Method for preparing acalabrutinib

Abstract

The present disclosure generally relates to improved processes for preparing 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide, particularly large-scale processes for manufacturing 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 intermediates employed in such processes.

Description

Technical Field

[0001] The present disclosure generally relates to improved methods for preparing 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide, particularly large-scale methods for manufacturing 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 employed in such methods. Background Art

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

[0003] Example 6 of U.S. Patent No. 9,290,504 discloses acalabrutinib and reports the synthesis shown in Scheme 1 below:

[0004] Scheme 1

[0005]

[0006] Research Disclosure Database No. 631028 (published digitally on October 6, 2016) reports the synthesis of acalabrutinib shown in Scheme 2 below:

[0007] Scheme 2

[0008]

[0009] However, the previously reported synthetic methods are not suitable for the manufacture of acalabrutinib on a large scale, especially on a commercial scale. The present disclosure provides improved methods that can be operated on a large scale and offer 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 yields, lower costs, and improved compliance with regulatory requirements for drug starting materials, intermediates, and products, etc.

[0010] Brief Description of the Invention

[0011] As described above, the present disclosure relates to improved large-scale methods for preparing acalabrutinib and / or intermediates employed in the preparation of acalabrutinib.

[0012] In one aspect, the present disclosure relates to a method for preparing a compound having the structure of formula (VIII):

[0013]

[0014] or a salt thereof, wherein the method comprises:

[0015] contacting a compound having the structure of formula (VII)

[0016]

[0017] 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 having the structure of formula (VIII), or a salt thereof, and one or more reaction by-products; and

[0018] selectively separating the compound having the structure of formula (VIII), or a salt thereof, from the reaction mixture relative to the one or more reaction by-products.

[0019] In another aspect, the present disclosure relates to a method for preparing a compound having the structure of formula (VII):

[0020]

[0021] or a salt thereof, wherein the method comprises:

[0022] contacting a compound having the structure of formula (V)

[0023]

[0024] or a salt thereof, with a compound having the structure of formula (VI):

[0025]

[0026] or a salt thereof, is contacted in an aqueous reaction medium comprising an organic solvent in the presence of a base and a palladium catalyst to form a reaction mixture comprising a compound having formula (VII), or a salt thereof;

[0027] The amount of water present in the reaction mixture is reduced to form a substantially anhydrous mixture comprising a compound having formula (VII), or a salt thereof; and

[0028] The compound having formula (VII), or a salt thereof, is isolated from the substantially anhydrous mixture.

[0029] In another aspect, the present disclosure relates to a method for preparing a compound having the structure of formula (VI):

[0030]

[0031] or a salt thereof, wherein the method comprises:

[0032] Contacting a compound having formula (IV):

[0033]

[0034] or a salt thereof, with an acidic medium under conditions sufficient to deprotect the compound having formula (IV) and form a reaction mixture comprising a compound having formula (VI), or a salt thereof, and a benzyl halide byproduct; and

[0035] Isolating the compound having formula (VI), or a salt thereof, from the reaction mixture under conditions sufficient to substantially avoid the formation of acetalamine impurities.

[0036] In another aspect, the present disclosure relates to a method for preparing a compound having the structure of formula (V):

[0037]

[0038] 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, and then contacting the acyl chloride intermediate in situ with 2-aminopyridine to form a reaction mixture comprising a compound having formula (V), or a salt thereof.

[0039] In another aspect, the present disclosure relates to a method for preparing a sulfate salt of a compound having the structure of formula (IV):

[0040]

[0041] wherein the method comprises:

[0042] Contacting a compound having the structure of formula (III)

[0043]

[0044] or a salt thereof is contacted with an aminating agent in a reaction medium to form a reaction mixture comprising a compound having formula (IV);

[0045] forming a sulfate salt of the compound having formula (IV); and

[0046] isolating the sulfate salt.

[0047] In another aspect, the present disclosure relates to a method for preparing a compound having the structure of formula (III):

[0048]

[0049] or a salt thereof, wherein the method comprises:

[0050] contacting a compound having the structure of formula (I)

[0051]

[0052] or a salt thereof, with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound having formula (II);

[0053]

[0054] or a salt thereof; and

[0055] brominating the compound having formula (II), or a salt thereof, with a brominating agent to provide a compound having the structure of formula (III):

[0056]

[0057] or a salt thereof;

[0058] wherein during the contacting step the temperature of the reaction medium is controlled in a manner sufficient to maintain at least about 80% chiral purity of the compound having formula (II), or a salt thereof.

[0059] In another aspect, the present disclosure relates to a method for preparing a compound having the structure of formula (II):

[0060]

[0061] or a salt thereof, wherein the method comprises:

[0062] contacting a compound having the structure of formula (I)

[0063]

[0064] or a salt thereof, is contacted with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound having the formula (II), or a salt thereof;

[0065] wherein during the contacting step, the temperature of the reaction medium is controlled in a manner sufficient to maintain at least about 80% chiral purity of the compound having the formula (II), or a salt thereof.

[0066] In another aspect, the present disclosure relates to a crystalline form of a compound having the structure of formula (VII):

[0067]

[0068] wherein the crystalline form is characterized by a powder X-ray diffraction pattern selected from:

[0069] a powder X-ray 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, and

[0070] a powder X-ray diffraction pattern comprising at least three peaks selected from the group consisting of: 7.4 ± 0.2° 2θ, 11.7 ± 0.2° 2θ, 12.5 ± 0.2° 2θ, 22.3 ± 0.2° 2θ, and 21.6 ± 0.2° 2θ.

[0071] In another aspect, the present disclosure relates to a crystalline form of a compound having the structure of formula (VII):

[0072]

[0073] wherein the crystalline form is characterized by a powder X-ray diffraction pattern that comprises 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.

[0074] In another aspect, the present disclosure relates to a crystalline sulfate of a compound having the structure of formula (IV):

[0075]

[0076] Figure 1 Illustrated is the powder X-ray diffraction pattern (PXRD) measured in reflection mode from a sample of the crystalline sulfate of benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (having a stoichiometric ratio of about one sulfate molecule and one bisulfate molecule per three free base molecules).

[0077] Figure 2 Illustrated is the X-ray powder diffraction pattern (PXRD) measured in reflection mode from a sample of the Form 2 crystalline form of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide.

[0078] Figure 3 Illustrated is the X-ray powder diffraction pattern (PXRD) measured in reflection mode from a sample of the Form 3 crystalline form of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide.

[0079] Figure 4 Illustrated is the X-ray powder diffraction pattern (PXRD) measured in reflection mode from a sample of the Form C crystalline form of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide. DETAILED DESCRIPTION

[0080] This written description uses examples to disclose the invention and also enables those skilled in the art to practice the invention, including making and using any salts, substances, or compositions disclosed herein, and performing any methods or processes disclosed herein. The patentable scope of the invention is defined by the claims and may include other examples that occur to those skilled in the art. If such other examples have elements that are identical to the literal language of the claims, or if they include equivalent elements that have insubstantial differences from the literal language of the claims, then these examples are intended to be covered within the scope of the claims.

[0081] I. Definition

[0082] The section headings used in this section and throughout the disclosure are not intended to be limiting.

[0083] In the case of listing numerical ranges, each intermediate number within the range is explicitly considered with the same precision. For example, for the range of 6 to 9, in addition to 6 and 9, the numbers 7 and 8 are also considered; and for the range of 6.0 to 7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly considered. In the same way, all listed ratios also include all sub-ratios that fall within the broader ratio.

[0084] The singular forms "a / an" and "the" include plural referents unless the context clearly indicates otherwise.

[0085] The term "about" generally refers to a numerical range that a person skilled in the art would consider equivalent to the recited value (i.e., having the same function or result). In many cases, the term "about" may include numbers that are rounded to the nearest significant digit.

[0086] Unless the context otherwise requires, the terms "comprise, comprises, and comprising" are used on the clear understanding that they are to be construed inclusively rather than exclusively, and the applicant wishes each of those words to be so construed when interpreting this patent, including the following claims.

[0087] 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.

[0088] The term "crystalline purity", when used in reference to a crystalline form of a compound, refers to the percentage of the crystalline form of the compound in a reference composition relative to another crystalline form or an amorphous form.

[0089] The abbreviations used throughout this disclosure have the meanings indicated in Table 1 below.

[0090] Table 1

[0091]

[0092]

[0093] For clarity, Table 2 below summarizes the compound identifiers, chemical names, and structures that are used interchangeably throughout this application with respect to each of the compounds discussed.

[0094] Table 2

[0095]

[0096]

[0097]

[0098]

[0099] This disclosure also discusses crystalline forms of certain compounds listed in Table 2, including X-ray powder diffraction patterns that characterize such crystalline forms. As is known in the art, depending on the testing conditions (such as equipment, sample preparation, or the machine used), X-ray powder diffraction patterns with one or more measurement errors can be obtained. Specifically, 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 these 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 reflection positions can be affected by the exact height at which the sample is positioned in the diffractometer and the zero-point correction of the diffractometer. The surface planarity of the sample may also have a minor effect. Thus, one of ordinary skill in the art will understand that the diffraction pattern data presented herein should not be construed as absolute, and any crystalline form that provides a powder diffraction pattern that is substantially consistent with those disclosed herein falls within the scope of this disclosure (for further information, see Jenkins, R and Snyder, R.L. ‘Introduction to X-Ray Powder Diffractometry’ John Wiley & Sons, 1996). II. US Patent No. 9,290,504 Synthesis Synthesis

[0100] As previously mentioned, the synthesis reported in Example 6 of U.S. Patent No. 9,290,504 is not suitable for large-scale manufacture of acalabrutinib. Among other limitations, the reported method does not provide information regarding the chiral or achiral purity of the intermediates, separates the intermediates at various points in the method using chromatography, and produces milligram quantities of the final product. The overall yield of acalabrutinib in this bench-scale synthesis starting from Compound I was approximately 5%.

[0101] III. Clinical Trial Supply Method

[0102] The following Scheme 3 illustrates the method subsequently developed to manufacture supplies of acalabrutinib for clinical trials. Each step of Scheme 3 is discussed in further detail throughout this disclosure.

[0103] Scheme 3

[0104]

[0105] Although this method was used to produce approximately 100 to 150 kilograms of acalabrutinib for clinical trials, the method lacks robustness, is difficult to operate, and has a long cycle time. Thus, this method is considered unsuitable for large-scale manufacture of acalabrutinib.

[0106] More specifically, the method of Scheme 3 has many limitations, including the following:

[0107] (1) During the step of producing compound (II), the racemization of the chiral center is difficult to control and results in the failure of several batches.

[0108] (2) Many environmentally unfriendly solvents are employed in several steps.

[0109] (3) One of the more problematic solvents employed is dichloromethane. Besides environmental considerations, the use of dichloromethane in steps involving amines also has another drawback, namely that the reaction of the amine with dichloromethane produces acetalamine impurities, sometimes even leading to batch failure. During the step of producing compound (VI), for example, a methylene-bridged dimer can be formed. Further, the acid-based liquid chromatography method used in conjunction with the step of producing compound (VI) cannot detect acetalamine impurities.

[0110] (4) The combined use of N,N-dimethylformamide and thionyl chloride for the production of compound (V) may potentially lead to the formation of toxic dimethylcarbamyl chloride.

[0111] (5) The coupling reaction in the step of producing compound (VII) is prone to termination. During the final step of producing acalabrutinib, the addition of more palladium catalyst increases the burden of the scavenging step, which already requires excessive repeated cycles using silica-based scavengers.

[0112] (6) Separating compound (VII) by filtration is difficult and not suitable for large-scale manufacturing. On a 50 kg scale, two pressure filters are required, and the product has to be manually discharged as a wet paste multiple times, and this only results in significant time loss.

[0113] (7) For the acylation to produce acalabrutinib, multiple batch failures occurred through multiple different failure modes.

[0114] (8) Using distillation precipitation to separate acalabrutinib does not provide control over the particle characteristics of the separated product.

[0115] IV. Large-Scale Method

[0116] In view of the limitations associated with the clinical trial supply method, an improved method has been developed that overcomes those limitations and is applicable to the large-scale manufacture of acalabrutinib. The following Scheme 4 illustrates a representative embodiment of this large-scale method for the manufacture of acalabrutinib. Each step of Scheme 4 is discussed in further detail throughout this disclosure.

[0117] Scheme 4

[0118] V. Preparation of Benzyl (2S)-2-(8-chloro-imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Compound II) Preparation

[0119] This disclosure relates in part to a method for preparing benzyl (2S)-2-(8-chloro-imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Compound II), or a salt thereof, from benzyl (2S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl]pyrrolidine-1-carboxylate (Compound I), or a salt thereof. The following Scheme 5 illustrates the general method:

[0120] Scheme 5

[0121]

[0122] Cyclizing Compound (I) to form the imidazole ring present in Compound (II) is advantageous because it imparts stability to the chiral center of the subsequent intermediate employed in the manufacture of acalabrutinib. However, since uncyclized Compound (I) readily racemizes under the acidic conditions of the cyclization reaction, there are problems with the clinical trial supply method. This unwanted racemization reaction is difficult to control and has led to the failure of multiple batches. Using nitrogen purge to remove the liberated hydrochloric acid limits the chiral erosion that occurs to some extent, but the degree of chiral erosion remains highly variable.

[0123] The clinical trial supply method employs a reaction temperature of about 80 °C and a catalytic loading of N,N-dimethylformamide of about 0.2 molar equivalents. 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 pure Compound (II). The lower catalytic loading of N,N-dimethylformamide employed in the clinical trial supply method results in a reaction rate that requires a higher temperature for reaction completion, which then leads to the observed chiral degradation. In contrast, the increased catalytic loading of N,N-dimethylformamide in this improved method results in a faster reaction rate and allows the reaction to be carried out at a lower temperature, which inhibits racemization. Chiral degradation is reduced, chiral integrity is maintained, and thus the yield is increased.

[0124] Accordingly, in one embodiment, this disclosure relates to a method for preparing a compound having the structure of formula (II):

[0125]

[0126] or a salt thereof, wherein the method comprises:

[0127] reacting a compound having the structure of formula (I)

[0128]

[0129] or a salt thereof is contacted with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound of formula (II), or a salt thereof;

[0130] wherein during the contacting step, the temperature of the reaction medium is controlled in a manner sufficient to maintain at least about 80% chiral purity of the compound of formula (II), or a salt thereof.

[0131] As described above, appropriately controlling the reaction temperature during the cyclization reaction is important for maintaining a suitable chiral purity of the product. Generally, the temperature of the reaction medium is controlled in a manner sufficient to maintain at least about 85% chiral purity of the compound of formula (II), or a salt thereof during the cyclization reaction. In one aspect, the temperature of the reaction medium is controlled in a manner sufficient to maintain at least about 90% chiral purity of the compound of formula (II), or a salt thereof during the contacting step. In another aspect, the temperature of the reaction medium is controlled in a manner sufficient to maintain at least about 95% chiral purity of the compound of formula (II), or a salt thereof during the contacting step. In yet another aspect, the temperature of the reaction medium is controlled in a manner sufficient to maintain at least about 99% chiral purity of the compound of formula (II), or a salt thereof during the contacting step.

[0132] Maintaining the reaction medium at a temperature of less than about 80 °C during the contacting step generally increases the chiral purity of the compound of formula (II) or a salt thereof. In one aspect, the reaction medium is maintained at a temperature of less than about 70 °C during the contacting step. In another aspect, the reaction medium is maintained at a temperature of less than about 60 °C during the contacting step. In yet another aspect, the reaction medium is maintained at a temperature of less than about 50 °C during the contacting step. In yet another aspect, the reaction medium is maintained at a temperature from about 30 °C to about 50 °C during the contacting step. In yet another aspect, the reaction medium is maintained at a temperature of about 40 °C during the contacting step.

[0133] The catalyst can comprise any suitable catalyst, particularly a catalyst selected from the group consisting of N,N-dimethylformamide and N-methyltoluidine. In one aspect, the catalyst comprises N,N-dimethylformamide. In another aspect, the catalyst comprises N-methyltoluidine. As described above, the amount of catalyst loaded into the reaction medium can also affect the chiral purity of the product. Relative to the compound of formula (I) or its salt, typically at least about 0.1 molar equivalent of the catalyst is loaded into the reaction medium. In one aspect, relative to the compound of formula (I) or its salt, at least about 0.4 molar equivalent of the catalyst is loaded into the reaction medium. In another aspect, relative to the compound of formula (I) or its salt, at least about 0.6 molar equivalent of the catalyst is loaded into the reaction medium. In another aspect, relative to the compound of formula (I) or its salt, at least about 0.1 to about 1.0 molar equivalent of the catalyst is loaded into the reaction medium. In another aspect, relative to the compound of formula (I) or its salt, at least about 0.4 to about 1.0 molar equivalent of the catalyst is loaded into the reaction medium. In another aspect, the catalyst comprises N,N-dimethylformamide, and from about 0.1 to about 1.0 molar equivalent of the catalyst is loaded into the reaction medium relative to the compound of formula (I) or its salt. In another aspect, the catalyst comprises N,N-dimethylformamide, and about 0.4 to about 1.0 molar equivalent of the catalyst is loaded into the reaction medium relative to the compound of formula (I) or its salt. In another aspect, the catalyst comprises N,N-dimethylformamide, and about 0.6 molar equivalent of the catalyst is loaded into the reaction medium relative to the compound of formula (I) or its salt.

[0134] The cyclizing agent can be any suitable cyclizing agent, particularly phosphorus oxychloride. The compound of formula (I) or its salt is typically contacted with about 0.7 to about 10 molar equivalents of the cyclizing agent relative to the compound of formula (I) or its salt. In one aspect, the compound of formula (I) or its salt is contacted with about 1.5 to about 2.5 molar equivalents of the cyclizing agent relative to the compound of formula (I) or its salt. In another aspect, the compound of formula (I) or its salt is contacted with about 2.0 molar equivalents of the cyclizing agent relative to the compound of formula (I) or its salt.

