of embodiment 234, wherein at least about 100 kilograms of the compound of formula (III) is charged to the batch reaction.

[0479] Embodiment 237 The process of embodiment 234, wherein at least about 200 kilograms of the compound of formula (III) is charged to the batch reaction.

[0480] Embodiment 238 The process of embodiment 234, wherein at least about 300 kilograms of the compound of formula (III) is charged to the batch reaction.

[0481] Embodiment 239. The process of any of embodiments 214-238, wherein the forming step comprises contacting a compound of formula (IV) with sulfuric acid to form a sulfate salt mixture comprising sulfate salt.

[0482] Embodiment 240. The process of embodiment 239, wherein the compound of formula (IV) is contacted with at least about 0.5 molar equivalents of sulfuric acid relative to the compound of formula (III).

[0483] Embodiment 241. The process of embodiment 239, wherein the compound of formula (IV) is contacted with about 1.25 to about 1.75 molar equivalents of sulfuric acid relative to the compound of formula (III).

[0484] Embodiment 242. The process of any of embodiments 214-241, wherein the stoichiometric process yield of the sulfate salt of Formula (IV) is at least about 50%.

[0485] Embodiment 243. The process of any of Embodiments 214-241, wherein the stoichiometric process yield of the sulfate salt of Formula (IV) is at least about 65%.

[0486] Embodiment 244. The process of any of Embodiments 214-241, wherein the stoichiometric process yield of the sulfate salt of Formula (IV) is at least about 80%.

[0487] Embodiment 245. A compound having the structure of Formula (II): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (I): [ka] or a salt thereof, with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound of formula (II), or a salt thereof; A process wherein the temperature of the reaction medium is controlled during the contacting step in a manner sufficient to maintain at least about 80% chiral purity with respect to the compound of formula (II), or a salt thereof.

[0488] Embodiment 246. The process of embodiment 245, wherein the cyclizing agent comprises phosphorus oxychloride.

[0489] Embodiment 247. The process of embodiment 245 or 246, wherein the catalyst comprises a catalyst selected from the group consisting of N,N-dimethylformamide and N-methylformanilide.

[0490] Embodiment 248. The process of embodiment 245 or 246, wherein the catalyst comprises N,N-dimethylformamide.

[0491] Embodiment 249. The process of any of embodiments 245-248, wherein the reaction medium comprises at least one solvent selected from the group consisting of aromatic hydrocarbons, chlorinated hydrocarbons, ethers, and nitriles.

[0492] Embodiment 250. The process of any of Embodiments 245-248, wherein the reaction medium comprises at least one compound selected from the group consisting of acetonitrile, butyronitrile, dichloromethane, toluene, anisole, tetrahydrofuran, and 2-methyltetrahydrofuran.

[0493] Embodiment 251. The process of any of embodiments 245 to 248, wherein the reaction medium comprises acetonitrile.

[0494] Embodiment 252. The process of any of Embodiments 245-251, wherein the compound of Formula (I), or a salt thereof, is contacted with about 0.7 to about 10 molar equivalents of a cyclizing agent relative to the compound of Formula (I), or a salt thereof.

[0495] Embodiment 253. The process of any of Embodiments 245-251, wherein the compound of Formula (I), or a salt thereof, is contacted with about 1.5 to about 2.5 molar equivalents of a cyclizing agent relative to the compound of Formula (I), or a salt thereof.

[0496] Embodiment 254. The process of any of Embodiments 245-251, wherein the compound of Formula (I), or a salt thereof, is contacted with about 2.0 molar equivalents of a cyclizing agent relative to the compound of Formula (I), or a salt thereof.

[0497] Embodiment 255. The process of any of Embodiments 245-254, wherein at least about 0.1 molar equivalents of catalyst relative to the compound of Formula (I), or salt thereof, is charged to the reaction medium.

[0498] Embodiment 256. The process of any of Embodiments 245 to 254, wherein about 0.1 to about 1.0 molar equivalents of catalyst relative to the compound of Formula (I), or salt thereof, is charged to the reaction medium.

[0499] Embodiment 257. The process of any of Embodiments 245-254, wherein at least about 0.4 molar equivalents of catalyst relative to the compound of Formula (I), or salt thereof, is charged to the reaction medium.

[0500] Embodiment 258. The process of any of Embodiments 245 to 254, wherein about 0.4 to about 1.0 molar equivalents of catalyst relative to the compound of Formula (I), or salt thereof, is charged to the reaction medium.

[0501] Embodiment 259. The process of any of embodiments 245 to 254, wherein the catalyst comprises N,N-dimethylformamide, and at least about 0.1 molar equivalents of catalyst relative to the compound of Formula (I), or salt thereof, is charged to the reaction medium.

