Process for preparation of Arrabutinib

Abstract

The present disclosure relates to a process for the preparation of Acarrabutinib. The present disclosure relates generally to an improved process for the preparation of 4-{8-amino-3-[(2S)-1-(butyl-2-alkynol) pyrrolidin-2-yl] imidazo [1, 5-a] pyrazin-1-yl}-N-(pyridin-2-yl)-benzamide, in particular to an improved process for the preparation of 4-{8-amino-3-[(2S)-1-(butyl-2-alkynol) pyrrolidin-2-yl] imidazo [1, 5-a] pyrazin-1-yl}-N-( The present invention relates to a large scale process for the manufacture of 4-{8-amino-3-[(2S)-1-(butyl-2-alkynol) pyrrolidin-2-yl] imidazo [1, 5-a] pyrazin-1-yl}-N-(pyridin-2-yl) benzamide, and intermediates employed in such processes.

Description

[0001] This application is a divisional application of the application patent application with the application number 201980055726.6, the title of which is “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” and the filing date of which is August 28, 2019. TECHNICAL FIELD

[0002] The present disclosure relates generally to improved 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, in particular to large scale processes employed in such processes for the manufacture 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 / or intermediates. BACKGROUND

[0003] 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 of acalabrutinib, is the active pharmaceutical ingredient in the pharmaceutical 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 previously treated with at least one therapy. Clinical trials are ongoing to evaluate the use of CALQUENCE® for the treatment of additional indications, including chronic lymphocytic leukemia and Waldenstrom’s macroglobulinemia .

[0004] Example 6 of U.S. Patent No. 9,290,504 discloses acalabrutinib and reports the synthesis shown in Scheme 1 below:

[0005] Scheme 1

[0006]

[0007] Research Disclosure Database Number 631028 (digitally published on October 6, 2016) reports the synthesis of acalabrutinib shown in Scheme 2 below:

[0008] Scheme 2

[0009] ​​

[0010] However, the previously reported synthetic methods are not suitable for the manufacture of acalabrutinib on a large scale, particularly a commercial scale. The present disclosure provides improved methods that can be operated on a large scale and provide one or more advantages over the previously reported synthetic methods, such as improved compound purity, improved compound isolation (e.g., filterability), reduced cycle time, less stringent process control requirements, higher yield, reduced cost, improved compliance with regulatory requirements for drug starting materials, intermediates, and products, and the like.

[0011] SUMMARY

[0012] As described above, the present disclosure relates to improved large scale processes for preparing acalabrutinib and / or intermediates employed in the preparation of acalabrutinib.

[0013] In one aspect, the present disclosure relates to a method for preparing a compound having the structure of Formula (VIII):

[0014]

[0015] or a salt thereof, wherein the method comprises:

[0016] contacting a compound having the structure of Formula (VII)

[0017]

[0018] or a salt thereof, with 2-butyneoic 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 byproducts; and

[0019] selectively isolating the compound of Formula (VIII), or a salt thereof, from the reaction mixture, relative to the one or more reaction byproducts.

[0020] In another aspect, the present disclosure relates to a method for preparing a compound having the structure of Formula (VII):

[0021]

[0022] or a salt thereof, wherein the method comprises:

[0023] contacting a compound having the structure of Formula (V)

[0024]

[0025] or a salt thereof, with a compound having the structure of Formula (VI):

[0026]

[0027] or salt thereof, with a base and a palladium catalyst in an aqueous reaction medium comprising an organic solvent to form a reaction mixture comprising a compound of Formula (VII), or salt thereof;

[0028] reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising a compound of Formula (VII), or salt thereof; and

[0029] isolating a compound of Formula (VII), or salt thereof, from the substantially anhydrous mixture.

[0030] In another aspect, the disclosure relates to a method for preparing a compound of the structure of Formula (VI):

[0031]

[0032] or salt thereof, wherein the method comprises:

[0033] contacting a compound of Formula (IV):

[0034]

[0035] or 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 salt thereof, and a benzyl halide byproduct; and

[0036] isolating a compound of Formula (VI), or salt thereof, from the reaction mixture under conditions sufficient to substantially avoid aminal impurity formation.

[0037] In another aspect, the disclosure relates to a method for preparing a compound of the structure of Formula (V):

[0038]

[0039] or salt thereof, wherein the method comprises contacting 4-carboxyphenylboronic acid, or salt thereof, with thionyl chloride and a catalyst in a reaction medium comprising an organic solvent to form an acid chloride intermediate, followed by contacting the acid chloride intermediate in situ with 2-aminopyridine to form a reaction mixture comprising a compound of Formula (V), or salt thereof.

[0040] In another aspect, the disclosure relates to a method for preparing a sulfate salt of a compound of the structure of Formula (IV):

[0041]

[0042] wherein the method comprises:

[0043] contacting a compound having the structure of Formula (III)

[0044]

[0045] or a salt thereof, with an aminating agent in a reaction medium to form a reaction mixture comprising a compound having the structure of Formula (IV);

[0046] forming a sulfate salt of the compound having the structure of Formula (IV); and

[0047] isolating the sulfate salt.

[0048] In another aspect, the present disclosure relates to a method for preparing a compound having the structure of Formula (III):

[0049]

[0050] or a salt thereof, wherein the method comprises:

[0051] contacting a compound having the structure of Formula (I)

[0052]

[0053] or a salt thereof, with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound having the structure of Formula (II);

[0054]

[0055] or a salt thereof; and

[0056] brominating the compound having the structure of Formula (II), or a salt thereof, with a brominating agent to provide a compound having the structure of Formula (III):

[0057]

[0058] or a salt thereof;

[0059] 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 of the compound having the structure of Formula (II), or a salt thereof.

[0060] In another aspect, the present disclosure relates to a method for preparing a compound having the structure of Formula (II):

[0061]

[0062] or a salt thereof, wherein the method comprises:

[0063] contacting a compound having the structure of Formula (I)

[0064]

[0065] or a salt thereof, with a cyclization agent in the presence of a catalyst in a reaction medium to form a compound of Formula (II), or a salt thereof;

[0066] 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 of the compound of Formula (II), or a salt thereof.

[0067] In another aspect, the disclosure relates to a crystalline form of a compound having the structure of Formula (VII):

[0068]

[0069] wherein the crystalline form is characterized by a reflection X-ray powder diffraction pattern selected from the group consisting of:

[0070] a reflection X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 9.9 ± 0.2 °2Q, 11.1 ± 0.2 °2Q, 12.8 ± 0.2 °2Q, 14.1 ± 0.2 °2Q, and 19.0 ± 0.2 °2Q, and

[0071] a reflection X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 7.4 ± 0.2 °2Q, 11.7 ± 0.2 °2Q, 12.5 ± 0.2 °2Q, 22.3 ± 0.2 °2Q, and 21.6 ± 0.2 °2Q.

[0072] In another aspect, the disclosure relates to a crystalline form of a compound having the structure of Formula (VII):

[0073]

[0074] 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 °2Q, 11.1 ± 0.2 °2Q, 12.8 ± 0.2 °2Q, 14.1 ± 0.2 °2Q, and 19.0 ± 0.2 °2Q.

[0075] In another aspect, the disclosure relates to a crystalline sulfate salt of a compound having the structure of Formula (IV):

[0076] BRIEF DESCRIPTION OF DRAWINGS

[0077] Figure 1X-ray powder diffraction patterns (PXRD) measured in reflection mode from a sample of crystalline sulfate salt of benzyl (2S)-2-(8-amino-l-bromoimidazo[l,5- a]pyrazin-3-yl)-l-pyrrolidinecarboxylate (having a stoichiometric ratio of about one sulfate molecule and one bisulfate molecule per three free base molecules) are illustrated.

[0078] Figure 2 X-ray powder diffraction patterns (PXRD) measured in reflection mode from a sample of Form 2 crystalline form of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[l,5- a]pyrazin-l-yl}-N-(2-pyridinyl)benzamide are illustrated.

[0079] Figure 3 X-ray powder diffraction patterns (PXRD) measured in reflection mode from a sample of Form 3 crystalline form of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[l,5- a]pyrazin-l-yl}-N-(2-pyridinyl)benzamide are illustrated.

[0080] Figure 4 X-ray powder diffraction patterns (PXRD) measured in reflection mode from a sample of Form C crystalline form of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[l,5- a]pyrazin-l-yl}-N-(2-pyridinyl)benzamide are illustrated. DETAILED DESCRIPTION

[0081] This written description uses examples to disclose the application and also to enable any person skilled in the art to practice the application, including making and using any of the disclosed salts, substances, or compositions, and performing any of the disclosed methods or processes. The patentable scope of the application is defined by the claims, and can 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 are substantively identical with elements of the claims, or if they include equivalent elements with non-substantive

[0082] I. Definitions

[0083] The section headings used in this section and throughout this disclosure are not intended to limit the scope of this disclosure.

[0084] Where a range of values is recited, it is specifically contemplated that each and every value between the recited upper and lower bounds is included. For example, a range of 6 to 9 is specifically contemplated to include the values of 7 and 8, in addition to 6 and 9. Similarly, a range of 6.0 to 7.0 is specifically contemplated to include the values of 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0, in addition to 6.0 and 7.0. In the same manner, all listed ratios are also meant to include all subratios falling within the broader ratios.

[0085] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0086] The term "about" generally refers to a range of numbers that a person of skill in the art would consider equivalent to the referenced value (i.e., having the same function or result). In many instances, the term "about" can include numbers that are rounded to the nearest significant figure.

[0087] The terms "comprise," "comprises," and "comprising," are used in their open-ended, explicitly inclusive sense, unless otherwise indicated by context, and are each construed to mean that what follows the term is included in the recited step or steps, but that other items not recited are also included in the recited step or steps, and that the recited step or steps will not be limited to the items specifically named. Unless otherwise required by context, the terms "comprise," "comprises," and "comprising" are used in their open-ended, explicitly inclusive sense, and are each construed to mean that what follows the term is included in the recited step or steps, but that other items not recited are also included in the recited step or steps, and that the recited step or steps will not be limited to the items specifically named.

[0088] The term "sulfate (2:3)" refers to a sulfate having a stoichiometric ratio of sulfate to free base of about 2:3, including sulfates having one sulfate molecule and one bisulfate molecule for every three free base molecules.

[0089] The term "crystalline purity," when used in reference to a crystalline form of a compound, refers to the percentage of a crystalline form of a compound in a reference composition relative to another crystalline form or an amorphous form.

[0090] The abbreviations used throughout this disclosure have the meanings indicated in Table 1 below.

[0091] Table 1

[0092]

[0093]

[0094] For clarity, Table 2 below summarizes the compound identifiers, chemical names, and structures that are used interchangeably throughout this application with respect to each compound discussed.

[0095] Table 2

[0096]

[0097]

[0098]

[0099]

[0100] The present disclosure also discusses crystalline forms of certain compounds listed in Table 2, including X-ray powder diffraction patterns characterizing such crystalline forms. It is known in the art that X-ray powder diffraction patterns can be obtained with one or more measurement errors depending on the testing conditions (such as equipment, sample preparation or machine used). In particular, it is generally known that the intensities of X-ray powder diffraction patterns can fluctuate depending on the measurement conditions and sample preparation. For example, one of ordinary skill in the art of X-ray powder diffraction will recognize that the relative intensities of the peaks can vary depending on the orientation of the sample being examined and the type and settings of the instrument used. One of ordinary skill in the art will also recognize that the position of the reflections can be affected by the exact height at which the sample is placed in the diffractometer and the zero-point correction of the diffractometer. The surface planarity of the sample can also have a subtle effect. Thus, one of ordinary skill in the art will understand that the diffraction pattern data presented herein should not be interpreted as absolute, and that any crystalline form providing a powder diffraction pattern substantially in accordance with those disclosed herein falls within the scope of the present disclosure (see Jenkins, R and Snyder, R.L. 'Introduction to X-Ray Powder Diffractometry' John Wiley & Sons, 1996 for further information).II. U.S. Patent No. 9,290,504 Synthesis

[0101] As previously mentioned, the synthesis reported in Example 6 of U.S. Patent No. 9,290,504 is not suitable for large scale manufacturing of acalabrutinib. Among other limitations, the reported method does not provide information on the chiral or achiral purity of the intermediates, employs chromatography to isolate intermediates at various points in the method, and produces milligram quantities of the final product. The overall yield of acalabrutinib in this small scale synthesis starting from Compound I is about 5%.

[0102] III. Clinical trial supply method

[0103] The following Scheme 3 illustrates the method subsequently developed to manufacture supplies of acalabrutinib for clinical trials. The individual steps of Scheme 3 are discussed in further detail throughout the present disclosure.

[0104] Scheme 3

[0105]

[0106] While this process was used to produce approximately 100 to 150 kilograms of acalabrutinib for clinical trials, the process lacks robustness, is difficult to operate and has long cycle times. Therefore, the process was not considered suitable for large scale manufacturing of acalabrutinib.

[0107] More specifically, the process of Scheme 3 has many limitations, including the following:

[0108] (1) During the step to produce compound (II), racemization of the chiral center is difficult to control and results in several batch failures.

[0109] (2) Many environmentally unfriendly solvents are employed in several steps.

[0110] (3) One of the more problematic solvents employed is dichloromethane. In addition to environmental considerations, the use of dichloromethane in steps involving amines has the additional drawback that the reaction of the amine with dichloromethane produces an aminal impurity that sometimes even results in batch failure. During the step to produce compound (VI), for example, a methylene-bridged dimer can be formed. Further, the acid-based liquid chromatography method used in conjunction with the step to produce compound (VI) does not detect the aminal impurity.

[0111] (4) The combined use of N,N-dimethylformamide and thionyl chloride to produce compound (V) can potentially lead to the formation of the toxic dimethylcarbamoyl chloride.

[0112] (5) The coupling reaction in the step to produce compound (VII) is prone to stop. During the final step to produce acalabrutinib, the addition of more palladium catalyst increases the burden on the clean-up step, which already needs to be used with excessive repeated cycles using silica-based scavengers.

[0113] (6) Isolation of compound (VII) by filtration is difficult and not suitable for large scale manufacturing. At a 50 kg scale, the use of two pressure filters is required, with multiple manual product discharges as a wet paste, and this only has a significant time loss.

[0114] (7) Multiple batch failures occurred with acylation to produce acalabrutinib through multiple different failure modes.

[0115] (8) The use of distillative precipitation to isolate acalabrutinib provides no control over the particle properties of the isolated product.

[0116] IV. Large scale method

[0117] In view of the limitations associated with the clinical trial supply process, an improved process was developed that overcomes those limitations and is suitable for large scale manufacturing of acalabrutinib. Scheme 4 below illustrates one representative example of this large scale process for manufacturing acalabrutinib. The individual steps of Scheme 4 are discussed in further detail throughout this disclosure.

[0118] Scheme 4

[0119]

[0120] V. Preparation of benzyl (2S)-2-(8-chloro-imidazo[l,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Compound II) Scheme 5

[0121] The present disclosure relates, in part, to a process for preparing benzyl (2S)-2-(8-chloro- imidazo[l,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 illustrates the general process:

[0122] Scheme 6

[0123]

[0124] Cyclization of Compound (I) to form the imidazole ring present in Compound (II) is advantageous because it imparts stability to the chiral center of the subsequent intermediates employed in the manufacture of acalabrutinib. However, the clinical trial supply process was problematic because the uncyclized Compound (I) was prone to racemization under the acidic conditions of the cyclization reaction. This undesirable racemization reaction was difficult to control and resulted in multiple batch failures. The use of nitrogen purging to remove liberated hydrochloric acid limited the extent of chiral erosion that occurred to some extent, but the extent of chiral erosion was still highly variable.

[0125] The clinical trial supply process employed a reaction temperature of about 80 °C with a catalytic loading of about 0.2 molar equivalents of N,N-dimethylformamide. It has been determined that increasing the N,N-dimethylformamide loading (e.g., to about 0.6 molar equivalents) and decreasing the reaction temperature (e.g., to about 40 °C) limits the observed chiral degradation and generally results in the production of chiral Compound (II). The lower N,N-dimethylformamide catalytic loading employed in the clinical trial supply process resulted in a reaction rate that required a higher temperature for reaction completion, which then resulted in the observed chiral degradation. In contrast, the increased N,N-dimethylformamide catalytic loading of the improved process resulted in a faster reaction rate and allowed the reaction to be run at a lower temperature, which inhibited racemization. Chiral degradation was reduced, chiral integrity was maintained, and thus yield was improved.

[0126] Therefore, in one embodiment, this disclosure relates to the preparation of compounds having the structure of formula (II):

[0127]

[0128] A method using a salt thereof, wherein the method comprises:

[0129] Compounds having the structure of formula (I)

[0130]

[0131] Or its salt, in contact with a cyclizing agent in the presence of a catalyst in a reaction medium, to form a compound having formula (II) or its salt;

[0132] The temperature of the reaction medium is controlled during the contact step in a manner sufficient to maintain at least about 80% chiral purity of the compound having formula (II) or its salt.

[0133] As stated above, proper control of the reaction temperature during the cyclization reaction is important for maintaining 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 of the compound having formula (II) or a salt thereof. In one aspect, the temperature of the reaction medium is controlled during the contact step in a manner sufficient to maintain at least about 90% chiral purity of the compound having formula (II) or a salt thereof. In another aspect, the temperature of the reaction medium is controlled during the contact step in a manner sufficient to maintain at least about 95% chiral purity of the compound having formula (II) or a salt thereof. In yet another aspect, the temperature of the reaction medium is controlled during the contact step in a manner sufficient to maintain at least about 99% chiral purity of the compound having formula (II) or a salt thereof.

[0134] Maintaining the reaction medium at a temperature below about 80°C during the contact step generally improves the chiral purity of compounds having formula (II) or their salts. In one aspect, the reaction medium is maintained at a temperature below about 70°C during the contact step. In another aspect, the reaction medium is maintained at a temperature below about 60°C during the contact step. In another aspect, the reaction medium is maintained at a temperature below about 50°C during the contact step. In another aspect, the reaction medium is maintained at a temperature from about 30°C to about 50°C during the contact step. In yet another aspect, the reaction medium is maintained at a temperature of about 40°C during the contact step.

[0135] The catalyst can comprise any suitable catalyst, particularly a catalyst selected from the group consisting of N,N-dimethylformamide and N-methylformanilide. In one aspect, the catalyst comprises N,N-dimethylformamide. In another aspect, the catalyst comprises N-methylformanilide. As noted above, the amount of catalyst loaded into the reaction medium can also affect the chiral purity of the product. Typically, at least about 0.1 molar equivalent of catalyst is loaded into the reaction medium relative to the compound of Formula (I) or salt thereof. In one aspect, at least about 0.4 molar equivalent of catalyst is loaded into the reaction medium relative to the compound of Formula (I) or salt thereof. In another aspect, at least about 0.6 molar equivalent of catalyst is loaded into the reaction medium relative to the compound of Formula (I) or salt thereof. In another aspect, at least about 0.1 to about 1.0 molar equivalent of catalyst is loaded into the reaction medium relative to the compound of Formula (I) or salt thereof. In another aspect, at least about 0.4 to about 1.0 molar equivalent of catalyst is loaded into the reaction medium relative to the compound of Formula (I) or salt thereof. In another aspect, the catalyst comprises N,N-dimethylformamide and from about 0.1 to about 1.0 molar equivalent of catalyst is loaded into the reaction medium relative to the compound of Formula (I) or salt thereof. In another aspect, the catalyst comprises N,N-dimethylformamide and about 0.4 to about 1.0 molar equivalent of catalyst is loaded into the reaction medium relative to the compound of Formula (I) or salt thereof. In another aspect, the catalyst comprises N,N-dimethylformamide and about 0.6 molar equivalent of catalyst is loaded into the reaction medium relative to the compound of Formula (I) or salt thereof.

[0136] The cyclization agent can be any suitable cyclization agent, particularly phosphorus oxychloride. Typically, the compound of Formula (I) or salt thereof is contacted with about 0.7 to about 10 molar equivalents of cyclization agent relative to the compound of Formula (I) or salt thereof. In one aspect, the compound of Formula (I) or salt thereof is contacted with about 1.5 to about 2.5 molar equivalents of cyclization agent relative to the compound of Formula (I) or salt thereof. In another aspect, the compound of Formula (I) or salt thereof is contacted with about 2.0 molar equivalents of cyclization agent relative to the compound of Formula (I) or salt thereof.

[0137] The reaction medium can be any suitable reaction medium, particularly a reaction medium comprising at least one solvent selected from the group consisting of aromatic hydrocarbons, chlorinated hydrocarbons, ethers, and nitriles. In one aspect, 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 aspect, the reaction medium comprises acetonitrile. The volume of the reaction medium is typically about 2 liters to about 20 liters of reaction medium per kilogram of compound of Formula (I) or salt thereof loaded into the reaction medium. In one aspect, the volume of the reaction medium is about 3 liters to about 10 liters of reaction medium per kilogram of compound of Formula (I) or salt thereof loaded into the reaction medium.

[0138] The contacting step is typically conducted as a batch reaction, particularly a batch reaction in which at least about 50 kilograms of compound of Formula (I) or salt thereof is loaded into the batch reaction. In one aspect, at least about 100 kilograms of compound of Formula (I) or salt thereof is loaded into the batch reaction. In another aspect, at least about 200 kilograms of compound of Formula (I) or salt thereof is loaded into the batch reaction. In another aspect, at least about 300 kilograms of compound of Formula (I) or salt thereof is loaded into the batch reaction.

[0139] The process typically provides a stoichiometric process yield of at least about 50% of the compound of Formula (II) or salt thereof. In one aspect, the stoichiometric process yield of the compound of Formula (II) or salt thereof is at least about 65%. In another aspect, the stoichiometric process yield of the compound of Formula (II) or salt thereof is at least about 80%. In another aspect, the stoichiometric process yield of the compound of Formula (II) or salt thereof is at least about 90%. Indeed, the improved process has been able to achieve approximately 95% yield of good quality material at scales in excess of 300 kg (input).

[0140] In another representative embodiment, the present disclosure is directed to a process for preparing a compound having the structure of Formula (II):

[0141]

[0142] or a salt thereof, wherein the process comprises:

[0143] contacting a compound having the structure of Formula (I)

[0144]

[0145] or a salt thereof, with phosphorus oxychloride in the presence of a catalyst in a reaction medium to form the compound of Formula (II), or a salt thereof;

[0146] wherein during the contacting step, the reaction medium is maintained at a temperature of less than about 80 °C;

[0147] wherein at least about 0.4 molar equivalents of catalyst are charged to the reaction medium relative to the compound of Formula (I) or salt thereof; and

[0148] wherein the compound of Formula (II) or salt thereof has a chiral purity of at least about 80%.

[0149] In one aspect, during the contacting step, the reaction medium is maintained at a temperature of less than about 70 °C; at least about 0.4 to about 1.0 molar equivalents of catalyst are charged to the reaction medium relative to the compound of Formula (I) or salt thereof; and the compound of Formula (II) or salt thereof has a chiral purity of at least about 85%. In another aspect, during the contacting step, the reaction medium is maintained at a temperature of less than about 60 °C; at least about 0.4 to about 1.0 molar equivalents of catalyst are charged to the reaction medium relative to the compound of Formula (I) or salt thereof; and the compound of Formula (II) or salt thereof has a chiral purity of at least about 90%. In another aspect, during the contacting step, the reaction medium is maintained at a temperature of from about 30 °C to about 50 °C; at least about 0.4 to about 1.0 molar equivalents of catalyst are charged to the reaction medium relative to the compound of Formula (I) or salt thereof; and the compound of Formula (II) or salt thereof has a chiral purity of at least about 90%. In another aspect, during the contacting step, the reaction medium is maintained at a temperature of about 40 °C; about 0.6 molar equivalents of catalyst are charged to the reaction medium relative to the compound of Formula (I) or salt thereof; and the compound of Formula (II) or salt thereof has a chiral purity of at least about 90%. In another aspect, the catalyst comprises N,N-dimethylformamide.

[0150] Scheme 6 below corresponds to the method described in Example 3 and illustrates one representative embodiment of an improved method for preparing compound (II).

[0151] Preparation of benzyl (2S)-2-(l-bromo-8-chloro-imidazo[l,5-a]pyrazin-3-yl)-pyrrolidine-1-carboxylate (Compound III)

[0152]

[0153] VI. Scheme 7 Scheme 8

[0154] This disclosure relates in part to a method 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. As previously described, compound (II) or a salt thereof is prepared from compound (I) or a salt thereof and then brominated to produce compound (III) or a salt thereof. The following scheme 7 illustrates the general method:

[0155] Preparation of benzyl (2S)-2-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3-yl)-l-pyrrolidinecarboxylate (Compound IV) and the corresponding sulfate salt (2:3)

[0156]

[0157] Therefore, in one embodiment, this disclosure relates to the preparation of compounds having the structure of formula (III):

[0158]

[0159] A method using a salt thereof, wherein the method comprises:

[0160] Compounds having the structure of formula (I)

[0161]

[0162] Or its salt, in contact with a cyclizing agent in the presence of a catalyst in a reaction medium, to form a compound having formula (II);

[0163]

[0164] or its salt; and

[0165] A compound having formula (II) or a salt thereof is brominated with a brominating agent to provide a compound having the structure of formula (III):

[0166]

[0167] or its salt;

[0168] The temperature of the reaction medium is controlled during the contact step in a manner sufficient to maintain at least about 80% chiral purity of the compound having formula (II) or its salt.

[0169] The brominating agent can be any suitable brominating agent, particularly N-bromosuccinimide. The compound of Formula (III), or salt thereof, can be prepared from the compound of Formula (II), or salt thereof, without first isolating the compound of Formula (II), or salt thereof, from the reaction mixture (i.e., in situ bromination, which can include a solvent exchange step), or, alternatively, the compound of Formula (II), or salt thereof, can be isolated from the reaction medium and then brominated to provide the compound of Formula (III), or salt thereof. In one aspect, the compound of Formula (III), or salt thereof, is prepared from the compound of Formula (II), or salt thereof, without first isolating the compound of Formula (II), or salt thereof, from the reaction mixture (i.e., in situ bromination). In another aspect, the compound of Formula (II), or salt thereof, is isolated from the reaction medium (e.g., a solvent exchange process comprising isolating an oil containing the compound of Formula (II), or salt thereof) and then brominated to provide the compound of Formula (III), or salt thereof.