[0135] 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 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 generally about 2 liters to about 20 liters of reaction medium per kilogram of the compound of formula (I) or its salt 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 the compound of formula (I) or its salt loaded into the reaction medium.

[0136] The contacting step is generally carried out as a batch reaction, in particular the following batch reaction, in which at least about 50 kg of the compound of formula (I) or its salt is loaded into the batch reaction. In one aspect, at least about 100 kg of the compound of formula (I) or its salt is loaded into the batch reaction. In another aspect, at least about 200 kg of the compound of formula (I) or its salt is loaded into the batch reaction. In another aspect, at least about 300 kg of the compound of formula (I) or its salt is loaded into the batch reaction.

[0137] The method generally provides a stoichiometric method yield of at least about 50% of the compound of formula (II) or its salt. In one aspect, the stoichiometric method yield of the compound of formula (II) or its salt is at least about 65%. In another aspect, the stoichiometric method yield of the compound of formula (II) or its salt is at least about 80%. In another aspect, the stoichiometric method yield of the compound of formula (II) or its salt is at least about 90%. In fact, the improved method has been able to achieve a good-quality material with a yield of about 95% on a scale of more than 300 kg (input).

[0138] In another representative embodiment, the present disclosure relates to a method for preparing a compound having the structure of formula (II):

[0139]

[0140] or its salt, wherein the method comprises:

[0141] contacting a compound having the structure of formula (I)

[0142]

[0143] or its salt, with phosphorus oxychloride in the presence of a catalyst in a reaction medium to form a compound of formula (II), or its salt;

[0144] During the contacting step, the reaction medium is maintained at a temperature of less than about 80 °C;

[0145] at least about 0.4 molar equivalents of a catalyst are charged to the reaction medium relative to the compound of formula (I) or a salt thereof; and

[0146] the chiral purity of the compound of formula (II) or a salt thereof is at least about 80%.

[0147] 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 a catalyst are charged to the reaction medium relative to the compound of formula (I) or a salt thereof; and the chiral purity of the compound of formula (II) or a 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 a catalyst are charged to the reaction medium relative to the compound of formula (I) or a salt thereof; and the chiral purity of the compound of formula (II) or a salt thereof is at least about 90%. In another aspect, during the contacting step, the reaction medium is maintained at a temperature ranging from about 30 °C to about 50 °C; at least about 0.4 to about 1.0 molar equivalents of a catalyst are charged to the reaction medium relative to the compound of formula (I) or a salt thereof; and the chiral purity of the compound of formula (II) or a 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 a catalyst are charged to the reaction medium relative to the compound of formula (I) or a salt thereof; and the chiral purity of the compound of formula (II) or a salt thereof is at least about 90%. In another aspect, the catalyst comprises N,N-dimethylformamide.

[0148] Scheme 6 below corresponds to the method described in Example 3 and illustrates a representative embodiment of an improved method for preparing compound (II).

[0149] Scheme 6

[0150]

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

[0152] 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:

[0153] Scheme 7

[0154]

[0155] Accordingly, in one embodiment, this disclosure relates to a method for preparing a compound having the structure of formula (III):

[0156]

[0157] or a salt thereof, wherein the method comprises:

[0158] contacting a compound having the structure of formula (I)

[0159]

[0160] or a salt thereof, with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound having the formula (II);

[0161]

[0162] or a salt thereof; and

[0163] brominating the compound having the formula (II), or a salt thereof, with a brominating agent to provide a compound having the structure of formula (III):

[0164]

[0165] or a salt thereof;

[0166] 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 formula (II), or a salt thereof.

[0167] The brominating agent can be any suitable brominating agent, particularly N-bromosuccinimide. The compound of formula (III), or a salt thereof, can be prepared from the compound of formula (II), or a salt thereof, without first separating the compound of formula (II), or a 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 a salt thereof, can be separated from the reaction medium and then brominated to provide the compound of formula (III), or a salt thereof. In one aspect, the compound of formula (III), or a salt thereof, is prepared from the compound of formula (II), or a salt thereof, without first separating the compound of formula (II), or a salt thereof, from the reaction mixture (i.e., in-situ bromination). In another aspect, the compound of formula (II), or a salt thereof, is separated from the reaction medium (e.g., a solvent exchange method involving separating an oil containing the compound of formula (II), or a salt thereof) and then brominated to provide the compound of formula (III), or a salt thereof.

[0168] Wherein the compound of formula (II), or a salt thereof, is separated from the reaction mixture and then contacted with a brominating agent in a bromination medium, and the bromination medium 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-methylpyrrolidone, N-butylpyrrolidone, dimethyl sulfoxide, dimethylacetamide, and dichloromethane. In another aspect, the bromination medium comprises N,N-dimethylformamide. In another aspect, the bromination medium comprises N-methylpyrrolidone.

[0169] The compound of formula (II), or a 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 a salt thereof). To avoid overreaction, it may be beneficial to "titrate" the brominating agent during the addition of the brominating agent, control the temperature of the reaction medium / bromination medium, and / or control measurements during repeated processes during the addition of the brominating agent. In one aspect, during the bromination step, the reaction medium / bromination medium is maintained at a temperature from about 5 °C to about 40 °C. In another aspect, during the bromination step, the reaction medium / bromination medium is maintained at a temperature of about 20 °C. In another aspect, the brominating agent is titrated into the reaction medium / bromination medium.

[0170] The method may further include separating the compound of formula (III) or a 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 a 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 a 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 a 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.

[0171] In the case where the compound (II) or a salt thereof is separated from the reaction mixture and then brominated, the bromination is generally carried out as a batch reaction, particularly the following batch reaction, in which at least about 50 kg of the compound of formula (II) or a salt thereof is loaded into the batch reaction. In one aspect, at least about 100 kg of the compound of formula (II) or a salt thereof is loaded into the batch reaction. In another aspect, at least about 200 kg of the compound of formula (II) or a salt thereof is loaded into the batch reaction. In another aspect, at least about 300 kg of the compound of formula (II) or a salt thereof is loaded into the batch reaction.

[0172] When the compound (II) or a salt thereof is brominated in situ, the in situ reaction is generally carried out as a batch reaction, particularly the following batch reaction, in which first at least about 50 kg of the compound of formula (I) or a salt thereof is loaded into the reaction. In one aspect, first at least about 100 kg of the compound of formula (I) or a salt thereof is loaded into the reaction. In another aspect, first at least about 200 kg of the compound of formula (I) or a salt thereof is loaded into the reaction. In another aspect, first at least about 300 kg of the compound of formula (I) or a salt thereof is loaded into the reaction.

[0173] Reacting the compound (II) or a salt thereof with a brominating agent (e.g., N-bromosuccinimide) to produce the compound (III) or a salt thereof generally works well and produces high-quality material in high yield. The method generally provides a stoichiometric method yield of at least about 50% of the compound of formula (III) or a salt thereof. In one aspect, the stoichiometric method yield of the compound of formula (III) or a salt thereof is at least about 65%. In another aspect, the stoichiometric method yield of the compound of formula (III) or a salt thereof is at least about 80%. In another aspect, the stoichiometric method yield of the compound of formula (III) or a salt thereof is at least about 90%. In fact, improved methods have been able to achieve good-quality material with a yield of about 95% on a scale of more than 300 kg (input).

[0174] In another representative embodiment, the present disclosure relates to a method for preparing a compound having the structure of formula (III):

[0175]

[0176] or a salt thereof, wherein the method comprises:

[0177] contacting a compound having the structure of formula (I)

[0178]

[0179] or a salt thereof with phosphorus oxychloride in the presence of a catalyst in a reaction medium to form a compound having the formula (II);

[0180]

[0181] or a salt thereof; and

[0182] brominating the compound of formula (II) or a salt thereof with N-bromosuccinimide to provide a compound having the structure of formula (III):

[0183]

[0184] or a salt thereof;

[0185] wherein during the contacting step, the reaction medium is maintained at a temperature of less than about 80 °C;

[0186] wherein at least about 0.4 molar equivalents of the catalyst are loaded into the reaction medium relative to the compound of formula (I) or a salt thereof; and

[0187] wherein the chiral purity of the compound of formula (II) or a salt thereof is at least about 80%.

[0188] In one aspect, during the contacting step, the reaction medium is maintained at a temperature less than about 70 °C; at least about 0.4 to about 1.0 molar equivalent of a catalyst is loaded into the reaction medium relative to the compound of formula (I) or a salt thereof; and the chiral purity of the compound of formula (II) or a salt thereof is at least about 85%. In another aspect, during the contacting step, the reaction medium is maintained at a temperature less than about 60 °C; at least about 0.4 to about 1.0 molar equivalent of a catalyst is loaded into the reaction medium relative to the compound of formula (I) or a salt thereof; and the chiral purity of the compound of formula (II) or a salt thereof is at least about 90%. In another aspect, during the contacting step, the reaction medium is maintained at a temperature from about 30 °C to about 50 °C; at least about 0.4 to about 1.0 molar equivalent of a catalyst is loaded into the reaction medium relative to the compound of formula (I) or a salt thereof; and the chiral purity of the compound of formula (II) or a 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 equivalent of a catalyst is loaded into the reaction medium relative to the compound of formula (I) or a salt thereof; and the chiral purity of the compound of formula (II) or a salt thereof is at least about 90%. In another aspect, the catalyst comprises N,N-dimethylformamide.

[0189] Scheme 8 below corresponds to the method described in Example 3 and illustrates a representative embodiment of an improved method for preparing compound (III), or a salt thereof.

[0190] Scheme 8

[0191]

[0192] VII. Preparation of Benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (Compound IV) and the corresponding sulfate (2:3) Preparation

[0193] This disclosure relates in part to a method for preparing benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (Compound IV), or a salt thereof, from benzyl (2S)-2-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Compound III), or a salt thereof. Scheme 9 below illustrates the general method:

[0194] Scheme 9

[0195]

[0196] As reflected in Scheme 9 above, compound (III) or its salt is aminated with an aminating agent (e.g., ammonia, ammonium hydroxide, etc.) to produce compound (IV), which may optionally be converted to a salt, particularly the sulfate salt of compound (IV), as further discussed below. Since the amination reaction may result in the presence of residual ammonia, it may be beneficial to reduce the amount of residual ammonia before forming the salt of compound (IV) (particularly in cases where the sulfate salt of compound (IV) is desired) (e.g., by distillation of the crude compound (IV) product). For example, if the residual ammonia present in compound (IV) is not sufficiently removed during the production of the sulfate salt, ammonium sulfate may be produced in addition to the sulfate salt of compound (IV), which would make it difficult to determine the precise stoichiometry of the resulting sulfate salt. From a regulatory perspective, it may be necessary to know the precise stoichiometry of the sulfate salt produced (e.g., in cases where the sulfate salt is a starting material registered for regulatory purposes).

[0197] 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):

[0198]

[0199] wherein the method comprises:

[0200] contacting a compound having the structure of formula (III)

[0201]

[0202] or its salt, with an aminating agent in a reaction medium to form a reaction mixture comprising a compound having the structure of formula (IV);

[0203] forming a sulfate salt of the compound having the structure of formula (IV); and

[0204] isolating the sulfate salt.

[0205] Typically, the sulfate salt of a 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 powder X-ray diffraction pattern that includes at least three peaks selected from the group consisting of: 7.7 ± 0.2° 2θ, 10.6 ± 0.2° 2θ, 11.1 ± 0.2° 2θ, 12.6 ± 0.2° 2θ, and 13.5 ± 0.2° 2θ. In another aspect, the crystalline sulfate salt is characterized by a powder X-ray diffraction pattern that includes 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.

[0206] 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 substantially in a pure phase.

[0207] The aminating agent can be any suitable aminating agent, particularly ammonia or ammonium hydroxide. In one aspect, the aminating agent is gaseous ammonia. In another aspect, the aminating agent is ammonium hydroxide. A compound having formula (III), or a salt thereof, is typically contacted with an effective amount of an aminating agent (e.g., about 5 to about 20 molar equivalents of the aminating agent relative to the compound having formula (III), or a salt thereof).

[0208] 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, 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 the reaction medium is typically from about 1.5 liters to about 40 liters of reaction medium per kilogram of the compound of formula (III) or its salt loaded into the reaction medium. In one aspect, the volume of the reaction medium is from about 2.0 liters to about 30 liters of reaction medium per kilogram of the compound of formula (III) or its salt loaded into the reaction medium.

[0209] During the contacting step, the reaction medium is typically maintained at a temperature above 70 °C. In one aspect, during the contacting step, the reaction medium is maintained at a temperature above 90 °C. In another aspect, during the contacting step, the reaction medium is maintained at a temperature from about 50 °C to about 100 °C. In another aspect, during the contacting step, the reaction medium is maintained at a temperature from about 60 °C to about 95 °C.

[0210] The contacting step is typically carried out as a batch reaction, particularly a batch reaction in which at least about 50 kg of the compound of formula (III) or its salt is loaded into the batch reaction. In one aspect, at least about 100 kg of the compound of formula (III) or its salt is loaded into the batch reaction. In another aspect, at least about 200 kg of the compound of formula (II) or its salt is loaded into the batch reaction. In another aspect, at least about 300 kg of the compound of formula (III) or its salt is loaded into the batch reaction.

[0211] In the case where the sulfate of compound (IV) is desired, the forming step typically comprises contacting the compound of formula (IV) with sulfuric acid to form a sulfate mixture comprising the sulfate. In one aspect, the compound of formula (IV) is contacted with at least about 0.8 molar equivalent of sulfuric acid relative to the compound of formula (III). In another aspect, the compound of formula (IV) is contacted with from about 1.25 to about 1.75 molar equivalents of sulfuric acid relative to the compound of formula (III).

[0212] The method optionally includes separating the compound of formula (IV) as a free base from the reaction mixture before the forming step. Separating the free base prior to salt conversion may be beneficial to reduce the amount of residual ammonia present and avoid potential problems associated with the presence of residual ammonia. In one aspect, the method includes separating the compound of formula (IV) as a free base from the reaction medium; contacting the free base with sulfuric acid to form a sulfate; and separating the sulfate. In another aspect, the method includes washing the reaction mixture to reduce the amount of ammonia present in the reaction mixture; separating 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; and separating the sulfate. In yet another aspect, the method includes washing the reaction mixture with an aqueous brine solution; distilling the washed reaction mixture to reduce the amount of ammonia present in the washed reaction mixture; separating 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; and separating the sulfate. In yet another aspect, the sulfate is separated by filtration.

[0213] The method generally provides a stoichiometric process yield of at least about 50% of the sulfate of the compound of formula (IV). In one aspect, the stoichiometric process yield of the sulfate of the compound of formula (IV) is at least about 65%. In another aspect, the stoichiometric process yield of the sulfate of formula (IV) is at least about 75%. In fact, the improved method has been able to achieve a good quality material with a yield of about 85% on a scale of more than 300 kg (input).

[0214] In another representative embodiment, the present disclosure relates to a method for preparing a sulfate of a compound having the structure of formula (IV):

[0215]

[0216] wherein the method comprises:

[0217] contacting a compound having the structure of formula (III)

[0218]

[0219] or a salt thereof, with an aminating agent in a reaction medium to form a reaction mixture comprising a compound of formula (IV);

[0220] separating the compound of formula (IV) as a free base from the reaction mixture;

[0221] contacting the free base with sulfuric acid to form a sulfate of the compound of formula (IV); and

[0222] separating the sulfate;

[0223] Wherein the sulfate has a stoichiometric ratio of one sulfate molecule and one bisulfate molecule to three free base molecules.

[0224] 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 that includes 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 that includes 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 that includes at least five peaks selected from the group of peaks.

[0225] Scheme 10 below corresponds to the method described in Example 5 and illustrates a representative embodiment of an improved method for preparing compound (II).

[0226] Scheme 10

[0227]

[0228] VIII. Preparation of 4-(2-pyridylcarbamoyl)phenyl]boronic acid (Compound V)

[0229] This disclosure relates in part to a method for preparing 4-(2-pyridyl-carbamoyl)phenyl]boronic acid (Compound V), or a salt thereof, from 4-carboxyphenylboronic acid or a salt thereof and 2-aminopyridine. Scheme 11 below illustrates the general method:

[0230] Scheme 11

[0231]

[0232] The clinical trial supply method reacts 4-carboxyphenylboronic acid with 2-aminopyridine to produce Compound (V). This coupling reaction is carried out in the presence of thionyl chloride and N,N-dimethylformamide. However, thionyl chloride and N,N-dimethylformamide can potentially react to produce toxic dimethylcarbamoyl chloride. To avoid this problem, the improved method uses a compound (e.g., tetrabutylammonium chloride) in place of N,N-dimethylformamide, which does not form this toxic by-product and provides improved safety during this step.

[0233] Thus, in one embodiment, the present disclosure relates to a method for preparing a compound having the structure of formula (V):

[0234]

[0235] 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, and then contacting the acyl chloride intermediate in situ with 2-aminopyridine to form a reaction mixture comprising a compound having formula (V), or a salt thereof. In one aspect, the method further comprises separating the compound having formula (V), or a salt thereof, from the reaction mixture.

[0236] A molar excess of 2-aminopyridine is typically loaded into the reaction medium relative to 4-carboxyphenylboronic acid, or a salt thereof. In one aspect, about 1.5 to about 5 molar equivalents of 2-aminopyridine are typically loaded into the reaction medium relative to 4-carboxyphenylboronic acid, or a salt thereof. In another aspect, about 1.5 to about 3.5 molar equivalents of 2-aminopyridine are loaded into the reaction medium relative to 4-carboxyphenylboronic acid, or a salt thereof. In another aspect, about 2 molar equivalents of 2-aminopyridine are loaded into the reaction medium relative to 4-carboxyphenylboronic acid, or a salt thereof.