[0502] Embodiment 260. The process of any of embodiments 245 to 254, wherein the catalyst comprises N,N-dimethylformamide, and about 0.1 to about 1.0 molar equivalents of catalyst relative to the compound of Formula (I), or salt thereof, is charged to the reaction medium.

[0503] Embodiment 261. The process of any of embodiments 245 to 254, wherein the catalyst comprises N,N-dimethylformamide, and at least about 0.4 molar equivalents of catalyst relative to the compound of Formula (I), or salt thereof, are charged to the reaction medium.

[0504] Embodiment 262. The process of any of embodiments 245 to 254, wherein the catalyst comprises N,N-dimethylformamide, and about 0.4 to about 1.0 molar equivalents of catalyst relative to the compound of Formula (I), or a salt thereof, is charged to the reaction medium.

[0505] Embodiment 263. The process of any of embodiments 245 to 254, wherein the catalyst comprises N,N-dimethylformamide, and at least about 0.6 molar equivalents of catalyst relative to the compound of Formula (I), or salt thereof, are charged to the reaction medium.

[0506] Embodiment 264. The process of any of embodiments 245 to 254, wherein the catalyst comprises N,N-dimethylformamide, and about 0.6 molar equivalents of catalyst relative to the compound of Formula (I), or a salt thereof, is charged to the reaction medium.

[0507] Embodiment 265. The process of any of Embodiments 245-264, wherein the temperature of the reaction medium is controlled during the contacting step in a manner sufficient to maintain at least about 90% chiral purity with respect to the compound of Formula (II), or a salt thereof.

[0508] Embodiment 266. The process of any of Embodiments 245-264, wherein the temperature of the reaction medium is controlled during the contacting step in a manner sufficient to maintain at least about 95% chiral purity with respect to the compound of Formula (II), or a salt thereof.

[0509] Embodiment 267. The process of any of embodiments 245-266, wherein the reaction medium is maintained at a temperature of less than about 80° C. during the contacting step.

[0510] Embodiment 268. The process of any of embodiments 245-266, wherein the reaction medium is maintained at a temperature of less than about 50° C. during the contacting step.

[0511] Embodiment 269. The process of any of embodiments 245-266, wherein the reaction medium is maintained at a temperature of from about 30°C to about 50°C during the contacting step.

[0512] Embodiment 270. The process of any of embodiments 245 to 269, wherein the reaction medium is maintained at a temperature of about 40° C. during the contacting step.

[0513] Embodiment 271. The process of any of Embodiments 245-270, wherein the volume of the reaction medium is from about 2 liters to about 20 liters of reaction medium per kilogram of the compound of Formula (I), or a salt thereof, charged to the reaction medium.

[0514] Embodiment 272. The process of any of Embodiments 245-270, wherein the volume of the reaction medium is from about 3 liters to about 10 liters of reaction medium per kilogram of the compound of Formula (I), or a salt thereof, charged to the reaction medium.

[0515] Embodiment 273. The process of any of embodiments 245 to 272, wherein the contacting step is carried out as a batch reaction.

[0516] Embodiment 274 The process of embodiment 273, wherein at least about 50 kilograms of a compound of formula (I) is charged to the batch reaction.

[0517] Embodiment 275. The process of embodiment 273, wherein at least about 100 kilograms of a compound of formula (I) is charged to the batch reaction.

[0518] Embodiment 276 The process of embodiment 273, wherein at least about 200 kilograms of a compound of formula (I) is charged to the batch reaction.

[0519] Embodiment 277 The process of embodiment 273, wherein at least about 300 kilograms of a compound of formula (I) is charged to the batch reaction.

[0520] Embodiment 278. The process of any of embodiments 245-277, wherein the stoichiometric process yield of the compound of Formula (II) is at least about 50%.

[0521] Embodiment 279. The process of any of embodiments 245-277, wherein the stoichiometric process yield of the compound of Formula (II) is at least about 65%.

[0522] Embodiment 280. The process of any of Embodiments 245-277, wherein the stoichiometric process yield of the compound of Formula (II) is at least about 80%.

[0523] Embodiment 281. A compound having the structure of Formula (III): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (I): [ka] or a salt thereof is contacted with a cyclizing agent in the presence of a catalyst in a reaction medium to produce a compound of formula (II): [ka] or forming a salt thereof; and The compound of formula (II) or a salt thereof is brominated with a brominating agent to obtain a compound having the structure of formula (III): [ka] or a salt thereof; A process wherein the temperature of the reaction medium is controlled during the contacting step in a manner sufficient to maintain at least about 80% chiral purity with respect to the compound of formula (II), or a salt thereof.