[0170] wherein the compound of Formula (II), or salt thereof, is isolated from the reaction mixture and then contacted with a brominating agent in a bromination medium, which can be any suitable bromination medium, particularly a bromination medium comprising at least one solvent selected from the group consisting of chlorinated hydrocarbons and polar aprotic solvents. In one aspect, 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 aspect, the bromination medium comprises N,N-dimethylformamide. In another aspect, the bromination medium comprises N-methylpyrrolidinone.

[0171] The compound of Formula (II), or salt thereof, is contacted with an effective amount of a brominating agent (e.g., about 0.8 to about 1.2 molar equivalents of the brominating agent relative to the compound of Formula (II), or salt thereof). To avoid over-reaction, it can be beneficial to control the temperature of the reaction medium / bromination medium during the addition of the brominating agent and / or to control the measurement during repeated processes performed during the addition of the brominating agent. In one aspect, the reaction medium / bromination medium is maintained at a temperature from about 5 °C to about 40 °C during the bromination step. In another aspect, the reaction medium / bromination medium is maintained at a temperature of about 20 °C during the bromination step. In another aspect, the brominating agent is titrated into the reaction medium / bromination medium.

[0172] The method can further comprise isolating the compound of Formula (III), or salt thereof, from the final reaction mixture. In one aspect, an aqueous solution is added to the final reaction mixture to precipitate the compound of Formula (III), or salt thereof. In another aspect, an aqueous solution having a basic pH is added to the final reaction mixture to precipitate the compound of Formula (III), or salt thereof. In another aspect, an aqueous sodium bicarbonate solution is added to the final reaction mixture to precipitate the compound of Formula (III), or salt thereof. In another aspect, the sodium bicarbonate solution is about 1 wt% to 10 wt% sodium bicarbonate. In another aspect, the sodium bicarbonate solution is about 2 wt% sodium bicarbonate.

[0173] In cases where compound (II), or salt thereof, is isolated from the reaction mixture and then brominated, the bromination is typically carried out as a batch reaction, particularly a batch reaction in which at least about 50 kilograms of the compound of Formula (II), or salt thereof, is charged to the batch reaction. In one aspect, at least about 100 kilograms of the compound of Formula (II), or salt thereof, is charged to the batch reaction. In another aspect, at least about 200 kilograms of the compound of Formula (II), or salt thereof, is charged to the batch reaction. In another aspect, at least about 300 kilograms of the compound of Formula (II), or salt thereof, is charged to the batch reaction.

[0174] In cases where compound (II), or salt thereof, is brominated in situ, the in situ reaction is typically carried out as a batch reaction, particularly a batch reaction in which at least about 50 kilograms of the compound of Formula (I), or salt thereof, is first charged to the reaction. In one aspect, at least about 100 kilograms of the compound of Formula (I), or salt thereof, is first charged to the reaction. In another aspect, at least about 200 kilograms of the compound of Formula (I), or salt thereof, is first charged to the reaction. In another aspect, at least about 300 kilograms of the compound of Formula (I), or salt thereof, is first charged to the reaction.

[0175] The reaction of compound (II), or salt thereof, with a brominating agent (e.g., N-bromosuccinimide) to produce compound (III), or salt thereof, typically works well and produces high quality material in high yield. The method typically provides at least about 50% stoichiometric process yield of the compound of Formula (III), or salt thereof. In one aspect, the stoichiometric process yield of the compound of Formula (III), or salt thereof, is at least about 65%. In another aspect, the stoichiometric process yield of the compound of Formula (III), or salt thereof, is at least about 80%. In another aspect, the stoichiometric process yield of the compound of Formula (III), or salt thereof, is at least about 90%. Indeed, the improved process has been able to achieve about 95% yield of high quality material at scales in excess of 300 kg (input).

[0176] In another representative embodiment, the present disclosure is directed to a method for preparing a compound having the structure of Formula (III):

[0177]

[0178] or a salt thereof, wherein the method comprises:

[0179] contacting a compound having the structure of Formula (I)

[0180]

[0181] or a salt thereof, with phosphorus oxychloride in the presence of a catalyst in a reaction medium to form a compound having the structure of Formula (II);

[0182]

[0183] or a salt thereof; and

[0184] brominating the compound having the structure of Formula (II), or a salt thereof, with N-bromosuccinimide to provide a compound having the structure of Formula (III):

[0185]

[0186] or a salt thereof;

[0187] wherein during the contacting step, the reaction medium is maintained at a temperature of less than about 80 °C;

[0188] wherein at least about 0.4 molar equivalents of catalyst are charged to the reaction medium relative to the compound having the structure of Formula (I), or a salt thereof; and

[0189] wherein the chiral purity of the compound having the structure of Formula (II), or a salt thereof, is at least about 80%.

[0190] In one aspect, during the contacting step, the reaction medium is maintained at a temperature of less than about 70 °C; at least about 0.4 to about 1.0 molar equivalents of catalyst is loaded into the reaction medium relative to the compound of formula (I), or salt thereof; and the chiral purity of the compound of formula (II), or salt thereof, is at least about 85%. In another aspect, during the contacting step, the reaction medium is maintained at a temperature of less than about 60 °C; at least about 0.4 to about 1.0 molar equivalents of catalyst is loaded into the reaction medium relative to the compound of formula (I), or salt thereof; and the chiral purity of the compound of formula (II), or salt thereof, is at least about 90%. In another aspect, during the contacting step, the reaction medium is maintained at a temperature of from about 30 °C to about 50 °C; at least about 0.4 to about 1.0 molar equivalents of catalyst is loaded into the reaction medium relative to the compound of formula (I), or salt thereof; and the chiral purity of the compound of formula (II), or salt thereof, is at least about 90%. In another aspect, during the contacting step, the reaction medium is maintained at a temperature of about 40 °C; about 0.6 molar equivalents of catalyst is loaded into the reaction medium relative to the compound of formula (I), or salt thereof; and the chiral purity of the compound of formula (II), or salt thereof, is at least about 90%. In another aspect, the catalyst comprises N,N-dimethylformamide.

[0191] Scheme 8 below corresponds to the method described in Example 3 and illustrates one representative embodiment of an improved method for preparing compound (III), or salt thereof.

[0192] Scheme 9

[0193]

[0194] VII. Scheme 10 Preparation of 4-(2-pyridinylcarbamoyl)phenyl]boronic acid (Compound V)

[0195] The present disclosure relates, in part, to a method for preparing benzyl (2S)-2-(8-amino- 1-bromoimidazo[l,5-a]pyrazin-3-yl)-l-pyrrolidinecarboxylate (Compound IV), or salt thereof, from benzyl (2S)-2-(l-bromo-8-chloro-imidazo[l,5-a]pyrazin-3-yl)pyrrolidine-l-carboxylate (Compound III), or salt thereof. Scheme 9 below illustrates the general method:

[0196] Scheme 11

[0197]

[0198] 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 produce compound (IV), which can optionally be converted to a salt, particularly a sulfate salt of compound (IV), as discussed further below. Because the amination reaction can result in the presence of residual ammonia, it can be beneficial to reduce the amount of residual ammonia prior to forming a salt of compound (IV) (particularly in the case where a sulfate salt of compound (IV) is desired) (e.g., by distillation of the crude compound (IV) product). For example, if residual ammonia present in compound (IV) is not sufficiently removed when producing a sulfate salt, inorganic ammonium sulfate can also be produced in addition to the sulfate salt of compound (IV), which would result in difficulty in determining the precise stoichiometry of the sulfate salt produced. From a regulatory perspective, it can be desirable to know the precise stoichiometry of the sulfate salt produced (e.g., in the case where the sulfate salt is a starting material that is registered for regulatory purposes).

[0199] Accordingly, in one embodiment, the present disclosure relates to a method for preparing a sulfate salt of a compound having the structure of Formula (IV):

[0200]

[0201] wherein the method comprises:

[0202] contacting a compound having the structure of Formula (III)

[0203]

[0204] or a salt thereof, with an aminating agent in a reaction medium to form a reaction mixture comprising a compound having Formula (IV);

[0205] forming a sulfate salt of the compound having Formula (IV); and

[0206] isolating the sulfate salt.

[0207] Typically, the sulfate salt of the compound having the structure of Formula (IV) has a stoichiometric ratio of one sulfate molecule and one bisulfate molecule to three free base molecules. In one aspect, the sulfate salt is a crystalline salt. In another aspect, the crystalline sulfate salt is characterized by a reflective X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 7.7 ± 0.2 °2Q, 10.6 ± 0.2 °2Q, 11.1 ± 0.2 °2Q, 12.6 ± 0.2 °2Q, and 13.5 ± 0.2 °2Q. In another aspect, the crystalline sulfate salt is characterized by a reflective X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 7.7 ± 0.2 °2Q, 10.6 ± 0.2 °2Q, 11.1 ± 0.2 °2Q, 12.6 ± 0.2 °2Q, 13.5 ± 0.2 °2Q, 17.4 ± 0.2 °2Q, 18.0 ± 0.2 °2Q, 18.9 ± 0.2 °2Q, 19.2 ± 0.2 °2Q, and 21.9 ± 0.2 °2Q.

[0208] The isolated crystalline sulfate salt typically has a crystalline purity of at least 50%. In one aspect, the isolated crystalline sulfate salt has a crystalline purity of at least 60%. In another aspect, the isolated crystalline sulfate salt has a crystalline purity of at least 70%. In another aspect, the isolated crystalline sulfate salt has a crystalline purity of at least 80%. In another aspect, the isolated crystalline sulfate salt has a crystalline purity of at least 90%. In another aspect, the isolated crystalline sulfate salt has a crystalline purity of at least 95%. In another aspect, the isolated crystalline sulfate salt has a crystalline purity of at least 96%. In another aspect, the isolated crystalline sulfate salt has a crystalline purity of at least 97%. In another aspect, the isolated crystalline sulfate salt has a crystalline purity of at least 98%. In another aspect, the isolated crystalline sulfate salt has a crystalline purity of at least 99%. In another aspect, the isolated crystalline sulfate salt is a substantially pure phase.

[0209] The aminating agent can be any suitable aminating agent, in particular ammonia or ammonium hydroxide. In one aspect, the aminating agent is gaseous ammonia. In another aspect, the aminating agent is ammonium hydroxide. The compound of Formula (III), or a salt thereof, is typically contacted with an effective amount of aminating agent (e.g., about 5 to about 20 molar equivalents of aminating agent relative to the compound of Formula (III), or a salt thereof).

[0210] The reaction medium can be any suitable reaction medium, in particular a reaction medium comprising 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 aspect, the reaction medium comprises at least one compound selected from the group consisting of methanol, ethanol, propanol, butanol, pentanol, N-methylpyrrolidone, and N,N-dimethylformamide. In another aspect, the reaction medium comprises a fatty alcohol. In another aspect, the reaction medium comprises butanol. In another aspect, the reaction medium comprises 2-butanol. The volume of reaction medium is typically from about 1.5 liters to about 40 liters of reaction medium per kilogram of compound of formula (III) or salt thereof loaded into the reaction medium. In one aspect, the volume of reaction medium is from about 2.0 liters to about 30 liters of reaction medium per kilogram of compound of formula (III) or salt thereof loaded into the reaction medium.

[0211] During the contacting step, the reaction medium is typically maintained at a temperature above 70 °C. In one aspect, the reaction medium is maintained at a temperature above 90 °C during the contacting step. In another aspect, the reaction medium is maintained at a temperature from about 50 °C to about 100 °C during the contacting step. In another aspect, the reaction medium is maintained at a temperature from about 60 °C to about 95 °C during the contacting step.

[0212] The contacting step is typically conducted as a batch reaction, in particular a batch reaction in which at least about 50 kilograms of compound of formula (III) or salt thereof is loaded into the batch reaction. In one aspect, at least about 100 kilograms of compound of formula (III) or salt thereof is loaded into the batch reaction. In another aspect, at least about 200 kilograms of compound of formula (II) or salt thereof is loaded into the batch reaction. In another aspect, at least about 300 kilograms of compound of formula (III) or salt thereof is loaded into the batch reaction.

[0213] In cases where a sulfate salt of compound (IV) is desired, the forming step typically comprises contacting the compound of formula (IV) with sulfuric acid to form a sulfate salt mixture comprising the sulfate salt. In one aspect, 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 aspect, 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).

[0214] The process optionally includes isolating the compound of formula (IV) as a free base from the reaction mixture prior to the forming step. Isolating the free base prior to salt conversion can be beneficial to reduce the amount of residual ammonia present and avoid potential issues associated with the presence of residual ammonia. In one aspect, the process includes isolating the compound of formula (IV) as a free base from the reaction medium; 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 to reduce the amount of ammonia present in the reaction mixture; isolating the compound of formula (IV) as a free base from the washed reaction medium; 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) as a free base from the distilled reaction medium; 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.

[0215] The process generally provides a stoichiometric process yield of at least about 50% of the sulfate salt of formula (IV). In one aspect, the stoichiometric process yield of the sulfate salt of the compound of formula (IV) is at least about 65%. In another aspect, the stoichiometric process yield of the sulfate salt of formula (IV) is at least about 75%. Indeed, the improved process has been able to achieve a quality material at about 85% yield at a scale of over 300 kg (input).

[0216] In another representative embodiment, the present disclosure is directed to a process for preparing a sulfate salt of a compound having the structure of formula (IV):

[0217]

[0218] wherein the process comprises:

[0219] contacting a compound having the structure of formula (III)

[0220]

[0221] or a salt thereof, with an aminating agent in a reaction medium to form a reaction mixture comprising a compound of formula (IV);

[0222] isolating the compound of formula (IV) as a free base from the reaction mixture;

[0223] contacting the free base with sulfuric acid to form a sulfate salt of the compound of formula (IV); and

[0224] isolating the sulfate salt;

[0225] The sulfate therein has a stoichiometric ratio of one sulfate molecule to one hydrogen sulfate molecule to three free base molecules.

[0226] In one aspect, the sulfate is a crystalline salt. In another aspect, the crystalline sulfate is characterized by a reflected X-ray powder diffraction pattern containing 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 is characterized by a reflected X-ray powder diffraction pattern containing 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 is characterized by a reflected X-ray powder diffraction pattern containing at least five 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.

[0227] The following scheme 10 corresponds to the method described in Example 5 and illustrates a representative embodiment of an improved method for preparing compound (II).

[0228] Scheme 12

[0229]

[0230] VIII. Preparation of l-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[l,5-a]pyrazin-8-amine (Compound VI)

[0231] This disclosure relates in part to a method for preparing 4-(2-pyridyl-carbamoyl)phenylboronic acid (compound V) or a salt thereof from 4-carboxyphenylboronic acid or a salt thereof and 2-aminopyridine. The following scheme 11 illustrates the general method:

[0232] Scheme 13

[0233]

[0234] The clinical trial supply method involves reacting 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 avoid this problem, an improved method replaces N,N-dimethylformamide with a compound (e.g., tetrabutylammonium chloride) that does not generate this toxic byproduct and provides improved safety during this step.

[0235] Accordingly, in one embodiment, the present disclosure relates to a method for preparing a compound having the structure of Formula (V):

[0236]

[0237] or a salt thereof, wherein the method comprises 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 acid chloride intermediate, and then contacting the acid chloride intermediate in situ with 2- aminopyridine to form a reaction mixture comprising the compound of Formula (V), or a salt thereof. In one aspect, the method further comprises isolating the compound of Formula (V), or a salt thereof, from the reaction mixture.

[0238] A molar excess of 2-aminopyridine is typically charged to the reaction medium relative to the 4-carboxyphenylboronic acid, or a salt thereof. In one aspect, about 1.5 to about 5 molar equivalents of 2-aminopyridine are typically charged to the reaction medium relative to the 4-carboxyphenylboronic acid, or a salt thereof. In another aspect, about 1.5 to about 3.5 molar equivalents of 2-aminopyridine are charged to the reaction medium relative to the 4-carboxyphenylboronic acid, or a salt thereof. In another aspect, about 2 molar equivalents of 2-aminopyridine are charged to the reaction medium relative to the 4-carboxyphenylboronic acid, or a salt thereof.

[0239] A molar excess of thionyl chloride is typically charged to the reaction medium relative to the 4-carboxyphenylboronic acid, or a salt thereof. In one aspect, the 4-carboxyphenylboronic acid, or a salt thereof, is contacted with about 2 to about 5 molar equivalents of thionyl chloride relative to the 4-carboxyphenylboronic acid, or a salt thereof. In another aspect, the 4-carboxyphenylboronic acid, or a salt thereof, is contacted with about 2 to about 3.5 molar equivalents of thionyl chloride relative to the 4-carboxyphenylboronic acid, or a salt thereof. In another aspect, the 4-carboxyphenylboronic acid, or a salt thereof, is contacted with about 2.75 molar equivalents of thionyl chloride relative to the 4-carboxyphenylboronic acid, or a salt thereof.

[0240] The catalyst can comprise any suitable catalyst, in particular a catalyst selected from the group consisting of tetrabutylammonium chloride and N-methyltoluidine. In one aspect, the catalyst comprises tetrabutylammonium chloride. In another aspect, the catalyst comprises N-methyltoluidine. In another aspect, the catalyst does not comprise N,N-dimethylformamide. About 0.01 to about 0.1 molar equivalents of catalyst are typically charged to the reaction medium relative to the 4-carboxyphenylboronic acid, or a salt thereof.

[0241] The reaction medium can be any suitable reaction medium, in particular a reaction medium comprising at least one solvent selected from the group consisting of: an aromatic hydrocarbon, an aromatic heterocycle, and a nitrile. In one aspect, the reaction medium comprises a compound selected from the group consisting of: toluene, acetonitrile, and pyridine. In another aspect, the reaction medium comprises toluene. In another aspect, the reaction medium does not comprise N,N-dimethylformamide. In another aspect, neither the reaction medium nor the catalyst comprises N,N-dimethylformamide. The volume of the reaction medium is typically from about 3 liters to about 30 liters of reaction medium per kilogram of 4-carboxyphenylboronic acid or salt thereof loaded into the reaction medium. In one aspect, 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 salt thereof loaded into the reaction medium.

[0242] During the contacting step, the reaction medium is typically maintained at a temperature from about 50 °C to about 90 °C. In one aspect, during the contacting step, the reaction medium is maintained at a temperature from about 60 °C to about 80 °C.

[0243] The contacting step is typically conducted as a batch reaction, in particular a batch reaction in which at least about 50 kilograms of 4-carboxyphenylboronic acid or salt thereof is loaded into the batch reaction. In one aspect, at least about 100 kilograms of 4-carboxyphenylboronic acid or salt thereof is loaded into the batch reaction.

[0244] The process typically provides a stoichiometric process yield of at least about 50% for the compound of formula (V) or salt thereof. In one aspect, the stoichiometric process yield of the compound of formula (V) or salt thereof is at least about 60%. In another aspect, the stoichiometric process yield of the compound of formula (V) or salt thereof is at least about 65%. In another aspect, the stoichiometric process yield of the compound of formula (V) or salt thereof is at least about 70%.

[0245] In another representative embodiment, the present disclosure is directed to a process for preparing a compound having the structure of formula (V):

[0246]

[0247] or a salt thereof, wherein the process comprises 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 acid chloride intermediate, followed by contacting the acid chloride intermediate in situ with 2-aminopyridine to form a reaction mixture comprising the compound of formula (V), or a salt thereof; wherein neither the reaction medium nor the catalyst comprises N,N-dimethylformamide.

[0248] In an aspect, the catalyst comprises a catalyst selected from the group consisting of tetrabutylammonium chloride and N-methyltoluidine. In an aspect, the catalyst comprises tetrabutylammonium chloride. In another aspect, the catalyst comprises N-methyltoluidine. In another aspect, during the contacting step, the reaction medium is maintained at a temperature from about 50 °C to about 90 °C. In another aspect, the process further comprises isolating the compound of Formula (V), or a salt thereof, from the reaction mixture.

[0249] Scheme 12 below corresponds to the process described in Example 11 and illustrates one representative embodiment of an improved process for preparing compound (V).

[0250] Scheme 14

[0251]

[0252] IX. Preparation of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[l,5-a]pyrazin-l-yl}-N-(2- pyridinyl)benzamide (Compound VII)

[0253] The present disclosure relates, in part, to a process for preparing 1-bromo-3-[(2S)-2- pyrrolidinyl]imidazo[l,5-a]pyrazin-8-amine (Compound VI), or a salt thereof, from benzyl (2S)-2-(8-amino-l-bromimidazo[l,5-a]pyrazin-3-yl)-l-pyrrolidinecarboxylate (Compound IV), or a salt thereof. Scheme 13 below illustrates the general process:

[0254] Scheme 15

[0255]

[0256] Due to the presence of the labile bromide on the imidazole ring, initial development efforts to avoid erosive acidic conditions by employing hydrogenation to deprotect Compound (IV), or a salt thereof, and provide Compound (VI), or a salt thereof, were unsuccessful. Further development efforts have encountered challenges related to the generation and / or removal of several impurities.

[0257] First, the deprotection reaction generates a benzyl halide (e.g., benzyl chloride) that can potentially further react with Compound (VI), or a salt thereof, to generate an N-benzyl impurity having the structure of Compound (IX):

[0258]

[0259] Second, the use of dichloromethane in the deprotection reaction can generate an aminal impurity having the structure of Compound (X):

[0260]

[0261] Third, an oxidation impurity having the structure of compound (XI) was observed in several batches of the process step:

[0262]

[0263] The improved process addresses the N-benzyl impurity by removing the benzyl halide from the reaction mixture containing the crude compound (VI) product prior to isolating compound (VI) or a salt thereof from the reaction mixture, for example, by extraction with heptane. The improved process addresses the acetal amine impurity by selecting a solvent that does not generate the acetal amine impurity, for example, replacing dichloromethane with 2-methyltetrahydrofuran. The improved process addresses the oxidation impurity by appropriately controlling the oxygen level in the reaction vessel during the process. Appropriate control of the inertion scheme (e.g., nitrogen purge) and vessel construction materials improves product quality by substantially preventing product discoloration and formation of the oxidation impurity observed in previous campaigns and eliminates the need for prior carbon treatment.

[0264] Accordingly, in one embodiment, the disclosure relates to a process for preparing a compound having the structure of formula (VI):

[0265]

[0266] or a salt thereof, wherein the process comprises:

[0267] contacting a compound having the structure of formula (IV):

[0268]

[0269] 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 byproduct;

[0270] removing at least a portion of the benzyl halide byproduct from the reaction mixture; and

[0271] isolating the compound of formula (VI), or a salt thereof, from the reaction mixture under conditions sufficient to substantially avoid formation of an acetal amine impurity.

[0272] In one aspect, the sulfate salt of the compound of formula (IV) is contacted with an acidic medium.

[0273] The acetal amine impurity generally comprises a compound having the structure of formula (X):

[0274]

[0275] or a salt thereof. In one aspect, the isolated compound of Formula (VI), or a salt thereof, contains less than 5% by weight of the aminal impurity. In another aspect, the isolated compound of Formula (VI), or a salt thereof, contains less than 3% by weight of the aminal impurity. In another aspect, the isolated compound of Formula (VI), or a salt thereof, contains less than 1% by weight of the aminal impurity.

[0276] In one aspect, the acidic medium is an aqueous acidic medium. The aqueous acidic medium typically contains an inorganic acid, in particular hydrochloric acid, and at least about 10 molar equivalents of acid, relative to the compound of Formula (IV), or a salt thereof. In one aspect, the aqueous acidic medium contains from about 10 to about 40 molar equivalents of acid, relative to the compound of Formula (IV), or a salt thereof. In another aspect, the aqueous acidic medium contains from 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 acidic medium is typically about 2 liters to about 10 liters of aqueous acidic medium per kilogram of the compound of Formula (IV), or a salt thereof, charged to the acidic medium. In one aspect, the volume of the aqueous acidic medium is about 3 liters to about 4 liters of aqueous acidic medium per kilogram of the compound of Formula (IV) or a salt thereof charged to the aqueous acidic medium. During the contacting step, the aqueous acidic medium is typically maintained at a temperature from about 25 °C to about 70 °C. In one aspect, during the contacting step, the aqueous acidic medium is maintained at a temperature from about 40 °C to about 50 °C.

[0277] In another embodiment, the method includes removing at least a portion of the benzyl halide byproduct from the reaction mixture; increasing the pH of the resulting reaction mixture to a basic pH to form a basic reaction medium comprising the compound of Formula (VI), or a salt thereof; and isolating the compound of Formula (VI), or a salt thereof, from the basic reaction mixture.

[0278] In another embodiment, the method 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 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 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 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 salt thereof, present in the reaction mixture is extracted into a waste organic phase. In another aspect, at least about 90% by weight of the benzyl halide by-product present in the reaction mixture and less than about 10% by weight of the compound of Formula (VI), or salt thereof, present in the reaction mixture is extracted into a waste organic phase. In another aspect, at least about 95% by weight of the benzyl halide by-product present in the reaction mixture and less than about 5% by weight of the compound of Formula (VI), or salt thereof, present in the reaction mixture is extracted into a waste organic phase.

[0279] The waste organic phase typically includes at least one solvent selected from the group consisting of alkyl hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons, and ethers. In one aspect, the waste organic phase includes 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 aspect, the waste organic phase includes heptane.

[0280] In additional embodiments, the method includes increasing the pH of the reaction mixture after the benzyl halide by-product extraction to form a basic reaction medium including the compound of Formula (VI), or salt thereof; and extracting the compound of Formula (VI), or salt thereof, from the basic reaction medium into a product organic phase. In one aspect, the method 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 (e.g., by adding sodium hydroxide) to a basic pH to form a basic reaction medium including the compound of Formula (VI), or salt thereof; extracting the compound of Formula (VI), or salt thereof, from the basic reaction medium into a product organic phase; and isolating the compound of Formula (VI), or salt thereof, from the product organic phase. The pH of the basic reaction mixture is typically 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.

[0281] The product organic phase typically comprises at least one solvent selected from the group consisting of alkyl hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons, and ethers. In one aspect, the product organic phase comprises at least one compound selected from the group consisting of 2-methyltetrahydrofuran and anisole. In another aspect, the product organic phase comprises 2-methyltetrahydrofuran. In another aspect, the product organic phase does not comprise dichloromethane.

[0282] It can be beneficial to wash the product organic phase (e.g., with water) prior to isolating the compound of Formula (VI), or salt thereof. It can also be beneficial to distill the product organic phase under conditions sufficient to reduce the amount of water present in the product organic phase prior to isolating the compound of Formula (VI), or salt thereof. In one aspect, the method 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 aspect, the product organic phase is distilled at atmospheric pressure. In another aspect, the product organic phase comprises 2-methyltetrahydrofuran and additional 2-methyltetrahydrofuran is charged to the product organic phase during the distillation step.