[0237] A molar excess of thionyl chloride is typically loaded into the reaction medium relative to 4-carboxyphenylboronic acid, or a salt thereof. In one aspect, 4-carboxyphenylboronic acid, or a salt thereof, is contacted with about 2 to about 5 molar equivalents of thionyl chloride relative to 4-carboxyphenylboronic acid, or a salt thereof. In another aspect, 4-carboxyphenylboronic acid, or a salt thereof, is contacted with about 2 to about 3.5 molar equivalents of thionyl chloride relative to 4-carboxyphenylboronic acid, or a salt thereof. In another aspect, 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.

[0238] The catalyst can comprise any suitable catalyst, particularly 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 equivalent of the catalyst is typically loaded into the reaction medium relative to 4-carboxyphenylboronic acid, or a salt thereof.

[0239] 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, aromatic heterocycles, and nitriles. 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 contain N,N-dimethylformamide. In another aspect, neither the reaction medium nor the catalyst contains N,N-dimethylformamide. The volume of the reaction medium is typically from about 3 liters to about 30 liters of reaction medium / kg of 4-carboxyphenylboronic acid or its salt 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 / kg of 4-carboxyphenylboronic acid or its salt loaded into the reaction medium.

[0240] 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.

[0241] The contacting step is typically carried out as a batch reaction, particularly the following batch reaction, in which at least about 50 kg of 4-carboxyphenylboronic acid or its salt is loaded into the batch reaction. In one aspect, at least about 100 kg of 4-carboxyphenylboronic acid or its salt is loaded into the batch reaction.

[0242] The method generally provides a stoichiometric method yield of at least about 50% of the compound of formula (V) or its salt. In one aspect, the stoichiometric method yield of the compound of formula (V) or its salt is at least about 60%. In another aspect, the stoichiometric method yield of the compound of formula (V) or its salt is at least about 65%. In another aspect, the stoichiometric method yield of the compound of formula (V) or its salt is at least about 70%.

[0243] In another representative embodiment, the present disclosure relates to a method for preparing a compound having the structure of formula (V):

[0244]

[0245] or its salt, wherein the method comprises contacting 4-carboxyphenylboronic acid, or its salt with thionyl chloride and a catalyst in a reaction medium comprising 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 of formula (V), or its salt; wherein neither the reaction medium nor the catalyst contains N,N-dimethylformamide.

[0246] In one aspect, the catalyst comprises 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, during the contacting step, the reaction medium is maintained at a temperature from about 50 °C to about 90 °C. In another aspect, the method further comprises separating a compound of formula (V), or a salt thereof, from the reaction mixture.

[0247] Scheme 12 below corresponds to the method described in Example 11 and illustrates one representative embodiment of an improved method for preparing compound (V).

[0248] Scheme 12

[0249]

[0250] IX. Preparation of 1-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (Compound VI)

[0251] This disclosure relates in part to a method for preparing 1-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (compound VI), or a salt thereof, from benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (compound IV), or a salt thereof. Scheme 13 below illustrates the general method:

[0252] Scheme 13

[0253]

[0254] Due to the presence of a labile bromide on the imidazole ring, initial development efforts to deprotect compound (IV) or a salt thereof by hydrogenation to provide compound (VI) or a salt thereof and avoid the initial development of erosive acidic conditions were unsuccessful. Further development efforts have encountered challenges related to the generation and / or removal of several impurities.

[0255] First, the deprotection reaction generates benzyl halide (e.g., benzyl chloride), which can potentially react further with compound (VI) or a salt thereof to produce an N-benzyl impurity having the structure of compound (IX):

[0256]

[0257] Second, the use of dichloromethane in the deprotection reaction can generate an acetalamine impurity having the structure of compound (X):

[0258]

[0259] Third, oxidative impurities having the structure of the following compound (XI) were observed in several batches of the method steps:

[0260]

[0261] The improved method addresses N-benzyl impurities by removing benzyl halides (e.g., by extraction with heptane) from the reaction mixture containing the crude compound (VI) product before separating the compound (VI) or its salt from the reaction mixture. The improved method addresses acetalamine impurities by selecting a solvent that does not form acetalamine impurities (e.g., replacing dichloromethane with 2-methyltetrahydrofuran). The improved method addresses oxidative impurities by appropriately controlling the oxygen level in the reaction vessel during the process. Appropriate control of the inerting protocol (e.g., nitrogen purge) and the container structural material improves the product quality by substantially preventing product discoloration and the formation of oxidative impurities observed in previous campaigns and eliminating the previous need for carbon treatment.

[0262] Thus, in one embodiment, the present disclosure relates to a method for preparing a compound having the structure of formula (VI):

[0263]

[0264] or a salt thereof, wherein the method comprises:

[0265] contacting a compound having formula (IV):

[0266]

[0267] or a salt thereof, with an acidic medium under conditions sufficient to deprotect the compound having formula (IV), or a salt thereof, and form a reaction mixture comprising a compound having formula (VI), or a salt thereof, and a benzyl halide by-product;

[0268] removing at least a portion of the benzyl halide by-product from the reaction mixture; and

[0269] separating the compound having formula (VI), or a salt thereof, from the reaction mixture under conditions sufficient to substantially avoid the formation of acetalamine impurities.

[0270] In one aspect, the sulfate salt of the compound having formula (IV) is contacted with the acidic medium.

[0271] Acetalamine impurities generally comprise compounds having the structure of formula (X):

[0272]

[0273] or a salt thereof. In one aspect, the isolated compound of formula (VI), or a salt thereof, comprises less than 5% by weight of acetalamine impurities. In another aspect, the isolated compound of formula (VI), or a salt thereof, comprises less than 3% by weight of acetalamine impurities. In yet another aspect, the isolated compound of formula (VI), or a salt thereof, comprises less than 1% by weight of acetalamine impurities.

[0274] In one aspect, the acidic medium is an aqueous acidic medium. Relative to the compound of formula (IV), or a salt thereof, the aqueous acidic medium typically comprises an inorganic acid, particularly hydrochloric acid, and at least about 10 molar equivalents of acid. In one aspect, relative to the compound of formula (IV), or a salt thereof, the aqueous acidic medium comprises from about 10 to about 40 molar equivalents of acid. In another aspect, relative to the compound of formula (IV), or a salt thereof, the aqueous acidic medium comprises from about 10 to about 25 molar equivalents of acid. The volume of the aqueous acidic medium is typically from about 2 liters to about 10 liters of aqueous acidic medium / kg of the compound of formula (IV), or a salt thereof, loaded into the acidic medium. In one aspect, the volume of the aqueous acidic medium is from about 3 liters to about 4 liters of aqueous acidic medium / kg of the compound of formula (IV) or a salt thereof loaded into 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.

[0275] In another embodiment, the method comprises removing at least a portion of the benzyl halide by-product 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.

[0276] 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 separating the compound of formula (VI), or a salt thereof. In one aspect, the benzyl halide by-product from the reaction mixture is selectively extracted into the waste organic phase relative to the compound of formula (VI), or a salt thereof. In another aspect, at least about 80% by weight of the benzyl halide by-product present in the reaction mixture is extracted into the waste organic phase. In another aspect, less than about 20% by weight of the compound of formula (VI), or a salt thereof, present in the reaction mixture is extracted into the waste organic phase. In another aspect, at least about 80% by weight of the benzyl halide by-product present in the reaction mixture and less than about 20% by weight of the compound of formula (VI), or a salt thereof, present in the reaction mixture are extracted into the 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 a salt thereof, present in the reaction mixture are extracted into the 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 a salt thereof, present in the reaction mixture are extracted into the waste organic phase.

[0277] The waste 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 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. In another aspect, the waste organic phase comprises heptane.

[0278] In a further embodiment, the method includes increasing the pH of the reaction mixture after the benzyl halide by-product extraction to form a basic reaction medium comprising the compound of formula (VI), or a salt thereof; and extracting the compound of formula (VI), or a salt thereof, from the basic reaction medium into a product organic phase. In one aspect, the method includes extracting at least a portion of the benzyl halide by-product from the reaction mixture into the 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 comprising the compound of formula (VI), or a salt thereof; extracting the compound of formula (VI), or a salt thereof, from the basic reaction medium into a product organic phase; and separating the compound of formula (VI), or a 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.

[0279] 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 contain dichloromethane.

[0280] It may be beneficial to wash the product organic phase (e.g., with water) prior to separating the compound of formula (VI), or a salt thereof. It may 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 separating the compound of formula (VI), or a 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 loaded into the product organic phase during the distillation step.

[0281] The compound of formula (VI), or a salt thereof, can be separated from the reaction mixture by any suitable means (in particular, crystallizing the compound of formula (VI), or a salt thereof, from the reaction mixture). In one aspect, the separation step comprises seeding the reaction mixture with a crystalline form of the compound of formula (VI), or a salt thereof, to promote crystallization. In another aspect, the separation step comprises seeding the reaction mixture with at least about 0.005 relative weight of a crystalline form of the compound of formula (VI), or a salt thereof, to promote crystallization. In another aspect, the separation step comprises seeding the reaction mixture with at least about 0.01 relative weight of a crystalline form of the compound of formula (VI), or a salt thereof, to promote crystallization. In another aspect, the separation step comprises seeding the reaction mixture with at least about 0.005 to about 0.02 relative weight of a crystalline form of the compound of formula (VI), or a salt thereof, to promote crystallization. It may also be beneficial to load an anti-solvent into the reaction mixture to promote crystallization. In one aspect, the anti-solvent is heptane.

[0282] The contacting step is typically carried out as a batch reaction, particularly the following batch reaction: wherein at least about 50 kg of the compound of formula (IV) or a salt thereof is first loaded into the reaction. In one aspect, at least about 100 kg of the compound of formula (IV), or a salt thereof, is first loaded into the reaction. In another aspect, at least about 200 kg of the compound of formula (IV), or a salt thereof, is first loaded into the reaction. In another aspect, at least about 300 kg of the compound of formula (IV), or a salt thereof, is first loaded into the reaction.

[0283] The method generally provides a stoichiometric method yield of at least about 50% of the compound of formula (VI) or a salt thereof. In one aspect, the stoichiometric method yield of the compound of formula (VI) or a salt thereof is at least about 65%. In another aspect, the stoichiometric method yield of the compound of formula (VI) or a salt thereof is at least about 75%. In yet another aspect, the stoichiometric method yield of the compound of formula (VI) or a salt thereof is at least about 80%. In fact, the improved method has been able to achieve a good-quality material with a yield of about 85% on a scale of more than 300 kg (input).

[0284] In another representative embodiment, the present disclosure relates to a method for preparing a compound having the structure of formula (VI):

[0285]

[0286] or a salt thereof, wherein the method comprises:

[0287] contacting a compound of formula (IV):

[0288]

[0289] or a salt thereof, with an acidic medium under conditions sufficient to deprotect the compound of formula (IV) or a salt thereof and form a reaction mixture comprising a compound of formula (VI) or a salt thereof and a benzyl halide by-product;

[0290] selectively extracting at least a portion of the benzyl halide by-product from the reaction mixture into a waste organic phase relative to the compound of formula (VI) or a salt thereof;

[0291] increasing the pH of the resulting reaction mixture to a pH greater than about 7.0 to form a basic reaction mixture;

[0292] selectively extracting at least a portion of the compound of formula (VI) or a salt thereof from the basic reaction mixture into a product organic phase; and

[0293] 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 a compound of formula (VI) or a salt thereof.

[0294] In one aspect, the waste organic phase comprises heptane. In another aspect, the product organic phase comprises 2-methyltetrahydrofuran. In yet another aspect, the waste organic phase comprises heptane and the product organic phase comprises 2-methyltetrahydrofuran. In yet another aspect, the method further comprises crystallizing the compound of formula (VI) or a salt thereof from the distilled organic phase.

[0295] The following Scheme 14 corresponds to the method described in Example 9 and illustrates a representative embodiment of an improved method for preparing Compound (VI).

[0296] Scheme 14

[0297]

[0298] X. Preparation of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridyl)benzamide (Compound VII) Preparation

[0299] This disclosure relates in part to a method for preparing 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (Compound VII), or a salt thereof, from [4-(2-pyridylcarbamoyl)phenyl]boronic acid (Compound V), or a salt thereof, and 1-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (Compound VI), or a salt thereof. The following Scheme 15 illustrates the general method:

[0300] Scheme 15

[0301]

[0302] The method employs a Suzuki reaction to couple Compound (V) and Compound (VI) to yield Compound (VII). The clinical trial supply method conducts the Suzuki coupling in an aqueous 2-butanol medium. The crude Compound (VII) is crystallized from the aqueous 2-butanol medium in a crystalline form (subsequently identified as the Form 2 crystalline form of Compound (VII)), which is extremely difficult to filter from the medium, even on a 50 kg scale. The Form 2 crystalline form of Compound (VII) is isolated as a thick clay-like product, which requires oven drying to remove the large amount of water adhering to the wet paste when discharged from the filter.

[0303] Efforts to improve the filterability of crystalline compound (VII) led to the discovery of two additional crystalline forms of compound (VII), designated as Form 3 and Form C. Form 2 has a very fine needle-like morphology and is believed to be a hemibutanol solvate hydrate. Form 3 has a needle-like morphology and is believed to be a butanol solvate. Form C is an anhydrate with an improved morphology that produces larger crystals. It was found that crystallization of compound (VII) from a non-aqueous (typically less than 5 wt% water) medium can produce Form 3 and / or Form C. Both crystalline forms filter faster than Form 2, but Form C also filters faster than Form 3. Accordingly, further efforts were focused on reducing or substantially removing any water present (e.g., by distillation) prior to the initial isolation of compound (VII) in order to reproducibly isolate compound (VII) as Form C.

[0304] Although removing water prior to isolating compound (VII) generally provides Form C, occasional batches still crystallize in the presence of varying amounts of Form 3. Further studies determined that Form C is the thermodynamic form at temperatures above approximately 75 °C. At this temperature, any Form 3 present generally converts to Form C in a relatively short period of time. By incorporating a temperature cycle prior to isolating compound (VII), Form C can be routinely produced as the thermodynamic form. Although conversion back from Form C to Form 3 can occur upon cooling below 75 °C (especially in the presence of residual water), this conversion is slow enough to allow cooling and filtration to occur without significant conversion back to Form 3.

[0305] Additionally, it was found advantageous to transfer the silica scavenger treatment from the final step of producing acalabrutinib from compound (VII) (as used in the clinical trial supply method) to the current step of producing compound (VII). This change in the silica scavenger treatment sequence provides a better balance of effective palladium removal versus product yield loss (due to the scavenger).

[0306] Furthermore, it was found that during the Suzuki reaction, long-term scale heating of the process (e.g., treatment at 80 °C and atmospheric distillation at 80 °C to 100 °C) leads to the formation of two impurities (compound (XII) and compound (XIII)) having the structures shown below:

[0307]

[0308] However, by employing lower temperatures (e.g., treatment below 60 °C and atmospheric distillation), the formation of these impurities can be suppressed.

[0309] Thus, in one embodiment, the present disclosure relates to a method for preparing a compound having the structure of formula (VII):

[0310]

[0311] or a salt thereof, wherein the method comprises:

[0312] contacting a compound having the structure of formula (V)

[0313]

[0314] or a salt thereof, with a compound having the structure of formula (VI):

[0315]

[0316] 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);

[0317] 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

[0318] isolating the compound having formula (VII), or a salt thereof, from the substantially anhydrous mixture.

[0319] The compound having formula (VII), or a salt thereof, is isolated from the substantially anhydrous mixture as a substantially crystalline form of the compound having formula (VII), or a salt thereof. In one aspect, the substantially crystalline form of the compound having formula (VII) is characterized by a powder X-ray diffraction pattern that comprises at least three peaks selected from the group consisting of: 9.9 ± 0.2° 2θ, 11.1 ± 0.2° 2θ, 12.8 ± 0.2° 2θ, 14.1 ± 0.2° 2θ, and 19.0 ± 0.2° 2θ. In another aspect, the substantially crystalline form of the compound having formula (VII) is characterized by a powder X-ray diffraction pattern that comprises at least three peaks selected from the group consisting of: 7.4 ± 0.2° 2θ, 8.9 ± 0.2° 2θ, 9.9 ± 0.2° 2θ, 11.1 ± 0.2° 2θ, 12.8 ± 0.2° 2θ, 14.1 ± 0.2° 2θ, 14.8 ± 0.2° 2θ, 19.0 ± 0.2° 2θ, and 21.6 ± 0.2° 2θ. In another aspect, the substantially crystalline form of the compound having formula (VII) is characterized by a powder X-ray diffraction pattern that comprises at least five peaks selected from the group of peaks. In another aspect, the substantially crystalline form is a substantially anhydrous crystalline form of the compound having formula (VII).

[0320] The substantially crystalline form of the compound of formula (VII) is isolated from a substantially anhydrous mixture that typically has at least 50% C-form crystallinity purity. In one aspect, the isolated substantially crystalline form has at least 60% C-form crystallinity purity. In another aspect, the isolated substantially crystalline form has at least 70% C-form crystallinity purity. In another aspect, the isolated substantially crystalline form has at least 80% C-form crystallinity purity. In another aspect, the isolated substantially crystalline form has at least 90% C-form crystallinity purity. In another aspect, the isolated substantially crystalline form has at least 95% C-form crystallinity purity. In another aspect, the isolated substantially crystalline form has at least 96% C-form crystallinity purity. In another aspect, the isolated substantially crystalline form has at least 97% C-form crystallinity purity. In another aspect, the isolated substantially crystalline form has at least 98% C-form crystallinity purity. In another aspect, the isolated substantially crystalline form has at least 99% C-form crystallinity purity. In another aspect, the isolated substantially crystalline form is a substantially pure C-form crystalline form.