[0524] Embodiment 282. The process of embodiment 281, wherein the brominating agent comprises N-bromosuccinimide.

[0525] Embodiment 283. The process of Embodiment 281 or 282, wherein the compound of Formula (II), or a salt thereof, is contacted with about 0.8 to about 1.2 molar equivalents of the brominating agent relative to the compound of Formula (I), or a salt thereof.

[0526] Embodiment 284. The process of any of Embodiments 281 to 283, wherein the compound of Formula (II), or a salt thereof, is isolated from the reaction medium prior to the bromination step.

[0527] Embodiment 285. The process of embodiment 284, wherein the compound of formula (II), or a salt thereof, is contacted with a brominating agent in a bromination medium comprising at least one solvent selected from the group consisting of chlorinated hydrocarbons and polar aprotic solvents.

[0528] Embodiment 286. The process of embodiment 284, wherein the compound of formula (II), or a salt thereof, is contacted with a brominating agent in a bromination medium comprising at least one solvent selected from the group consisting of N,N-dimethylformamide, N-methylpyrrolidinone, N-butylpyrrolidinone, dimethylsulfoxide, dimethylacetamide, and dichloromethane.

[0529] Embodiment 287. The process of embodiment 284, wherein the compound of formula (II), or a salt thereof, is contacted with a brominating agent in a bromination medium comprising N,N-dimethylformamide.

[0530] Embodiment 288. The process of embodiment 284, wherein the compound of formula (II), or a salt thereof, is contacted with a brominating agent in a bromination medium comprising N-methylpyrrolidinone.

[0531] Embodiment 289. The process of any of Embodiments 284 to 288, wherein the bromination medium is maintained at a temperature of from about 5°C to about 40°C during the bromination step.

[0532] Embodiment 290. The process of any of Embodiments 284-288, wherein the bromination medium is maintained at a temperature of about 20° C. during the bromination step.

[0533] Embodiment 291. The process of any of embodiments 284 to 290, wherein the bromination step is carried out as a batch reaction.

[0534] Embodiment 292 The process of embodiment 291, wherein at least about 50 kilograms of the compound of formula (II) is charged to the batch reaction.

[0535] Embodiment 293 The process of embodiment 291, wherein at least about 100 kilograms of the compound of formula (II) is charged to the batch reaction.

[0536] Embodiment 294 The process of embodiment 291, wherein at least about 200 kilograms of the compound of formula (II) is charged to the batch reaction.

[0537] Embodiment 295. The process of embodiment 291, wherein at least about 300 kilograms of the compound of formula (II) is charged to the batch reaction.

[0538] Embodiment 296. The process of any of embodiments 284 to 295, wherein the process comprises isolating the compound of formula (III), or a salt thereof, from the bromination medium.

[0539] Embodiment 297. The process of embodiment 296, wherein an aqueous solution is added to the bromination medium to isolate the compound of formula (III), or a salt thereof.

[0540] Embodiment 298. The process of embodiment 296, wherein an aqueous solution having a basic pH is added to the bromination medium to isolate the compound of formula (III), or a salt thereof.

[0541] Embodiment 299. The process of embodiment 296, wherein aqueous sodium bicarbonate is added to the bromination mixture to isolate the compound of formula (III), or a salt thereof.

[0542] Embodiment 300. The process of embodiment 299, wherein the sodium bicarbonate solution is about 1% to 10% by weight sodium bicarbonate.

[0543] Embodiment 301. The process of embodiment 299, wherein the sodium bicarbonate solution is about 2% by weight sodium bicarbonate.

[0544] Embodiment 302. The process of any of embodiments 281-283, wherein the compound of Formula (III), or a salt thereof, is prepared from the compound of Formula (II), or a salt thereof, without isolating the compound of Formula (II), or a salt thereof, from the reaction mixture.

[0545] Embodiment 303. The process of any of Embodiments 281-302, wherein the stoichiometric process yield of the compound of Formula (III) is at least about 50%.

[0546] Embodiment 304. The process of any of Embodiments 281-302, wherein the stoichiometric process yield of the compound of Formula (III) is at least about 65%.

[0547] Embodiment 305. The process of any of Embodiments 281-302, wherein the stoichiometric process yield of the compound of Formula (III) is at least about 80%.