[0283] The compound of Formula (VI), or salt thereof, can be isolated from the reaction mixture by any suitable means (in particular, crystallizing the compound of Formula (VI), or salt thereof, from the reaction mixture). In one aspect, the isolation step comprises seeding the reaction mixture with a crystalline form of the compound of Formula (VI), or salt thereof, to facilitate crystallization. In another aspect, the isolation step comprises seeding the reaction mixture with at least about 0.005 relative weights of a crystalline form of the compound of Formula (VI), or salt thereof, to facilitate crystallization. In another aspect, the isolation step comprises seeding the reaction mixture with at least about 0.01 relative weights of a crystalline form of the compound of Formula (VI), or salt thereof, to facilitate crystallization. In another aspect, the isolation step comprises seeding the reaction mixture with at least about 0.005 to about 0.02 relative weights of a crystalline form of the compound of Formula (VI), or salt thereof, to facilitate crystallization. It can also be beneficial to charge an anti-solvent to the reaction mixture to facilitate crystallization. In one aspect, the anti-solvent is heptane.

[0284] The contacting step is typically performed as a batch reaction, in particular a batch reaction in which at least about 50 kilograms of the compound of Formula (IV), or salt thereof, is initially charged to the reaction. In one aspect, at least about 100 kilograms of the compound of Formula (IV), or salt thereof, is initially charged to the reaction. In another aspect, at least about 200 kilograms of the compound of Formula (IV), or salt thereof, is initially charged to the reaction. In another aspect, at least about 300 kilograms of the compound of Formula (IV), or salt thereof, is initially charged to the reaction.

[0285] The process generally provides a chemical stoichiometric process yield of at least about 50% of the compound of formula (VI), or salt thereof. In one aspect, the chemical stoichiometric process yield of the compound of formula (VI), or salt thereof, is at least about 65%. In another aspect, the chemical stoichiometric process yield of the compound of formula (VI), or salt thereof, is at least about 75%. In another aspect, the chemical stoichiometric process yield of the compound of formula (VI), or salt thereof, is at least about 80%. Indeed, the improved process has been able to achieve a quality material at about 85% yield at scales in excess of 300 kg (input).

[0286] In another representative embodiment, the present disclosure is directed to a process for preparing a compound having the structure of formula (VI):

[0287]

[0288] or a salt thereof, wherein the process comprises:

[0289] contacting a compound of formula (IV):

[0290]

[0291] or a salt thereof, with an acidic medium under conditions sufficient to deprotect the compound of formula (IV), or salt thereof, and form a reaction mixture comprising a compound of formula (VI), or salt thereof, and a benzyl halide byproduct;

[0292] selectively extracting at least a portion of the benzyl halide byproduct from the reaction mixture into a waste organic phase relative to the compound of formula (VI), or salt thereof;

[0293] increasing the pH of the resulting reaction mixture to a pH greater than about 7.0 to form a basic reaction mixture;

[0294] selectively extracting at least a portion of the compound of formula (VI), or salt thereof, from the basic reaction mixture into a product organic phase; and

[0295] 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 salt thereof.

[0296] In one aspect, the waste organic phase comprises heptane. In another aspect, the product organic phase comprises 2-methyltetrahydrofuran. In another aspect, the waste organic phase comprises heptane and the product organic phase comprises 2-methyltetrahydrofuran. In another aspect, the process further comprises crystallizing the compound of formula (VI), or salt thereof, from the distilled organic phase.

[0297] Scheme 14 below corresponds to the method described in Example 9 and illustrates one representative example of an improved method for preparing compound (VI).

[0298] Scheme 16

[0299]

[0300] X. Preparation of acalabrutinib (Compound VIII) Scheme 17

[0301] The present disclosure is directed, in part, to methods for preparing 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[l,5-a]pyrazin-l-yl}-N-(2-pyridyl)benzamide (Compound VII), or a salt thereof, from [4-(2-pyridylcarbamoyl)phenyl]boronic acid (Compound V), or a salt thereof, and l-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[l,5-a]pyrazin-8-amine (Compound VI), or a salt thereof. Scheme 15 below illustrates the general method:

[0302] Scheme 18

[0303]

[0304] The method employs a Suzuki reaction to couple Compound (V) and Compound (VI) to produce Compound (VII). The clinical trial supply method performed the Suzuki coupling in an 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. The Form 2 crystalline form of Compound (VII) was isolated as a thick, clay-like product, which required oven drying to remove the large amount of water that adhered to the wet paste as it was discharged from the filter.

[0305] Efforts to improve the filterability of crystallized compound (VII) led to the discovery of two additional crystalline forms of compound (VII), designated as the Form 3 crystalline form and the Form C crystalline form. The Form 2 crystalline form has a very fine acicular morphology and is believed to be a hemibutanol solvate hydrate. The Form 3 crystalline form has an acicular morphology and is believed to be a butanol solvate. The Form C crystalline form is an anhydrate with improved morphology that produces larger crystals. Crystallization of compound (VII) from non-aqueous (typically less than 5% water by weight) media was found to produce the Form 3 crystalline form and / or the Form C crystalline form. Both crystalline forms filter faster than the Form 2 crystalline form, but the Form C crystalline form also filters faster than the Form 3 crystalline form. Accordingly, further efforts focused on reducing or substantially removing any water present prior to the initial isolation of compound (VII) (e.g., by distillation) in order to repeatedly isolate compound (VII) as the Form C crystalline form.

[0306] While removing water prior to isolating compound (VII) generally provides the Form C crystalline form, occasionally a batch would still crystallize with varying amounts of the Form 3 crystalline form present. Further investigation determined that the Form C crystalline form is the thermodynamic form at temperatures above about 75 °C. At this temperature, any Form 3 crystalline form present would typically convert to the Form C crystalline form over a relatively short period of time. By incorporating a temperature cycle prior to isolating compound (VII), the Form C crystalline form could routinely be produced as the thermodynamic form. While conversion from the Form C crystalline form back to the Form 3 crystalline form can occur upon cooling below 75 °C (particularly in the presence of residual water), the conversion is sufficiently slow to allow cooling and filtration to occur without significant conversion back to the Form 3 crystalline form.

[0307] Additionally, it was discovered that it was advantageous to move the silica scavenger treatment from the final step in the production of acalabrutinib from compound (VII) (as used in the clinical trial supply process) to the current step in the production of compound (VII). This change in the sequence of the silica scavenger treatment provided a better balance of effective palladium removal versus loss of product yield (scavenger).

[0308] Further, it was discovered that during the Suzuki reaction, long-term scale heating of the process (e.g., processing at 80 °C and atmospheric distillation at 80 °C to 100 °C) resulted in the formation of two impurities (compound (XII) and compound (XIII)) having the structures shown below:

[0309]

[0310] However, by employing lower temperatures (e.g., processing below 60 °C and atmospheric distillation), the formation of these impurities can be suppressed.

[0311] Accordingly, in one embodiment, the disclosure relates to a method for preparing a compound having the structure of Formula (VII):

[0312]

[0313] or a salt thereof, wherein the method comprises:

[0314] contacting a compound having the structure of Formula (V)

[0315]

[0316] or a salt thereof, with a compound having the structure of Formula (VI):

[0317]

[0318] or a salt thereof, in the presence of a base and a palladium catalyst in an aqueous reaction medium comprising an organic solvent to form a reaction mixture comprising a compound having Formula (VII);

[0319] reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising a compound having Formula (VII), or a salt thereof; and

[0320] isolating a compound having Formula (VII), or a salt thereof, from the substantially anhydrous mixture.

[0321] A compound having Formula (VII), or a salt thereof, isolated from a substantially anhydrous mixture, as a substantially crystalline form of a compound having Formula (VII), or a salt thereof. In one aspect, a substantially crystalline form of a compound having Formula (VII) is characterized by a reflective X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 9.9 ± 0.2 °2Q, 11.1 ± 0.2 °2Q, 12.8 ± 0.2 °2Q, 14.1 ± 0.2 °2Q, and 19.0 ± 0.2 °2Q. In another aspect, a substantially crystalline form of a compound having Formula (VII) is characterized by a reflective X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 7.4 ± 0.2 °2Q, 8.9 ± 0.2 °2Q, 9.9 ± 0.2 °2Q, 11.1 ± 0.2 °2Q, 12.8 ± 0.2 °2Q, 14.1 ± 0.2 °2Q, 14.8 ± 0.2 °2Q, 19.0 ± 0.2 °2Q, and 21.6 ± 0.2 °2Q. In another aspect, a substantially crystalline form of a compound having Formula (VII) is characterized by a reflective X-ray powder diffraction pattern comprising at least five peaks selected from the group of peaks. In another aspect, the substantially crystalline form is a substantially anhydrous crystalline form of a compound having Formula (VII).

[0322] The substantially crystalline form of the compound of Formula (VII) is isolated from a substantially anhydrous mixture that typically has at least 50% crystalline purity of Form C. In one aspect, the isolated substantially crystalline form has at least 60% crystalline purity of Form C. In another aspect, the isolated substantially crystalline form has at least 70% crystalline purity of Form C. In another aspect, the isolated substantially crystalline form has at least 80% crystalline purity of Form C. In another aspect, the isolated substantially crystalline form has at least 90% crystalline purity of Form C. In another aspect, the isolated substantially crystalline form has at least 95% crystalline purity of Form C. In another aspect, the isolated substantially crystalline form has at least 96% crystalline purity of Form C. In another aspect, the isolated substantially crystalline form has at least 97% crystalline purity of Form C. In another aspect, the isolated substantially crystalline form has at least 98% crystalline purity of Form C. In another aspect, the isolated substantially crystalline form has at least 99% crystalline purity of Form C. In another aspect, the isolated substantially crystalline form is a substantially pure phase Form C.

[0323] 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. Typically, at least about 0.1 molar equivalent of the alkali metal halide is charged to the aqueous reaction medium relative to the compound of Formula (VI), or salt thereof. In one aspect, about 0.1 to about 1.0 molar equivalent of the alkali metal halide is charged to the aqueous reaction medium relative to the compound of Formula (VI), or salt thereof. In one aspect, about 0.1 to about 1.0 molar equivalent of potassium iodide is charged to the aqueous reaction medium relative to the compound of Formula (VI), or salt thereof. In another aspect, about 0.2 to about 0.4 molar equivalent of potassium iodide is charged to the aqueous reaction medium relative to the compound of Formula (VI), or salt thereof.

[0324] Typically, the compound of Formula (VI), or salt thereof, is contacted with about 0.5 to about 1.5 molar equivalent of the compound of Formula (V), or salt thereof, relative to the compound of Formula (VI), or salt thereof. In one aspect, the compound of Formula (VI), or salt thereof, is contacted with about 0.8 to about 1.2 molar equivalent of the compound of Formula (V), or salt thereof, relative to the compound of Formula (VI), or salt thereof. In another aspect, the compound of Formula (VI), or salt thereof, is contacted with about 0.9 to about 1.1 molar equivalent of the compound of Formula (V), or salt thereof, relative to the compound of Formula (VI), or salt thereof.

[0325] 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, tripropylamine, diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, methyldicyclohexylamine, and potassium phosphate. In one aspect, the base comprises triethylamine. In another aspect, the base comprises potassium carbonate. In another aspect, the base comprises triethylamine and potassium carbonate. Typically, about 0.5 to about 10 molar equivalents of base are charged to the aqueous reaction medium relative to the compound of Formula (VI), or salt thereof. In one aspect, the base comprises triethylamine, and about 0.5 to about 10 molar equivalents of triethylamine are charged to the aqueous reaction medium relative to the compound of Formula (VI), or salt thereof. In another aspect, the base comprises triethylamine, and about 1.0 to about 2.0 molar equivalents of triethylamine are charged to the aqueous reaction medium relative to the compound of Formula (VI), or salt thereof. In another aspect, the base comprises potassium carbonate, and about 0.5 to about 10.0 molar equivalents of potassium carbonate are charged to the aqueous reaction medium relative to the compound of Formula (VI), or salt thereof. In another aspect, the base comprises potassium carbonate, and about 2.0 to about 3.0 molar equivalents of potassium carbonate are charged to the aqueous reaction medium relative to the compound of Formula (VI), or salt thereof. In another aspect, the base comprises potassium carbonate, and about 2.3 to about 2.7 molar equivalents of potassium carbonate are charged to the aqueous reaction medium relative to the compound of Formula (VI), or salt thereof.

[0326] The palladium catalyst can be any suitable palladium catalyst, particularly a catalyst comprising bis-(tert-butyldicyclohexylphosphine)palladium(II) dichloride. Typically, about 0.002 to about 0.05 molar equivalents of palladium catalyst are charged to the aqueous reaction medium relative to the compound of Formula (VI), or salt thereof. In one aspect, about 0.007 to about 0.013 molar equivalents of palladium catalyst are charged to the aqueous reaction medium relative to the compound of Formula (VI), or salt thereof.

[0327] The organic solvent can be any suitable organic solvent, particularly an organic solvent selected from the group consisting of: aromatic hydrocarbons, alcohols, ketones, ethers, esters, and nitriles. In one aspect, 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 aspect, the organic solvent comprises 2-butanol.

[0328] The volume of the aqueous reaction medium is typically about 10 to about 20 liters per kilogram of a compound having formula (VI) or a salt thereof loaded into the aqueous reaction medium. In one aspect, the volume ratio of water to organic solvent in the aqueous reaction medium is about 1:3 to about 3:1. During the contact step, the aqueous reaction medium is typically maintained at a temperature from about 50°C to about 100°C. In another aspect, during the contact step, the aqueous reaction medium is maintained at a temperature from about 70°C to about 90°C.

[0329] In one embodiment, the reduction step includes separating the reaction mixture into an aqueous waste phase and an organic phase comprising a compound having formula (VII). In one aspect, the reduction step further includes distilling the organic phase under conditions sufficient to reduce the amount of water present in the organic phase and providing a substantially anhydrous mixture. In another aspect, the method further includes washing the organic phase with water prior to distillation.

[0330] In another embodiment, the organic phase is treated with a silica remover prior to distillation. In one aspect, the organic phase is treated with the silica remover for at least two hours prior to distillation. The silica remover typically comprises propanethiol-functionalized silica. In another aspect, the silica remover comprises QuadraSil. TM MP. The method may further include 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 method further includes washing the organic phase with an aqueous salt solution after catalyst removal and before distillation.

[0331] In another embodiment, the reduction step includes separating the reaction mixture into an aqueous waste phase and an organic phase comprising a compound having formula (VII) or a salt thereof; washing the organic phase with water; treating the organic phase with a silica remover; removing the silica remover 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.

[0332] The distillation of the organic phase can be carried out under suitable conditions, particularly by vacuum distillation. On one hand, the organic phase is distilled by continuous horizontal vacuum distillation. On the other hand, the organic phase is distilled at a temperature not exceeding about 60°C. On another hand, the organic phase is distilled at a temperature from about 50°C to about 60°C. On another hand, the organic phase contains an alcohol. On another hand, the organic phase is replenished with an alcohol during the distillation step. On another hand, the organic phase contains 2-butanol. On another hand, the organic phase is replenished with 2-butanol during the distillation step.

[0333] The substantially anhydrous mixture typically contains less than about 5% water by weight. In one aspect, the substantially anhydrous mixture contains less than about 3% water by weight. In another aspect, the substantially anhydrous mixture contains less than about 1% water by weight.

[0334] The isolation step typically comprises crystallizing the compound of Formula (VII) from the substantially anhydrous mixture as the Form C crystalline form. To ensure that the product crystallizes as the Form 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 of time that the substantially anhydrous mixture is maintained at a temperature (or temperature range) of at least about 70 °C prior to the initiation of cooling will depend on the temperature (or temperature range) selected. At higher temperatures, a shorter holding period is typically required to convert any non-Form C crystalline forms present to the Form C crystalline form. However, the temperature selected should not result in degradation of the compound of Formula (VII) or exceed the boiling point of the substantially anhydrous mixture. Additionally, stirring the substantially anhydrous mixture during the holding period and / or seeding the substantially anhydrous mixture with the Form C crystalline form can be beneficial in further reducing the duration of any holding period required. Thus, in various embodiments, the substantially anhydrous mixture is maintained at a selected temperature (or temperature range) for a period of time after the initiation of crystallization and prior to the initiation of cooling, wherein the selected temperature (or temperature range) and period of time are sufficient to produce the Form C crystalline form of the compound of Formula (VII) upon cooling of the substantially anhydrous mixture.

[0335] In one aspect, the substantially anhydrous mixture is heated to a temperature of at least about 80 °C. In another aspect, the temperature is at least about 85 °C. In another aspect, the temperature is at least about 90 °C. In another aspect, the temperature is at least about 95 °C. In another aspect, the temperature is from about 70 °C to about 105 °C. In another aspect, the temperature is from about 75 °C to about 105 °C. In another aspect, the temperature is from about 80 °C to about 105 °C. In another aspect, the temperature is from about 85 °C to about 105 °C. In another aspect, the temperature is from about 90 °C to about 105 °C.

[0336] In one aspect, the selected temperature is sufficiently high such that no further holding period is required prior to the initiation of cooling. In another aspect, the holding period prior to cooling is at least about 15 minutes. In another aspect, the holding period prior to cooling is at least about 30 minutes. In another aspect, the holding period prior to cooling is at least about 1 hour. In another aspect, the holding period prior to cooling is at least about 1.5 hours. In another aspect, the holding period prior to cooling is at least about 2 hours.

[0337] In one aspect, the temperature is at least about 75 °C and the hold period prior to cooling is at least about two hours. In another aspect, the temperature is at least about 80 °C and the hold period is at least about 1.5 hours. In another aspect, the temperature is at least about 85 °C and the hold period is at least about 1 hour. In another aspect, the temperature is at least about 90 °C and the hold period is at least about 15 minutes. In another aspect, the temperature is at least about 90 °C and no hold period is required. In another aspect, the temperature is from about 75 °C to about 105 °C and the hold period is from about 15 minutes to about 3 hours. In another aspect, the temperature is from about 80 °C to about 105 °C and the hold period is from about 15 minutes to about 3 hours. In another aspect, the temperature is from about 85 °C to about 105 °C and the hold period is from about 15 minutes to about 3 hours. In another aspect, the temperature is from about 90 °C to about 105 °C and the hold period is from about 5 minutes to about 2 hours. In another aspect, the temperature is from about 90 °C to about 105 °C and no further hold period is required prior to cooling.

[0338] In each of the above aspects, the substantially anhydrous mixture can be seeded with the Form 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 Form C crystalline form, maintained at a temperature of from about 85 °C to about 105 °C for a hold period of from about 5 minutes to about 3 hours, and then cooled to crystallize the compound of Formula (VII).

[0339] The contacting step is typically carried out as a batch reaction, in particular a batch reaction in which at least about 25 kilograms of the compound of Formula (VI), or a salt thereof, is initially charged to the reaction. In one aspect, at least about 50 kilograms of the compound of Formula (VI), or a salt thereof, is initially charged to the reaction. In another aspect, at least about 75 kilograms of the compound of Formula (VI), or a salt thereof, is initially charged to the reaction. In another aspect, at least about 100 kilograms of the compound of Formula (VI), or a salt thereof, is initially charged to the reaction.

[0340] The process typically provides a stoichiometric process yield of at least about 50% of the compound of Formula (VII), or a salt thereof. In one aspect, the stoichiometric process yield of the compound of Formula (VII), or a salt thereof, is at least about 65%. In another aspect, the stoichiometric process yield of the compound of Formula (VII), or a salt thereof, is at least about 75%. Indeed, the improved process has been able to achieve approximately 80% yield of good quality material at scales in excess of 100 kg (input). Furthermore, the improved process has a faster filtration time which significantly reduces the cycle time of the process to less than one week.

[0341] In another representative embodiment, the present disclosure is directed to a process for preparing a compound having the structure of Formula (VII):

[0342]

[0343] or a salt thereof, wherein the method comprises:

[0344] contacting a compound having the structure of Formula (V)

[0345]

[0346] or a salt thereof, with a compound having the structure of Formula (VI):

[0347]

[0348] or a salt thereof, in the presence of a base and a palladium catalyst in an aqueous reaction medium comprising an organic solvent to form a reaction mixture comprising a compound having the structure of Formula (VII);

[0349] separating the reaction mixture into an aqueous waste phase and an organic phase comprising a compound having the structure of Formula (VII), or a salt thereof;

[0350] treating the organic phase with a silica scavenger;

[0351] removing the silica scavenger from the organic phase;

[0352] distilling the organic phase under conditions sufficient to reduce the amount of water present in the organic phase and form a substantially anhydrous mixture comprising a compound having the structure of Formula (VII), or a salt thereof; and

[0353] crystallizing a compound having the structure of Formula (VII) from the substantially anhydrous mixture;

[0354] wherein the compound having the structure of Formula (VII) is crystallized in a Form C crystalline form.

[0355] In one aspect, the method further comprises washing the organic phase with water prior to the treating step. In another aspect, the method further comprises washing the organic phase with an aqueous brine solution after the removing step and prior to the distilling step. In another aspect, the organic phase is distilled by vacuum distillation during which time dry butanol is added to the organic phase and functions to remove water present. In another aspect, the substantially anhydrous mixture is maintained at a temperature greater than 75 °C until any crystalline form present is substantially converted to the Form C crystalline form prior to isolating the compound having the structure of Formula (VII) from the substantially anhydrous mixture.

[0356] Scheme 16 below corresponds to the method described in Example 14 and illustrates one representative embodiment of an improved method for preparing compound (VII).

[0357] Additional Examples

[0358]

[0359] XII. Examples

[0360] The present disclosure is directed, in part, to methods for preparing acalabrutinib, or a salt thereof, from 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[l,5-a]pyrazin-l-yl}-N-(2-pyridinyl)- benzamide (Compound VII), and 2-butynoic acid, or a salt thereof. Scheme 17 below illustrates a general method:

[0361] Example 1: Preparation of benzyl (2S)-2-(l-bromo-8-chloro-imidazo[l,5-a]-pyrazin-3- yl)pyrrolidine-1-carboxylate (Compound (III))

[0362]

[0363] Reacting Compound (VII) with 2-butynoic acid in the presence of a coupling agent to produce acalabrutinib. This coupling step is difficult to operate in a clinical trial supply process. Adding a small excess of 2-butynoic acid to Compound (VII) in dichloromethane resulted in a thick mixture containing butynoate salt of Compound (VII) that was difficult to stir. Subsequent addition of triethylamine to the thick mixture did not significantly improve the viscosity. However, adding triethylamine prior to the addition of 2-butynoic acid avoided the formation of the butynoate salt of Compound (VII) and resulted in a relatively thin stirrable slurry. However, subsequent addition of the coupling agent (e.g., 1-propylphosphonic anhydride) to the resulting slurry was difficult to control and had a narrow in-process control window in order to meet the quality standards for the acalabrutinib product. Underaddition of 1-propylphosphonic anhydride did not consume all of the starting material (i.e., Compound (VII)) and excess addition resulted in the formation of impurities having the structure of Compound (XIV):

[0364]

[0365] In subsequent acalabrutinib product isolation, both unreacted Compound (VII) and Compound (XIV) impurities were difficult to remove and were the cause of multiple batch failures in the clinical trial supply process.

[0366] It was discovered that the use of a sequential extraction method could overcome the difficulties associated with removing both impurities. First, acalabrutinib was selectively extracted from the reaction mixture with respect to the compound (XIV) impurity into an aqueous phase having a first acidic pH (e.g., pH 1.8 to 2.2), and the reaction mixture containing the compound (XIV) impurity was discarded. The pH of the aqueous phase containing acalabrutinib was then adjusted to a second pH (e.g., pH 4.5 to 5.0), and acalabrutinib was selectively extracted from the aqueous phase with respect to the compound (VII) impurity into an organic phase, and the aqueous phase containing the compound (VII) impurity was discarded. As a result of the sequential extraction method, the unwanted impurities from the final product were effectively removed, and thus the 1 -propylphosphonic anhydride addition did not require the same level of rigorous control as in the clinical trial supply method, and the 1 -propylphosphonic anhydride addition was more robust.

[0367] Another problem encountered in the clinical trial supply method involved solvent exchange from dichloromethane to ethanol, which employed multiple “put and take” distillation cycles. The acalabrutinib product would persist in an oily or gummy state prior to final crystallization. It was discovered that the kinetics of acalabrutinib crystallization from ethanol were abnormally slow. The point of oil crystallization could not be controlled, and the crystallized acalabrutinib produced an undesirable amount of crystallization solvent. Thus, the inclusion of dichloromethane in the acalabrutinib crystal lattice was a concern in the clinical trial supply method. A more controlled procedure has now been developed that employs a constant level vacuum distillation (e.g., 18 to 20 relative volumes at 50 °C), which maintains acalabrutinib in solution throughout the distillation (even with complete replacement of the dichloromethane solvent with ethanol) and avoids the oiliness problem. Once the distillation is complete, seeding with crystallized acalabrutinib and maintaining the seeded solution at an appropriate temperature (e.g., 50 °C) results in a controlled crystallization, where the acalabrutinib product can be isolated and has consistent particulate properties. Crystallization further purifies the acalabrutinib product, particularly with respect to any over-acylated byproducts that are present.

[0368] Thus, in one embodiment, the disclosure relates to a method for preparing a compound having the structure of Formula (VIII):

[0369]

[0370] or a salt thereof, wherein the method comprises:

[0371] a compound having the structure of Formula (VII)

[0372]

[0373] or a salt thereof, with 2-butyneoic 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 byproducts; and

[0374] selectively isolating the compound of Formula (VIII), or a salt thereof, from the reaction mixture relative to the one or more byproducts.

[0375] As previously described, the order of addition for the process can have an impact. Typically, the contacting step comprises adding the compound of Formula (VII), or a salt thereof, and the base to the reaction medium; adding the 2-butyneoic acid, or a salt thereof, to the reaction medium comprising the compound of Formula (VII), or a salt thereof, and the base; and adding the 1-propylphosphonic anhydride to the reaction medium comprising the compound of Formula (VII), or a salt thereof; 2-butyneoic acid, or a salt thereof; and the base.

[0376] In another embodiment, the present disclosure relates to a process for preparing a compound of the structure of Formula (VIII):

[0377]

[0378] or a salt thereof, wherein the process comprises:

[0379] a compound of the structure of Formula (VII)

[0380]

[0381] or a salt thereof, with 2-butyneoic 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; unreacted compound of Formula (VII), or a salt thereof; and a reaction byproduct; wherein the reaction byproduct comprises a compound of the structure of Formula (XIV):

[0382]

[0383] or a salt thereof; and

[0384] 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.