[0321] 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 loaded into the aqueous reaction medium relative to the compound of formula (VI), or a salt thereof. In one aspect, typically about 0.1 to about 1.0 molar equivalent of the alkali metal halide is loaded into the aqueous reaction medium relative to the compound of formula (VI), or a salt thereof. In one aspect, about 0.1 to about 1.0 molar equivalent of potassium iodide is loaded into the aqueous reaction medium relative to the compound of formula (VI), or a salt thereof. In another aspect, about 0.2 to about 0.4 molar equivalent of potassium iodide is loaded into the aqueous reaction medium relative to the compound of formula (VI), or a salt thereof.

[0322] The compound of formula (VI), or a salt thereof, is typically contacted with about 0.5 to about 1.5 molar equivalents of the compound of formula (V), or a salt thereof, relative to the compound of formula (VI), or a salt thereof. In one aspect, the compound of formula (VI), or a salt thereof, is contacted with about 0.8 to about 1.2 molar equivalents of the compound of formula (V), or a salt thereof, relative to the compound of formula (VI), or a salt thereof. In another aspect, the compound of formula (VI), or a salt thereof, is contacted with about 0.9 to about 1.1 molar equivalents of the compound of formula (V), or a salt thereof, relative to the compound of formula (VI), or a salt thereof.

[0323] 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 yet another aspect, the base comprises triethylamine and potassium carbonate. Relative to the compound of formula (VI), or a salt thereof, typically about 0.5 to about 10 molar equivalents of the base are loaded into the aqueous reaction medium. In one aspect, the base comprises triethylamine, and about 0.5 to about 10 molar equivalents of triethylamine are loaded into the aqueous reaction medium relative to the compound of formula (VI), or a salt thereof. In another aspect, the base comprises triethylamine, and about 1.0 to about 2.0 molar equivalents of triethylamine are loaded into the aqueous reaction medium relative to the compound of formula (VI), or a salt thereof. In yet another aspect, the base comprises potassium carbonate, and about 0.5 to about 10.0 molar equivalents of potassium carbonate are loaded into the aqueous reaction medium relative to the compound of formula (VI), or a salt thereof. In yet another aspect, the base comprises potassium carbonate, and about 2.0 to about 3.0 molar equivalents of potassium carbonate are loaded into the aqueous reaction medium relative to the compound of formula (VI), or a salt thereof. In yet another aspect, the base comprises potassium carbonate, and about 2.3 to about 2.7 molar equivalents of potassium carbonate are loaded into the aqueous reaction medium relative to the compound of formula (VI), or a salt thereof.

[0324] The palladium catalyst can be any suitable palladium catalyst, particularly a catalyst comprising bis(tert-butylbicyclohexylphosphine)palladium(II) dichloride. Relative to the compound of formula (VI), or a salt thereof, typically about 0.002 to about 0.05 molar equivalents of the palladium catalyst are loaded into the aqueous reaction medium. In one aspect, about 0.007 to about 0.013 molar equivalents of the palladium catalyst are loaded into the aqueous reaction medium relative to the compound of formula (VI), or a salt thereof.

[0325] 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.

[0326] The volume of the aqueous reaction medium is typically from about 10 liters to about 20 liters of aqueous reaction medium / kg of the compound of formula (VI) or its salt loaded into the aqueous reaction medium. In one aspect, for the aqueous reaction medium, the volume ratio of water to organic solvent is from about 1:3 to about 3:1. During the contacting step, the aqueous reaction medium is typically maintained at a temperature from about 50 °C to about 100 °C. In one aspect, during the contacting step, the aqueous reaction medium is maintained at a temperature from about 70 °C to about 90 °C.

[0327] In one embodiment, the reducing step comprises separating the reaction mixture into an aqueous waste phase and an organic phase comprising the compound of formula (VII). In one aspect, the reducing step further comprises distilling the organic phase under conditions sufficient to reduce the amount of water present in the organic phase and providing a substantially anhydrous mixture. In another aspect, the method further comprises washing the organic phase with water prior to distillation.

[0328] In further embodiments, the organic phase is treated with a silica scavenger prior to distillation. In one aspect, the organic phase is treated with a silica scavenger for a period of at least two hours prior to distillation. The silica scavenger typically comprises propanethiol-functionalized silica. In one aspect, the silica scavenger comprises QuadraSil TM MP. The method may further comprise removing the silica scavenger from the organic phase prior to distillation. In one aspect, the silica scavenger is removed from the organic phase by filtration prior to distillation. In another aspect, the method further comprises washing the organic phase with an aqueous brine solution after removal of the catalyst and prior to distillation.

[0329] In another embodiment, the reducing step comprises separating the reaction mixture into an aqueous waste phase and an organic phase comprising the compound of formula (VII), or its salt; washing the organic phase with water; treating the organic phase with a silica scavenger; removing the silica scavenger from the organic phase; washing the organic phase with an aqueous brine solution; and distilling the organic phase under conditions sufficient to reduce the amount of water present in the organic phase.

[0330] Distillation of the organic phase can be carried out under suitable conditions, in particular by vacuum distillation of the organic phase. In one aspect, the organic phase is distilled by continuous horizontal vacuum distillation. In another aspect, the organic phase is distilled at a temperature not exceeding about 60 °C. In another aspect, the organic phase is distilled at a temperature from about 50 °C to about 60 °C. In another aspect, the organic phase comprises an alcohol. In another aspect, the organic phase is supplemented with an alcohol during the distillation step. In another aspect, the organic phase comprises 2-butanol. In another aspect, the organic phase is supplemented with 2-butanol during the distillation step.

[0331] Substantially anhydrous mixtures generally contain less than about 5% by weight of water. In one aspect, the substantially anhydrous mixture contains less than about 3% by weight of water. In another aspect, the substantially anhydrous mixture contains less than about 1% by weight of water.

[0332] The separation step generally involves crystallizing the compound of formula (VII) from the substantially anhydrous mixture as the C-type crystalline form. To ensure that the product crystallizes as the C-type 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 for which the substantially anhydrous mixture is maintained at a temperature of at least about 70 °C (or temperature range) before the start of cooling will depend on the chosen temperature (or temperature range). At higher temperatures, generally a shorter holding period is required to convert any non-C-type crystalline forms present to the C-type crystalline form. However, the temperature chosen should not cause 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 C-type crystalline form may be beneficial to further reduce the duration of any required holding period. Thus, in various embodiments, after the start of crystallization and before the start of cooling, the substantially anhydrous mixture is maintained at a chosen temperature (or temperature range) for a period of time, wherein the chosen temperature (or temperature range) and period of time are sufficient to produce substantially the C-type crystalline form of the compound of formula (VII) upon cooling the substantially anhydrous mixture.

[0333] 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.

[0334] In one aspect, the chosen temperature is high enough such that no further holding period is required before the start of cooling. In another aspect, the holding period before cooling is at least about 15 minutes. In another aspect, the holding period before cooling is at least about 30 minutes. In another aspect, the holding period before cooling is at least about 1 hour. In another aspect, the holding period before cooling is at least about 1.5 hours. In another aspect, the holding period before cooling is at least about 2 hours.

[0335] In one aspect, the temperature is at least about 75 °C and the holding period before cooling is at least about two hours. In another aspect, the temperature is at least about 80 °C and the holding period is at least about 1.5 hours. In another aspect, the temperature is at least about 85 °C and the holding period is at least about 1 hour. In another aspect, the temperature is at least about 90 °C and the holding period is at least about 15 minutes. In another aspect, the temperature is at least about 90 °C and no holding period is required. In another aspect, the temperature is from about 75 °C to about 105 °C and the holding 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 holding 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 holding 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 holding 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 holding period before cooling is required.

[0336] In each of the above aspects, the substantially anhydrous mixture can be inoculated with the 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 inoculated with the C-crystalline form, maintained at a temperature from about 85 °C to about 105 °C for a holding period from about 5 minutes to about 3 hours, and then cooled to crystallize the compound of formula (VII).

[0337] The contacting step is typically carried out as a batch reaction, particularly the following batch reaction: wherein at least about 25 kg of the compound of formula (VI) or its salt is first loaded into the reaction. In one aspect, at least about 50 kg of the compound of formula (VI), or its salt is first loaded into the reaction. In another aspect, at least about 75 kg of the compound of formula (VI), or its salt is first loaded into the reaction. In another aspect, at least about 100 kg of the compound of formula (VI), or its salt is first loaded into the reaction.

[0338] The method typically provides a stoichiometric method yield of at least about 50% of the compound of formula (VII) or its salt. In one aspect, the stoichiometric method yield of the compound of formula (VII) or its salt is at least about 65%. In another aspect, the stoichiometric method yield of the compound of formula (VII) or its salt is at least about 75%. In fact, the improved method has been able to achieve good quality material with a yield of about 80% on a scale of more than 100 kg (input). In addition, the improved method has a faster filtration time, which significantly reduces the cycle time of the method to less than one week.

[0339] In another representative embodiment, the present disclosure relates to a method for preparing a compound having the structure of formula (VII):

[0340]

[0341] or a salt thereof, wherein the method comprises:

[0342] contacting a compound having the structure of formula (V)

[0343]

[0344] or a salt thereof, with a compound having the structure of formula (VI):

[0345]

[0346] or a salt thereof, in an aqueous reaction medium comprising an organic solvent in the presence of a base and a palladium catalyst to form a reaction mixture comprising a compound having formula (VII);

[0347] separating the reaction mixture into an aqueous waste phase and an organic phase comprising the compound having formula (VII), or a salt thereof;

[0348] treating the organic phase with a silica scavenger;

[0349] removing the silica scavenger from the organic phase;

[0350] distilling the organic phase under conditions sufficient to reduce the amount of water present in the organic phase and forming a substantially anhydrous mixture comprising the compound having (VII), or a salt thereof; and

[0351] crystallizing the compound having formula (VII) from the substantially anhydrous mixture;

[0352] wherein the compound having formula (VII) crystallizes as a C-type crystalline form.

[0353] In one aspect, the method further comprises washing the organic phase with water before the treatment step. In another aspect, the method further comprises washing the organic phase with an aqueous brine solution after the removal step and before the distillation step. In another aspect, the organic phase is distilled by vacuum distillation, during which dry butanol is added to the organic phase and functions to remove the water present. In another aspect, before separating the compound having formula (VII) from the substantially anhydrous mixture, the substantially anhydrous mixture is maintained at a temperature above 75 °C until any crystalline form present is substantially converted to the C-type crystalline form.

[0354] The following Scheme 16 corresponds to the method described in Example 14 and illustrates a representative embodiment of an improved method for preparing compound (VII).

[0355] Scheme 16

[0356]

[0357] XII. Preparation of Acalabrutinib (Compound VIII)

[0358] This disclosure relates in part to a method for preparing acalabrutinib, or a salt thereof, from 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)-benzamide (Compound VII), and 2-butynoic acid, or a salt thereof. Scheme 17 below illustrates the general method:

[0359] Scheme 17

[0360]

[0361] Compound (VII) is reacted 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 method. Adding a small excess of 2-butynoic acid to Compound (VII) in dichloromethane produces a thicker mixture that contains the butynoate salt of Compound (VII) which is difficult to stir. Subsequently adding triethylamine to the thick mixture does not significantly improve the viscosity. However, adding triethylamine before adding 2-butynoic acid avoids the formation of the butynoate salt of Compound (VII) and produces a relatively thin stirrable slurry. However, subsequently adding a coupling agent (e.g., 1-propylphosphonic anhydride) to the resulting slurry is difficult to control and has a narrow process control window to meet the quality standards of the acalabrutinib product. Insufficient addition of 1-propylphosphonic anhydride does not consume all of the starting material (i.e., Compound (VII)), and over-addition results in the formation of impurities having the structure of Compound (XIV):

[0362]

[0363] In the subsequent separation of the acalabrutinib product, both unreacted Compound (VII) and Compound (XIV) impurities are difficult to remove and are the cause of multiple batch failures in the clinical trial supply method.

[0364] It has been found that the use of a sequential extraction method can overcome the difficulties associated with removing two impurities. First, acalabrutinib is selectively extracted from the reaction mixture into an aqueous phase having a first acidic pH (e.g., pH 1.8 to 2.2) relative to the compound (XIV) impurity, and the reaction mixture containing the compound (XIV) impurity is discarded. Then the pH of the aqueous phase containing acalabrutinib is adjusted to a second pH (e.g., pH 4.5 to 5.0), and acalabrutinib is selectively extracted from the aqueous phase into an organic phase relative to the compound (VII) impurity, and the aqueous phase containing the compound (VII) impurity is discarded. Since the sequential extraction method results in effective removal of unwanted impurities from the final product, the addition of 1-propylphosphonic anhydride does not require the strict control as in the clinical trial supply method, and the addition of 1-propylphosphonic anhydride is more stable.

[0365] Another problem encountered in the clinical trial supply method involves the solvent exchange from dichloromethane to ethanol, which employs multiple "put and take" distillation cycles. Prior to final crystallization, the acalabrutinib product would continuously oilify or gelatinize. It has been found that the kinetics of crystallization of acalabrutinib from ethanol is abnormally slow. The point of oil crystallization cannot be controlled, and the crystallized acalabrutinib produces an undesired amount of crystalline solvent. Thus, the inclusion of dichloromethane in the acalabrutinib lattice is a concern in the clinical trial supply method. A more controlled procedure has now been developed that employs continuous horizontal vacuum distillation (e.g., at 50 °C, 18 to 20 relative volumes), which maintains acalabrutinib in solution throughout the distillation (even when the dichloromethane solvent is completely replaced by ethanol) and avoids the oilification problem. Once the distillation is complete, the solution is seeded with crystallized acalabrutinib and the seeded solution is maintained at a suitable temperature (e.g., 50 °C), which results in controlled crystallization where the acalabrutinib product can be isolated and has consistent particulate properties. Crystallization further purifies the acalabrutinib product, especially for any over-acylated by-products present.

[0366] Thus, in one embodiment, the present disclosure relates to a method for preparing a compound having the structure of formula (VIII):

[0367]

[0368] or a salt thereof, wherein the method comprises:

[0369] reacting a compound having the structure of formula (VII)

[0370]

[0371] or a salt thereof, is contacted 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 having formula (VIII) and one or more reaction by-products; and

[0372] the compound having formula (VIII), or a salt thereof, is selectively separated from the reaction mixture relative to the one or more by-products.

[0373] As previously mentioned, the order of addition in the method can have an effect. Generally, the contacting step comprises adding a compound having formula (VII), or a salt thereof, and the base to the reaction medium; adding the 2-butynoic acid, or a salt thereof, to the reaction medium comprising the compound having formula (VII), or a salt thereof, and the base; and adding the 1-propylphosphonic anhydride to the reaction medium comprising the compound having formula (VII), or a salt thereof; 2-butynoic acid, or a salt thereof; and the base.

[0374] In another embodiment, the present disclosure relates to a method for preparing a compound having the structure of formula (VIII):

[0375]

[0376] or a salt thereof, wherein the method comprises:

[0377] contacting a compound having the structure of formula (VII)

[0378]

[0379] 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 having formula (VIII), or a salt thereof; an unreacted compound having formula (VII), or a salt thereof; and reaction by-products, wherein the reaction by-products comprise a compound having the structure of formula (XIV):

[0380]

[0381] or a salt thereof; and

[0382] the compound having formula (VIII), or a salt thereof, is selectively separated from the reaction mixture relative to the compound having formula (VII), or a salt thereof, and the compound having formula (XIV), or a salt thereof.

[0383] In one aspect, the selectively isolated compound of formula (VIII), or a salt thereof, contains less than about 1.0 wt% of the compound of formula (VII), or a salt thereof. In another aspect, the selectively isolated compound of formula (VIII), or a salt thereof, contains less than about 0.8 wt% of the compound of formula (VII), or a salt thereof. In another aspect, the selectively isolated compound of formula (VIII), or a salt thereof, contains less than about 0.6 wt% of the compound of formula (VII), or a salt thereof. In another aspect, the selectively isolated compound of formula (VIII), or a salt thereof, contains less than about 0.4 wt% of the compound of formula (VII), or a salt thereof. In another aspect, the selectively isolated compound of formula (VIII), or a salt thereof, contains less than about 0.3 wt% of the compound of formula (VII), or a salt thereof. In another aspect, the selectively isolated compound of formula (VIII), or a salt thereof, contains less than about 1.0 wt% of the compound of formula (XIV), or a salt thereof. In another aspect, the selectively isolated compound of formula (VIII), or a salt thereof, contains less than about 0.8 wt% of the compound of formula (XIV), or a salt thereof. In another aspect, the selectively isolated compound of formula (VIII), or a salt thereof, contains less than about 0.6 wt% of the compound of formula (XIV), or a salt thereof. In another aspect, the selectively isolated compound of formula (VIII), or a salt thereof, contains less than about 0.4 wt% of the compound of formula (XIV), or a salt thereof. In another aspect, the selectively isolated compound of formula (VIII), or a salt thereof, contains less than about 0.3 wt% of the compound of formula (XIV), or a salt thereof. In another aspect, the selectively isolated compound of formula (VIII), or a salt thereof, contains less than about 1.0 wt% of the compound of formula (VII), or a salt thereof, and less than about 1.0 wt% of the compound of formula (XIV), or a salt thereof. In another aspect, the selectively isolated compound of formula (VIII), or a salt thereof, contains less than about 0.8 wt% of the compound of formula (VII), or a salt thereof, and less than about 0.8 wt% of the compound of formula (XIV), or a salt thereof. In another aspect, the selectively isolated compound of formula (VIII), or a salt thereof, contains less than about 0.6 wt% of the compound of formula (VII), or a salt thereof, and less than about 0.6 wt% of the compound of formula (XIV), or a salt thereof. In another aspect, the selectively isolated compound of formula (VIII), or a salt thereof, contains less than about 0.4 wt% of the compound of formula (VII), or a salt thereof, and less than about 0.4 wt% of the compound of formula (XIV), or a salt thereof.In another aspect, the selectively separated compound of formula (VIII), or a salt thereof, contains less than about 0.3% by weight of the compound of formula (VII), or a salt thereof, and less than about 0.3% by weight of the compound of formula (XIV), or a salt thereof.