[0548] Embodiment 306. A compound of Formula (VII), or a salt thereof, A compound having the structure of formula (V): [ka] or a salt thereof, with a compound having the structure of formula (VI): [ka] or a salt thereof in a reaction medium comprising water and an organic solvent in the presence of a base and a palladium catalyst to form a reaction mixture comprising a compound of formula (VII), or a salt thereof; reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising a compound of formula (VII), or a salt thereof; and The process of embodiment 1, prepared by a process comprising isolating the compound of formula (VII), or a salt thereof, from a substantially anhydrous mixture.

[0549] Embodiment 307. A compound of formula (VI), or a salt thereof, Compound of formula (IV) [ka] or a salt thereof, with an acidic medium under conditions sufficient to deprotect the compound of formula (IV), or a salt thereof, and form a reaction mixture comprising a compound of formula (VI), or a salt thereof, and a benzyl halide by-product; and The process of embodiment 306, wherein the compound is prepared by a process comprising isolating the compound of formula (VI), or a salt thereof, from the reaction mixture under conditions sufficient to substantially avoid formation of an aminal impurity.

[0550] Embodiment 308. The process of embodiment 306, wherein the compound of formula (V), or a salt thereof, is prepared by a process comprising contacting 4-carboxyphenylboronic acid, or a salt thereof, with thionyl chloride and a catalyst in a reaction medium comprising an organic solvent to form an acyl chloride intermediate, followed by in situ contact with 2-aminopyridine to form a reaction mixture comprising the compound of formula (V), or a salt thereof.

[0551] Embodiment 309. The compound of formula (VI) or a salt thereof Compounds of formula (IV): [ka] or a salt thereof, with an acidic medium under conditions sufficient to deprotect the compound of formula (IV), or a salt thereof, and form a reaction mixture comprising a compound having the structure of formula (VI), or a salt thereof, and a benzyl halide by-product; and isolating a compound of formula (VI), or a salt thereof, from a reaction mixture under conditions sufficient to substantially avoid the formation of an aminal impurity; and The process of embodiment 306, wherein the compound of formula (V), or a salt thereof, is prepared by a process comprising contacting 4-carboxyphenylboronic acid, or a salt thereof, with thionyl chloride and a catalyst in a reaction medium comprising an organic solvent to form an acyl chloride, followed by in situ contacting with 2-aminopyridine to form a reaction mixture comprising the compound of formula (V), or a salt thereof.

[0552] Embodiment 310. The compound of Formula (IV), or a salt thereof, is a sulfate salt; and the sulfate salt is: A compound having the structure of formula (III): [ka] or a salt thereof, with an aminating agent in a reaction medium to form a reaction mixture comprising a compound of formula (IV); forming a sulfate salt of a compound of formula (IV); and The process of any of embodiments 306 to 309, wherein the compound is prepared by a process comprising isolating the sulfate salt.

[0553] Embodiment 311. A compound of formula (III), or a salt thereof, A compound having the structure of formula (I): [ka] or a salt thereof is contacted with a cyclizing agent in the presence of a catalyst in a reaction medium to produce a compound of formula (II): [ka] or forming a salt thereof; and brominating a compound of formula (II), or a salt thereof, with a brominating agent to provide a compound having a structure of formula (III), or a salt thereof; 311. The process of embodiment 310, wherein the temperature of the reaction medium is controlled during the contacting step in a manner sufficient to maintain at least about 80% chiral purity with respect to the compound of Formula (II), or a salt thereof.

[0554] Embodiment 312. A compound having the structure of formula (VIII): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (V): [ka] or a salt thereof, with a compound having the structure of formula (VI): [ka] or a salt thereof in an aqueous reaction medium containing an organic solvent in the presence of a base and a palladium catalyst to produce a compound having a structure of formula (VII): [ka] or a salt thereof; reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising a compound of formula (VII), or a salt thereof; isolating the compound of formula (VII), or a salt thereof, from the substantially anhydrous mixture; and A process comprising converting a compound of formula (VII), or a salt thereof, into a compound of formula (VIII).

[0555] Embodiment 313. A compound having the structure of formula (VIII): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (IV): [ka] or a salt thereof, by deprotecting a compound of formula (IV) and preparing a compound having the structure of formula (VI): [ka] or a salt thereof, and a benzyl halide by-product; isolating the compound of formula (VI), or a salt thereof, from the reaction mixture under conditions sufficient to substantially avoid the formation of an aminal impurity; and A process comprising converting a compound of formula (VI), or a salt thereof, into a compound of formula (VIII), or a salt thereof.

[0556] Embodiment 314. A compound having the structure of formula (VIII): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (III): [ka] or a salt thereof is contacted with an aminating agent in a reaction medium to produce a compound having the structure of formula (IV): [ka] forming a reaction mixture comprising: forming a sulfate salt of the compound of formula (IV); isolating the sulfate salt; and converting a sulfate salt to a compound of formula (VIII), or a salt thereof.