[0385] In an aspect, 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. In another aspect, the selectively isolated compound of Formula (VIII), or salt thereof, comprises less than about 0.8% by weight of the compound of Formula (VII), or salt thereof. In another aspect, the selectively isolated compound of Formula (VIII), or salt thereof, comprises less than about 0.6% by weight of the compound of Formula (VII), or salt thereof. In another aspect, the selectively isolated compound of Formula (VIII), or salt thereof, comprises less than about 0.4% by weight of the compound of Formula (VII), or salt thereof. In another aspect, the selectively isolated compound of Formula (VIII), or salt thereof, comprises less than about 0.3% by weight of the compound of Formula (VII), or salt thereof. In another aspect, 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. In another aspect, the selectively isolated compound of Formula (VIII), or salt thereof, comprises less than about 0.8% by weight of the compound of Formula (XIV), or salt thereof. In another aspect, the selectively isolated compound of Formula (VIII), or salt thereof, comprises less than about 0.6% by weight of the compound of Formula (XIV), or salt thereof. In another aspect, the selectively isolated compound of Formula (VIII), or salt thereof, comprises less than about 0.4% by weight of the compound of Formula (XIV), or salt thereof. In another aspect, the selectively isolated compound of Formula (VIII), or salt thereof, comprises less than about 0.3% by weight of the compound of Formula (XIV), or salt thereof. In another aspect, 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, and less than about 1.0% by weight of the compound of Formula (XIV), or salt thereof. In another aspect, the selectively isolated compound of Formula (VIII), or salt thereof, comprises less than about 0.8% by weight of the compound of Formula (VII), or salt thereof, and less than about 0.8% by weight of the compound of Formula (XIV), or salt thereof. In another aspect, the selectively isolated compound of Formula (VIII), or salt thereof, comprises less than about 0.6% by weight of the compound of Formula (VII), or salt thereof, and less than about 0.6% by weight of the compound of Formula (XIV), or salt thereof. In another aspect, the selectively isolated compound of Formula (VIII), or salt thereof, comprises less than about 0.4% by weight of the compound of Formula (VII), or salt thereof, and less than about 0.4% by weight of the compound of Formula (XIV), or salt thereof.In another aspect, the selectively isolated compound of Formula (VIII), or salt thereof, comprises less than about 0.3 wt% of the compound of Formula (VII), or salt thereof, and less than about 0.3 wt% of the compound of Formula (XIV), or salt thereof.

[0386] In another embodiment, the present disclosure relates to a method for preparing a compound having the structure of Formula (VIII):

[0387]

[0388] or salt thereof, wherein the method comprises:

[0389] contacting a compound having the structure of Formula (VII)

[0390]

[0391] or salt thereof, with 2-butyneoic acid, or 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 salt thereof; unreacted compound of Formula (VII), or salt thereof; and a reaction byproduct, wherein the reaction byproduct comprises a compound having the structure of Formula (XIV):

[0392]

[0393] or salt thereof;

[0394] extracting at least a portion of the compound of Formula (VIII), or salt thereof, from the reaction mixture into an aqueous phase, wherein the compound of Formula (VIII), or salt thereof, is selectively extracted into the aqueous phase relative to the compound of Formula (XIV), or salt thereof;

[0395] adjusting the pH of the aqueous phase; and

[0396] extracting at least a portion of the compound of Formula (VIII), or salt thereof, from the aqueous phase into an organic phase, wherein the compound of Formula (VIII), or salt thereof, is selectively extracted into the organic phase relative to the compound of Formula (VII), or salt thereof.

[0397] In one aspect, the contacting step comprises adding the compound of formula (VII), and the base to the reaction medium; adding the 2-butynoic acid to the reaction medium comprising the compound of formula (VII), and the base; and adding the 1 -propylphosphonic anhydride to the reaction medium comprising the compound of formula (VII), 2-butynoic acid, and base. In another aspect, the reaction mixture is washed with water and the washed reaction mixture is separated into an aqueous phase and a waste phase, wherein the compound of formula (VIII) is selectively extracted into the aqueous phase. In another aspect, 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.

[0398] Generally, the compound of formula (VII) is contacted with at least about 0.5 molar equivalents of 2-butynoic acid, relative to the compound of formula (VII). In one aspect, 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 aspect, 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 aspect, the compound of formula (VII) is contacted with about 1.2 molar equivalents of 2-butynoic acid, relative to the compound of formula (VII).

[0399] Generally, at least about 0.3 molar equivalents of 1 -propylphosphonic anhydride are charged to the reaction medium, relative to the compound of formula (VII). In one aspect, at least about 0.5 molar equivalents of 1 -propylphosphonic anhydride are charged to the reaction medium, relative to the compound of formula (VII). In another aspect, at least about 1.0 molar equivalents of 1 -propylphosphonic anhydride are charged to the reaction medium, relative to the compound of formula (VII). In another aspect, about 0.3 to about 3.0 molar equivalents of 1 -propylphosphonic anhydride are charged to the reaction medium, relative to the compound of formula (VII). In another aspect, about 0.5 to about 2.0 molar equivalents of 1 -propylphosphonic anhydride are charged to the reaction medium, relative to the compound of formula (VII). In another aspect, about 0.7 to about 1.5 molar equivalents of 1 -propylphosphonic anhydride are charged to the reaction medium, relative to the compound of formula (VII). In another aspect, about 1.0 to about 1.2 molar equivalents of 1 -propylphosphonic anhydride are charged to the reaction medium, relative to the compound of formula (VII).

[0400] The base can be any suitable base, particularly a base comprising at least one compound selected from the group consisting of triethylamine, tripropylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate. In one aspect, the base comprises triethylamine. Typically, about 1.0 to about 10.0 molar equivalents of base are charged to the reaction medium relative to the compound of Formula (VII). In one aspect, about 2.0 to about 5.0 molar equivalents of base are charged to the reaction medium relative to the compound of Formula (VII). In another aspect, about 2.4 to about 3.0 molar equivalents of base are charged to the reaction medium relative to the compound of Formula (VII).

[0401] 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 aspect, the reaction medium comprises at least one solvent selected from the group consisting of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, t-amyl alcohol, acetone, methyl isobutyl ketone, 2-butanol, methyl ethyl ketone, acetonitrile, and ethyl acetate. In another aspect, the reaction medium comprises dichloromethane. The volume of the reaction medium is typically about 5 liters to about 20 liters of reaction medium per kilogram of the compound of Formula (VII) charged to the reaction medium. During the contacting step, the reaction medium is typically maintained at a temperature from about 10 °C to about 30 °C.

[0402] Generally, after completion of the aqueous phase extraction, 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”). In an aspect, after completion of the aqueous phase extraction, the aqueous phase comprises greater than about 80 area% of the compound of Formula (VIII), as measured by HPLC. In another aspect, after completion of the aqueous phase extraction, the aqueous phase comprises greater than about 85 area% of the compound of Formula (VIII), as measured by HPLC. In another aspect, after completion of the aqueous phase extraction, the aqueous phase comprises greater than about 90 area% of the compound of Formula (VIII), as measured by HPLC. In another aspect, after completion of the aqueous phase extraction, the aqueous phase comprises less than about 1.0 area% of the compound of Formula (XIV), as measured by HPLC. In another aspect, after completion of the aqueous phase extraction, the aqueous phase comprises less than about 0.8 area% of the compound of Formula (XIV), as measured by HPLC. In another aspect, after completion of the aqueous phase extraction, the aqueous phase comprises less than about 0.5 area% of the compound of Formula (XIV), as measured by HPLC. In another aspect, after completion of the aqueous phase extraction, the aqueous phase comprises less than about 0.2 area% of the compound of Formula (XIV), as measured by HPLC. In another aspect, after completion of the aqueous phase extraction, the aqueous phase comprises less than about 0.1 area% of the compound of Formula (XIV), as measured by HPLC. In another aspect, after completion of the aqueous phase extraction, the aqueous 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 (XIV), as measured by HPLC. In another aspect, after completion of the aqueous phase extraction, the aqueous 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 (XIV), as measured by HPLC. In another aspect, after completion of the aqueous phase extraction, 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. In another aspect, after completion of the aqueous phase extraction, 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. In another aspect, after completion of the aqueous phase extraction, 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. During the aqueous phase extraction step, the aqueous phase generally has a pH of less than about 2.5. In an aspect, during the aqueous phase extraction step, the aqueous phase has a pH from about 1.8 to about 2.2.

[0403] Generally, after the organic phase extraction is complete, the organic phase contains 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. In one aspect, after the organic phase extraction is complete, the organic phase contains greater than about 80 area% of the compound of Formula (VIII), as measured by HPLC. In another aspect, after the organic phase extraction is complete, the organic phase contains greater than about 85 area% of the compound of Formula (VIII), as measured by HPLC. In another aspect, after the organic phase extraction is complete, the organic phase contains greater than about 90 area% of the compound of Formula (VIII), as measured by HPLC. In another aspect, after the organic phase extraction is complete, the organic phase contains less than about 1.0 area% of the compound of Formula (VII), as measured by HPLC. In another aspect, after the organic phase extraction is complete, the organic phase contains less than about 0.8 area% of the compound of Formula (VII), as measured by HPLC. In another aspect, after the organic phase extraction is complete, the organic phase contains less than about 0.6 area% of the compound of Formula (VII), as measured by HPLC. In another aspect, after the organic phase extraction is complete, the organic phase contains less than about 0.4 area% of the compound of Formula (VII), as measured by HPLC. In another aspect, after the organic phase extraction is complete, the organic phase contains less than about 0.3 area% of the compound of Formula (VII), as measured by HPLC. In another aspect, after the organic phase extraction is complete, the organic phase contains 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. In another aspect, after the organic phase extraction is complete, the organic phase contains 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. In another aspect, after the organic phase extraction is complete, the organic phase contains 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. In another aspect, after the organic phase extraction is complete, the organic phase contains 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. In another aspect, after the organic phase extraction is complete, the organic phase contains 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. During the organic phase extraction step, the aqueous phase generally has a pH of greater than about 4.0. In one aspect, during the organic phase extraction step, the aqueous phase has a pH of from about 4.5 to about 5.0.

[0404] The organic phase can comprise any suitable solvent, particularly at least one solvent selected from the group consisting of alkyl hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ketones, ethers, esters, and nitriles. In one aspect, the organic phase comprises at least one compound selected from the group consisting of dichloromethane, and 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 aspect, the organic phase comprises dichloromethane.

[0405] 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 aspect, the organic phase comprises an organic phase solvent, and the method further comprises exchanging the organic phase solvent with a replacement solvent to form a crystallization mixture comprising the compound of Formula (VIII). In another aspect, the compound of Formula (VIII) is crystallized from the crystallization mixture. In another aspect, the crystallization mixture is seeded with a crystalline form of the compound of Formula (VIII). In another aspect, the crystallization mixture is seeded with at least about 0.01 relative weights of the crystalline form. In another aspect, the crystallization mixture is seeded with at least about 0.02 relative weights of the crystalline form. In another aspect, the crystallization mixture is seeded with at least about 0.03 relative weights of the crystalline form. In another aspect, the crystalline form is an anhydrate crystalline form.

[0406] The organic phase solvent can comprise any suitable solvent, particularly a polar solvent. In one aspect, the organic phase solvent comprises at least one solvent selected from the group consisting of chlorinated hydrocarbons and ethers. In another aspect, the organic phase solvent comprises at least one compound selected from the group consisting of dichloromethane and 2-methyltetrahydrofuran. In another aspect, the organic phase solvent comprises dichloromethane.

[0407] The replacement solvent can comprise any suitable solvent. In one aspect, the replacement solvent comprises an alcohol. In another aspect, the replacement solvent comprises ethanol. In another aspect, the boiling point of the organic phase solvent is lower than the boiling point of the replacement solvent. In another aspect, the boiling point of the organic phase solvent is at least about 20 °C lower than the boiling point of the replacement solvent. In another aspect, the organic phase solvent comprises a polar solvent and the replacement solvent comprises an alcohol. In another aspect, the organic phase solvent comprises dichloromethane and the replacement solvent comprises ethanol.

[0408] In one embodiment, the organic phase solvent is replaced with a replacement solvent by continuous horizontal distillation. In one aspect, the continuous horizontal distillation is conducted during the continuous distillation under conditions sufficient to maintain the compound of Formula (VIII) in solution. In another aspect, the continuous horizontal distillation is continuous horizontal vacuum distillation. In another aspect, the replacement solvent is charged during the distillation in an amount sufficient to maintain at least about 15 relative volumes of total solvent per kilogram of the compound of Formula (VIII). In another aspect, the replacement solvent is charged during the distillation in an amount sufficient to maintain at least about 18 relative volumes of total solvent per kilogram of the compound of Formula (VIII). In another aspect, the continuous horizontal vacuum distillation is conducted at a temperature of no more than about 60 °C.

[0409] It can generally be beneficial to maintain the crystallization mixture at a temperature greater than about 40 °C for a period of time after the onset of crystallization (e.g., after seeding). In one aspect, the crystallization mixture is maintained at a temperature greater than about 40 °C for at least about one hour after the onset of crystallization. In another aspect, the crystallization mixture is maintained at a temperature greater than about 40 °C for at least about two hours after the onset of crystallization. In another aspect, the crystallization mixture is maintained at a temperature greater than about 40 °C for at least about three hours after the onset of crystallization. In another aspect, the crystallization mixture is maintained at a temperature greater than about 40 °C for at least about four hours after the onset of crystallization. In another aspect, the crystallization mixture is maintained at a temperature greater than about 40 °C for at least about five hours after the onset of crystallization. In another aspect, the crystallization mixture is seeded with a crystalline form of the compound of Formula (VIII). In another aspect, the crystallization mixture is cooled to a temperature of about 20 °C over a period of at least five hours prior to isolating the compound of Formula (VIII). In another aspect, the crystallization mixture is seeded with a crystalline form of the compound of Formula (VIII), maintained at a temperature greater than about 40 °C for at least about five hours, and then cooled to a temperature of about 20 °C over a period of at least five hours prior to isolating the compound of Formula (VIII).

[0410] The contacting step is typically conducted as a batch reaction, in particular a batch reaction in which at least about 25 kilograms of the compound of Formula (VII), or a salt thereof, is initially charged to the reaction. In one aspect, at least about 50 kilograms of the compound of Formula (VII), or a salt thereof, is initially charged to the reaction. In another aspect, at least about 75 kilograms of the compound of Formula (VII), or a salt thereof, is initially charged to the reaction. In another aspect, at least about 100 kilograms of the compound of Formula (VII), or a salt thereof, is initially charged to the reaction.

[0411] The process generally provides a chemical stoichiometric process yield of at least about 50% of the compound of formula (VIII), or salt thereof. In one aspect, the chemical stoichiometric process yield of the compound of formula (VIII), or salt thereof, is at least about 60%. In another aspect, the chemical stoichiometric process yield of the compound of formula (VIII), or salt thereof, is at least about 65%. In another aspect, the chemical stoichiometric process yield of the compound of formula (VIII), or salt thereof, is at least about 70%. Indeed, the improved process has been able to achieve a quality material at about 75% yield at scales in excess of 100 kg (input).

[0412] In another representative embodiment, the present disclosure is directed to a process for preparing a compound having the structure of formula (VIII):

[0413]

[0414] or salt thereof, wherein the process comprises:

[0415] contacting a compound having the structure of formula (VII)

[0416]

[0417] or salt thereof, with 2-butyneoic acid, or 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 reaction byproducts, wherein the reaction byproducts comprise a compound having the structure of formula (XIV):

[0418]

[0419] or salt thereof;

[0420] extracting at least a portion of the compound of formula (VIII), or salt thereof, from the reaction mixture into an aqueous phase having a pH from 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);

[0421] adjusting the pH of the aqueous phase to about 4.5 to about 5.0; and

[0422] extracting at least a portion of the compound of formula (VIII) 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).

[0423] In an aspect, the contacting step comprises adding the compound of formula (VII), and the base to the reaction medium; adding the 2-butynoic acid to the reaction medium comprising the compound of formula (VII), and the base; and adding the 1-propylphosphonic anhydride to the reaction medium comprising the compound of formula (VII), 2-butynoic acid, and base. In another aspect, the reaction mixture is washed with water and the washed reaction mixture is separated into an aqueous phase and a waste phase, wherein the compound of formula (VIII) is selectively extracted into the aqueous phase. In another aspect, the organic phase comprises an organic phase solvent, and the method further comprises exchanging the organic phase solvent with a replacement solvent to form a crystallization mixture comprising the compound of formula (VIII). In another aspect, the method further comprises isolating the compound of formula (VIII) from the crystallization mixture. In another aspect, 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 five hours after crystallization begins.

[0424] Scheme 18 below corresponds to the method described in Example 17 and illustrates one representative embodiment of an improved method for preparing compound (VI).

[0425] Example 2: Preparation of benzyl (2S)-2-(8-chloro-imidazo[l,5-a]pyrazin-3-yl)pyrrolidine- 1-carboxylate (Compound (II))

[0426]

[0427] XIII. Table 3

[0428] Various embodiments of each of the above-described methods can be combined to provide further embodiments of the overall method of preparing acalabrutinib. The embodiments described below are representative embodiments further describing the overall method. They are intended to be illustrative and not limiting of the overall method.

[0429] In one embodiment, a compound of the structure of formula (VIII):

[0430]

[0431] or a salt thereof, is prepared by a method comprising:

[0432] contacting a compound of the structure of formula (VII)

[0433]

[0434] 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 byproducts; and

[0435] selectively separating the compound of Formula (VIII), or salt thereof, from the reaction mixture relative to the one or more byproducts;

[0436] The compound of Formula (VII), or salt thereof, is prepared by a process comprising:

[0437] contacting a compound of Formula (V)

[0438]

[0439] or salt thereof, with a compound of Formula (VI):

[0440]

[0441] or salt thereof, in the presence of a base and a palladium catalyst in an aqueous reaction medium comprising an organic solvent to form a reaction mixture comprising a compound of Formula (VII);

[0442] reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising a compound of Formula (VII), or salt thereof; and

[0443] separating the compound of Formula (VII), or salt thereof, from the substantially anhydrous mixture.

[0444] In another embodiment, a compound of Formula (VIII):

[0445]

[0446] or salt thereof, is prepared by a process comprising:

[0447] contacting a compound of Formula (VII)

[0448]

[0449] or salt thereof, with 2-butyneoic acid, or 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 salt thereof; unreacted compound of Formula (VII), or salt thereof; and a reaction byproduct, wherein the reaction byproduct comprises a compound of Formula (XIV):

[0450]

[0451] or salt thereof;

[0452] extracting at least a portion of the compound of Formula (VIII), or salt thereof, from the reaction mixture into an aqueous phase, wherein the compound of Formula (VIII), or salt thereof, is selectively extracted into the aqueous phase relative to the compound of Formula (XIV), or salt thereof;

[0453] adjusting the pH of the aqueous phase; and

[0454] extracting at least a portion of the compound of Formula (VIII), or salt thereof, from the aqueous phase into an organic phase, wherein the compound of Formula (VIII), or salt thereof, is selectively extracted into the organic phase relative to the compound of Formula (VII), or salt thereof;

[0455] wherein the compound of structure of Formula (VII), or salt thereof, is prepared by a process comprising:

[0456] contacting a compound of structure of Formula (V)

[0457]

[0458] or salt thereof, with a compound of structure of Formula (VI):

[0459]

[0460] or salt thereof, in the presence of a base and a palladium catalyst in an aqueous reaction medium comprising an organic solvent to form a reaction mixture comprising a compound of Formula (VII), or salt thereof;

[0461] reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising a compound of Formula (VII), or salt thereof; and

[0462] isolating the compound of Formula (VII), or salt thereof, from the substantially anhydrous mixture.

[0463] In another embodiment, the process further comprises preparing the compound of structure of Formula (VI), or salt thereof, by a process comprising:

[0464] contacting a compound of Formula (IV):

[0465]

[0466] or salt thereof, with an acidic medium under conditions sufficient to deprotect the compound of Formula (IV), or salt thereof, and form a reaction mixture comprising a compound of Formula (VI), or salt thereof, and a benzyl halide byproduct;

[0467] removing at least a portion of the benzyl halide byproduct from the reaction mixture; and

[0468] isolating the compound of Formula (VI), or salt thereof, from the reaction mixture under conditions sufficient to substantially avoid formation of an aminal impurity.

[0469] In another embodiment, the method further comprises preparing the compound of structure of Formula (V), or salt thereof, by a method comprising contacting 4-carboxyphenylboronic acid, or salt thereof, with thionyl chloride and a catalyst in a reaction medium comprising an organic solvent to form an acyl chloride intermediate, which is then contacted in situ with 2-aminopyridine to form a reaction mixture comprising the compound of Formula (V), or salt thereof.

[0470] In another embodiment, the method further comprises preparing the compound of structure of Formula (IV), or salt thereof, by a method comprising contacting a compound of structure of Formula (III)

[0471]

[0472] or salt thereof, with an amine-forming agent in a reaction medium to form a reaction mixture comprising the compound of Formula (IV);

[0473] forming a sulfate salt of the compound of Formula (IV); and

[0474] isolating the sulfate salt.

[0475] In another embodiment, the method further comprises preparing the compound of structure of Formula (III), or salt thereof, by a method comprising contacting a compound of structure of Formula (I)

[0476]

[0477] or salt thereof, with a cyclization agent in the presence of a catalyst in a reaction medium to form the compound of Formula (II);

[0478]

[0479] or salt thereof; and

[0480] brominating the compound of Formula (II), or salt thereof, with a brominating agent to provide the compound of structure of Formula (III):

[0481]

[0482] or salt thereof;

[0483] 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 of the compound of Formula (II), or salt thereof.

[0484] In another embodiment, the disclosure relates to a method for preparing a compound having the structure of Formula (VIII):

[0485]

[0486] or a salt thereof, wherein the method comprises:

[0487] contacting a compound having the structure of Formula (V)

[0488]

[0489] or a salt thereof, with a compound having the structure of Formula (VI):

[0490]

[0491] or a salt thereof, in the presence of a base and a palladium catalyst in an aqueous reaction medium comprising an organic solvent to form a reaction mixture comprising a compound having the structure of Formula (VII):

[0492]

[0493] or a salt thereof;

[0494] reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising the compound having the structure of Formula (VII), or a salt thereof;

[0495] isolating the compound having the structure of Formula (VII), or a salt thereof, from the substantially anhydrous mixture; and

[0496] converting the compound having the structure of Formula (VII), or a salt thereof, to a compound having the structure of Formula (VIII), or a salt thereof.

[0497] In another embodiment, the disclosure relates to a method for preparing a compound having the structure of Formula (VIII):

[0498]

[0499] or a salt thereof, wherein the method comprises:

[0500] contacting a compound having the structure of Formula (IV)

[0501]

[0502] or a salt thereof, with an acidic medium under conditions sufficient to deprotect the compound having the structure of Formula (IV), or a salt thereof, and form a compound comprising the structure of Formula (VI):

[0503]

[0504] or salts thereof, and benzyl halide byproducts;

[0505] removing at least a portion of the benzyl halide byproducts from the reaction mixture;

[0506] 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; and

[0507] converting the compound of Formula (VI), or a salt thereof, to a compound of Formula (VIII), or a salt thereof.

[0508] In another embodiment, the present disclosure relates to a method for preparing a compound having the structure of Formula (VIII):

[0509]

[0510] or a salt thereof, wherein the method comprises:

[0511] contacting a compound having the structure of Formula (III)

[0512]

[0513] or a salt thereof, with an aminating agent in a reaction medium to form a reaction mixture comprising a compound having the structure of Formula (IV):

[0514]

[0515] forming a sulfate salt of the compound of Formula (IV);

[0516] isolating the sulfate salt; and

[0517] converting the sulfate salt to a compound of Formula (VIII), or a salt thereof.

[0518] In another embodiment, the present disclosure relates to a method for preparing a compound having the structure of Formula (VIII):

[0519]

[0520] or a salt thereof, wherein the method comprises:

[0521] contacting a compound having the structure of Formula (I)

[0522]

[0523] or a salt thereof, with a cyclization agent in the presence of a catalyst in a reaction medium to form a compound of Formula (II);

[0524]

[0525] or a salt thereof;

[0526] brominating a compound of formula (II), or a salt thereof, with a brominating agent to provide a compound having the structure of formula (III):

[0527]

[0528] or a salt thereof; and

[0529] converting the compound of formula (III), or a salt thereof, to a compound of formula (VIII), or a salt thereof;

[0530] 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 of the compound of formula (II), or a salt thereof.

[0531] In another embodiment, the present disclosure relates to a method for preparing a compound having the structure of formula (VIII):

[0532]

[0533] or a salt thereof, wherein the method comprises:

[0534] contacting a compound having the structure of formula (I)

[0535]

[0536] or a salt thereof, with a cyclization agent in the presence of a catalyst in a reaction medium to form a compound having the structure of formula (II):

[0537]

[0538] or a salt thereof; and

[0539] converting the compound of formula (II), or a salt thereof, to a compound of formula (VIII), or a salt thereof;

[0540] 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 of the compound of formula (II), or a salt thereof.

[0541] Overall, the improved large scale process has reduced batch failures and provides high quality acalabrutinib that can be routinely manufactured from compound (I) in large scale at greater than 32% yield.

[0542] XIV. Example 3: Preparation of benzyl (2S)-2-(l-bromo-8-chloro-imidazo[l,5-a]pyrazin-3- yl)pyrrolidine-1-carboxylate (Compound (III))

[0543] Example 4: Preparation of the sulfate salt of benzyl (2S)-2-(8-amino-l-bromoimidazo[l,5- a]pyrazin-3-yl)-l-pyrrolidinecarboxylate (sulfate salt of Compound (IV)) Example 5: Preparation of the sulfate salt (2:3) of benzyl (2S)-2-(8-amino-l- bromoimidazo[l,5-a]pyrazin-3-yl)-l-pyrrolidinecarboxylate (Compound (IV))

[0544]

[0545] Benzyl (2S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl]pyrrolidine-1-carboxylate (Compound (I); 179.4 kg, 1.00 mol. equiv.) was mixed with acetonitrile (809.6 kg, 4.5 relative volumes) and N,N-dimethylformamide (6.8 kg, 0.1 mol. equiv.) and phosphorus oxychloride (140.2 kg, 1.9 mol. equiv.) was added slowly, maintaining the temperature below 25 °C. The reaction mixture was heated at 72 °C to 82 °C under a nitrogen purge to remove the hydrochloric acid released until the reaction showed completion. The mixture was allowed to cool to 35 °C to 45 °C and then concentrated to approximately 3.6 relative volumes while maintaining the temperature below 45 °C. Acetonitrile (350.2 kg, 1.95 relative volumes) was added and the mixture concentrated to approximately 3.6 relative volumes while maintaining the temperature below 45 °C, this was further repeated once. The mixture was cooled to 15 °C to 25 °C and then slowly transferred to a cooled solution of sodium bicarbonate (136.6 kg, 8.0 mol. equiv.), water (1139 L, 6.3 relative volumes) and ice (375.8 kg, 2.1 relative volumes).