[0384] In another embodiment, the present disclosure relates to a method for preparing a compound having the structure of formula (VIII):

[0385]

[0386] or a salt thereof, wherein the method comprises:

[0387] contacting a compound having the structure of formula (VII)

[0388]

[0389] or a salt thereof, with 2-butynoic acid, or a salt thereof, in the presence of 1-propylphosphonic anhydride and a base, in a reaction medium, to form a reaction mixture comprising a compound of formula (VIII), or a salt thereof; the unreacted compound of formula (VII), or a salt thereof; and reaction by-products, wherein the reaction by-products comprise a compound having the structure of formula (XIV):

[0390]

[0391] or a salt thereof;

[0392] 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;

[0393] adjusting the pH of the aqueous phase; and

[0394] 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.

[0395] In one aspect, the contacting step includes adding a compound having formula (VII) and the base to the reaction medium; adding the 2-butynoic acid to the reaction medium comprising the compound having formula (VII) and the base; and adding the 1-propylphosphonic anhydride to the reaction medium comprising the compound having formula (VII), 2-butynoic acid, and the 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 having formula (VIII) is selectively extracted into the aqueous phase. In another aspect, the method further includes separating the compound having formula (VIII) from the organic phase into which the compound having formula (VIII) has been selectively extracted.

[0396] Generally, the compound having formula (VII) is contacted with at least about 0.5 molar equivalents of 2-butynoic acid relative to the compound having formula (VII). In one aspect, the compound having formula (VII) is contacted with about 0.5 to about 5.0 molar equivalents of 2-butynoic acid relative to the compound having formula (VII). In another aspect, the compound having formula (VII) is contacted with about 1.0 to about 1.3 molar equivalents of 2-butynoic acid relative to the compound having formula (VII). In another aspect, the compound having formula (VII) is contacted with about 1.2 molar equivalents of 2-butynoic acid relative to the compound having formula (VII).

[0397] Generally, at least about 0.3 molar equivalents of 1-propylphosphonic anhydride are loaded into the reaction medium relative to the compound having formula (VII). In one aspect, at least about 0.5 molar equivalents of 1-propylphosphonic anhydride are loaded into the reaction medium relative to the compound having formula (VII). In another aspect, at least about 1.0 molar equivalents of 1-propylphosphonic anhydride are loaded into the reaction medium relative to the compound having formula (VII). In another aspect, about 0.3 to about 3.0 molar equivalents of 1-propylphosphonic anhydride are loaded into the reaction medium relative to the compound having formula (VII). In another aspect, about 0.5 to about 2.0 molar equivalents of 1-propylphosphonic anhydride are loaded into the reaction medium relative to the compound having formula (VII). In another aspect, about 0.7 to about 1.5 molar equivalents of 1-propylphosphonic anhydride are loaded into the reaction medium relative to the compound having formula (VII). In another aspect, about 1.0 to about 1.2 molar equivalents of 1-propylphosphonic anhydride are loaded into the reaction medium relative to the compound having formula (VII).

[0398] The base can be any suitable base, particularly a base comprising at least one compound selected from the group consisting of: triethylamine, 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 the base are loaded into the reaction medium relative to the compound of formula (VII). In one aspect, about 2.0 to about 5.0 molar equivalents of the base are loaded into the reaction medium relative to the compound of formula (VII). In another aspect, about 2.4 to about 3.0 molar equivalents of the base are loaded into the reaction medium relative to the compound of formula (VII).

[0399] 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, tert-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 to about 20 liters of reaction medium / kg of the compound of formula (VII) loaded into the reaction medium. During the contacting step, the reaction medium is typically maintained at a temperature from about 10 °C to about 30 °C.

[0400] Typically, after completion of the aqueous extraction, as measured by high performance liquid chromatography (“HPLC”), 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). In one aspect, after completion of the aqueous extraction, as measured by HPLC, the aqueous phase comprises greater than about 80 area % of the compound of formula (VIII). In another aspect, after completion of the aqueous extraction, as measured by HPLC, the aqueous phase comprises greater than about 85 area % of the compound of formula (VIII). In another aspect, after completion of the aqueous extraction, as measured by HPLC, the aqueous phase comprises greater than about 90 area % of the compound of formula (VIII). In another aspect, after completion of the aqueous extraction, as measured by HPLC, the aqueous phase comprises less than about 1.0 area % of the compound of formula (XIV). In another aspect, after completion of the aqueous extraction, as measured by HPLC, the aqueous phase comprises less than about 0.8 area % of the compound of formula (XIV). In another aspect, after completion of the aqueous extraction, as measured by HPLC, the aqueous phase comprises less than about 0.5 area % of the compound of formula (XIV). In another aspect, after completion of the aqueous extraction, as measured by HPLC, the aqueous phase comprises less than about 0.2 area % of the compound of formula (XIV). In another aspect, after completion of the aqueous extraction, as measured by HPLC, the aqueous phase comprises less than about 0.1 area % of the compound of formula (XIV). In another aspect, after completion of the aqueous extraction, as measured by HPLC, 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). In another aspect, after completion of the aqueous extraction, as measured by HPLC, 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). In another aspect, after completion of the aqueous extraction, as measured by HPLC, 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). In another aspect, after completion of the aqueous extraction, as measured by HPLC, 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). In another aspect, after completion of the aqueous extraction, as measured by HPLC, 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). During the aqueous extraction step, the aqueous phase typically has a pH of less than about 2.5. In one aspect, during the aqueous extraction step, the aqueous phase has a pH from about 1.8 to about 2.2.

[0401] Typically, after the organic phase extraction is complete, as measured by HPLC, 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). In one aspect, after the organic phase extraction is complete, as measured by HPLC, the organic phase contains greater than about 80 area % of the compound of formula (VIII). In another aspect, after the organic phase extraction is complete, as measured by HPLC, the organic phase contains greater than about 85 area % of the compound of formula (VIII). In another aspect, after the organic phase extraction is complete, as measured by HPLC, the organic phase contains greater than about 90 area % of the compound of formula (VIII). In another aspect, after the organic phase extraction is complete, as measured by HPLC, the organic phase contains less than about 1.0 area % of the compound of formula (VII). In another aspect, after the organic phase extraction is complete, as measured by HPLC, the organic phase contains less than about 0.8 area % of the compound of formula (VII). In another aspect, after the organic phase extraction is complete, as measured by HPLC, the organic phase contains less than about 0.6 area % of the compound of formula (VII). In another aspect, after the organic phase extraction is complete, as measured by HPLC, the organic phase contains less than about 0.4 area % of the compound of formula (VII). In another aspect, after the organic phase extraction is complete, as measured by HPLC, the organic phase contains less than about 0.3 area % of the compound of formula (VII). In another aspect, after the organic phase extraction is complete, as measured by HPLC, 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). In another aspect, after the organic phase extraction is complete, as measured by HPLC, 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). In another aspect, after the organic phase extraction is complete, as measured by HPLC, 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). In another aspect, after the organic phase extraction is complete, as measured by HPLC, 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). In another aspect, after the organic phase extraction is complete, as measured by HPLC, 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). During the organic phase extraction step, the aqueous phase typically has a pH greater than about 4.0. In one aspect, during the organic phase extraction step, the aqueous phase has a pH from about 4.5 to about 5.0.

[0402] 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.

[0403] The compound having formula (VIII) can be separated from the organic phase by any suitable means, particularly by crystallizing the compound having 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 having formula (VIII). In another aspect, the compound having formula (VIII) crystallizes from the crystallization mixture. In another aspect, the crystallization mixture is seeded with a crystalline form of the compound having formula (VIII). In another aspect, the crystallization mixture is seeded with at least about 0.01 relative weight of the crystalline form. In another aspect, the crystallization mixture is seeded with at least about 0.02 relative weight of the crystalline form. In another aspect, the crystallization mixture is seeded with at least about 0.03 relative weight of the crystalline form. In another aspect, the crystalline form is an anhydrous crystalline form.

[0404] 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.

[0405] 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.

[0406] In one embodiment, the organic phase solvent is replaced with a replacement solvent by continuous horizontal distillation. In one aspect, the continuous horizontal distillation during continuous distillation is carried out 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, during distillation, the replacement solvent is loaded 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, during distillation, the replacement solvent is loaded 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 carried out at a temperature not exceeding about 60 °C.

[0407] It may generally be beneficial to maintain the crystallization mixture at a temperature greater than about 40 °C for a period of time after crystallization has begun (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 crystallization has begun. In another aspect, the crystallization mixture is maintained at a temperature greater than about 40 °C for at least about two hours after crystallization has begun. In another aspect, the crystallization mixture is maintained at a temperature greater than about 40 °C for at least about three hours after crystallization has begun. In another aspect, the crystallization mixture is maintained at a temperature greater than about 40 °C for at least about four hours after crystallization has begun. In another aspect, the crystallization mixture is maintained at a temperature greater than about 40 °C for at least about five hours after crystallization has begun. In another aspect, the crystallization mixture is seeded with the crystalline form of the compound of formula (VIII). In another aspect, before separating the compound of formula (VIII), the crystallization mixture is cooled to a temperature of about 20 °C over a period of at least five hours. In another aspect, the crystallization mixture is seeded with the 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 before separating the compound of formula (VIII).

[0408] The contacting step is generally carried out as a batch reaction, particularly the following batch reaction: wherein at least about 25 kg of the compound of formula (VII) or a salt thereof is first loaded into the reaction. In one aspect, at least about 50 kg of the compound of formula (VII), or a salt thereof is first loaded into the reaction. In another aspect, at least about 75 kg of the compound of formula (VII), or a salt thereof is first loaded into the reaction. In another aspect, at least about 100 kg of the compound of formula (VII), or a salt thereof is first loaded into the reaction.

[0409] The method generally provides a stoichiometric method yield of at least about 50% of the compound of formula (VIII) or a salt thereof. In one aspect, the stoichiometric method yield of the compound of formula (VIII) or a salt thereof is at least about 60%. In another aspect, the stoichiometric method yield of the compound of formula (VIII) or a salt thereof is at least about 65%. In yet another aspect, the stoichiometric method yield of the compound of formula (VIII) or a salt thereof is at least about 70%. In fact, the improved method has been able to achieve a good quality material with a yield of about 75% on a scale of more than 100 kg (input).

[0410] In another representative embodiment, the present disclosure relates to a method for preparing a compound having the structure of formula (VIII):

[0411]

[0412] or a salt thereof, wherein the method comprises:

[0413] contacting a compound having the structure of formula (VII)

[0414]

[0415] 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 the compound of formula (VIII), the unreacted compound of formula (VII), and reaction by-products, wherein the reaction by-products comprise a compound having the structure of formula (XIV):

[0416]

[0417] or a salt thereof;

[0418] extracting at least a portion of the compound of formula (VIII), or a salt thereof, 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);

[0419] adjusting the pH of the aqueous phase to about 4.5 to about 5.0; and

[0420] 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).

[0421] In one aspect, the contacting step comprises adding a 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 separating 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 commences.

[0422] Scheme 18 below corresponds to the method described in Example 17 and illustrates one representative embodiment of an improved method for preparing compound (VI).

[0423] Scheme 18

[0424]

[0425] XIII. Additional Examples

[0426] The various embodiments of the individual methods described above can be combined to provide further embodiments of the overall method for preparing acalabrutinib. The embodiments described below are representative embodiments further describing the overall method. They are intended to illustrate and not limit the overall method.

[0427] In one embodiment, a compound having the structure of formula (VIII):

[0428]

[0429] or a salt thereof, is prepared by a method comprising:

[0430] contacting a compound having the structure of formula (VII)

[0431]

[0432] 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 the compound of formula (VIII) and one or more reaction by-products; and

[0433] Selectively separate the compound of formula (VIII), or a salt thereof, from the reaction mixture relative to the one or more by-products;

[0434] The compound of formula (VII), or a salt thereof, is prepared by a method comprising:

[0435] Contacting a compound of formula (V)

[0436]

[0437] or a salt thereof, with a compound of formula (VI):

[0438]

[0439] 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);

[0440] 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

[0441] Separating the compound of formula (VII), or a salt thereof, from the substantially anhydrous mixture.

[0442] In another embodiment, a compound of formula (VIII):

[0443]

[0444] or a salt thereof, is prepared by a method comprising:

[0445] Contacting a compound of formula (VII)

[0446]

[0447] or a salt thereof, with 2-butynoic acid, or a salt thereof, in the presence of a coupling agent and a base, in a reaction medium, to form a reaction mixture comprising a compound of formula (VIII), or a salt thereof; unreacted compound of formula (VII), or a salt thereof; and reaction by-products, wherein the reaction by-products comprise a compound of formula (XIV):

[0448]

[0449] or a salt thereof;

[0450] Extract at least a portion of the compound of formula (VIII), or a salt thereof, from the reaction mixture into the 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;

[0451] Adjust the pH of the aqueous phase; and

[0452] Extract at least a portion of the compound of formula (VIII), or a salt thereof, from the aqueous phase into the 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;

[0453] Wherein the compound of formula (VII), or a salt thereof, is prepared by a method comprising:

[0454] Contact a compound of formula (V)

[0455]

[0456] or a salt thereof, with a compound of formula (VI):

[0457]

[0458] 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 the compound of formula (VII), or a salt thereof;

[0459] Reduce the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising the compound of formula (VII), or a salt thereof; and

[0460] Separate the compound of formula (VII), or a salt thereof, from the substantially anhydrous mixture.

[0461] In another embodiment, the method further comprises preparing the compound of formula (VI), or a salt thereof, by a method comprising:

[0462] Contact a compound of formula (IV):

[0463]

[0464] 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 the compound of formula (VI), or a salt thereof, and a benzyl halide by-product;

[0465] Remove at least a portion of the benzyl halide by-product from the reaction mixture; and

[0466] The compound of formula (VI), or a salt thereof, is separated from the reaction mixture under conditions sufficient to substantially avoid the formation of acetalamine impurities.

[0467] In another embodiment, the method further comprises preparing a compound of formula (V), or a salt thereof, by a method comprising contacting 4-carboxyphenylboronic acid, or a salt thereof, with thionyl chloride and a catalyst in a reaction medium comprising an organic solvent to form an acyl chloride intermediate, which is then contacted in situ with 2-aminopyridine to form a reaction mixture comprising a compound of formula (V), or a salt thereof.

[0468] In another embodiment, the method further comprises preparing a compound of formula (IV), or a salt thereof, by a method comprising contacting a compound of formula (III)

[0469]

[0470] or a salt thereof, with an aminating agent in a reaction medium to form a reaction mixture comprising a compound of formula (IV);

[0471] forming a sulfate salt of the compound of formula (IV); and

[0472] isolating the sulfate salt.

[0473] In another embodiment, the method further comprises preparing a compound of formula (III), or a salt thereof, by a method comprising contacting a compound of formula (I)

[0474]

[0475] or a salt thereof, with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound of formula (II);

[0476]

[0477] or a salt thereof; and

[0478] brominating the compound of formula (II), or a salt thereof, with a brominating agent to provide a compound of formula (III):

[0479]

[0480] or a salt thereof;

[0481] 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.

[0482] In another embodiment, the present disclosure relates to a method for preparing a compound having the structure of formula (VIII):

[0483]

[0484] or a salt thereof, wherein the method comprises:

[0485] contacting a compound having the structure of formula (V)

[0486]

[0487] or a salt thereof, with a compound having the structure of formula (VI):

[0488]

[0489] or a salt thereof, in an aqueous reaction medium comprising an organic solvent in the presence of a base and a palladium catalyst to form a reaction mixture comprising a compound having the structure of formula (VII):

[0490]

[0491] or a salt thereof;

[0492] 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;

[0493] isolating the compound of formula (VII), or a salt thereof, from the substantially anhydrous mixture; and

[0494] converting the compound of formula (VII), or a salt thereof, to a compound of formula (VIII), or a salt thereof.

[0495] In another embodiment, the present disclosure relates to a method for preparing a compound having the structure of formula (VIII):

[0496]

[0497] or a salt thereof, wherein the method comprises:

[0498] contacting a compound having the structure of formula (IV)

[0499]

[0500] 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 compound having the structure of formula (VI):

[0501]

[0502] a reaction mixture of or its salt and a benzyl halide by-product;

[0503] removing at least a portion of the benzyl halide by-product from the reaction mixture;

[0504] separating a compound of formula (VI) or its salt from the reaction mixture under conditions sufficient to substantially avoid the formation of acetalamine impurities; and

[0505] converting a compound of formula (VI) or its salt to a compound of formula (VIII) or its salt.

[0506] In another embodiment, the present disclosure relates to a method for preparing a compound having the structure of formula (VIII):

[0507]

[0508] or its salt, wherein the method comprises:

[0509] contacting a compound having the structure of formula (III)

[0510]

[0511] or its salt with an aminating agent in a reaction medium to form a reaction mixture comprising a compound having the structure of formula (IV):

[0512]

[0513] forming a sulfate salt of the compound of formula (IV);

[0514] isolating the sulfate salt; and

[0515] converting the sulfate salt to a compound of formula (VIII) or its salt.

[0516] In another embodiment, the present disclosure relates to a method for preparing a compound having the structure of formula (VIII):

[0517]

[0518] or its salt, wherein the method comprises:

[0519] contacting a compound having the structure of formula (I)

[0520]

[0521] or its salt with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound of formula (II);

[0522]

[0523] or a salt thereof;

[0524] Brominating a compound of formula (II), or a salt thereof, with a brominating agent to provide a compound having the structure of formula (III):

[0525]

[0526] or a salt thereof; and

[0527] Converting the compound of formula (III), or a salt thereof, into a compound of formula (VIII), or a salt thereof;

[0528] 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.

[0529] In another embodiment, the present disclosure relates to a method for preparing a compound having the structure of formula (VIII):

[0530]

[0531] or a salt thereof, the method comprising:

[0532] Contacting a compound having the structure of formula (I)

[0533]

[0534] 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):

[0535]

[0536] or a salt thereof; and

[0537] Converting the compound of formula (II), or a salt thereof, into a compound of formula (VIII), or a salt thereof;

[0538] 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.