[0557] Embodiment 315. A compound having the structure of Formula (VIII): [ka] or a salt thereof, the process comprising: A compound having the structure of formula (I): [ka] or a salt thereof is contacted with a cyclizing agent in the presence of a catalyst in a reaction medium to produce a compound of formula (II): [ka] or forming a salt thereof; The compound of formula (II) or a salt thereof is brominated with a brominating agent to obtain a compound having the structure of formula (III): [ka] or a salt thereof; and converting a compound of formula (III), or a salt thereof, into a compound of formula (VIII), or a salt thereof; A process wherein the temperature of the reaction medium is controlled during the contacting step in a manner sufficient to maintain at least about 80% chiral purity with respect to the compound of formula (II), or a salt thereof.

[0558] All references (patent and non-patent) cited above are incorporated by reference into this patent application. The discussion of these references is intended merely to summarize the assertions made by their authors. No admission is made that any reference (or any portion of any reference) is relevant prior art (or any prior art). Applicant reserves the right to challenge the accuracy and pertinence of the cited references.

Claims

1. Compounds having the structure of formula (VII): 【Chemistry 1】 or a process for preparing the salt thereof, wherein the process is Compounds having the structure of formula (V): 【Chemistry 2】 or a salt thereof, a compound having the structure of formula (VI): 【Transformation 3】 Alternatively, contact the salt thereof with an aqueous reaction medium containing an organic solvent in the presence of a base and a palladium catalyst to form a reaction mixture containing the compound of formula (VII) or a salt thereof; To reduce the amount of water present in the reaction mixture to form a substantially anhydrous mixture containing the compound of formula (VII) or a salt thereof; and A process comprising isolating the compound of formula (VII), or a salt thereof, from the substantially anhydrous mixture.

2. The process according to claim 1, wherein the isolation step includes filtering the substantially anhydrous mixture.

3. The process according to claim 1 or 2, wherein the aqueous reaction medium further comprises an alkali metal halide.

4. The aforementioned reduction process is The reaction mixture is separated into an aqueous phase to be discarded and an organic phase containing the compound of formula (VII); Wash the aforementioned organic phase with water; Treating the aforementioned organic phase with a silica scavenger; Removing the silica scavenger from the organic phase; Washing the aforementioned organic phase with an aqueous salt solution; and The process according to any one of claims 1 to 3, comprising distilling the organic phase under conditions sufficient to reduce the amount of water present in the organic phase.

5. The process according to any one of claims 1 to 4, wherein the substantially anhydrous mixture contains less than about 5% by weight of water.

6. Compounds having the structure of formula (VI): 【Chemistry 4】 or a process for preparing the salt thereof, wherein the process is Compound of formula (IV): 【Transformation 5】 Or, contact the salt thereof with an acidic medium under conditions sufficient to deprotect the compound of formula (IV) and to form a reaction mixture containing the compound of formula (VI), or its salt, and a benzyl halide byproduct; To remove at least a portion of the benzyl halogen by-product from the reaction mixture; and A process comprising isolating the compound of formula (VI), or a salt thereof, from the reaction mixture under conditions sufficient to substantially avoid the formation of aminal impurities.

7. The isolation step described above is Removing at least a portion of the benzyl halogen by-product from the reaction mixture; Raising the pH of the resulting reaction mixture to a basic pH to form a basic reaction medium containing the compound of formula (VI) or a salt thereof; and The process according to claim 6, comprising isolating the compound of formula (VI) or a salt thereof from the basic reaction mixture.

8. The isolation step described above is Extracting at least a portion of the benzyl halogen by-product from the reaction mixture into a discarded organic phase; Raise the pH of the resulting reaction mixture to a basic pH to form a basic reaction medium containing the compound of formula (VI) or a salt thereof; Extracting the compound of formula (VI), or a salt thereof, from the basic reaction medium into the product organic phase; and The process according to claim 6, comprising isolating the compound of formula (VI) or a salt thereof from the product organic phase.

9. The isolation step described above is Selectively extracting at least a portion of the benzyl halogen by-product from the reaction mixture into an organic phase discarded for the compound of formula (VI); Raise the pH of the resulting reaction mixture to a pH above approximately 7.0 to form a basic reaction mixture; Selectively extracting at least a portion of the compound of the preceding formula (VI) from the basic reaction mixture into the product organic phase; and The process according to claim 6, comprising distilling the product organic phase under conditions sufficient to reduce the amount of water present in the product organic phase to form a distilled organic phase containing the compound of formula (VI).

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