[0546] The product was then extracted from the mixture twice with dichloromethane (905 kg, 5.0 relative volumes). The combined organic extracts were then washed with a solution of sodium bicarbonate (1 14.4 kg) in water (1 139 L), then 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 filter cake twice with dichloromethane (909 kg). The solvent was removed by vacuum distillation to about 1.0 relative volumes, maintaining the temperature below 40 °C. N-methylpyrrolidinone (819 kg, 4.6 relative volumes) was added to dissolve the mixture, followed by incremental addition of N-bromosuccinimide (77.3 kg, about 1.1 mol. equiv.), stirring at 20-30 °C after each loading until deemed complete. The mixture was then added to a solution of sodium bicarbonate (21.8 kg) in water (1092 L), and the product was then extracted with dichloromethane (1500 kg, 8.4 relative volumes) and then dichloromethane (907 kg, 5.1 relative volumes). The organic phases were combined and washed with water (682 L) three times, and then washed with water (382 L) a further eight times. The organic solution was concentrated to about 1.0 relative volumes and concentrated from heptane (191 kg, 1.1 relative volumes) before adding heptane (191 kg, 1.1 relative volumes) to crystallise. Filtration and drying gave 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%.

[0547] However, the above process conditions often result in batches with reduced chiral purity and yield, and sometimes even batch failure. The liberated hydrochloric acid creates acidic conditions which result in racemisation of the benzyl (2S)-2-[(3-chloropyrazin-2-yl)methylaminocarbamoyl]-pyrrolidine-1 -carboxylate starting material. Although the use of a nitrogen purge to remove the liberated hydrochloric acid reduces the extent of racemisation, control of the extent of chiral erosion is still highly variable.

[0548] Figure 1 Example 6: Analysis of the sulfate salt of benzyl (2S)-2-(8-amino-l-bromoimidazo[l,5- a]pyrazin-3-yl)-l-pyrrolidinecarboxylate (sulfate salt of Compound (IV))

[0549]

[0550] 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[l,5-a]pyrazin-3-yl)pyrrolidine- 1-carboxylate was evaluated relative to the conditions of Example 1. As described below, increasing the amount of N,N- dimethylformamide catalyst to at least 0.6 mol. equivalents increased the rate of reaction and allowed the reaction to be run at lower temperatures. These changes in process conditions increased the yield and provided improved control over the chiral purity of the product.

[0551] Benzyl (2S)-2-[(3-chloropyrazin-2-yl)methylaminocarbonyl]pyrrolidine- 1-carboxylate (Compound (I), 1.00 g) was combined with acetonitrile (5 ml) in four small vials with magnetic stir bars and N,N-dimethylformamide (0.08, 0.12, 0.16, and 0.20 g; 0.4, 0.6, 0.8, and 1.0 mol. equivalents) was added. Phosphorus oxychloride (0.82 g, 2.0 mol. equivalents) was added to each vial and the contents were stirred for 15 minutes, then placed in a heating block preheated to 42 °C, and stirred. The temperature of the contents of the vials reached 41 °C. At 1, 3, 5, and 21 hours, 0.50 ml samples were withdrawn from each vial. The samples were quenched into 10 ml saturated sodium bicarbonate solution, extracted into 5 ml methyl tert-butyl ether, and the organic layers were separated and dried over magnesium sulfate. The extracts were analyzed for purity and chirality by HPLC. The results are shown in Table 3 below.

[0552] Confirmation of salt stoichiometry

[0553]

[0554]

[0555] Table 4 Single crystal X-ray diffraction analysis

[0556]

[0557] In view of the results of Example 2 and the scaled-up modified process, the synthesis described in Example 1 was modified. The modified process provided improved yields and largely avoided the racemization problems previously encountered during cyclization.

[0558] Benzyl (2S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl]pyrrolidine-1-carboxylate (Compound (I), 337.5 kg, 1.00 mol. equiv.) was mixed with acetonitrile (1688 L, 5.0 relative volumes) and N,N-dimethylformamide (39.5 kg, 0.6 mol. equiv.) and phosphorus oxychloride (276.1 kg, 2.0 mol. equiv.) was added slowly, 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 solution of cooled sodium bicarbonate (605.1 kg, 8.0 mol. equiv.) and water (3375 L, 10.0 relative volumes). The product was then extracted from the mixture with methyl tert-butyl ether (1013 L, 3.0 relative volumes) three times. The combined organic extracts were then washed with a solution of sodium bicarbonate (151.3 kg, 2.0 mol. equiv.) in water (2025 L, 6.0 relative volumes), then washed with a 25% w / w aqueous brine solution (675 kg, 2.0 relative weight), and then recycled through a bag filter containing magnesium sulfate. The solvent was removed by vacuum distillation (jacket temperature 30 °C) to give a dark red oil. N,N-dimethylformamide (1350 L, 4.0 relative volumes) was added to dissolve the oil, followed by incremental addition of N-bromosuccinimide (160.3 kg, 1.0 mol. equiv.) with stirring at 20 °C after each load. After the reaction was deemed complete, the temperature was maintained below 10 °C, the mixture was cooled to 5 °C and a 2% w / w aqueous sodium bicarbonate solution (2531 L, 7.5 relative volumes) was added slowly to precipitate the product. The mixture was filtered and washed with a pre-mixed solution of water (675 L, 2.0 relative volumes) and N,N-dimethylformamide (338 L, 1.0 relative volumes), and then washed twice with water (675 L, 2.0 relative volumes). The resulting solid was returned to the reactor and re-slurried in water (1688 L, 5.0 relative volumes). The product was isolated and washed twice with water (675 L, 2.0 relative volumes), and dried under vacuum at 45 °C to give solid benzyl (2S)-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%.

[0559] The compound exists as a mixture of conformers in solution and the resonance is quoted for the major conformer only.1H NMR (500 MHz, 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 = 12.3 Hz, 1H), 4.99 (d, J = 12.3 Hz, 1H), 5.41 (dd, J = 7.7, 4.6 Hz, 1H), 6.67 - 6.71 (m, 2H), 7.08 - 7.13 (m, 2H), 7.16 - 7.22 (m, 2H), 8.28 (d, J = 5.0 Hz, 1H).13C NMR (126 MHz, 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.

[0560] X-ray powder diffraction analysis Figure 1

[0561]

[0562] Benzyl (2S)-2-(l-bromo-8-chloro-imidazo[l,5-a]pyrazin-3-yl)pyrrolidine-l-carboxylate (Compound (III), 90.0 kg, 1.00 mol. equiv.) was mixed with isopropanol (351 kg, 3.0 relative weight) and N-methylpyrrolidinone (180 kg, 2.0 relative weight) in a sealed autoclave. Ammonia (451 kg, 5.0 relative weight) was pumped into the mixture, which was then heated to 90 °C to 95 °C until the reaction was complete. The reaction mixture was cooled to 50 °C to 60 °C and added to water (900 kg, 10.0 relative volume). It was cooled to 20 °C to 30 °C and extracted with dichloromethane (957 kg, 10.6 relative weight), and then extracted with dichloromethane (360 kg, 4.0 relative weight). The organic phases were combined and washed with water, and then concentrated to about 2.5 relative volume. Maintaining the temperature below 25 °C, ethanol (574 kg, 6.4 relative weight) was added to the mixture and then concentrated sulfuric acid (30.4 kg, 1.5 mol. equiv.) was slowly added. The resulting slurry was cooled to 0 °C to 5 °C and then filtered and dried under vacuum at 40 °C to obtain an off-white crystalline solid which was the sulfate salt of benzyl (2S)-2-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3-yl)-l-pyrrolidinecarboxylate (Compound (IV), 89.2 kg, 83.5% based on monosulfate assumption).

[0563] Table 5 Example 7: Preparation of l-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[l,5-a]pyrazin-8-amine (Compound (VI))

[0564]

[0565] The synthesis described in Example 4 assumes a 1:1 free base to salt ratio for the final product, but the assay and mass balance do not agree. Therefore, the synthesis was further modified as described below to obtain a final product with a defined stoichiometry that can satisfy regulatory requirements for characterization of intermediates used in the manufacture of a registered drug substance. The presence of inorganic ammonium sulfate in the Example 4 product resulted in difficulty in accurately determining the stoichiometry of the sulfate salt. The modified method below removes residual ammonia prior to generation of the sulfate salt and essentially eliminates this problem.

[0566] Benzyl (2S)-2-(l-bromo-8-chloro-imidazo[l,5-a]pyrazin-3-yl)pyrrolidine-l-carboxylate (Compound (III), 336.5 kg, 1.00 mol. equiv.) was mixed with 2-butanol (1683 L, 5.0 relative volumes) and 30% w / w ammonium hydroxide (841 kg, 2.5 relative weights) 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 a 50:50 salt:water solution (337 L, 1.0 relative volumes) and then distilled under vacuum at about 40 °C to about one third of its volume. 2-Butanol (1346 L, 4.0 relative volumes) and water (841 L, 2.5 relative volumes) were added to dissolve the oil and the lower aqueous phase was removed and discarded. The organic phase was filtered to remove interfacial material and then 93% sulfuric acid (122.2 kg, 1.5 mol. equiv.) was added slowly maintaining the temperature below 25 °C. The resulting slurry was cooled to 0-5 °C and then filtered, washed with 10% v / v aqueous 2-butanol (673 L, 2.0 relative volumes) and then dried under vacuum at 40 °C to give an off-white crystalline solid which was benzyl (2S)-2-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3-yl)-l-pyrrolidine-carboxylate (Compound (IV), 324.4 kg, 87.2% calculated as sulfate of sulfate (2:3).

[0567] The compound exists as a mixture of conformers in solution and the resonance is quoted for the major conformer only.1H NMR (500 MHz, 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 = 12.1 Hz, 1H), 5.02 (d, J = 12.1 Hz, 1H), 5.30 (dd, J = 7.6, 5.3 Hz, 1H), 6.79-6.84 (m, 3H), 7.12-7.22 (m, 3H), 7.73 (d, J = 6.0 Hz, 1H), 9.48 (br s, 2H).13C NMR (126 MHz, 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 Example 8: Preparation of l-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[l,5-a]pyrazin-8-amine (Compound (VI))

[0568] ​​ ​

[0569] A. ​

[0570] Purified benzyl(2S)-2-(8-amino-1-bromoimidazolo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (compound (IV) free base, 500 mg) was combined with ethanol (8 ml) in four vials equipped with magnetic stir bar, and concentrated sulfuric acid (0.25, 0.50, 0.75, and 1.0 mol. equivalents) was added. The mixture was kept in this state for one hour, and then cooled to 0 °C for one hour, followed by filtration and drying under vacuum. The results are presented in Table 4 below, demonstrating that the stoichiometry is inconsistent with the previously assumed 1:1 salt ratio, but consistent with a 2:3 ratio.

[0571] ​

[0572]

[0573] B. ​

[0574] Single crystals of the sulfate of benzyl(2S)-2-(8-amino-1-bromoimidazolo[1,5-a]pyrazin-3-yl)-1-pyrrolidine carboxylate (compound (IV)) were grown by slow evaporation from dimethyl sulfoxide. Suitable crystals for single-crystal X-ray diffraction were identified and analyzed by single-crystal diffraction. Details of the crystal data: 3(C 18 H 19 BrN5O2) . SO4 . HSO4 . H2O.,M r =1463.02, trigonal crystal system, R3 (No.146),

[0575] α=90°, β=90°, γ=120°, T = 100(2)K, Z = 3, Z' = 0.33333, μ(CuKα) = 3.748, 30561 reflections were measured, and a unique 3873 reflections (R) were used in all calculations. int =0.0306). The final wR2 is 0.0791 (all data) and R1 is 0.0292 (I>2(I)). Flack parameter = -0.023(5).

[0576] The stoichiometry was confirmed as three molecules of benzyl (2S)-2-(8-amino-1- bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate with one molecule of sulfate and one molecule of hydrogen sulfate. Although analysis of the crystal structure also identified one molecule of water / three molecules of benzyl (2S)-2-(8-amino-1- bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate, further diffraction studies and thermal analysis indicated that this can be variable without having a substantial impact on the overall structure or salt stoichiometry.

[0577] C. ​

[0578] X-ray powder diffraction data was collected by mounting a powder sample of benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (Compound (IV)) sulfate onto a silicon wafer holder and analyzing the sample using a Bruker D4 Endeavour diffractometer The sample was measured in reflection geometry in a theta-2 theta scan mode configuration over a scan range of 2° to 40° 2 theta, with 0.12 second exposure / 0.02° increment. The X-rays were generated by a long fine focus copper tube operating at 40 kV and 40 mA. The resulting X-ray diffraction pattern is shown in ​ wherein the selected peaks and relative intensities are reported in Table 5 below.

[0579] ​

[0580]

[0581]

[0582] Characteristic peaks of this crystalline form include peaks at 7.7, 10.6, 11.1, 12.6, 13.5, 17.4, 18.0, 18.9, 19.2, and 21.9 ± 0.2° 2 theta, in particular peaks at 7.7, 10.6, 11.1, 12.6, and 13.5 ± 0.2° 2 theta.

[0583] ​ ​

[0584]

[0585] Benzyl (2S)-2-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3-yl)-l-pyrrolidinecarboxylate (Compound (IV), 261 kg, 1.0 mol. equiv.) sulfate salt (2:3) and concentrated aqueous hydrochloric acid (996 L, 3.8 relative weights) were combined and heated to 40-50 °C for at least two hours under an inert atmosphere. The batch was cooled and washed with methyl tert-butyl ether (192 kg, 4 x 0.73 relative weights) four times. An aqueous sodium hydroxide solution was added slowly with cooling to achieve a pH greater than 12. The product was extracted with dichloromethane (3632 kg, 13.9 relative weights), clarified with celite, and then decolorized with palladium on carbon (13 kg, 0.05 relative weights). The organic extract was concentrated to approximately 0.86 relative volume at atmospheric pressure. Methyl tert-butyl ether (519 L, 1.99 relative weights) was added, the mixture was cooled to 20 °C, and the resulting slurry was filtered and washed with a mixture of methyl tert-butyl ether, then dried under vacuum at 40 °C to yield solid l-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[l,5-a]pyrazin-8-amine (Compound (VI), 119 kg, 78% yield).

[0586] ​ ​

[0587]

[0588] Benzyl (2S)-2-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3-yl)-l-pyrrolidinecarboxylate (Compound (IV), 370 kg) sulfate salt (2:3) and concentrated aqueous hydrochloric acid were combined and heated to 50 °C for at least six hours. The batch was cooled and washed with methyl tert-butyl ether and then washed with heptane. An aqueous sodium hydroxide solution was added slowly with cooling to achieve a pH greater than 12. The product was extracted with dichloromethane and methanol was added. The solution was clarified with celite, and then decolorized with palladium on carbon. The organic extract was concentrated and exchanged to methyl tert-butyl ether at atmospheric pressure. The resulting mixture was cooled, the resulting slurry was filtered and washed with a mixture of methyl tert-butyl ether, and then dried under vacuum to yield solid l-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[l,5-a]pyrazin-8-amine (Compound (VI), 188.8 kg). This product required further purification to remove the aminal impurity by slurrying in ethyl acetate, filtering, and washing the filter cake with ethyl acetate.

[0589] Example 9: Preparation of l-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[l,5- a]pyrazin-8-amine (Compound (VI)) Example 10: Preparation of [4-(2-pyridylcarbamoyl)phenyl]boronic acid (Compound (V))

[0590]

[0591] The synthesis exemplified in Examples 7 and 8 sometimes resulted in elevated impurities (e.g. aminal impurities when dichloromethane was used as the extraction solvent) and poor operability. Accordingly, the process described below was developed to improve the purity of the final product.

[0592] Benzyl (2S)-2-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3-yl)-l-pyrrolidinecarboxylate (Compound (IV), 343 kg, 1.0 mol. equiv.) sulfate salt (2:3) and 37% w / w aqueous hydrochloric acid (1142 L, 3.33 relative volumes) were combined and heated to 40 °C for 14 hours under an inert atmosphere. The batch was cooled and washed with heptane twice (1715 L, 5.0 relative volumes). A 30% w / w aqueous sodium hydroxide solution (104.4 kg, 1.10 mol. eq.) was added slowly with cooling to achieve a pH greater than 10. The product was extracted with 2-methyltetrahydrofuran twice (2401 L, 7.0 relative volumes) and the combined extracts were washed with water (343 L, 1.0 relative volume) before being concentrated under atmospheric pressure to a volume of 3.5 relative volumes. 2-Methyltetrahydrofuran (1029 L, 3.0 relative volumes) was added and the mixture was concentrated under atmospheric pressure to a volume of 1200 L, 3.5 relative volumes. The mixture was cooled to 70 °C and crystalline l-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[l,5-a]pyrazin-8-amine (Compound (VI), 0.34 kg, 0.001 relative weight) was added to seed the mixture. The mixture was cooled to 20 °C and heptane (686 L, 2.0 relative volumes) was added. The resulting slurry was filtered and washed with a mixture of 2-methyltetrahydrofuran (309 L, 0.90 relative volumes) and heptane (206 L, 0.60 relative volumes) before being dried under vacuum at 40 °C to give a yellow-brown crystalline solid, l-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[l,5-a]pyrazin-8-amine (Compound (VI), 168 kg, 84% yield).

[0593] 1H NMR (500 MHz, 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, 6.7 Hz, 1H), 6.61 (br s, 2H), 6.96 (d, J = 5.0 Hz, 1H), 7.70 (d, J = 5.0 Hz, 1H).13C NMR (126 MHz, DMSO-d6) δ 25.7, 29.4, 46.5, 54.0, 105.1, 107.5, 115.3, 128.1, 142.8, 150.8.

[0594] Example 11: Preparation of [4-(2-pyridylcarbamoyl)phenyl]boronic acid (Compound (V))

[0595]

[0596] At 50 °C, 4-carboxyphenylboronic acid (116.0 kg, 1.0 mol. equiv.) was mixed with toluene (696 kg, 6.0 relative volumes) and N,N-dimethylformamide (2.0 kg, 0.04 mol. equiv.). To the slurry was slowly charged thionyl chloride (249.5 kg, 3.0 mol. equiv.). The reaction was heated to 60 °C and stirred for 8 hours, then cooled. The mixture was then concentrated under vacuum to remove 348 L (3.0 relative volumes) of solvent, and then toluene (348 L, 3.0 relative volumes) was added. This was repeated three more times to remove excess thionyl chloride. The mixture was then concentrated under vacuum to remove 348 L (3.0 relative volumes) of solvent, and then pyridine (348 L, 3.0 relative volumes) was added. This was repeated once to remove toluene. Pyridine (580 L, 5.0 relative volumes) was added to the slurry and the mixture was cooled to -5 °C. A solution of 2-aminopyridine (131.6 kg, 2.0 mol. equiv.) in pyridine (232.0 L, 2.0 relative volumes) was added as fast 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 relative volumes) of solvent. The reaction mixture was adjusted to a temperature of 65-70 °C, water (116 L, 1.0 relative volumes) was added, and the mixture was stirred at a temperature of 65-70 °C for 12 hours. Toluene (232 L, 2.0 relative volumes) was charged at a temperature of 65-70 °C, and then water (928 L, 8.0 relative volumes) was charged. The mixture was then cooled to 20 °C and filtered. The filter cake was washed with water (464 L, 4.0 relative volumes) four times, and dried at 50 °C to obtain [4-(2-pyridinylaminocarbonyl)phenyl]-boronic acid (Compound (V), 141.8 kg, 83.8% of theory) as a white crystalline solid.

[0597] Example 12: Preparation of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[l,5- a]pyrazin-l-yl}-N-(2-pyridyl)benzamide (Compound (VII))

[0598]

[0599] The synthesis described in Example 10 was further modified, in particular to identify a suitable replacement solvent for N,N-dimethylformamide that would reduce the potential formation of unwanted side products, in particular dimethylcarbamoyl chloride.

[0600] At 50 °C, 4-carboxyphenylboronic acid (7.0 g, 1.0 mol. equiv.) was mixed with toluene (66.5 ml, 9.5 relative volumes) and tetrabutylammonium chloride (0.59 g, 0.05 mol. equiv.). To the slurry was slowly charged thionyl chloride (13.8 g, 2.75 mol. equiv.) followed by a toluene (3.5 ml, 0.5 relative volumes) rinse. The reaction was heated to 70 °C and stirred for at least six hours then cooled. The mixture was then concentrated under vacuum to approximately 4.0 relative volumes and then added to a solution of 2-aminopyridine (7.94 g, 2.0 mol. equiv.) in pyridine (35 ml, 5.0 relative volumes) followed by a pyridine (7 ml, 1.0 relative volumes) rinse. 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 relative volumes. Water (7 ml, 1.0 relative volumes) was added and the mixture stirred at 70 °C for at least one hour. Water (56 ml, 8.0 relative volumes) was charged at 70 °C. The mixture was then cooled to 20 °C and filtered. The filter cake was washed with water (28 ml, 4.0 relative volumes) four times and dried at 50 °C to yield a white crystalline solid [4-(2-pyridinylaminocarbonyl)phenyl]-boronic acid (Compound (V), 8.79 kg, 85% of theory).

[0601] This compound exists as a mixture of conformers in solution and the resonance is quoted for the major conformer only.1H NMR (500 MHz, DMSO-d6) δ 7.16 (ddd, J = 7.2, 4.9, 0.9 Hz, 1H), 7.83 (ddd, J = 8.3, 7.2, 1.9 Hz, 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, 0.8 Hz, 1H), 10.74 (s, 1H).13C NMR (126 MHz, DMSO-d6) δ 114.7, 119.8, 126.8, 134.0, 135.3, 138.1, 138.3, 147.9, 152.2, 166.1.

[0602] Figure 2 Figure 1

[0603]

[0604] (Compound (V), 44.7 kg, 1.05 mol. equiv.) with bis-(tert-butyldicyclohexylphosphine)dichloropalladium(II)) (0.61 kg, 0.005 mol. equiv.), potassium iodide (9.0 kg, 0.30 relative volume) and triethylamine (54 kg, 3.0 mol. equiv.) in water (422 L, 8.45 relative volumes) and 2-butanol (184 L, 4.55 relative volumes). The reaction mixture was then heated to 82 °C for at least 24 hours under nitrogen. The reaction mixture was slowly cooled to about 23 °C and then subjected to thermal cycling by warming to about 42 °C, cooling to about 23 °C and warming to about 42 °C.

[0605] Water (727 L, 15 relative volumes) was then added slowly and the mixture cooled to about 20 °C before being filtered and washed with water. The filtration and washing cycle was very slow. During processing, two filters and multiple drains were required, which typically took 3 to 4 days to complete. X-ray powder diffraction of the material isolated in this filtration step gave a pattern consistent with the diffraction pattern of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]- imidazo[1,5-a]pyrazin-1 -yl}-N-(2-pyridyl)benzamide (Compound (VII)) Form 2 (i.e. Form 2). Example 13: Preparation of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[l,5- a]pyrazin-l-yl}-N-(2-pyridyl)benzamide (Compound (VII)) Example 14: Preparation of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[l,5- a]pyrazin-l-yl}-N-(2-pyridyl)benzamide (Compound (VII)) Further drying of the water-wet product was achieved by refluxing in heptane (964 L) under Dean Stark conditions for 29 hours and then filtering and drying under vacuum at 45 °C to give 4-{8-amino-3-[(2S)-2-pyrrolidinyl]-imidazo[1,5-a]pyrazin-1 -yl}-N-(2-pyridyl)benzamide (Compound (VII), 61.6 kg, 81.5%) as a yellow crystalline solid. Figure 4 Example 15: X-ray powder diffraction analysis of 4-{8-amino-3-[(2S)-2- pyrrolidinyl]imidazo[l,5-a]pyrazin-l-yl}-N-(2-pyridyl)benzamide (Compound (VII))

[0606]

[0607] Further modifications to the synthesis described in Example 12 were made, in particular to improve the filtration of the crude product and to reduce the cycle time of the synthesis.

[0608] ​To a solution of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[l,5-a]pyrazin-l- yl}-N-(2-pyridyl)benzamide (Compound (VII), 26.8 kg, 75%) in 2-butanol (106 L, 4.0 relative volumes) was added 2-butanol (53 L, 2.0 relative volumes) followed by heptane (53 L, 2.0 relative volumes) at 45 °C. The mixture was stirred for 18 hours at 45 °C. The mixture was filtered and washed with 2-butanol (53 L, 2.0 relative volumes) followed by 2-butanol (53 L, 2.0 relative volumes) and then heptane (53 L, 2.0 relative volumes) at 45 °C. The wet cake was dried under vacuum at 45 °C to give 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[l,5-a]pyrazin-l-yl}-N-(2- pyridyl)benzamide (Compound (VII), 26.8 kg, 75%) as a yellow crystalline solid. The filtration and washing cycle was achieved in less than 24 hours using a single discharge on one filter.

[0609] Solid 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[l,5-a]pyrazin-l-yl}-N-(2- pyridinyl)benzamide (Compound (VII), 40.6 kg, 1.0 mol. equiv.) was purified by slurrying in 1 M aqueous potassium carbonate solution (162.4 L, 4.0 relative volumes) to remove the impurity 4-[8-amino-3-[(2S)-pyrrolidin-2-yl]imidazo[l,5- a]pyrazin-l-yl]benzoic acid (Compound (XII)), followed by filtration and washing with water (81.2 L, 2.0 relative volumes), and then washing with heptane (81.2 L, 2.0 relative volumes) to obtain yellow crystalline 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[l,5-a]pyrazin-l-yl}-N-(2- pyridinyl)benzamide (Compound (VII), 39.7 kg, 98%). In addition to the 4-[8-amino-3-[(2S)-pyrrolidin-2-yl]imidazo[l,5-a]pyrazin-l-yl]benzoic acid (Compound (XII)) impurity, another impurity, 4-[8-amino-3-[(2S)-l-[4-[8-amino-3-[(2S)-pyrrolidin-2-yl]imidazo[l,5-a]pyrazin-l-yl]benzoyl]pyrrolidin-2-yl]imidazo[l,5-a]pyrazin-l-yl]-N-(2-pyridinyl)benzamide (Compound (XIII)) was observed and was not removed by this repeated work-up.