[0539] Generally, the improved large-scale method has reduced batch failures and provides high-quality acalabrutinib that can be routinely manufactured on a large scale from compound (I) in a yield greater than 32%.

[0540] XIV. Examples

[0541] Example 1: Preparation of Benzyl (2S)-2-(1-bromo-8-chloro-imidazo[1,5-a]-pyrazin-3-yl)pyrrolidine-1-carboxylate (Compound (III))

[0542]

[0543] Benzyl (2S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl]pyrrolidine-1-carboxylate (Compound (I); 179.4 kg, 1.00 mol. equivalent) was mixed with acetonitrile (809.6 kg, 4.5 relative weight) and N,N-dimethylformamide (6.8 kg, 0.1 mol. equivalent), and phosphorus oxychloride (140.2 kg, 1.9 mol. equivalent) was slowly added while maintaining the temperature below 25 °C. The reaction mixture was heated under a nitrogen purge at 72 °C to 82 °C to remove the liberated hydrochloric acid until the reaction showed completion. The mixture was cooled to 35 °C to 45 °C and then concentrated to about 3.6 relative volume while maintaining the temperature below 45 °C. Acetonitrile (350.2 kg, 1.95 relative weight) was added and the mixture was concentrated to about 3.6 relative volume while maintaining the temperature below 45 °C, and this operation 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. equivalent), water (1139 L, 6.3 relative weight), and ice (375.8 kg, 2.1 relative weight).

[0544] The product was then extracted from the mixture twice with dichloromethane (905 kg, 5.0 relative weight). The combined organic extracts were then washed with a solution of sodium bicarbonate (114.4 kg) in water (1139 L), then with a solution of sodium chloride (75 kg) in water (376 L), filtered through diatomaceous earth (18 kg), and then filtered through silica (40 kg). The silica cake was washed twice with dichloromethane (909 kg). Maintaining the temperature below 40 °C, the solvent was removed by vacuum distillation to about 1.0 relative volume. N-Methylpyrrolidone (819 kg, 4.6 relative weight) was added to dissolve the mixture, followed by the incremental addition of N-bromosuccinimide (77.3 kg, about 1.1 mol. equiv.). After each addition, the mixture was stirred at 20 °C to 30 °C until the reaction was considered 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 weight) and then with dichloromethane (907 kg, 5.1 relative weight). The combined organic phases were washed three times with water (682 L) and then an additional eight times with water (382 L). The organic solution was concentrated to about 1.0 relative volume and concentrated from heptane (191 kg, 1.1 relative volume) before adding heptane (191 kg, 1.1 relative volume) for crystallization. It was filtered and dried to obtain solid benzyl (2S)-2-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Compound (III), 152.2 kg, 75.6%). Enantiomeric excess = 97.8%.

[0545] However, the above method conditions often result in batches with reduced chiral purity and yield, and sometimes even lead to batch failures. The released hydrochloric acid creates acidic conditions, which cause the racemization of the benzyl (2S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl]-pyrrolidine-1-carboxylate starting material. Although using nitrogen purging to remove the released hydrochloric acid reduces the extent of racemization, the control of the degree of chiral erosion remains highly variable.

[0546] Example 2: Preparation of Benzyl (2S)-2-(8-chloro-imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Compound (II))

[0547]

[0548] Relative to the conditions of Example 1, the effect of lowering the reaction temperature and increasing the N,N-dimethylformamide loading on the chiral purity of benzyl (2S)-2-(8-chloro-imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate was evaluated. As described below, increasing the amount of N,N-dimethylformamide catalyst to at least 0.6 mol. equivalent increased the reaction rate and allowed the reaction to proceed at a lower temperature. These changes in the method conditions increased the yield and provided improved control over the chiral purity of the product.

[0549] Benzyl (2S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl]pyrrolidine-1-carboxylate (Compound (I), 1.00 g) was combined with acetonitrile (5 ml) in four 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. equivalent) was added. Phosphorus oxychloride (0.82 g, 2.0 mol. equivalent) 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 inside the vial reached 41 °C. Samples of 0.50 ml were withdrawn from each vial at 1, 3, 5 and 21 hours. The samples were quenched into 10 ml of saturated sodium bicarbonate solution, extracted into 5 ml of methyl tert-butyl ether, and the organic layer was separated and dried over magnesium sulfate. The purity and chirality of the extracts were analyzed by HPLC. The results are shown in Table 3 below.

[0550] Table 3

[0551]

[0552]

[0553] Example 3: Preparation of Benzyl (2S)-2-(1-bromo-8-chloro-imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Compound (III))

[0554]

[0555] In view of the results of Example 2 and the modified method carried out on a large scale, the synthesis described in Example 1 was modified. The modified method provided improved yields and largely avoided the racemization problems previously encountered during cyclization.

[0556] Benzyl (2S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl]pyrrolidine-1-carboxylate (Compound (I), 337.5 kg, 1.00 mol. equivalent) was mixed with acetonitrile (1688 L, 5.0 relative volume) and N,N-dimethylformamide (39.5 kg, 0.6 mol. equivalent), and phosphorus oxychloride (276.1 kg, 2.0 mol. equivalent) was added slowly while maintaining the temperature below 30 °C. The reaction mixture was heated at 40 °C for 3 hours. The mixture was cooled and then slowly transferred to a solution of sodium bicarbonate (605.1 kg, 8.0 mol. equivalent) and water (3375 L, 10.0 relative volume). The product was then extracted from the mixture three times with methyl tert-butyl ether (1013 L, 3.0 relative volume). The combined organic extracts were washed with a solution of sodium bicarbonate (151.3 kg, 2.0 mol. equivalent) in water (2025 L, 6.0 relative volume), then with a 25% w / w aqueous brine solution (675 kg, 2.0 relative weight), and then circulated 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 volume) was added to dissolve the oil, and then N-bromosuccinimide (160.3 kg, 1.0 mol. equivalent) was added incrementally with stirring at 20 °C after each addition. After the reaction was considered complete, the temperature was maintained below 10 °C, the mixture was cooled to 5 °C, and a 2% w / w aqueous sodium bicarbonate (2531 L, 7.5 relative volume) solution was added slowly to precipitate the product. The mixture was filtered and washed with a premixed solution of water (675 L, 2.0 relative volume) and N,N-dimethylformamide (338 L, 1.0 relative volume), and then washed twice with water (675 L, 2.0 relative volume). The resulting solid was returned to the reactor and redissolved in water (1688 L, 5.0 relative volume). The product was isolated and washed twice with water (675 L, 2.0 relative volume), and dried in vacuo at 45 °C to obtain the 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%.

[0557] The compound exists as a mixture of conformational isomers in solution and the resonances are cited only for the major conformational isomer. 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.

[0558] Example 4: Preparation of the Sulfate of Benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (Sulfate of Compound (IV))

[0559]

[0560] Benzyl (2S)-2-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Compound (III), 90.0 kg, 1.00 mol. equivalent) was mixed with isopropanol (351 kg, 3.0 relative weight) and N-methylpyrrolidone (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 approximately 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. equivalent) was added slowly. 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-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (Compound (IV), 89.2 kg, 83.5%, based on the assumption of the monosulfate salt).

[0561] Example 5: Preparation of the Sulfate (2:3) of Benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (Compound (IV))

[0562]

[0563] The synthesis described in Example 4 assumed a free base to salt ratio of 1:1 for the final product, but the assay and mass balance were inconsistent. Therefore, the synthesis was further modified as described below to obtain a final product with a defined stoichiometry that could meet the regulatory requirements for characterizing intermediates used in the preparation of registered drug substances. The presence of inorganic ammonium sulfate in the Example 4 product made it difficult to accurately determine the stoichiometry of the sulfate salt. The modified method below removed residual ammonia prior to forming the sulfate salt and essentially eliminated this problem.

[0564] Benzyl (2S)-2-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Compound (III), 336.5 kg, 1.00 mol. equivalent) was mixed with 2-butanol (1683 L, 5.0 relative volume) and 30% w / w ammonium hydroxide (841 kg, 2.5 relative weight) in a sealed autoclave and heated to 90 °C to 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 volume) and then distilled under vacuum at about 40 °C to about one-third of its volume. 2-Butanol (1346 L, 4.0 relative volume) and water (841 L, 2.5 relative volume) 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, while maintaining the temperature below 25 °C, 93% sulfuric acid (122.2 kg, 1.5 mol. equivalent) was added slowly. The resulting slurry was cooled to 0 °C to 5 °C and then filtered, washed with 10% v / v aqueous 2-butanol (673 L, 2.0 relative volume) and then dried under vacuum at 40 °C to obtain an off-white crystalline solid, which was benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidine-carboxylate (Compound (IV), 324.4 kg, 87.2%, calculated as the sulfate (2:3) of the sulfate).

[0565] The compound exists as a mixture of conformational isomers in solution and the resonances are cited only for the major conformational isomer. 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 diffraction pattern consistent with Figure 1 that.

[0566] Example 6: Analysis of the Sulfate of Benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (Sulfate of Compound (IV))

[0567] A. Confirmation of Salt Stoichiometry

[0568] Purified benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (Compound (IV) free base, 500 mg) was combined with ethanol (8 ml) in four vials equipped with magnetic stir bars and concentrated sulfuric acid (0.25, 0.50, 0.75, and 1.0 mol. equiv.) was added. It was held for one hour and then cooled to 0 °C for one hour, then filtered and dried under vacuum. The results are presented in Table 4 below and demonstrate that the stoichiometry is not consistent with the previously assumed 1:1 salt ratio but is consistent with a 2:3 ratio.

[0569] Table 4

[0570]

[0571] B. Single Crystal X-Ray Diffraction Analysis

[0572] Single crystals of the sulfate salt of benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (Compound (IV)) were grown by slow evaporation from dimethyl sulfoxide. Suitable crystals for single X-ray diffraction were identified and analyzed. Details of the crystal data: 3(C 18 H 19 BrN5O2) . SO4 . HSO4 . H2O.,M r = 1463.02, trigonal system, R3 (No. 146), α = 90°, β = 90°, γ = 120°, T = 100(2) K, Z = 3, Z' = 0.33333, μ(CuKα) = 3.748, 30561 reflections were measured, and 3873 unique reflections (R int = 0.0306) were used in all calculations. The final wR2 was 0.0791 (all data) and R1 was 0.0292 (I > 2(I)). Flack parameter = -0.023(5).

[0573] The stoichiometry was confirmed to be 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 bisulfate. Although the 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 could be variable without substantially affecting the overall structure or salt stoichiometry.

[0574] C. X-Ray Powder Diffraction Analysis

[0575] X-ray powder diffraction data were collected by mounting a powder of benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (Compound (IV)) sulfate on a silicon wafer holder and analyzing the sample using a Bruker D4 Endeavour diffractometer. The sample was measured in a θ-2θ scan mode in reflection geometry over a 2° to 40° 2θ scan range with a 0.12 s exposure / 0.02° increment. X-rays were generated by a copper long fine focus tube operating at 40 kV and 40 mA. The resulting X-ray diffraction pattern is shown in Figure 1 and the selected peaks and relative intensities are reported in Table 5 below.

[0576] Table 5

[0577]

[0578]

[0579] 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° 2θ, particularly peaks at 7.7, 10.6, 11.1, 12.6 and 13.5 ± 0.2° 2θ.

[0580] Example 7: Preparation of 1-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (Compound (VI)) Preparation

[0581]

[0582] Under an inert atmosphere, the sulfate (2:3) of benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (Compound (IV), 261 kg, 1.0 mol. equivalent) and aqueous concentrated hydrochloric acid (996 L, 3.8 relative weight) were mixed and heated to 40 °C to 50 °C for at least two hours. The batch was cooled and washed four times with methyl tert-butyl ether (192 kg, 4 x 0.73 relative weight). Aqueous sodium hydroxide solution was added slowly, with cooling, to reach a pH greater than 12. The product was extracted with dichloromethane (3632 kg, 13.9 relative weight), clarified with diatomaceous earth, and then decolorized with palladium on carbon (13 kg, 0.05 relative weight). At atmospheric pressure, the organic extract was concentrated to about 0.86 relative volume. Methyl tert-butyl ether (519 L, 1.99 relative weight) 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, and then dried under vacuum at 40 °C to obtain the solid 1-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (Compound (VI), 119 kg, 78% yield).

[0583] Example 8: Preparation of 1-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (Compound (VI)) Preparation

[0584]

[0585] The sulfate (2:3) of benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (Compound (IV), 370 kg) and aqueous concentrated hydrochloric acid were mixed and heated to 50 °C for at least six hours. The batch was cooled and washed with methyl tert-butyl ether and then with heptane. Aqueous sodium hydroxide solution was added slowly, with cooling, to reach a pH greater than 12. The product was extracted with dichloromethane and methanol was added. The solution was clarified with diatomaceous earth, and then decolorized with palladium on carbon. At atmospheric pressure, the organic extract was concentrated and exchanged into methyl tert-butyl ether. 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 obtain the solid 1-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (Compound (VI), 188.8 kg). This product needed further purification to remove the acetalamine impurity by slurrying in ethyl acetate, filtering, and washing the filter cake with ethyl acetate.

[0586] Example 9: Preparation of 1-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (Compound (VI)) Preparation

[0587]

[0588] The synthesis exemplified in Examples 7 and 8 sometimes results in elevated impurities (e.g., acetalamine impurities when using dichloromethane as the extraction solvent) and poor operability. Therefore, the method described below was developed to improve the purity of the final product.

[0589] Under an inert atmosphere, the sulfate (2:3) of benzyl (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (Compound (IV), 343 kg, 1.0 mol. equivalent) and 37% w / w aqueous hydrochloric acid solution (1142 L, 3.33 relative volume) were mixed and heated to 40 °C for 14 hours. The batch was cooled and washed twice with heptane (1715 L, 5.0 relative volume). 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 twice with 2-methyltetrahydrofuran (2401 L, 7.0 relative volume) and the combined extracts were washed with water (343 L, 1.0 relative volume), then concentrated to a volume of 3.5 relative volume at atmospheric pressure. 2-Methyltetrahydrofuran (1029 L, 3.0 relative volume) was added, and the mixture was concentrated to a volume of 1200 L, 3.5 relative volume at atmospheric pressure. The mixture was cooled to 70 °C and crystalline 1-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (Compound (VI), 0.34 kg, 0.001 relative weight) was added to seed the mixture. The mixture was cooled to 20 °C, and heptane (686 L, 2.0 relative volume) was added. The resulting slurry was filtered and washed with a mixture of 2-methyltetrahydrofuran (309 L, 0.90 relative volume) and heptane (206 L, 0.60 relative volume), then dried under vacuum at 40 °C to obtain a yellowish-brown crystalline solid 1-bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (Compound (VI), 168 kg, 84% yield).

[0590] 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.

[0591] Example 10: Preparation of [4-(2-pyridylcarbamoyl)phenyl]boronic acid (Compound (V))

[0592]

[0593] At 50 °C, 4-carboxyphenylboronic acid (116.0 kg, 1.0 mol equivalent) was mixed with toluene (696 kg, 6.0 relative volumes) and N,N-dimethylformamide (2.0 kg, 0.04 mol equivalent). Thionyl chloride (249.5 kg, 3.0 mol equivalent) was slowly loaded into the slurry. 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 equivalent) 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 °C to 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 °C to 70 °C, water (116 L, 1.0 relative volume) was added, and the mixture was stirred at 65 °C to 70 °C for 12 hours. Toluene (232 L, 2.0 relative volumes) was added at a temperature of 65 °C to 70 °C, and then water (928 L, 8.0 relative volumes) was added. The mixture was then cooled to 20 °C and filtered. The filter cake was washed four times with water (464 L, 4.0 relative volumes) and dried at 50 °C to obtain the white crystalline solid [4-(2-pyridylcarbamoyl)phenyl]-boronic acid (Compound (V), 141.8 kg, 83.8% of theory).

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

[0595]

[0596] Further modify the synthesis described in Example 10, in particular to identify a suitable alternative solvent to N,N-dimethylformamide that will reduce the potential formation of unwanted by-products, especially dimethylcarbamoyl chloride.

[0597] At 50 °C, 4-carboxyphenylboronic acid (7.0 g, 1.0 mol. equiv) was mixed with toluene (66.5 ml, 9.5 relative volume) and tetrabutylammonium chloride (0.59 g, 0.05 mol. equiv). Thionyl chloride (13.8 g, 2.75 mol. equiv) was slowly loaded into the slurry, followed by a toluene (3.5 ml, 0.5 relative volume) wash. The reaction was heated to 70 °C and stirred for at least six hours, then cooled. The mixture was then concentrated in vacuo to approximately 4.0 relative volume, and then pyridine (56 ml, 8.0 relative volume) was added. The mixture was then concentrated in vacuo to approximately 4.0 relative volume and then added to a solution of 2-aminopyridine (7.94 g, 2.0 mol. equiv) in pyridine (35 ml, 5.0 relative volume), followed by a pyridine (7 ml, 1.0 relative volume) wash. The reaction was slowly heated to 70 °C and stirred for at least 18 hours. The mixture was then concentrated in vacuo to approximately 3.0 relative volume. Water (7 ml, 1.0 relative volume) was added and the mixture was stirred at 70 °C for at least one hour. Water (56 ml, 8.0 relative volume) was loaded at 70 °C. The mixture was then cooled to 20 °C and filtered. The filter cake was washed four times with water (28 ml, 4.0 relative volume) and dried at 50 °C to obtain the white crystalline solid [4-(2-pyridylcarbamoyl)phenyl]-boronic acid (Compound (V), 8.79 kg, 85% of theory).

[0598] The compound exists as a mixture of conformational isomers in solution and resonances are cited only for the major conformational isomer. 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.