[0610] Analysis protocol Analysis of the crystalline form 2

[0611]

[0612] While the process described in Example 13 resulted in improved filtration and cycle times, two unwanted impurities were formed due to the long heating times under the process conditions. Therefore, the process was further modified, inter alia, to reduce the formation of these impurities and to improve the purity of the final product.

[0613] (Compound (VII), 1.15 kg, 0.01 relative weight) and then distilled under vacuum (0.2 bar) while maintaining a constant volume of 1840 L (16 relative volumes) in the vessel by re-adding 2-butanol (1610 L, 14.0 relative volumes) and maintaining the temperature below 60 °C. The mixture was then distilled (under 0.2 bar) to a volume of 1380 L (12.0 relative volumes) maintaining the temperature below 60 °C. Heating was continued at 80 °C for two hours, then cooled to 20 °C and filtered. The product was washed with 2-butanol (460 L, 4.0 relative volumes), then 2-butanol (230 L, 2.0 relative volumes), followed by heptane (230 L, 2.0 relative volumes) and dried under vacuum at 45 °C to a yellow crystalline solid 4-{8-amino-3-[(2S)-2-pyrrolidinyl]-imidazo[l,5-a]pyrazin-l-yl}-N-(2-pyridinyl)- benzamide (Compound VII, 131.7 kg, 80.4%). The filtration and washing cycle was achieved in less than 24 hours using a single discharge and one filter.

[0614] 1H NMR (500 MHz, 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 = 6.8 Hz, 2H), 4.55 (t, J = 7.2 Hz, 1H), 6.11 (br s, 2H), 7.07 (d, J = 5.0 Hz, 1H), 7.17 (ddd, J = 7.4, 4.9, 0.9 Hz, 1H), 7.72 - 7.75 (m, 2H), 7.77 (d, J = 5.0 Hz, 1H), 7.85 (ddd, J = 8.4, 7.4, 2.0 Hz, 1H), 8.13 - 8.16 (m, 2H), 8.20 - 8.23 (m, 1H), 8.39 (ddd, J = 4.9, 2.0, 0.9 Hz, 1H), 10.82 (br s, 1H).13C NMR (126 MHz, 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 obtained crystalline solid gave a diffractogram consistent with that of Form C (i.e., Form C), as reported in Table 1. Figure 2

[0615] Table 6 Analysis of the crystalline form 3

[0616] A. Figure 3

[0617] Crystalline samples of Form 2, Form 3 and Form C of 4-{8-amino-3-[(2S)-2- pyrrolidinyl]imidazo[l,5-a]pyrazin-l-yl}-N-(2-pyridinyl)benzamide (Compound (VII)) were analyzed by X-ray powder diffraction. The samples were mounted on silicon wafer holders and analyzed using a PANalytical CubiX PRO diffractometer The samples were measured in reflection geometry in a theta-theta configuration over a scan range of 2 to 40 °2theta, with a nominal 25 second exposure per 0.02° increment. The X-rays were generated by a long fine focus copper tube operating at 45 kV and 40 mA. The results for the crystalline Form 2, Form 3 and Form C are reported in the following A, B and C sections, respectively.

[0618] B. Table 7

[0619] ​A sample of Form 2 crystalline 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[l,5- a]pyrazin-l-yl}-N-(2-pyridinyl)benzamide (Compound (VII)) was analyzed by X-ray powder diffraction. The resulting X-ray diffraction pattern is shown in Analysis of the crystalline form C Table 6 below.

[0620] Figure 4

[0621]

[0622]

[0623] 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° 2Θ, particularly peaks at 5.0, 5.7, 7.2, 9.9, and / or 11.2 ± 0.2° 2Θ. As previously noted, the product isolated from the first filtration of Example 12 corresponds to Form 2 crystalline form.

[0624] C. Table 8

[0625] A sample of Form 3 crystalline 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[l,5- a]pyrazin-l-yl}-N-(2-pyridinyl)benzamide (Compound (VII)) was analyzed by X-ray powder diffraction, which was produced by slurrying Form 2 in pure butanol for 7 days at ambient conditions. The resulting X-ray diffraction pattern is shown in Peak Table 7 below.

[0626] Relative intensity

[0627]

[0628]

[0629] 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° 2Θ, particularly peaks at 7.4, 11.7, 12.5, 22.3, and / or 21.6 ± 0.2° 2Θ.

[0630] D. Peak

[0631] A sample of Form C crystalline 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[l,5- a]pyrazin-l-yl}-N-(2-pyridinyl)benzamide (Compound (VII)) was analyzed by X-ray powder diffraction. The resulting X-ray diffraction pattern is shown in Relative intensity Table 8 below.

[0632] Example 16: Preparation of 4-{8-amino-3-[(2S)-l-(but-2-ynoyl)pyrrolidin-2- yl]imidazo[l,5-a]pyrazin-l-yl}-N-(pyridin-2-yl)benzamide (Compound (VIII))

[0633] Example 17: Preparation of 4-{8-amino-3-[(2S)-l-(but-2-ynoyl)pyrrolidin-2- yl]imidazo[l,5-a]pyrazin-l-yl}-N-(pyridin-2-yl)benzamide (Compound (VIII)) Example 18: Preparation of benzyl (2S)-2-[(3-chloropyrazin-2-yl)methyl- carbamoyl]pyrrolidine- 1-carboxylate (Compound (I)) Preparation of Compound (7) Preparation of benzyl (2S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl]- pyrrolidine- 1-carboxylate (Compound (I)) 7.4 1 17.8 23 8.9 1 19.0 46 9.9 7 19.5 10 11.1 11 19.9 17 12.8 37 20.9 13 14.1 100 21.6 99 14.8 21 22.1 33 15.2 11 22.9 82 15.8 13 23.9 15 17.0 22 24.8 29 17.6 15

[0634] The Form 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° 2Θ, in particular peaks at 9.9, 11.1, 12.8, 14.1, and 19.0 ± 0.2° 2Θ. As previously described, the product isolated from the filtration of Example 14 corresponds to the Form C crystalline form.

[0635] Step 1 Step 2

[0636]

[0637] Compound (VII), 70 kg, 1.0 mol. equiv.) and 2-butyneoic acid (17.5 kg, 1.2 mol. equiv.) were mixed in dichloromethane (1537 kg, 22 relative volumes) to give a thick slurry. Triethylamine (44.5 kg, 2.5 mol. equiv.) was added followed by 1 -propylphosphonic anhydride (T3P) (ca. 111.4 kg, 1.0 mol. equiv.) (additional aliquots of T3P were added in portions until the reaction was deemed complete). The resulting organic solution of the product was washed twice with water (525 kg, 7.5 relative volumes) and then concentrated to ca. 2 to 3 relative volumes. Water (700 kg, 10.0 relative volumes) was added and then the mixture was acidified with 6M aqueous hydrochloric acid to reach a pH of ca. 2, then the organic phase was separated which was discarded. The aqueous layer (containing the product) was washed three times with 2-methyltetrahydrofuran (478 kg, 8.0 relative volumes) and then washed twice more with 2-methyltetrahydrofuran (180 kg, 3.0 relative volumes). Dichloromethane (742 kg, 8.0 relative volumes) was added to the aqueous phase and the mixture was adjusted to a pH of 7.0 to 8.5 with triethylamine (variable amount) to extract the product into the organic phase. The organic phase was separated out and washed twice with water (350 kg, 5.0 relative volumes) and then filtered through carbon and then re-treated with Quadrasil-MP (17.5 kg, 0.25 relative weight) with each wash of the spent scavenger filter cake with methanol until the palladium specification was met. The filtrate was concentrated to 5 relative volumes. Ethanol (276 kg, 5 relative volumes) was added and concentrated to 5 relative volumes and this operation was further repeated twice. 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 relative volumes) and then the wet cake was returned to the vessel and dissolved in methanol (831 kg, 15 relative volumes) at 60 °C. The filtrate was concentrated to 5 relative volumes. Ethanol (276 kg, 5 relative volumes) was added and concentrated to 5 relative volumes 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 relative volumes) and then dried under vacuum at 50 °C to give acalabrutinib (Compound VIII, 52.2 kg, 64%) as a white crystalline solid.

[0638] Step 3 Step 4

[0639]

[0640] The synthesis described in Example 17 was further modified, in particular to allow greater flexibility in the operating conditions, while still producing the product with adequate purity. Among other advantages, the modified synthesis led to improved removal of certain impurities.

[0641] A slurry of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[l,5-a]pyrazin-l-yl}-N-(2- pyridyl)-benzamide (Compound (VII), 131.7 kg, 1.0 mol. equiv.) in dichloromethane (955 L, 7.25 relative volumes) and triethylamine (90.1 kg, 2.7 mol. equiv.) was prepared. 2-Butynoic acid (33.3 kg, 1.2 mol. equiv.) in dichloromethane (263.4 L, 2.0 relative volumes) was added, followed by 1 -propylphosphonic anhydride (T3P) (50% w / w solution in dichloromethane, 209.8 kg, 1.0 mol. equiv.). The resulting organic solution of the product was washed twice with water (658.5 L, 5.0 relative volumes) and then water (1317 L, 10.0 relative volumes) was added. The mixture was then acidified to approximately pH 2.2 with 6M aqueous hydrochloric acid and then 2M aqueous hydrochloric acid was added to reach pH 1.8 to 2.2, then the organic phase was separated and discarded. Dichloromethane (1317 L, 10.0 relative volumes) was added to the aqueous phase and the mixture was adjusted to pH 4.5 to 5.0 with triethylamine. The organic phase was separated and the aqueous phase was re-extracted with dichloromethane (527 L, 4.0 relative volumes). The combined dichloromethane extracts were screened and the organic phase was concentrated to approximately 5.0 relative volumes. Ethanol (1712 L, 13.0 relative volumes) was added and the mixture was distilled (approximately 360 mbar) maintaining a constant volume (18.0 relative volumes) by the addition of ethanol (1580 L, 12.0 relative volumes). A portion of the crystalline 4-{8-amino-3-[(2S)-l-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[l,5-a]pyrazin-l-yl}-N-(pyridin-2-yl)benzamide (Compound (VIII), 1.32 kg, 0.01 relative weight) was added as seed and the solution was held at 50 °C for 10 hours to crystallise the product. The mixture was then cooled over 7 hours and filtered. The product was washed twice with ethanol (527 L, 4.0 relative volumes) and then dried under vacuum at 50 °C to give acalabrutinib as a white crystalline solid (Compound VIII, 113.6 kg, 74%).

[0642] The compound exists as a mixture of conformers in solution and the resonance is quoted for the major conformer only.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 = 5.1 Hz, 1H), 7.17 (ddd, J = 7.4, 4.8, 0.8 Hz, 1H), 7.70 - 7.73 (m, 2H), 7.78 (d, J = 5.1 Hz, 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, 0.8 Hz, 1H), 10.83 (s, 1H).13C NMR (126 MHz, 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.

[0643] Selected examples ​

[0644]

[0645] A. ​

[0646] To a solution of (2S)-1-benzyloxycarbonylpyrrolidine-2-carboxylic acid (1.039 kg, 1.0 mol. Eq.) and toluene (6.3 L, 6.0 relative volumes) was added thionyl chloride (0.75 kg, 1.5 mol. Eq.) and the mixture was stirred at 30 °C for 7 hours. At 35 °C to 45 °C under vacuum, the reaction mixture was concentrated (to approximately 4.5 relative volumes). At 35 °C to 45 °C under vacuum, toluene (2.1 L, 2.0 relative volumes) was added and the reaction mixture was concentrated (to approximately 4.5 relative volumes). The assay of the product (compound (7)) (5.6 kg @ 18.3% w / w = 1.03 kg, 91.8% yield) was tested.

[0647] B. ​ ​

[0648] ​Diphenylformimidate (Compound (1), 1.44 kg, 1.0 mol. equiv.) and glycine methyl ester hydrochloride (Compound (2), 1.099 kg, 1.1 mol. equiv.) were mixed in acetonitrile (7.2 L, 5.0 relative volumes) at 35 °C to 40 °C for 3 hours. Cool to 20 °C to 25 °C and filter, washing the cake twice with acetonitrile (2.88 L, 2.0 relative volumes). Measure the assay of the product (Compound (3)) (10.05 kg @ 18.9% w / w = 1.9 kg, 94.4% yield) solution.

[0649] ​ Add 2,3-dipyrazine (Compound (4), 0.911 kg, 1.0 mol. equiv.) and cesium carbonate (2.39 kg, 1.2 mol. equiv.) to the filtrate solution (10.05 kg @ 18.9% w / w = 1.9 kg, 1.2 mol. equiv.) and heat the mixture to 80 °C to 85 °C for 13 hours. Cool to 20 °C to 25 °C to filter, washing the cake twice with acetonitrile (1.8 L, 2.0 relative volumes). Measure the assay of the product (Compound (5)) (14.7 kg @ 13.3% w / w = 1.96 kg, 89.0% yield) solution.

[0650] ​ Add water (3.6 kg, 2.0 relative volumes) to the acetonitrile solution of Compound (5) (13.5 kg @ 13.3% w / w = 1.8 kg) and distill the mixture under vacuum to 2.5 relative volumes. Further add water (3.6 kg, 2.0 relative volumes) and distill the mixture under vacuum to 3.5 relative volumes. Add concentrated hydrochloric acid (1.8 L, 1.0 relative volumes of the amount of Compound (5)) and heat to 80 °C to 85 °C for 7 hours. Cool to 20 °C and wash the aqueous phase with a mixture of toluene (5.4 L, 3.0 relative volumes) and acetonitrile (3.6 L, 2.0 relative volumes) and then further wash with toluene (5.4 L, 3.0 relative volumes). Measure the assay of the aqueous phase containing Compound (6) (10.25 kg @ 5.9% w / w = 0.605 kg, 85.8% yield).

[0651] ​To a solution of compound (6) (6.1 kg @ 5.9% w / w = 0.36 kg, 1.0 mol. equiv.) was added 25% aqueous NaOH solution (to approx. pH = 8-9). At 10-15 °C, toluene (1.8 L, 5.0 relative volumes) and a solution of compound (7) (in toluene) (4.4 kg @ 18.3% w / w = 0.805 kg, 1.2 mol. equiv.) were added (while loading the reaction mixture with 25% aqueous sodium hydroxide, the pH was maintained at 8-9). Stirring was continued for three hours and the mixture was extracted with a mixture of toluene (1.8 L, 5.0 relative volumes) and acetonitrile (1.44 L, 4.0 relative volumes), then separated and the aqueous phase was extracted with a mixture of toluene (1.8 L, 5.0 relative volumes) and acetonitrile (0.72 L, 2.0 relative volumes). The organic phases were combined and washed with brine (1.8 L, 5.0 relative volumes) and then with water (1.8 L, 5.0 relative volumes).

[0652] The organic phase was concentrated under vacuum at 40-45 °C (to approx. 5.0 relative volumes) and the mixture was heated to 60 °C. Stirring was continued for 15 minutes to obtain a solution, then the mixture was cooled to 50 °C. Methyl tert-butyl ether (1.6 L, 4.4 relative volumes) was added dropwise to the mixture until a suspension was observed. The mixture was cooled to 5-10 °C for 3 hours and stirring was continued for 12 hours. The wet cake was filtered and dried (at 45 °C) to isolate the product (compound (I), (920.0 g, 96.3%) (72% yield from 2,3-dipyrazine). The compound exists as a mixture of conformers in solution and the resonances are quoted for the major conformer only. 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, 3.5 Hz, 1H), 4.43 (dd, J = 16.2, 5.4 Hz, 1H), 4.49 (dd, J = 16.2, 5.4 Hz, 1H), 4.98 (d, J = 13.0 Hz, 1H), 5.04 (d, J = 13.0 Hz, 1H), 7.24-7.31 (m, 5H), 8.39 (d, J = 2.4 Hz, 1H), 8.49 (t, J = 5.4 Hz, 1H), 8.53 (d, J = 2.4 Hz, 1H). 13C NMR (126 MHz, 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.

[0653] XV. ​

[0654] Example 1. A method for preparing a compound having the structure of Formula (VIII):

[0655]

[0656] or a salt thereof, wherein the method comprises:

[0657] contacting a compound having the structure of Formula (VII)

[0658]

[0659] or a salt thereof, with 2-butyneoic 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 byproducts; and

[0660] selectively isolating the compound of Formula (VIII), or a salt thereof, from the reaction mixture, relative to the one or more reaction byproducts.

[0661] Example 2. The method of Example 1, wherein the contacting step comprises:

[0662] adding the compound of Formula (VII), or a salt thereof, and the base to the reaction medium;

[0663] adding the 2-butyneoic acid, or a salt thereof, to the reaction medium comprising the compound of Formula (VII), or a salt thereof, and the base; and

[0664] adding the 1-propylphosphonic anhydride to the reaction medium comprising the compound of Formula (VII), or a salt thereof; 2-butyneoic acid, or a salt thereof; and the base.

[0665] Example 3. The method of Example 1 or 2, wherein the method comprises:

[0666] contacting a compound having the structure of Formula (VII)

[0667]

[0668] or a salt thereof, with 2-butyneoic 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; unreacted compound of Formula (VII), or a salt thereof; and reaction byproducts; wherein the reaction byproducts comprise a compound having the structure of Formula (XIV):

[0669]

[0670] or a salt thereof; and

[0671] selectively separating 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.

[0672] In some embodiments, the method of any one of embodiments 1-3, wherein the method comprises:

[0673] contacting a compound having the structure of Formula (VII)

[0674]

[0675] or a salt thereof, with 2-butyneoic 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; unreacted compound of Formula (VII), or a salt thereof; and reaction byproducts; wherein the reaction byproducts comprise a compound having the structure of Formula (XIV):

[0676]

[0677] or a salt thereof;

[0678] extracting at least a portion of the compound of Formula (VIII), or a salt thereof, from the reaction mixture into an aqueous phase, wherein 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;

[0679] adjusting the pH of the aqueous phase; and

[0680] 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.

[0681] Example 5. The method of either of Examples 3 or 4, wherein the selectively isolated compound of Formula (VIII), or a salt thereof, comprises less than about 1.0 wt% of a compound of Formula (VII), or a salt thereof.

[0682] Example 6. The method of either of Examples 3 or 4, wherein the selectively isolated compound of Formula (VIII), or a salt thereof, comprises less than about 1.0 wt% of a compound of Formula (XIV), or a salt thereof.

[0683] Example 7. The method of either of Examples 3 or 4, wherein the selectively isolated compound of Formula (VIII), or a salt thereof, comprises less than about 1.0 wt% of a compound of Formula (VII), or a salt thereof, and less than about 1.0 wt% of a compound of Formula (XIV), or a salt thereof.

[0684] Example 8. The method of any one of Examples 4 to 7, wherein the reaction mixture is washed with water and the washed reaction mixture is separated into an aqueous phase and a waste phase, wherein the compound of Formula (VIII) is selectively extracted into the aqueous phase.

[0685] Example 9. The method of any one of Examples 4 to 8, wherein the method further comprises isolating the compound of Formula (VIII) from the organic phase into which the compound of Formula (VIII) has been selectively extracted.

[0686] Example 10. The method of any one of Examples 4 to 9, wherein after aqueous phase extraction is complete, the aqueous phase comprises greater than about 75 area% of the compound of Formula (VIII), as measured by high performance liquid chromatography.

[0687] Example 11. The method of any one of Examples 4 to 9, wherein after aqueous phase extraction is complete, the aqueous phase comprises less than about 2.0 area% of the compound of Formula (XIV), as measured by high performance liquid chromatography.

[0688] Example 12. The method of any one of Examples 4 to 9, wherein after aqueous phase extraction is complete, 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.

[0689] Example 13. The method of any one of Examples 4 to 12, wherein after organic phase extraction is complete, the organic phase comprises at least about 75 area% of the compound of Formula (VIII), as measured by high performance liquid chromatography.

[0690] Example 14. The method of any one of Examples 4 to 12, wherein after organic phase extraction is complete, the organic phase comprises less than about 2.0 area% of the compound of formula (VII), as measured by high performance liquid chromatography.

[0691] Example 15. The method of any one of Examples 4 to 12, wherein after organic phase extraction is complete, 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.

[0692] Example 16. The method of any one of Examples 4 to 15, wherein the aqueous phase has a pH of less than about 2.5 during the aqueous phase extraction step.

[0693] Example 17. The method of any one of Examples 4 to 15, wherein the aqueous phase has a pH of from about 1.8 to about 2.2 during the aqueous phase extraction step.

[0694] Example 18. The method of any one of Examples 4 to 15, wherein the aqueous phase has a pH of greater than about 4.0 during the organic phase extraction step.

[0695] Example 19. The method of any one of Examples 4 to 15, wherein the aqueous phase has a pH of from about 4.5 to about 5.0 during the organic phase extraction step.

[0696] Example 20. The method of any one of Examples 4 to 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.

[0697] Example 21. The method of any one of Examples 4 to 19, wherein the reaction medium comprises at least one solvent selected from the group consisting of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, t-amyl alcohol, acetone, methyl isobutyl ketone, 2-butanol, methyl ethyl ketone, acetonitrile, and ethyl acetate.

[0698] Example 22. The method of any one of Examples 4 to 19, wherein the reaction medium comprises dichloromethane.

[0699] Example 23. The method of any one of Examples 4 to 22, wherein the base comprises at least one compound selected from the group consisting of triethylamine, tripropylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.

[0700] Example 24. The method of any one of Examples 4 to 22, wherein the base comprises triethylamine.

[0701] Example 25. The method of any one of Examples 4 to 24, wherein the organic phase comprises at least one solvent selected from the group consisting of alkyl hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ketones, ethers, esters, and nitriles.

[0702] Example 26. The method of any one of Examples 4 to 24, wherein the organic phase comprises at least one compound selected from the group consisting of dichloromethane, methyltetrahydrofuran, and 2-methyltetrahydrofuran, t-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.

[0703] Example 27. The method of any one of Examples 4 to 24, wherein the organic phase comprises dichloromethane.

[0704] Example 28. The method of any one of Examples 4 to 27, wherein the compound of Formula (VII) is contacted with about 0.5 to about 5.0 molar equivalents of 2-butyneoic acid relative to the compound of Formula (VII).

[0705] Example 29. The method of any one of Examples 4 to 27, wherein the compound of Formula (VII) is contacted with about 1.0 to about 1.3 molar equivalents of 2-butyneoic acid relative to the compound of Formula (VII).

[0706] Example 30. The method of any one of Examples 4 to 27, wherein the compound of Formula (VII) is contacted with about 1.2 molar equivalents of 2-butyneoic acid relative to the compound of Formula (VII).

[0707] Example 31. The method of any one of Examples 4 to 30, wherein about 0.3 to about 3.0 molar equivalents of 1-propylphosphonic anhydride is charged to the reaction medium relative to the compound of Formula (VII).

[0708] Example 32. The method of any one of Examples 4 to 30, wherein about 0.5 to about 2.0 molar equivalents of 1-propylphosphonic anhydride is charged to the reaction medium relative to the compound of Formula (VII).

[0709] Example 33. The method of any one of Examples 4 to 30, wherein about 0.7 to about 1.5 molar equivalents of 1-propylphosphonic anhydride is charged to the reaction medium relative to the compound of Formula (VII).

[0710] Example 34. The method of any one of Examples 4 to 30, wherein about 1.0 to about 1.2 molar equivalents of 1 -propylphosphonic anhydride are charged to the reaction medium relative to the compound of Formula (VII).

[0711] Example 35. The method of any one of Examples 4 to 34, wherein about 1.0 to about 10.0 molar equivalents of base are charged to the reaction medium relative to the compound of Formula (VII).

[0712] Example 36. The method of any one of Examples 4 to 34, wherein about 2.0 to about 5.0 molar equivalents of base are charged to the reaction medium relative to the compound of Formula (VII).

[0713] Example 37. The method of any one of Examples 4 to 34, wherein about 2.4 to about 3.0 molar equivalents of base are charged to the reaction medium relative to the compound of Formula (VII).

[0714] Example 38. The method of any one of Examples 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.

[0715] Example 39. The method of any one of Examples 4 to 38, wherein the volume of the reaction medium is about 5 liters to about 20 liters of reaction medium per kilogram of the compound of Formula (VII) charged to the reaction medium.

[0716] Example 40. The method of any one of Examples 4 to 39, wherein the contacting step is performed as a batch reaction.

[0717] Example 41. The method of Example 40, wherein at least about 25 kilograms of the compound of Formula (VII) is charged to the batch reaction.

[0718] Example 42. The method of Example 40, wherein at least about 50 kilograms of the compound of Formula (VII) is charged to the batch reaction.

[0719] Example 43. The method of Example 40, wherein at least about 75 kilograms of the compound of Formula (VII) is charged to the batch reaction.

[0720] Example 44. The method of Example 40, wherein at least about 100 kilograms of the compound of Formula (VII) is charged to the batch reaction.

[0721] Example 45. The method of any one of Examples 4 to 44, wherein the compound of Formula (VIII) is isolated from the organic phase by crystallization.

[0722] Example 46. The method of any one of Examples 4 to 44, wherein the organic phase comprises an organic phase solvent, and the method further comprises exchanging the organic phase solvent with a replacement solvent to form a crystallization mixture comprising a compound of Formula (VIII).

[0723] Example 47. The method of Example 46, wherein the method further comprises crystallizing a compound of Formula (VIII) from the crystallization mixture.

[0724] Example 48. The method of Example 47, wherein the crystallization mixture is seeded with a crystalline form of the compound of Formula (VIII).

[0725] Example 49. The method of Example 48, wherein the crystallization mixture is seeded with at least about 0.01 relative weight of the crystalline form.

[0726] Example 50. The method of Example 49, wherein the crystallization mixture is seeded with at least about 0.03 relative weight of the crystalline form.

[0727] Example 51. The method of any one of Examples 48 to 50, wherein the crystalline form is an anhydrate crystalline form.

[0728] Example 52. The method of any one of Examples 46 to 51, wherein the organic phase solvent comprises a polar solvent.

[0729] Example 53. The method of any one of Examples 46 to 51, wherein the organic phase solvent comprises at least one solvent selected from the group consisting of a chlorinated hydrocarbon and an ether.

[0730] Example 54. The method of any one of Examples 46 to 51, wherein the organic phase solvent comprises at least one compound selected from the group consisting of dichloromethane and 2-methyltetrahydrofuran.

[0731] Example 55. The method of any one of Examples 46 to 51, wherein the organic phase solvent comprises dichloromethane.

[0732] Example 56. The method of any one of Examples 46 to 55, wherein the replacement solvent comprises an alcohol.

[0733] Example 57. The method of any one of Examples 46 to 55, wherein the replacement solvent comprises ethanol.

[0734] Example 58. The method of any one of Examples 46-51, wherein the organic phase solvent comprises a polar solvent and the replacement solvent comprises an alcohol.

[0735] Example 59. The method of any one of Examples 46-51, wherein the organic phase solvent comprises dichloromethane and the replacement solvent comprises ethanol.

[0736] Example 60. The method of any one of Examples 46-51, wherein the boiling point of the organic phase solvent is lower than the boiling point of the replacement solvent.

[0737] Example 61. The method of Example 60, wherein the boiling point of the organic phase solvent is at least about 20 °C lower than the boiling point of the replacement solvent.

[0738] Example 62. The method of any one of Examples 46-61, wherein the organic phase solvent is replaced with the replacement solvent by continuous level distillation.

[0739] Example 63. The method of Example 62, wherein the continuous level distillation is conducted under conditions sufficient to maintain a solution of the compound of Formula (VIII) during the continuous distillation.

[0740] Example 64. The method of Example 62 or 63, wherein the continuous level distillation is continuous level vacuum distillation.

[0741] Example 65. The method of any one of Examples 62-64, wherein the replacement solvent is loaded during distillation in an amount sufficient to maintain at least about 15 relative volumes of total solvent per kilogram of the compound of Formula (VIII).

[0742] Example 66. The method of any one of Examples 62-64, wherein the replacement solvent is loaded during distillation in an amount sufficient to maintain at least about 18 relative volumes of total solvent per kilogram of the compound of Formula (VIII).

[0743] Example 67. The method of any one of Examples 62-66, wherein the continuous level vacuum distillation is conducted at a temperature of no more than about 60 °C.

[0744] Example 68. The method of any one of Examples 46-67, wherein the crystallization mixture is seeded with a crystalline form of the compound of Formula (VIII) and is maintained at a temperature greater than about 40 °C for at least about five hours after seeding.

[0745] Example 69. The method of any one of Examples 46-68, wherein the crystalline mixture is cooled to a temperature of about 20 °C over a period of at least five hours prior to isolating the compound of Formula (VIII).

[0746] Example 70. The method of any one of Examples 1-69, wherein the stoichiometric process yield of the compound of Formula (VIII) is at least about 50%.

[0747] Example 71. The method of any one of Examples 1-69, wherein the stoichiometric process yield of the compound of Formula (VIII) is at least about 60%.

[0748] Example 72. A crystalline form of a compound having the structure of Formula (VII):

[0749]

[0750] wherein the crystalline form is characterized by a reflective X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 9.9 ± 0.2 °2Q, 11.1 ± 0.2 °2Q, 12.8 ± 0.2 °2Q, 14.1 ± 0.2 °2Q, and 19.0 ± 0.2 °2Q.

[0751] Example 73. A method for making a compound having the structure of Formula (VII):

[0752]

[0753] or a salt thereof, wherein the method comprises:

[0754] contacting a compound having the structure of Formula (V)

[0755]

[0756] or a salt thereof, with a compound having the structure of Formula (VI):

[0757]

[0758] or a salt thereof, in the presence of a base and a palladium catalyst in an aqueous reaction medium comprising an organic solvent to form a reaction mixture comprising a compound of Formula (VII), or a salt thereof;

[0759] 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

[0760] isolating a compound of Formula (VII), or a salt thereof, from the substantially anhydrous mixture.

[0761] Example 74. The method of Example 73, wherein the isolating step comprises filtering the substantially anhydrous mixture.

[0762] Example 75. The method of Example 73 or 74, wherein the aqueous reaction medium further comprises an alkali metal halide.

[0763] Example 76. The method of Example 73 or 74, wherein the aqueous reaction medium further comprises an alkali metal iodide.

[0764] Example 77. The method of Example 73 or 74, wherein the aqueous reaction medium further comprises potassium iodide.

[0765] Example 78. The method of any one of Examples 73-77, wherein the organic solvent comprises at least one solvent selected from the group consisting of an aromatic hydrocarbon, an alcohol, a ketone, an ether, an ester, and a nitrile.

[0766] Example 79. The method of any one of Examples 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.

[0767] Example 80. The method of any one of Examples 73-77, wherein the organic solvent comprises 2-butanol.

[0768] Example 81. The method of any one of Examples 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, tripropylamine, diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, methyl dicyclohexylamine, and potassium phosphate.

[0769] Example 82. The method of any one of Examples 73-80, wherein the base comprises triethylamine.

[0770] Example 83. The method of any one of Examples 73-80, wherein the base comprises potassium carbonate.

[0771] Example 84. The method of any one of Examples 73-80, wherein the base comprises triethylamine and potassium carbonate.

[0772] Example 85. The method of any one of Examples 73-84, wherein the palladium catalyst comprises bis(tert-butyldicyclohexylphosphine)palladium(II) dichloride.

[0773] Embodiment 86. The method of any one 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).

[0774] Embodiment 87. The method of any one 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).

[0775] Embodiment 88. The method of any one 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).

[0776] Embodiment 89. The method of any one of embodiments 77-88, wherein about 0.1 to about 1.0 molar equivalents of potassium iodide is charged to the aqueous reaction medium relative to the compound of Formula (VI).

[0777] Embodiment 90. The method of any one of embodiments 77-88, wherein about 0.2 to about 0.4 molar equivalents of potassium iodide is charged to the aqueous reaction medium relative to the compound of Formula (VI).

[0778] Embodiment 91. The method of any one of embodiments 73-90, wherein about 0.5 to about 10 molar equivalents of a base is charged to the aqueous reaction medium relative to the compound of Formula (VI).

[0779] Embodiment 92. The method of any one of embodiments 73-90, wherein the base comprises triethylamine and about 0.5 to about 10 molar equivalents of triethylamine is charged to the aqueous reaction medium relative to the compound of Formula (VI).

[0780] Embodiment 93. The method of any one of embodiments 73-90, wherein the base comprises triethylamine and about 1.0 to about 2.0 molar equivalents of triethylamine is charged to the aqueous reaction medium relative to the compound of Formula (VI).

[0781] Embodiment 94. The method of any one of embodiments 73-90, wherein the base comprises potassium carbonate and about 0.5 to about 10.0 molar equivalents of potassium carbonate is charged to the aqueous reaction medium relative to the compound of Formula (VI).

[0782] Embodiment 95. The process of any one of embodiments 73-90, wherein the base comprises potassium carbonate and about 2.0 to about 3.0 molar equivalents of potassium carbonate are charged to the aqueous reaction medium relative to the compound of Formula (VI).

[0783] Embodiment 96. The process of any one of embodiments 73-90, wherein the base comprises potassium carbonate and about 2.3 to about 2.7 molar equivalents of potassium carbonate are charged to the aqueous reaction medium relative to the compound of Formula (VI).

[0784] Embodiment 97. The process of any one of embodiments 73-96, wherein about 0.002 to about 0.05 molar equivalents of palladium catalyst are charged to the aqueous reaction medium relative to the compound of Formula (VI).

[0785] Embodiment 98. The process of any one of embodiments 73-96, wherein about 0.007 to about 0.013 molar equivalents of palladium catalyst are charged to the aqueous reaction medium relative to the compound of Formula (VI).

[0786] Embodiment 99. The process of any one 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.

[0787] Embodiment 100. The process of any one 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.

[0788] Embodiment 101. The process of any one of embodiments 73-100, wherein the aqueous reaction medium has a volume of about 10 liters to about 20 liters of aqueous reaction medium per kilogram of the compound of Formula (VI) charged to the aqueous reaction medium.

[0789] Embodiment 102. The process of any one of embodiments 73-101, wherein the aqueous reaction medium has a volume ratio of water to organic solvent of about 1:3 to about 3:1.

[0790] Embodiment 103. The process of any one of embodiments 73-101, wherein the contacting step is conducted as a batch reaction.

[0791] 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.

[0792] 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.

[0793] Embodiment 106. The method of embodiment 103, wherein at least about 75 kilograms of the compound of formula (VI) is charged into the batch reaction.

[0794] Embodiment 107. The method of embodiment 103, wherein at least about 100 kilograms of the compound of formula (VI) is charged into the batch reaction.

[0795] Embodiment 108. The method of any one of embodiments 73-107, wherein the reducing step comprises separating the reaction mixture into an aqueous waste phase and an organic phase comprising a compound of formula (VII).

[0796] Embodiment 109. The method 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 and provide a substantially water-free mixture.

[0797] Embodiment 110. The method of embodiment 109, wherein the method further comprises washing the organic phase with water prior to distillation.

[0798] Embodiment 111. The method of any one of embodiments 109 or 110, wherein the organic phase is treated with a silica scavenger prior to distillation.

[0799] Embodiment 112. The method of any one of embodiments 109-111, wherein the organic phase is treated with a silica scavenger for a period of at least two hours prior to distillation.

[0800] Embodiment 113. The method of embodiment 111 or 112, wherein the silica scavenger comprises propyl mercaptan functionalized silica.

[0801] Embodiment 114. The method of embodiment 111 or 112, wherein the silica scavenger comprises QuadraSil TM MP.

[0802] Embodiment 115. The method of any one of embodiments 111-114, wherein the method further comprises removing the silica scavenger from the organic phase prior to distillation.

[0803] Embodiment 116. The method of any one of embodiments 111-114, wherein the method further comprises removing the silica scavenger from the organic phase by filtration prior to distillation.

[0804] Example 117. The method as in Example 115 or 116, wherein the method further comprises washing the organic phase with an aqueous brine solution after removal of the catalyst and prior to distillation.

[0805] Example 118. The method as in any one of Examples 109-117, wherein the reducing step comprises:

[0806] separating the reaction mixture into an aqueous waste phase and an organic phase comprising a compound of Formula (VII);

[0807] washing the organic phase with water;

[0808] treating the organic phase with a silica scavenger;

[0809] removing the silica scavenger from the organic phase;

[0810] washing the organic phase with an aqueous brine solution; and

[0811] distilling the organic phase under conditions sufficient to reduce the amount of water present in the organic phase.

[0812] Example 119. The method as in any one of Examples 109-118, wherein the organic phase is distilled by vacuum distillation.

[0813] Example 120. The method as in any one of Examples 109-118, wherein the organic phase is distilled by sustained level vacuum distillation.

[0814] Example 121. The method as in any one of Examples 109-120, wherein the organic phase is distilled at a temperature of no more than about 60 °C.

[0815] Example 122. The method as in any one of Examples 109-120, wherein the organic phase is distilled at a temperature of from about 50 °C to about 60 °C.

[0816] Example 123. The method as in any one of Examples 109-122, wherein the organic phase comprises an alcohol.

[0817] Example 124. The method as in Example 123, wherein the organic phase is replenished with an alcohol during the distilling step.

[0818] Example 125. The method as in any one of Examples 109-122, wherein the organic phase comprises 2-butanol.

[0819] Example 126. The method as in Example 125, wherein the organic phase is replenished with 2-butanol during the distilling step.

[0820] Example 127. The method of any one of Examples 73-126, wherein the substantially anhydrous mixture comprises less than about 5% water by weight.

[0821] Example 128. The method of any one of Examples 73-126, wherein the substantially anhydrous mixture comprises less than about 3% water by weight.

[0822] Example 129. The method of any one of Examples 73-128, wherein the isolating step comprises crystallizing the compound of Formula (VII) from the substantially anhydrous mixture.

[0823] Example 130. The method of Example 129, wherein the substantially anhydrous mixture is seeded with a crystalline form of the compound of Formula (VII).

[0824] Example 131. The method of Example 129 or 130, wherein the substantially anhydrous mixture is maintained at a temperature of at least about 70 °C for a period of at least two hours after the start of crystallization.

[0825] Example 132. The method of Example 129 or 130, wherein the substantially anhydrous mixture is maintained at a temperature of at least about 70 °C for a period of at least two hours after the start of crystallization and then cooled to crystallize the compound of Formula (VII).

[0826] Example 133. The method of any one of Examples 73-132, wherein the stoichiometric process yield of the compound of Formula (VII) is at least about 50%.

[0827] Example 134. The method of any one of Examples 73-132, wherein the stoichiometric process yield of the compound of Formula (VII) is at least about 65%.

[0828] Example 135. The method of any one of Examples 73-132, wherein the stoichiometric process yield of the compound of Formula (VII) is at least about 75%.

[0829] Example 136. A method for preparing a compound having the structure of Formula (VI):

[0830]

[0831] or a salt thereof, wherein the method comprises:

[0832] crystallizing a compound of Formula (IV):

[0833]

[0834] 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 byproduct;

[0835] removing at least a portion of the benzyl halide byproduct from the reaction mixture; and

[0836] 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.

[0837] In some embodiments, the method of any one of embodiments 136-141, wherein the isolating step comprises:

[0838] removing at least a portion of the benzyl halide byproduct from the reaction mixture;

[0839] increasing 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

[0840] isolating the compound of Formula (VI), or a salt thereof, from the basic reaction mixture.

[0841] In some embodiments, the method of any one of embodiments 136-141, wherein the isolating step comprises:

[0842] extracting at least a portion of the benzyl halide byproduct from the reaction mixture into a waste organic phase;

[0843] increasing 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;

[0844] extracting the compound of Formula (VI), or a salt thereof, from the basic reaction medium into a product organic phase; and

[0845] isolating the compound of Formula (VI), or a salt thereof, from the product organic phase.

[0846] In some embodiments, the method of any one of embodiments 136-141, wherein the acidic medium is an aqueous acidic medium.

[0847] In some embodiments, the method of any one of embodiments 136-141, wherein a sulfate salt of the compound of Formula (IV) is contacted with the acidic medium.

[0848] In some embodiments, the method of any one of embodiments 136-141, wherein the acidic medium comprises an inorganic acid.

[0849] Example 142. The method of any one of embodiments 136-140, wherein the acidic medium comprises hydrochloric acid.

[0850] Example 143. The method of any one 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.

[0851] Example 144. The method of any one of embodiments 136-142, wherein the acidic medium comprises from about 10 to about 40 molar equivalents of acid relative to the compound of Formula (IV), or salt thereof.

[0852] Example 145. The method of any one of embodiments 136-142, wherein the acidic medium comprises from about 10 to about 25 molar equivalents of acid relative to the compound of Formula (IV), or salt thereof.

[0853] Example 146. The method of any one of embodiments 136-145, wherein the volume of the acidic medium is about 2 liters to about 10 liters of acidic medium per kilogram of the compound of Formula (IV), or salt thereof, loaded into the acidic medium.

[0854] Example 147. The method of any one of embodiments 136-145, wherein the volume of the acidic medium is about 3 liters to about 4 liters of acidic medium per kilogram of the compound of Formula (IV), or salt thereof, loaded into the acidic medium.

[0855] Example 148. The method of any one 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.

[0856] Example 149. The method of any one of embodiments 136-147, wherein the acidic medium is maintained at a temperature of from about 40 °C to about 50 °C during the contacting step.

[0857] Example 150. The method of any one of embodiments 136-149, wherein the contacting step is performed as a batch reaction.

[0858] Example 151. The method of embodiment 150, wherein at least about 50 kilograms of the compound of Formula (IV) is loaded into the batch reaction.

[0859] Example 152. The method of embodiment 150, wherein at least about 100 kilograms of the compound of Formula (IV) is loaded into the batch reaction.

[0860] Example 153. The method of Example 150, wherein at least about 200 kilograms of the compound of Formula (IV) is charged to the batch reaction.

[0861] Example 154. The method of Example 150, wherein at least about 300 kilograms of the compound of Formula (IV) is charged to the batch reaction.

[0862] Example 155. The method of any one of Examples 136-154, wherein the method comprises selectively extracting at least a portion of the benzyl halide byproduct from the reaction mixture into a discarded organic phase prior to the separating step relative to the compound of Formula (VI).

[0863] Example 156. The method of Example 155, wherein at least about 80 weight percent of the compound of the benzyl halide byproduct present in the reaction mixture is extracted into the discarded organic phase.

[0864] Example 157. The method of Example 155, wherein less than about 20 weight percent of the compound of Formula (VI) present in the reaction mixture is extracted into the discarded organic phase.

[0865] Example 158. The method of Example 155, wherein at least about 80 weight percent of the compound of the benzyl halide byproduct present in the reaction mixture and less than about 20 weight percent of the compound of Formula (VI) present in the reaction mixture is extracted into the discarded organic phase.

[0866] Example 159. The method of Example 155, wherein at least about 90 weight percent of the compound of the benzyl halide byproduct present in the reaction mixture and less than about 10 weight percent of the compound of Formula (VI) present in the reaction mixture is extracted into the discarded organic phase.

[0867] Example 160. The method of Example 155, wherein at least about 95 weight percent of the compound of the benzyl halide byproduct present in the reaction mixture and less than about 5 weight percent of the compound of Formula (VI) present in the reaction mixture is extracted into the discarded organic phase.

[0868] Example 161. The method of any one of Examples 155-160, wherein the discarded organic phase comprises at least one solvent selected from the group consisting of an alkyl hydrocarbon, an aromatic hydrocarbon, a chlorinated hydrocarbon, and an ether.

[0869] Example 162. The method of any one of embodiments 155-160, wherein the waste 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.

[0870] Example 163. The method of any one of embodiments 155-160, wherein the waste organic phase comprises heptane.

[0871] Example 164. The method of any one of embodiments 155-163, wherein the method further comprises:

[0872] increasing the pH of the reaction mixture after the benzyl halide byproduct is extracted to form a basic reaction medium comprising a compound of Formula (VI), or a salt thereof; and

[0873] extracting the compound of Formula (VI), or a salt thereof, from the basic reaction medium into a product organic phase.

[0874] Example 165. The method of embodiment 164, wherein the pH of the basic reaction mixture is at least about 8.0.

[0875] Example 166. The method of embodiment 164, wherein the pH of the basic reaction mixture is at least about 10.0.

[0876] Example 167. The method of any one of embodiments 164-166, wherein the product organic phase comprises at least one solvent selected from the group consisting of an alkyl hydrocarbon, an aromatic hydrocarbon, a chlorinated hydrocarbon, and an ether.

[0877] Example 168. The method of any one 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.

[0878] Example 169. The method of any one of embodiments 164-166, wherein the product organic phase comprises 2-methyltetrahydrofuran.

[0879] Example 170. The method of any one of embodiments 164-169, wherein the method further comprises washing the product organic phase with water.

[0880] Example 171. The method of any one of embodiments 164-170, wherein the method further comprises distilling the product organic phase under conditions sufficient to reduce the amount of water present in the product organic phase.

[0881] Example 172. The process of Example 171, wherein the product organic phase comprises 2-methyltetrahydrofuran and additional 2-methyltetrahydrofuran is charged to the product organic phase during the distillation step.

[0882] Example 173. The process of Example 171 or 172, wherein the product organic phase is distilled at atmospheric pressure.

[0883] Example 174. The process of any one of Examples 136 to 173, wherein the isolating step comprises crystallizing the compound of Formula (VI).

[0884] Example 175. The process of Example 174, wherein the isolating step further comprises seeding with a crystalline form of the compound of Formula (VI) to facilitate crystallization.

[0885] Example 176. The process of Example 174, wherein the isolating step comprises seeding with at least about 0.0005 relative weight of a crystalline form of the compound of Formula (VI) to facilitate crystallization.

[0886] Example 177. The process of Example 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 facilitate crystallization.

[0887] Example 178. The process of any one of Examples 175 to 177, wherein the process further comprises charging an antisolvent to facilitate crystallization.

[0888] Example 179. The process of Example 178, wherein the antisolvent is heptane.

[0889] Example 180. The process of Example 136, wherein the isolating step comprises:

[0890] selectively extracting at least a portion of the benzyl halide byproduct from the reaction mixture into a waste organic phase relative to the compound of Formula (VI);

[0891] increasing the pH of the resulting reaction mixture to a pH greater than about 7.0 to form a basic reaction mixture;

[0892] selectively pre-extracting at least a portion of the compound of Formula (VI) from the basic reaction mixture into a product organic phase; and

[0893] 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).

[0894] Example 181. The method of Example 180, wherein the method further comprises crystallizing the compound of Formula (VI) from the distilled organic phase.

[0895] Example 182. The method of any one of Examples 136-181, wherein the aminal impurity comprises a compound having the structure of Formula (X):

[0896]

[0897] or a salt thereof.

[0898] Example 183. The method of any one of Examples 136-182, wherein the isolated compound of Formula (VI), or a salt thereof, comprises less than 5% by weight of the aminal impurity.

[0899] Example 184. The method of any one of Examples 136-182, wherein the isolated compound of Formula (VI), or a salt thereof, comprises less than 3% by weight of the aminal impurity.

[0900] Example 185. The method of any one of Examples 136-182, wherein the isolated compound of Formula (VI), or a salt thereof, comprises less than 1% by weight of the aminal impurity.

[0901] Example 186. The method of any one of Examples 136-185, wherein the stoichiometric method yield of the compound of Formula (VI) is at least about 50%.

[0902] Example 187. The method of any one of Examples 136-185, wherein the stoichiometric method yield of the compound of Formula (VI) is at least about 65%.

[0903] Example 188. The method of any one of Examples 136-185, wherein the stoichiometric method yield of the compound of Formula (VI) is at least about 80%.

[0904] Example 189. A method for preparing a compound having the structure of Formula (V):

[0905]

[0906] or a salt thereof, wherein the method comprises 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 contacting the acyl chloride intermediate in situ with 2- aminopyridine to form a reaction mixture comprising the compound of Formula (V), or a salt thereof.

[0907] Embodiment 190. The method of Embodiment 189, wherein the method further comprises isolating the compound of Formula (V), or a salt thereof, from the reaction mixture.

[0908] Embodiment 191. The method of Embodiment 189 or 190, wherein the catalyst comprises tetrabutylammonium chloride.

[0909] Embodiment 192. The method of Embodiment 189 or 190, wherein the catalyst comprises N-methylbenzenamine.

[0910] Embodiment 193. The method of Embodiment 189 or 190, wherein the catalyst does not comprise N,N-dimethylformamide.

[0911] Embodiment 194. The method of any one of Embodiments 189-193, wherein the reaction medium does not comprise N,N-dimethylformamide.

[0912] Embodiment 195. The method of any one 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.

[0913] Embodiment 196. The method of any one of Embodiments 189-194, wherein the organic solvent comprises a compound selected from the group consisting of toluene, acetonitrile, and pyridine.

[0914] Embodiment 197. The method of any one of Embodiments 189-194, wherein the organic solvent comprises toluene.

[0915] Embodiment 198. The method of any one of Embodiments 189-197, wherein the volume of reaction medium is 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.

[0916] Embodiment 199. The method of any one of Embodiments 189-197, wherein the volume of 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.

[0917] Embodiment 200. The method of any one of Embodiments 189-199, wherein the reaction medium is maintained at a temperature from about 50 °C to about 90 °C during the contacting step.

[0918] Embodiment 201. The method of any one of Embodiments 189-199, wherein the reaction medium is maintained at a temperature from about 60 °C to about 80 °C during the contacting step.

[0919] Example 202. The method of any one of Examples 189 to 201, wherein the contacting step is performed as a batch reaction.

[0920] Example 203. The method of any one of Examples 189 to 202, wherein 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.

[0921] Example 204. The method of any one of Examples 189 to 202, wherein 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.

[0922] Example 205. The method of any one of Examples 189 to 202, wherein 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.

[0923] Example 206. The method of any one of Examples 189 to 205, wherein about 1.5 to about 5 molar equivalents of 2-aminopyridine is charged to the reaction medium relative to 4-carboxyphenylboronic acid, or a salt thereof.

[0924] Example 207. The method of any one of Examples 189 to 205, wherein about 1.5 to about 3.5 molar equivalents of 2-aminopyridine is charged to the reaction medium relative to 4-carboxyphenylboronic acid, or a salt thereof.

[0925] Example 208. The method of any one of Examples 189 to 205, wherein about 2 molar equivalents of 2-aminopyridine is charged to the reaction medium relative to 4-carboxyphenylboronic acid, or a salt thereof.

[0926] Example 209. The method of any one of Examples 189 to 208, wherein the stoichiometric process yield of the compound of Formula (V) is at least about 50%.

[0927] Example 210. The method of any one of Examples 189 to 208, wherein the stoichiometric process yield of the compound of Formula (V) is at least about 70%.

[0928] Example 211. A crystalline sulfate salt of a compound having the structure of Formula (IV):

[0929]

[0930] Example 212. The crystalline sulfate salt of Example 211, wherein the crystalline sulfate salt has a stoichiometric ratio of one sulfate molecule and one bisulfate molecule to three free base molecules.

[0931] Example 213. The crystalline sulfate salt of Example 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 °2Q, 10.6 ± 0.2 °2Q, 11.1 ± 0.2 °2Q, 12.6 ± 0.2 °2Q, and 13.5 ± 0.2 °2Q.

[0932] Example 214. A method for preparing a sulfate salt of a compound having the structure of Formula (IV):

[0933]

[0934] wherein the method comprises:

[0935] contacting a compound having the structure of Formula (III)

[0936]

[0937] or a salt thereof, with an aminating agent in a reaction medium to form a reaction mixture comprising a compound of Formula (IV);

[0938] forming a sulfate salt of the compound of Formula (IV); and

[0939] isolating the sulfate salt.

[0940] Example 215. The method of Example 214, wherein the sulfate salt has a stoichiometric ratio of one sulfate molecule and one bisulfate molecule to three free base molecules.

[0941] Example 216. The method of Example 214 or 215, wherein the method comprises isolating the compound of Formula (IV) as a free base from the reaction mixture prior to the forming step.

[0942] Example 217. The method of Example 214 or 215, wherein the method comprises:

[0943] isolating the compound of Formula (IV) as a free base from the reaction medium;

[0944] contacting the free base with sulfuric acid to form the sulfate salt; and

[0945] isolating the sulfate salt.