[0599] Example 12: Preparation of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridyl)benzamide (Compound (VII)) Preparation

[0600]

[0601] 1-Bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (Compound (VI), 49.7 kg, 1.00 mol. equiv.) and [4-(2-pyridylcarbamoyl)phenyl]boronic acid (Compound (V), 44.7 kg, 1.05 mol. equiv.) were mixed with bis(tert-butyl dicyclohexylphosphine)palladium(II) dichloride (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 volume) and 2-butanol (184 L, 4.55 relative volume). The reaction mixture was then heated to 82 °C and maintained under nitrogen for at least 24 hours. The reaction mixture was slowly cooled to about 23 °C and then subjected to a thermal cycle by heating to about 42 °C, cooling to about 23 °C, and heating to about 42 °C.

[0602] Water (727 L, 15 relative volume) was then slowly added and the mixture was cooled to about 20 °C, then filtered and washed with water. The filtration and washing cycles were very slow. During the process, two filters and multiple discharges were required, which usually took 3 to 4 days to complete. The X-ray powder diffraction of the material separated in this filtration step gave a diffraction pattern consistent with Figure 2 (i.e., Type 2) diffraction Figure 1 A diffraction pattern consistent with. The water-wet product was further dried by refluxing in heptane (964 L) for 29 hours under Dean Stark conditions and then filtered and dried under vacuum at 45 °C to obtain the yellow crystalline solid 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%). Example 13: Preparation of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridyl)benzamide (Compound (VII)) Preparation

[0603]

[0604] The synthesis described in Example 12 was further modified, particularly to improve the filtration of the crude product and reduce the cycle time of the synthesis.

[0605] 1-Bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (Compound (VI), 26.5 kg, 1.00 mol. equiv.) and [4-(2-pyridylcarbamoyl)phenyl]boronic acid (Compound (V), 25 kg, 1.10 mol. equiv.) were mixed with bis(tert-butyl dicyclohexylphosphine)palladium(II) dichloride (0.64 kg, 0.01 mol. equiv.), potassium iodide (4.7 kg, 0.30 relative volume), and triethylamine (28.9 kg, 1.50 mol. equiv.) in water (224 L, 8.45 relative volume) and 2-butanol (120 L, 4.55 relative volume). The reaction mixture was then heated to 82 °C for 15 h. At 75 °C to 82 °C, the reaction mixture was diluted with 2-butanol (149 L, 5.6 relative volume), water (11 L, 0.4 relative volume), and 3 M aqueous potassium carbonate solution (53 L, 2.0 relative volume), and the aqueous layer was removed and discarded. At 80 °C, the organic layer was treated with QuadraSil MP (5.3 kg, 0.20 relative weight) for 18 h. At 80 °C, the scavenger was removed by filtration and washed with 2-butanol (27 L, 1.0 relative volume). At a temperature of 75 °C to 82 °C, the organic mixture was washed with a solution of water (56 L, 2.1 relative volume) and 3 M aqueous potassium carbonate (9 L, 0.33 relative volume), and then washed with water (55 L, 2.0 relative volume) at a temperature of 75 °C to 82 °C. 2-Butanol was added to adjust the solution volume to 16 relative volume, and the mixture was distilled at atmospheric pressure while maintaining a constant volume of approximately 16 relative volume in the vessel by further addition of 2-butanol until the mixture reached a temperature above 97 °C. The mixture was seeded with 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridyl)benzamide (Compound (VII), 0.13 kg, 0.005 relative weight) and further distilled at atmospheric pressure to reduce the volume to approximately 10 relative volume. The mixture was slowly cooled to 20 °C, then filtered and washed with 2-butanol (106 L, 4.0 relative volume), then washed with 2-butanol (53 L, 2.0 relative volume) followed by heptane (53 L, 2.0 relative volume), and dried at 45 °C under vacuum to a yellow crystalline solid, 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridyl)benzamide (Compound (VII), 26.8 kg, 75%). The filtration and wash cycle was achieved in less than 24 h using a single discharge on one filter.

[0606] The solid 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (Compound (VII), 40.6 kg, 1.0 mol. equivalent) was purified by slurrying in 1 M aqueous potassium carbonate solution (162.4 L, 4.0 relative volume) to remove the impurity 4-[8-amino-3-[(2S)-pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]benzoic acid (Compound (XII)), followed by filtration and washing with water (81.2 L, 2.0 relative volume), and then washing with heptane (81.2 L, 2.0 relative volume) to obtain the yellow crystalline 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (Compound (VII), 39.7 kg, 98%). In addition to the impurity 4-[8-amino-3-[(2S)-pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]benzoic acid (Compound (XII)), another impurity, 4-[8-amino-3-[(2S)-1-[4-[8-amino-3-[(2S)-pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]benzoyl]pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]-N-(2-pyridinyl)benzamide (Compound (XIII)), was observed and not removed by this repeated work.

[0607] Example 14: Preparation of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridyl)benzamide (Compound (VII)) Preparation

[0608]

[0609] Although the method described in Example 13 led to improved filtration and cycle times, two unwanted impurities were formed due to prolonged heating under the conditions of this method. Therefore, the method was further modified, in particular, to reduce the formation of these impurities and improve the purity of the final product.

[0610] 1-Bromo-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-8-amine (Compound (VI), 115.0 kg, 1.00 mol. equivalent) and [4-(2-pyridylcarbamoyl)phenyl]boronic acid (Compound (V), 96.7 kg, 0.98 mol. equivalent) were mixed with bis(tert-butyl(dicyclohexyl)phosphine)palladium(II) dichloride (2.8 kg, 0.01 mol. equivalent), potassium iodide (20.3 kg, 0.30 mol. equivalent) and potassium carbonate (135.2 kg, 2.40 mol. equivalent) in water (920 L, 8.0 relative volume) and 2-butanol (978 L, 8.5 relative volume). The reaction mixture was then heated to 80 °C for 16 hours. The layers were separated and the aqueous layer discarded. The organic layer was diluted with 2-butanol (460 L, 4.0 relative volume), washed at 60 °C with water (575 L, 5.0 relative volume) and then water (460 L, 4.0 relative volume), and then treated at 60 °C with QuadraSil MP (23 kg, 0.20 relative weight) for 9 hours. The scavenger was removed by filtration at 60 °C and washed with 2-butanol (173 L, 1.5 relative volume). The resulting mixture was washed at 60 °C with a solution of sodium chloride (46 kg, 0.40 relative weight) in water (230 L, 2.0 relative volume). The mixture was seeded with crystalline 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridyl)benzamide (Compound (VII), 1.15 kg, 0.01 relative weight) and then distilled under vacuum (0.2 bar), maintaining a constant volume of 1840 L (16 relative volume) in the vessel by readdition of 2-butanol (1610 L, 14.0 relative volume) and maintaining the temperature below 60 °C. The mixture was then distilled (at 0.2 bar) to a volume of 1380 L (12.0 relative volume), maintaining the temperature below 60 °C. It was heated to 80 °C for two hours, then cooled to 20 °C and filtered. The product was washed with 2-butanol (460 L, 4.0 relative volume), then 2-butanol (230 L, 2.0 relative volume), subsequently heptane (230 L, 2.0 relative volume), and dried in vacuo at 45 °C to give the yellow crystalline solid 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridyl)benzamide (Compound VII, 131.7 kg, 80.4%). The filtration and wash cycle was achieved in less than 24 hours using a single discharge and one filter.

[0611] 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. The X-ray powder diffraction of the obtained crystalline solid gave a diffraction pattern consistent with that of Figure 4 i.e., Form C).

[0612] Example 15: X-ray powder diffraction analysis of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridyl)benzamide (Compound (VII)) Analysis protocol

[0613] A. Analysis of crystalline form 2

[0614] Crystalline samples of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (Compound (VII)), Forms 2, 3, and C were analyzed by X-ray powder diffraction. The samples were mounted on a silicon wafer holder and analyzed using a PANalytical CubiX PRO diffractometer The samples were measured in reflection geometry in a θ-θ configuration over a 2° to 40° 2θ scan range with a nominal 25 second exposure / 0.02° increment. X-rays were generated by a copper fine focus long tube operating at 45 kV and 40 mA. The results for crystalline Forms 2, 3, and C are reported in Sections A, B, and C below, respectively.

[0615] B. Figure 2

[0616] Analyze a sample of the type 2 crystalline form of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (Compound (VII)) by X-ray powder diffraction. The resulting X-ray diffraction pattern is shown in Table 6 and the selected peaks and relative intensities are reported in Table 6 below.

[0617] Analysis of crystalline form 3

[0618]

[0619]

[0620] The type 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 the peaks at 5.0, 5.7, 7.2, 9.9 and / or 11.2 ± 0.2° 2θ. As previously mentioned, the product separated by the first filtration in Example 12 corresponds to the type 2 crystalline form.

[0621] C. Figure 3

[0622] Analyze a sample of the type 3 crystalline form of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (Compound (VII)) by X-ray powder diffraction, which is produced by slurrying the type 2 in pure butanol for 7 days under ambient conditions. The resulting X-ray diffraction pattern is shown in Table 7 and the selected peaks and relative intensities are reported in Table 7 below.

[0623] Analysis of crystalline form C

[0624]

[0625]

[0626] The type 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 the peaks at 7.4, 11.7, 12.5, 22.3 and / or 21.6 ± 0.2° 2θ.

[0627] D. Figure 4

[0628] A sample of crystalline Form C of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (Compound (VII)) was analyzed by X-ray powder diffraction. The resulting X-ray diffraction pattern is shown in Table 8 and the selected peaks and relative intensities are reported in Table 8 below.

[0629] Peak

[0630] Relative intensity Peak Relative intensity Example 16: Preparation of 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide (Compound (VIII)) 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

[0631] Crystalline Form C 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, particularly peaks at 9.9, 11.1, 12.8, 14.1 and 19.0 ± 0.2° 2θ. As previously mentioned, the product isolated by filtration from Example 14 corresponds to Crystalline Form C.

[0632] Example 17: Preparation of 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide (Compound (VIII)) Example 18: Preparation of benzyl (2S)-2-[(3-chloropyrazin-2-yl)methyl-carbamoyl]pyrrolidine-1-carboxylate (Compound (I))

[0633]

[0634] 4-{8-Amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (Compound (VII), 70 kg, 1.0 mol. equiv.) and 2-butynoic 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 considered complete). The organic solution of the resulting 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 6 M aqueous hydrochloric acid to reach ca. pH 2, then the organic phase was separated off and discarded. The aqueous layer (containing the product) was washed three times with 2-methyltetrahydrofuran (478 kg, 8.0 relative volumes) and then 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 pH 7.0 to 8.5 with triethylamine (variable amount) to extract the product into the organic phase. The organic phase was separated off and washed twice with water (350 kg, 5.0 relative volumes), then filtered through carbon, then treated repeatedly with Quadrasil-MP (17.5 kg, 0.25 relative weight), washing the spent scavenger cake each time 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 the mixture was concentrated to 5 relative volumes, and this was further repeated twice. Then the mixture was heated to 50 °C, cooled to 20 °C, and filtered. The product was washed twice with ethanol (55 kg, 1.0 relative volume) and then the wet filter 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 the mixture was concentrated to 5 relative volumes, and this was repeated once. Then the mixture was heated to 50 °C, cooled to 20 °C, and filtered. The product was washed twice with ethanol (55 kg, 1.0 relative volume) and then dried under vacuum at 50 °C to obtain the white crystalline solid acalabrutinib (Compound VIII, 52.2 kg, 64%).

[0635] Preparation of Compound (7) Example 19: Preparation of benzyl (2S)-2-[(3-chloropyrazin-2-yl)methylcarbamoyl]-pyrrolidine-1-carboxylate (Compound (I))

[0636]

[0637] Further modify the synthesis described in Example 17, particularly to allow for greater flexibility under operating conditions while still producing a product with appropriate purity. Among other advantages, the modified synthesis results in improved removal of certain impurities.

[0638] 4-{8-Amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (Compound (VII), 131.7 kg, 1.0 mol. equivalent) was slurried in dichloromethane (955 L, 7.25 relative volume) and triethylamine (90.1 kg, 2.7 mol. equivalent). 2-Butynoic acid (33.3 kg, 1.2 mol. equivalent) in dichloromethane (263.4 L, 2.0 relative volume) was added, followed by 1-propylphosphonic anhydride (T3P) (50% w / w dichloromethane solution, 209.8 kg, 1.0 mol. equivalent). The resulting organic solution of the product was washed twice with water (658.5 L, 5.0 relative volume) and then water (1317 L, 10.0 relative volume) was added. The mixture was then acidified to about pH 2.2 with 6M aqueous hydrochloric acid and then 2M aqueous hydrochloric acid was added to reach pH 1.8 to 2.2, and then the organic phase was separated and discarded. Dichloromethane (1317 L, 10.0 relative volume) 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 volume). The combined dichloromethane extracts were filtered and the organic phase was concentrated to about 5.0 relative volume. Ethanol (1712 L, 13.0 relative volume) was added and the mixture was distilled (about 360 mbar), maintaining a constant volume (18.0 relative volume) by adding ethanol (1580 L, 12.0 relative volume). A portion of the crystalline 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide (Compound (VIII), 1.32 kg, 0.01 relative weight) was added as a seed and the solution was held at 50 °C for 10 hours to crystallize the product. The mixture was then cooled over 7 hours and filtered. The product was washed twice with ethanol (527 L, 4.0 relative volume) and then dried under vacuum at 50 °C to obtain the white crystalline solid acalabrutinib (Compound VIII, 113.6 kg, 74%).

[0639] The compound exists as a mixture of conformational isomers in solution and the resonances are cited only for the major conformational isomer. 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.

[0640] Step 1: Step 2:

[0641]

[0642] A. Step 3:

[0643] 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 volume) was added thionyl chloride (0.75 kg, 1.5 mol.Eq.), and the mixture was stirred at 30 °C for 7 h. The reaction mixture was concentrated (to about 4.5 relative volume) under vacuum at 35 °C to 45 °C. Under vacuum at 35 °C to 45 °C, toluene (2.1 L, 2.0 relative volume) was added and the reaction mixture was concentrated (to about 4.5 relative volume). Determination of the solution of the test product (Compound (7)) (5.6 kg @ 18.3% w / w = 1.03 kg, 91.8% yield).

[0644] B. Step 4: Selected examples

[0645] ​At 35 °C to 40 °C, diphenylmethanimine (Compound (1), 1.44 kg, 1.0 mol. equivalent) and glycine methyl ester hydrochloride (Compound (2), 1.099 kg, 1.1 mol. equivalent) were mixed in acetonitrile (7.2 L, 5.0 relative volume) for 3 hours. It was cooled to 20 °C to 25 °C and filtered, and the cake was washed twice with acetonitrile (2.88 L, 2.0 relative volume). Determination of the solution of the product (Compound (3)) (10.05 kg @ 18.9% w / w = 1.9 kg, 94.4% yield) was measured.

[0646] ​ 2,3-Dipyrazine (Compound (4), 0.911 kg, 1.0 mol. equivalent) and cesium carbonate (2.39 kg, 1.2 mol. equivalent) were added to the filtrate solution (10.05 kg @ 18.9% w / w = 1.9 kg, 1.2 mol. equivalent) and the mixture was heated to 80 °C to 85 °C for 13 hours. It was cooled to 20 °C to 25 °C for filtration, and the cake was washed twice with acetonitrile (1.8 L, 2.0 relative volume). Determination of the solution of the product (Compound (5)) (14.7 kg @ 13.3% w / w = 1.96 kg, 89.0% yield) was measured.

[0647] ​ Water (3.6 kg, 2.0 relative volume) was added to the acetonitrile solution of Compound (5) (13.5 kg @ 13.3% w / w = 1.8 kg), and the mixture was distilled under vacuum to 2.5 relative volume. Further water (3.6 kg, 2.0 relative volume) was added and the mixture was distilled under vacuum to 3.5 relative volume. Concentrated hydrochloric acid (1.8 L, 1.0 relative volume of the amount of Compound (5)) was added and heated to 80 °C to 85 °C for 7 hours. It was cooled to 20 °C, and the aqueous phase was washed with a mixture of toluene (5.4 L, 3.0 relative volume) and acetonitrile (3.6 L, 2.0 relative volume), and then further washed with toluene (5.4 L, 3.0 relative volume). Determination of the aqueous phase containing Compound (6) (10.25 kg @ 5.9% w / w = 0.605 kg, 85.8% yield) was measured.

[0648] ​To a solution of compound (6) (6.1 kg @ 5.9% w / w = 0.36 kg, 1.0 mol. equivalent) was added 25% aqueous NaOH solution (to about pH = 8 - 9). At 10 °C to 15 °C, toluene (1.8 L, 5.0 relative volume) and a solution of compound (7) (in toluene) (4.4 kg @ 18.3% w / w = 0.805 kg, 1.2 mol. equivalent) were added, (while loading 25% aqueous sodium hydroxide into the reaction mixture to maintain the pH value at 8 to 9). Stirring was continued for three hours, and the mixture was extracted with a mixture of toluene (1.8 L, 5.0 relative volume) and acetonitrile (1.44 L, 4.0 relative volume), then separated and the aqueous phase was extracted with a mixture of toluene (1.8 L, 5.0 relative volume) and acetonitrile (0.72 L, 2.0 relative volume). The organic phases were combined and washed with brine (1.8 L, 5.0 relative volume), and then washed with water (1.8 L, 5.0 relative volume).

[0649] At 40 °C to 45 °C under vacuum, the organic phase was concentrated (to about 5.0 relative volume) 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 volume) was added dropwise to the mixture until a suspension was observed. The mixture was cooled to 5 °C to 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). This compound exists as a mixture of conformational isomers in solution and the resonances are cited only for the major conformational isomer). 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). 1313C 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。

[0650] XV. ​

[0651] Example 1. A method for preparing a compound having the structure of formula (VIII):

[0652]

[0653] or a salt thereof, wherein the method comprises:

[0654] contacting a compound having the structure of formula (VII)

[0655]

[0656] 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 having the structure of formula (VIII), or a salt thereof, and one or more reaction by-products; and

[0657] selectively separating, relative to the one or more reaction by-products, the compound having the structure of formula (VIII), or a salt thereof, from the reaction mixture.