[0946] Example 218. The method of either of Examples 214 or 215, wherein the method comprises:

[0947] washing the reaction mixture to reduce the amount of ammonia present in the reaction mixture;

[0948] isolating the compound of Formula (IV) as a free base from the washed reaction medium;

[0949] contacting the free base with sulfuric acid to form the sulfate salt; and

[0950] isolating the sulfate salt.

[0951] Example 219. The method of either of Examples 214 or 215, wherein the method comprises:

[0952] washing the reaction mixture with a saline solution;

[0953] distilling the washed reaction mixture to reduce the amount of ammonia present in the washed reaction mixture;

[0954] isolating the compound of Formula (IV) as a free base from the distilled reaction medium;

[0955] contacting the free base with sulfuric acid to form the sulfate salt; and

[0956] isolating the sulfate salt.

[0957] Example 220. The method of any one of Examples 214 to 219, wherein the method further comprises isolating the sulfate salt by filtration.

[0958] Example 221. The method of any one of Examples 214 to 220, wherein the aminating agent is ammonia.

[0959] Example 222. The method of any one of Examples 214 to 220, wherein the aminating agent is ammonium hydroxide.

[0960] Example 223. The method of any one of Examples 214 to 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.

[0961] Example 224. The method of any one of Examples 214 to 221, wherein the reaction medium comprises at least one compound selected from the group consisting of methanol, ethanol, propanol, butanol, pentanol, N-methylpyrrolidone, and N,N-dimethylformamide.

[0962] Example 225. The method of any one of Examples 214 to 221, wherein the reaction medium comprises a fatty alcohol.

[0963] Example 226. The method of any one of Examples 214 to 221, wherein the reaction medium comprises butanol.

[0964] Example 227. The method of any one of Examples 214 to 221, wherein the reaction medium comprises 2-butanol.

[0965] Example 228. The method of any one of Examples 214 to 227, wherein the reaction medium is maintained at a temperature greater than 70 °C during the contacting step.

[0966] Example 229. The method of any one of Examples 214 to 227, wherein the reaction medium is maintained at a temperature greater than 90 °C during the contacting step.

[0967] Example 230. The method of any one of Examples 214 to 227, wherein the reaction medium is maintained at a temperature from about 50 °C to about 100 °C during the contacting step.

[0968] Example 231. The method of any one of Examples 214 to 227, wherein the reaction medium is maintained at a temperature from about 60 °C to about 95 °C during the contacting step.

[0969] Example 232. The method of any one of Examples 214 to 231, wherein the volume of the reaction medium is about 1.5 liters to about 40 liters of reaction medium per kilogram of compound of Formula (III), or salt thereof, charged to the reaction medium.

[0970] Example 233. The method of any one of Examples 214 to 231, wherein the volume of the reaction medium is about 2.0 liters to about 30 liters of reaction medium per kilogram of compound of Formula (III), or salt thereof, charged to the reaction medium.

[0971] Example 234. The method of any one of Examples 214 to 233, wherein the contacting step is conducted as a batch reaction.

[0972] Example 235. The method of Example 234, wherein at least about 50 kilograms of compound of Formula (III) is charged to the batch reaction.

[0973] Example 236. The method of Example 234, wherein at least about 100 kilograms of compound of Formula (III) is charged to the batch reaction.

[0974] Embodiment 237. The method of Embodiment 234, wherein at least about 200 kilograms of the compound of Formula (III) is charged to the batch reaction.

[0975] Embodiment 238. The method of Embodiment 234, wherein at least about 300 kilograms of the compound of Formula (III) is charged to the batch reaction.

[0976] Embodiment 239. The method of any one of Embodiments 214-238, wherein the forming step comprises contacting the compound of Formula (IV) with sulfuric acid to form the sulfate salt mixture comprising the sulfate salt.

[0977] Embodiment 240. The method 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).

[0978] Embodiment 241. The method 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).

[0979] Embodiment 242. The method of any one of Embodiments 214-241, wherein the stoichiometric process yield of the sulfate salt of Formula (IV) is at least about 50%.

[0980] Embodiment 243. The method of any one of Embodiments 214-241, wherein the stoichiometric process yield of the sulfate salt of Formula (IV) is at least about 65%.

[0981] Embodiment 244. The method of any one of Embodiments 214-241, wherein the stoichiometric process yield of the sulfate salt of Formula (IV) is at least about 80%.

[0982] Embodiment 245. A method for preparing a compound having the structure of Formula (II):

[0983]

[0984] or a salt thereof, wherein the method comprises:

[0985] contacting a compound having the structure of Formula (I)

[0986]

[0987] or a salt thereof, with a cyclization agent in the presence of a catalyst in a reaction medium to form a compound of Formula (II), or a salt thereof;

[0988] 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 of the compound of Formula (II), or salt thereof.

[0989] Embodiment 246. The method of Embodiment 245, wherein the cyclizing agent comprises phosphorus oxychloride.

[0990] Embodiment 247. The method of Embodiments 245 or 246, wherein the catalyst comprises a catalyst selected from the group consisting of N,N-dimethylformamide and N-methyltoluidine.

[0991] Embodiment 248. The method of Embodiments 245 or 246, wherein the catalyst comprises N,N-dimethylformamide.

[0992] Embodiment 249. The method of any one of Embodiments 245 to 248, wherein the reaction medium comprises at least one solvent selected from the group consisting of an aromatic hydrocarbon, a chlorinated hydrocarbon, an ether, and a nitrile.

[0993] Embodiment 250. The method of any one of Embodiments 245 to 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.

[0994] Embodiment 251. The method of any one of Embodiments 245 to 248, wherein the reaction medium comprises acetonitrile.

[0995] Embodiment 252. The method of any one of Embodiments 245 to 251, wherein the compound of Formula (I), or salt thereof, is contacted with about 0.7 to about 10 molar equivalents of the cyclizing agent relative to the compound of Formula (I), or salt thereof.

[0996] Embodiment 253. The method of any one of Embodiments 245 to 251, wherein the compound of Formula (I), or 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 salt thereof.

[0997] Embodiment 254. The method of any one of Embodiments 245 to 251, wherein the compound of Formula (I), or salt thereof, is contacted with about 2.0 molar equivalents of the cyclizing agent relative to the compound of Formula (I), or salt thereof.

[0998] Embodiment 255. The method of any one of Embodiments 245 to 254, wherein at least about 0.1 molar equivalents of the catalyst are charged to the reaction medium relative to the compound of Formula (I), or salt thereof.

[0999] Embodiment 256. The method of any one of embodiments 245 to 254, wherein about 0.1 to about 1.0 molar equivalents of the catalyst is loaded into the reaction medium relative to the compound of Formula (I), or salt thereof.

[1000] Embodiment 257. The method of any one of embodiments 245 to 254, wherein at least about 0.4 molar equivalents of the catalyst is loaded into the reaction medium relative to the compound of Formula (I), or salt thereof.

[1001] Embodiment 258. The method of any one of embodiments 245 to 254, wherein about 0.4 to about 1.0 molar equivalents of the catalyst is loaded into the reaction medium relative to the compound of Formula (I), or salt thereof.

[1002] Embodiment 259. The method of any one of embodiments 245 to 254, wherein the catalyst comprises N,N-dimethylformamide, and at least about 0.1 molar equivalents of the catalyst is loaded into the reaction medium relative to the compound of Formula (I), or salt thereof.

[1003] Embodiment 260. The method of any one of embodiments 245 to 254, wherein the catalyst comprises N,N-dimethylformamide, and from about 0.1 to about 1.0 molar equivalents of the catalyst is loaded into the reaction medium relative to the compound of Formula (I), or salt thereof.

[1004] Embodiment 261. The method of any one of embodiments 245 to 254, wherein the catalyst comprises N,N-dimethylformamide, and at least about 0.4 molar equivalents of the catalyst is loaded into the reaction medium relative to the compound of Formula (I), or salt thereof.

[1005] Embodiment 262. The method of any one of embodiments 245 to 254, wherein the catalyst comprises N,N-dimethylformamide, about 0.4 to about 1.0 molar equivalents of the catalyst is loaded into the reaction medium relative to the compound of Formula (I), or salt thereof.

[1006] Embodiment 263. The method of any one of embodiments 245 to 254, wherein the catalyst comprises N,N-dimethylformamide, and at least about 0.6 molar equivalents of the catalyst is loaded into the reaction medium relative to the compound of Formula (I), or salt thereof.

[1007] Embodiment 264. The method of any one of embodiments 245 to 254, wherein the catalyst comprises N,N-dimethylformamide, and about 0.6 molar equivalents of the catalyst are charged to the reaction medium relative to the compound of Formula (I), or the salt thereof.

[1008] Embodiment 265. The method of any one of embodiments 245 to 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 of the compound of Formula (II), or the salt thereof.

[1009] Embodiment 266. The method of any one of embodiments 245 to 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 of the compound of Formula (II), or the salt thereof.

[1010] Embodiment 267. The method of any one of embodiments 245 to 266, wherein the reaction medium is maintained at a temperature of less than about 80 °C during the contacting step.

[1011] Embodiment 268. The method of any one of embodiments 245 to 266, wherein the reaction medium is maintained at a temperature of less than about 50 °C during the contacting step.

[1012] Embodiment 269. The method of any one of embodiments 245 to 266, wherein the reaction medium is maintained at a temperature of from about 30 °C to about 50 °C during the contacting step.

[1013] Embodiment 270. The method of any one of embodiments 245 to 269, wherein the reaction medium is maintained at a temperature of about 40 °C during the contacting step.

[1014] Embodiment 271. The method of any one of embodiments 245 to 270, wherein the volume of the reaction medium is about 2 liters to about 20 liters of reaction medium per kilogram of the compound of Formula (I), or the salt thereof, charged to the reaction medium.

[1015] Embodiment 272. The method of any one of embodiments 245 to 270, wherein the volume of the reaction medium is about 3 liters to about 10 liters of reaction medium per kilogram of the compound of Formula (I), or the salt thereof, charged to the reaction medium.

[1016] Embodiment 273. The method of any one of embodiments 245 to 272, wherein the contacting step is conducted as a batch reaction.

[1017] Example 274. The method of Example 273, wherein at least about 50 kilograms of the compound of Formula (I) is charged to the batch reaction.

[1018] Example 275. The method of Example 273, wherein at least about 100 kilograms of the compound of Formula (I) is charged to the batch reaction.

[1019] Example 276. The method of Example 273, wherein at least about 200 kilograms of the compound of Formula (I) is charged to the batch reaction.

[1020] Example 277. The method of Example 273, wherein at least about 300 kilograms of the compound of Formula (I) is charged to the batch reaction.

[1021] Example 278. The method of any one of Examples 245-277, wherein the compound of Formula (II) has a stoichiometric process yield of at least about 50%.

[1022] Example 279. The method of any one of Examples 245-277, wherein the compound of Formula (II) has a stoichiometric process yield of at least about 65%.

[1023] Example 280. The method of any one of Examples 245-277, wherein the compound of Formula (II) has a stoichiometric process yield of at least about 80%.

[1024] Example 281. A method for preparing a compound having the structure of Formula (III):

[1025]

[1026] or a salt thereof, wherein the method comprises:

[1027] contacting a compound having the structure of Formula (I)

[1028]

[1029] or a salt thereof, with a cyclization agent in the presence of a catalyst in a reaction medium to form a compound of Formula (II);

[1030]

[1031] or a salt thereof; and

[1032] brominating the compound of Formula (II), or a salt thereof, with a brominating agent to provide a compound having the structure of Formula (III):

[1033]

[1034] or a salt thereof;

[1035] 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 of the compound of Formula (II), or a salt thereof.

[1036] Embodiment 282. The method of Embodiment 281, wherein the brominating agent comprises N-bromosuccinimide.

[1037] Embodiment 283. The method of Embodiments 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 (II), or a salt thereof.

[1038] Embodiment 284. The method of any one 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.

[1039] Embodiment 285. The method of Embodiment 284, wherein the compound of Formula (II), or a salt thereof, is contacted with the brominating agent in a bromination medium comprising at least one solvent selected from the group consisting of a chlorinated hydrocarbon and a polar aprotic solvent.

[1040] Embodiment 286. The method of Embodiment 284, wherein the compound of Formula (II), or a salt thereof, is contacted with the 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.

[1041] Embodiment 287. The method of Embodiment 284, wherein the compound of Formula (II), or a salt thereof, is contacted with the brominating agent in a bromination medium comprising N,N-dimethylformamide.

[1042] Embodiment 288. The method of Embodiment 284, wherein the compound of Formula (II), or a salt thereof, is contacted with the brominating agent in a bromination medium comprising N-methylpyrrolidinone.

[1043] Embodiment 289. The method of any one 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.

[1044] Embodiment 290. The method of any one of Embodiments 284 to 288, wherein the bromination medium is maintained at a temperature of about 20 °C during the bromination step.

[1045] Embodiment 291. The method of any one of embodiments 284 to 290, wherein the bromination step is carried out as a batch reaction.

[1046] Embodiment 292. The method of embodiment 291, wherein at least about 50 kilograms of the compound of formula (II) is loaded into the batch reaction.

[1047] Embodiment 293. The method of embodiment 291, wherein at least about 100 kilograms of the compound of formula (II) is loaded into the batch reaction.

[1048] Embodiment 294. The method of embodiment 291, wherein at least about 200 kilograms of the compound of formula (II) is loaded into the batch reaction.

[1049] Embodiment 295. The method of embodiment 291, wherein at least about 300 kilograms of the compound of formula (II) is loaded into the batch reaction.

[1050] Embodiment 296. The method of any one of embodiments 284 to 295, wherein the method comprises isolating the compound of formula (III), or a salt thereof, from the bromination medium.

[1051] Embodiment 297. The method of embodiment 296, wherein an aqueous solution is added to the bromination medium to isolate the compound of formula (III), or a salt thereof.

[1052] Embodiment 298. The method 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.

[1053] Embodiment 299. The method of embodiment 296, wherein an aqueous sodium bicarbonate solution is added to the bromination mixture to isolate the compound of formula (III), or a salt thereof.

[1054] Embodiment 300. The method of embodiment 299, wherein the sodium bicarbonate solution is about 1 to 10 weight percent sodium bicarbonate.

[1055] Embodiment 301. The method of embodiment 299, wherein the sodium bicarbonate solution is about 2 weight percent sodium bicarbonate.

[1056] Embodiment 302. The method of any one of embodiments 281 to 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.

[1057] Example 303. The method of any one of embodiments 281-302, wherein the stoichiometric process yield of the compound of Formula (III) is at least about 50%.

[1058] Example 304. The method of any one of embodiments 281-302, wherein the stoichiometric process yield of the compound of Formula (III) is at least about 65%.

[1059] Example 305. The method of any one of embodiments 281-302, wherein the stoichiometric process yield of the compound of Formula (III) is at least about 80%.

[1060] Example 306. The method of embodiment 1, wherein the compound of Formula (VII), or salt thereof, is prepared by a method comprising:

[1061] contacting a compound of the structure of Formula (V)

[1062]

[1063] or salt thereof, with a compound of the structure of Formula (VI):

[1064]

[1065] or salt thereof, in the presence of a base and a palladium catalyst, in a reaction medium comprising water and an organic solvent, to form a reaction mixture comprising a compound of Formula (VII), or salt thereof;

[1066] reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising a compound of Formula (VII), or salt thereof; and

[1067] isolating the compound of Formula (VII), or salt thereof, from the substantially anhydrous mixture.

[1068] Example 307. The method of embodiment 306, wherein the compound of Formula (VI), or salt thereof, is prepared by a method comprising:

[1069] contacting a compound of Formula (IV):

[1070]

[1071] or salt thereof, with an acidic medium under conditions sufficient to deprotect the compound of Formula (IV), or salt thereof, and form a reaction mixture comprising a compound of Formula (VI), or salt thereof, and a benzyl halide byproduct; and

[1072] isolating the compound of Formula (VI), or salt thereof, from the reaction mixture under conditions sufficient to substantially avoid formation of an acetal amine impurity.

[1073] Example 308. The method of Example 306, wherein the compound of Formula (V), or salt thereof, is prepared by a method comprising contacting 4-carboxyphenylboronic acid, or salt thereof, with thionyl chloride and a catalyst in a reaction medium comprising an organic solvent to form an acyl chloride intermediate, then contacting the acyl chloride intermediate in situ with 2- aminopyridine to form a reaction mixture comprising the compound of Formula (V), or salt thereof.

[1074] Example 309. The method of Example 306, wherein:

[1075] the compound of Formula (VI), or salt thereof, is prepared by a method comprising:

[1076] the compound of Formula (IV):

[1077]

[1078] or salt thereof, with an acidic medium under conditions sufficient to deprotect the compound of Formula (IV), or salt thereof, and form a reaction mixture comprising the compound of Formula (VI), or salt thereof, and a benzyl halide byproduct; and

[1079] isolating the compound of Formula (VI), or salt thereof, from the reaction mixture under conditions sufficient to substantially avoid formation of an acetal amine impurity; and

[1080] the compound of Formula (V), or salt thereof, is prepared by a method comprising contacting 4-carboxyphenylboronic acid, or salt thereof, with thionyl chloride and a catalyst in a reaction medium comprising an organic solvent to form an acyl chloride, then contacting the acyl chloride in situ with 2- aminopyridine to form a reaction mixture comprising the compound of Formula (V), or salt thereof.

[1081] Example 310. The method of any one of Examples 306-309, wherein the compound of Formula (IV), or salt thereof, is a sulfate salt; and the sulfate salt is prepared by a method comprising:

[1082] contacting a compound of Formula (III)

[1083]

[1084] or salt thereof, with an amine-forming agent in a reaction medium to form a reaction mixture comprising the compound of Formula (IV);

[1085] forming a sulfate salt of the compound of Formula (IV); and

[1086] isolating the sulfate salt.

[1087] Example 311. The method of Example 310, wherein the compound of formula (III), or salt thereof, is prepared by a method comprising:

[1088] contacting a compound having the structure of formula (I)

[1089]

[1090] or salt thereof, with a cyclization agent in the presence of a catalyst in a reaction medium to form a compound of formula (II);

[1091]

[1092] or salt thereof; and

[1093] brominating the compound of formula (II), or salt thereof, with a brominating agent to provide a compound having the structure of formula (III), or salt thereof;

[1094] 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 of the compound of formula (II), or salt thereof.

[1095] Example 312. A method for preparing a compound having the structure of formula (VIII):

[1096]

[1097] or salt thereof, wherein the method comprises:

[1098] contacting a compound having the structure of formula (V)

[1099]

[1100] or salt thereof, with a compound having the structure of formula (VI):

[1101]

[1102] or salt thereof, in the presence of a base and a palladium catalyst in an aqueous reaction medium comprising an organic solvent to form a reaction mixture comprising a compound having the structure of formula (VII):

[1103]

[1104] or salt thereof;

[1105] reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising a compound of Formula (VII), or salt thereof;

[1106] isolating the compound of Formula (VII), or salt thereof, from the substantially anhydrous mixture; and

[1107] converting the compound of Formula (VII), or salt thereof, to a compound of Formula (VIII).

[1108] Example 313. A method for preparing a compound having the structure of Formula (VIII):

[1109]

[1110] or salt thereof, wherein the method comprises:

[1111] contacting a compound having the structure of Formula (IV)

[1112]

[1113] or salt thereof, with an acidic medium under conditions sufficient to deprotect the compound of Formula (IV) and form a reaction mixture comprising a compound having the structure of Formula (VI):

[1114]

[1115] or salt thereof, and a benzyl halide byproduct;

[1116] isolating the compound of Formula (VI), or salt thereof, from the reaction mixture under conditions sufficient to substantially avoid aminal impurity formation; and

[1117] converting the compound of Formula (VI), or salt thereof, to a compound of Formula (VIII), or salt thereof.

[1118] Example 314. A method for preparing a compound having the structure of Formula (VIII):

[1119]

[1120] or salt thereof, wherein the method comprises:

[1121] contacting a compound having the structure of Formula (III)

[1122]

[1123] or salt thereof, with an amine-forming agent in a reaction medium to form a reaction mixture comprising a compound having the structure of Formula (IV):

[1124]

[1125] forming a sulfate salt of the compound of Formula (IV);

[1126] isolating the sulfate salt; and

[1127] converting the sulfate salt to a compound of Formula (VIII), or a salt thereof.

[1128] Example 315. A method for preparing a compound having the structure of Formula (VIII):

[1129]

[1130] or a salt thereof, wherein the method comprises:

[1131] contacting a compound having the structure of Formula (I)

[1132]

[1133] or a salt thereof, with a cyclization agent in the presence of a catalyst in a reaction medium to form a compound of Formula (II);

[1134]

[1135] or a salt thereof;

[1136] brominating the compound of Formula (II), or a salt thereof, with a brominating agent to provide a compound having the structure of Formula (III):

[1137]

[1138] or a salt thereof; and

[1139] converting the compound of Formula (III), or a salt thereof, to a compound of Formula (VIII), or a salt thereof;

[1140] 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 of the compound of Formula (II), or a salt thereof.

[1141] ***********

[1142] All of the above-referenced (patent and non-patent) documents are incorporated by reference in this patent application. Discussion of the references states what their authors assert, and applicants reserve the right to challenge correctness and pertain relevance of the referenced documents.

Claims

1. A crystalline form of a compound having the structure of formula (VII): The crystalline form is characterized by a reflectance X-ray powder diffraction pattern selected from the following: A reflected 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, 12.8±0.2°2θ, 14.1±0.2°2θ, and 19.0±0.2°2θ, and A reflected 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, 12.5±0.2°2θ, 22.3±0.2°2θ, and 21.6±0.2°2θ.

2. The crystalline form as claimed in claim 1, wherein the crystalline form is characterized by a reflected 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.

3. A method for preparing a compound having the structure of formula (VII): A method using a salt thereof, wherein the method comprises: Compounds having the structure of formula (V) Or its salts, and compounds having the structure of formula (VI): Or its salt, in the presence of a base and a palladium catalyst, are contacted in an aqueous reaction medium containing an organic solvent to form a reaction mixture comprising the compound having formula (VII) or its salt. The amount of water present in the reaction mixture is reduced to form a substantially anhydrous mixture comprising the compound having formula (VII) or a salt thereof; and Separate the compound having formula (VII) or its salt from the substantially anhydrous mixture.

4. The method of claim 3, wherein the separation step comprises filtering the substantially anhydrous mixture.

5. The method of claim 3 or 4, wherein the aqueous reaction medium further comprises an alkali metal halide.

6. The method of any one of claims 3 to 5, wherein the reducing step comprises: The reaction mixture is separated into an aqueous waste phase and an organic phase containing the compound having formula (VII); Wash the organic phase with water; The organic phase was treated with a silica remover. Remove the silica remover from the organic phase; The organic phase was washed with an aqueous salt solution. and The organic phase is distilled under conditions sufficient to reduce the amount of water present in the organic phase.

7. The method of any one of claims 3 to 6, wherein the substantially anhydrous mixture contains less than about 5% by weight of water.

8. A method for preparing a compound having the structure of formula (VI): A method using a salt thereof, wherein the method comprises: Compounds having formula (IV): Or its salt, contacted with an acidic medium under conditions sufficient to deprotect the compound having formula (IV) and forming a reaction mixture comprising the compound having formula (VI), or its salt, and a benzyl halide byproduct; Remove at least a portion of the benzyl halide byproduct from the reaction mixture; and The compound having formula (VI), or its salt, is separated from the reaction mixture under conditions sufficient to substantially avoid the formation of acetal amine impurities.

9. The method of claim 8, wherein the separation step comprises: Remove at least a portion of the benzyl halide byproduct from the reaction mixture; The pH of the resulting reaction mixture is increased to an alkaline pH to form an alkaline reaction medium comprising the compound having formula (VI) or a salt thereof; and Separate the compound having formula (VI) or its salt from the alkaline reaction mixture.

10. The method of claim 8, wherein the separation step comprises: Extract at least a portion of the benzyl halide byproduct from the reaction mixture into the discarded organic phase; The pH of the resulting reaction mixture is increased to an alkaline pH to form an alkaline reaction medium containing the compound having formula (VI) or a salt thereof; The compound having formula (VI), or a salt thereof, is extracted from the alkaline reaction medium into the product organic phase; and Separate the compound having formula (VI) or its salt from the organic phase of the product.

11. The method of claim 8, wherein the separation step comprises: Relative to the compound having formula (VI), at least a portion of the benzyl halide byproduct is selectively extracted from the reaction mixture into a discarded organic phase; The pH of the resulting reaction mixture was increased to a value greater than about 7.0 to form an alkaline reaction mixture; At least a portion of the compound having formula (VI) is selectively pre-extracted from the alkaline reaction mixture into the product organic phase; and The product organic phase is distilled under conditions sufficient to reduce the amount of water present in the product organic phase to form a distilled organic phase containing the compound having (VI).

12. An aid for preparing compounds having the structure of formula (V): A method comprising contacting 4-carboxyphenylboronic acid, or a salt thereof, with thionyl chloride and a catalyst in a reaction medium containing an organic solvent to form an acyl chloride intermediate, and then contacting the acyl chloride intermediate in situ with 2-aminopyridine to form a reaction mixture comprising the compound having formula (V), or a salt thereof.

13. A crystalline sulfate of a compound having the structure of formula (IV):

14. The crystalline sulfate of claim 13, wherein the crystalline sulfate is characterized by a reflected 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.

15. A method for preparing sulfates of compounds having the structure of formula (IV): The method includes: Compounds having the structure of formula (III) Or its salt, contacted with an amination agent in a reaction medium to form a reaction mixture comprising the compound having formula (IV); The sulfate of the compound having formula (IV) is formed; and Separate the sulfate.

16. An aid for preparing a compound having the structure of formula (II): A method using a salt thereof, wherein the method comprises: Compounds having the structure of formula (I) Or its salt, in contact with a cyclizing agent in the presence of a catalyst in a reaction medium, to form the compound having formula (II) or its salt; The temperature of the reaction medium is controlled during the contact step in a manner sufficient to maintain at least about 80% chiral purity of the compound having formula (II) or its salt.

17. A method for preparing a compound having the structure of formula (III): A method using a salt thereof, wherein the method comprises: Compounds having the structure of formula (I) Or its salt, in contact with a cyclizing agent in the presence of a catalyst in a reaction medium, to form a compound having formula (II); or its salt; and The compound having formula (II) or a salt thereof is brominated with a brominating agent to provide a compound having the structure of formula (III): or its salt; The temperature of the reaction medium is controlled during the contact step in a manner sufficient to maintain at least about 80% chiral purity of the compound having formula (II) or its salt.

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