[0658] Example 2. The method according to Example 1, wherein the contacting step comprises:

[0659] adding the compound having the structure of formula (VII), or a salt thereof, and the base to the reaction medium;

[0660] adding the 2-butynoic acid, or a salt thereof, to the reaction medium comprising the compound having the structure of formula (VII), or a salt thereof, and the base; and

[0661] adding the 1-propylphosphonic anhydride to the reaction medium comprising the compound having the structure of formula (VII), or a salt thereof; 2-butynoic acid, or a salt thereof; and the base.

[0662] Example 3. The method according to Example 1 or 2, wherein the method comprises:

[0663] contacting a compound having the structure of formula (VII)

[0664]

[0665] Or a salt thereof, is contacted 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 having the formula (VIII), or a salt thereof; an unreacted compound having the formula (VII), or a salt thereof; and reaction by-products; wherein the reaction by-products comprise a compound having the structure of formula (XIV):

[0666]

[0667] or a salt thereof; and

[0668] The compound having the formula (VIII), or a salt thereof, is selectively separated from the reaction mixture relative to the compound having the formula (VII), or a salt thereof, and the compound having the formula (XIV), or a salt thereof.

[0669] Example 4. The method according to Example 1 or 2, wherein the method comprises:

[0670] A compound having the structure of formula (VII)

[0671]

[0672] or a salt thereof, is contacted 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 having the formula (VIII), or a salt thereof; an unreacted compound having the formula (VII), or a salt thereof; and reaction by-products; wherein the reaction by-products comprise a compound having the structure of formula (XIV):

[0673]

[0674] or a salt thereof;

[0675] At least a portion of the compound having the formula (VIII), or a salt thereof, is extracted from the reaction mixture into the aqueous phase, wherein the compound having the formula (VIII), or a salt thereof, is selectively extracted into the aqueous phase relative to the compound having the formula (XIV), or a salt thereof;

[0676] The pH of the aqueous phase is adjusted; and

[0677] At least a portion of the compound having the formula (VIII), or a salt thereof, is extracted from the aqueous phase into the organic phase, wherein the compound having the formula (VIII), or a salt thereof, is selectively extracted into the organic phase relative to the compound having the formula (VII), or a salt thereof.

[0678] Example 5. The method according to Example 3 or 4, wherein the selectively isolated compound of formula (VIII), or a salt thereof, comprises less than about 1.0% by weight of the compound of formula (VII), or a salt thereof.

[0679] Example 6. The method according to Example 3 or 4, wherein the selectively isolated compound of formula (VIII), or a salt thereof, comprises less than about 1.0% by weight of the compound of formula (XIV), or a salt thereof.

[0680] Example 7. The method according to Example 3 or 4, wherein the selectively isolated compound of formula (VIII), or a salt thereof, comprises less than about 1.0% by weight of the compound of formula (VII), or a salt thereof, and less than about 1.0% by weight of the compound of formula (XIV), or a salt thereof.

[0681] Example 8. The method according to 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.

[0682] Example 9. The method according to any one of Examples 4 to 8, wherein the method further comprises separating the compound of formula (VIII) from the organic phase into which the compound of formula (VIII) has been selectively extracted.

[0683] Example 10. The method according to any one of Examples 4 to 9, wherein after completion of the aqueous phase extraction, as measured by high performance liquid chromatography, the aqueous phase comprises greater than about 75 area % of the compound of formula (VIII).

[0684] Example 11. The method according to any one of Examples 4 to 9, wherein after completion of the aqueous phase extraction, as measured by high performance liquid chromatography, the aqueous phase comprises less than about 2.0 area % of the compound of formula (XIV).

[0685] Example 12. The method according to any one of Examples 4 to 9, wherein after completion of the aqueous phase extraction, as measured by high performance liquid chromatography, 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).

[0686] Example 13. The method according to any one of Examples 4 to 12, wherein after completion of the organic phase extraction, as measured by high performance liquid chromatography, the organic phase comprises at least about 75 area % of the compound of formula (VIII).

[0687] Example 14. The method according to any one of Examples 4 to 12, wherein after the organic phase extraction is completed, the organic phase contains less than about 2.0 area % of the compound having the formula (VII), as measured by high performance liquid chromatography.

[0688] Example 15. The method according to any one of Examples 4 to 12, wherein after the organic phase extraction is completed, the organic phase contains at least about 75 area % of the compound having the formula (VIII) and less than about 2.0 area % of the compound having the formula (VII), as measured by high performance liquid chromatography.

[0689] Example 16. The method according to 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.

[0690] Example 17. The method according to any one of Examples 4 to 15, wherein the aqueous phase has a pH ranging from about 1.8 to about 2.2 during the aqueous phase extraction step.

[0691] Example 18. The method according to any one of Examples 4 to 15, wherein the aqueous phase has a pH greater than about 4.0 during the organic phase extraction step.

[0692] Example 19. The method according to any one of Examples 4 to 15, wherein the aqueous phase has a pH ranging from about 4.5 to about 5.0 during the organic phase extraction step.

[0693] Example 20. The method according to 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.

[0694] Example 21. The method according to 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, tert-amyl alcohol, acetone, methyl isobutyl ketone, 2-butanol, methyl ethyl ketone, acetonitrile, and ethyl acetate.

[0695] Example 22. The method according to any one of Examples 4 to 19, wherein the reaction medium comprises dichloromethane.

[0696] Example 23. The method according to 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.

[0697] Example 24. The method according to any one of Examples 4 to 22, wherein the base comprises triethylamine.

[0698] Example 25. The method according to 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.

[0699] Example 26. The method according to 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, 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.

[0700] Example 27. The method according to any one of Examples 4 to 24, wherein the organic phase comprises dichloromethane.

[0701] Example 28. The method according to 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-butynoic acid relative to the compound of formula (VII).

[0702] Example 29. The method according to 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-butynoic acid relative to the compound of formula (VII).

[0703] Example 30. The method according to any one of Examples 4 to 27, wherein the compound of formula (VII) is contacted with about 1.2 molar equivalents of 2-butynoic acid relative to the compound of formula (VII).

[0704] Example 31. The method according to any one of Examples 4 to 30, wherein about 0.3 to about 3.0 molar equivalents of 1-propylphosphonic anhydride are loaded into the reaction medium relative to the compound of formula (VII).

[0705] Example 32. The method according to any one of Examples 4 to 30, wherein about 0.5 to about 2.0 molar equivalents of 1-propylphosphonic anhydride are loaded into the reaction medium relative to the compound of formula (VII).

[0706] Example 33. The method according to any one of Examples 4 to 30, wherein about 0.7 to about 1.5 molar equivalents of 1-propylphosphonic anhydride are loaded into the reaction medium relative to the compound of formula (VII).

[0707] Example 34. The method according to any one of Examples 4 to 30, wherein about 1.0 to about 1.2 molar equivalents of 1-propylphosphonic anhydride are loaded into the reaction medium relative to the compound having formula (VII).

[0708] Example 35. The method according to any one of Examples 4 to 34, wherein about 1.0 to about 10.0 molar equivalents of a base are loaded into the reaction medium relative to the compound having formula (VII).

[0709] Example 36. The method according to any one of Examples 4 to 34, wherein about 2.0 to about 5.0 molar equivalents of a base are loaded into the reaction medium relative to the compound having formula (VII).

[0710] Example 37. The method according to any one of Examples 4 to 34, wherein about 2.4 to about 3.0 molar equivalents of a base are loaded into the reaction medium relative to the compound having formula (VII).

[0711] Example 38. The method according to any one of Examples 4 to 37, wherein during the contacting step, the reaction medium is maintained at a temperature from about 10 °C to about 30 °C.

[0712] Example 39. The method according to any one of Examples 4 to 38, wherein the volume of the reaction medium is about 5 to about 20 liters of reaction medium per kilogram of the compound having formula (VII) loaded into the reaction medium.

[0713] Example 40. The method according to any one of Examples 4 to 39, wherein the contacting step is carried out as a batch reaction.

[0714] Example 41. The method according to Example 40, wherein at least about 25 kg of the compound having formula (VII) are loaded into the batch reaction.

[0715] Example 42. The method according to Example 40, wherein at least about 50 kg of the compound having formula (VII) are loaded into the batch reaction.

[0716] Example 43. The method according to Example 40, wherein at least about 75 kg of the compound having formula (VII) are loaded into the batch reaction.

[0717] Example 44. The method according to Example 40, wherein at least about 100 kg of the compound having formula (VII) are loaded into the batch reaction.

[0718] Example 45. The method according to any one of Examples 4 to 44, wherein the compound having formula (VIII) is separated from the organic phase by crystallization.

[0719] Example 46. The method according to 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 crystalline mixture comprising a compound of formula (VIII).

[0720] Example 47. The method according to Example 46, wherein the method further comprises crystallizing the compound of formula (VIII) from the crystalline mixture.

[0721] Example 48. The method according to Example 47, wherein the crystalline mixture is seeded with a crystalline form of the compound of formula (VIII).

[0722] Example 49. The method according to Example 48, wherein the crystalline mixture is seeded with at least about 0.01 relative weight of the crystalline form.

[0723] Example 50. The method according to Example 49, wherein the crystalline mixture is seeded with at least about 0.03 relative weight of the crystalline form.

[0724] Example 51. The method according to any one of Examples 48 to 50, wherein the crystalline form is an anhydrous crystalline form.

[0725] Example 52. The method according to any one of Examples 46 to 51, wherein the organic phase solvent comprises a polar solvent.

[0726] Example 53. The method according to any one of Examples 46 to 51, wherein the organic phase solvent comprises at least one solvent selected from the group consisting of chlorinated hydrocarbons and ethers.

[0727] Example 54. The method according to 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.

[0728] Example 55. The method according to any one of Examples 46 to 51, wherein the organic phase solvent comprises dichloromethane.

[0729] Example 56. The method according to any one of Examples 46 to 55, wherein the replacement solvent comprises an alcohol.

[0730] Example 57. The method according to any one of Examples 46 to 55, wherein the replacement solvent comprises ethanol.

[0731] Example 58. The method according to any one of Examples 46 to 51, wherein the organic phase solvent comprises a polar solvent and the alternative solvent comprises an alcohol.

[0732] Example 59. The method according to any one of Examples 46 to 51, wherein the organic phase solvent comprises dichloromethane and the alternative solvent comprises ethanol.

[0733] Example 60. The method according to any one of Examples 46 to 51, wherein the boiling point of the organic phase solvent is lower than the boiling point of the alternative solvent.

[0734] Example 61. The method according to Example 60, wherein the boiling point of the organic phase solvent is at least about 20 °C lower than the boiling point of the alternative solvent.

[0735] Example 62. The method according to any one of Examples 46 to 61, wherein the organic phase solvent is replaced with the alternative solvent by continuous horizontal distillation.

[0736] Example 63. The method according to Example 62, wherein the continuous horizontal distillation during continuous distillation is carried out under conditions sufficient to maintain the compound of formula (VIII) in the solution.

[0737] Example 64. The method according to Example 62 or 63, wherein the continuous horizontal distillation is continuous horizontal vacuum distillation.

[0738] Example 65. The method according to any one of Examples 62 to 64, wherein the alternative solvent is loaded during distillation in an amount sufficient to maintain at least about 15 relative volumes of total solvent / kg of the compound of formula (VIII).

[0739] Example 66. The method according to any one of Examples 62 to 64, wherein the alternative solvent is loaded during distillation in an amount sufficient to maintain at least about 18 relative volumes of total solvent / kg of the compound of formula (VIII).

[0740] Example 67. The method according to any one of Examples 62 to 66, wherein the continuous horizontal vacuum distillation is carried out at a temperature not exceeding about 60 °C.

[0741] Example 68. The method according to any one of Examples 46 to 67, wherein the crystallization mixture is inoculated 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 inoculation.

[0742] Example 69. The method according to any one of Examples 46 to 68, wherein the crystallization mixture is cooled to a temperature of about 20 °C over a period of at least five hours before separating the compound of formula (VIII).

[0743] Example 70. The method according to any one of Examples 1 to 69, wherein the stoichiometric process yield of the compound of formula (VIII) is at least about 50%.

[0744] Example 71. The method according to any one of Examples 1 to 69, wherein the stoichiometric process yield of the compound of formula (VIII) is at least about 60%.

[0745] Example 72. A crystalline form of a compound having the structure of formula (VII):

[0746]

[0747] wherein the crystalline form is characterized by a powder X-ray diffraction pattern that includes 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.

[0748] Example 73. A method for preparing a compound having the structure of formula (VII):

[0749]

[0750] or a salt thereof, wherein the method comprises:

[0751] contacting a compound having the structure of formula (V)

[0752]

[0753] or a salt thereof, with a compound having the structure of formula (VI):

[0754]

[0755] 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;

[0756] 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

[0757] separating the compound of formula (VII), or a salt thereof, from the substantially anhydrous mixture.

[0758] Example 74. The method according to Example 73, wherein the separating step comprises filtering the substantially anhydrous mixture.

[0759] Example 75. The method according to Example 73 or 74, wherein the aqueous reaction medium further comprises an alkali metal halide.

[0760] Example 76. The method according to Example 73 or 74, wherein the aqueous reaction medium further comprises an alkali metal iodide.

[0761] Example 77. The method according to Example 73 or 74, wherein the aqueous reaction medium further comprises potassium iodide.

[0762] Example 78. The method according to any one of Examples 73 to 77, wherein the organic solvent comprises at least one solvent selected from the group consisting of aromatic hydrocarbons, alcohols, ketones, ethers, esters, and nitriles.

[0763] Example 79. The method according to any one of Examples 73 to 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.

[0764] Example 80. The method according to any one of Examples 73 to 77, wherein the organic solvent comprises 2-butanol.

[0765] Example 81. The method according to any one of Examples 73 to 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, methyldicyclohexylamine, and potassium phosphate.

[0766] Example 82. The method according to any one of Examples 73 to 80, wherein the base comprises triethylamine.

[0767] Example 83. The method according to any one of Examples 73 to 80, wherein the base comprises potassium carbonate.

[0768] Example 84. The method according to any one of Examples 73 to 80, wherein the base comprises triethylamine and potassium carbonate.

[0769] Example 85. The method according to any one of Examples 73 to 84, wherein the palladium catalyst comprises bis(tert-butylbicyclohexylphosphine)palladium(II) dichloride.

[0770] Example 86. The method according to any one of Examples 73 to 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).

[0771] Example 87. The method according to any one of Examples 73 to 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).

[0772] Example 88. The method according to any one of Examples 73 to 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).

[0773] Example 89. The method according to any one of Examples 77 to 88, wherein about 0.1 to about 1.0 molar equivalent of potassium iodide is loaded into the aqueous reaction medium relative to the compound of formula (VI).

[0774] Example 90. The method according to any one of Examples 77 to 88, wherein about 0.2 to about 0.4 molar equivalent of potassium iodide is loaded into the aqueous reaction medium relative to the compound of formula (VI).

[0775] Example 91. The method according to any one of Examples 73 to 90, wherein about 0.5 to about 10 molar equivalents of a base is loaded into the aqueous reaction medium relative to the compound of formula (VI).

[0776] Example 92. The method according to any one of Examples 73 to 90, wherein the base comprises triethylamine and about 0.5 to about 10 molar equivalents of triethylamine is loaded into the aqueous reaction medium relative to the compound of formula (VI).

[0777] Example 93. The method according to any one of Examples 73 to 90, wherein the base comprises triethylamine and about 1.0 to about 2.0 molar equivalents of triethylamine is loaded into the aqueous reaction medium relative to the compound of formula (VI).

[0778] Example 94. The method according to any one of Examples 73 to 90, wherein the base comprises potassium carbonate and about 0.5 to about 10.0 molar equivalents of potassium carbonate is loaded into the aqueous reaction medium relative to the compound of formula (VI).

[0779] Example 95. The method according to any one of Examples 73 to 90, wherein relative to the compound of formula (VI), the base comprises potassium carbonate and about 2.0 to about 3.0 molar equivalents of potassium carbonate are loaded into the aqueous reaction medium.

[0780] Example 96. The method according to any one of Examples 73 to 90, wherein relative to the compound of formula (VI), the base comprises potassium carbonate and about 2.3 to about 2.7 molar equivalents of potassium carbonate are loaded into the aqueous reaction medium.

[0781] Example 97. The method according to any one of Examples 73 to 96, wherein relative to the compound of formula (VI), about 0.002 to about 0.05 molar equivalents of a palladium catalyst are loaded into the aqueous reaction medium.

[0782] Example 98. The method according to any one of Examples 73 to 96, wherein relative to the compound of formula (VI), about 0.007 to about 0.013 molar equivalents of a palladium catalyst are loaded into the aqueous reaction medium.

[0783] Example 99. The method according to any one of Examples 73 to 98, wherein during the contacting step, the aqueous reaction medium is maintained at a temperature from about 50 °C to about 100 °C.

[0784] Example 100. The method according to any one of Examples 73 to 98, wherein during the contacting step, the aqueous reaction medium is maintained at a temperature from about 70 °C to about 90 °C.

[0785] Example 101. The method according to any one of Examples 73 to 100, wherein the volume of the aqueous reaction medium is about 10 to about 20 liters of aqueous reaction medium per kilogram of the compound of formula (VI) loaded into the aqueous reaction medium.

[0786] Example 102. The method according to any one of Examples 73 to 101, wherein for the aqueous reaction medium, the volume ratio of water to organic solvent is about 1:3 to about 3:1.

[0787] Example 103. The method according to any one of Examples 73 to 101, wherein the contacting step is carried out as a batch reaction.

[0788] Example 104. The method according to Example 103, wherein at least about 25 kg of the compound of formula (VI) are loaded into the batch reaction.

[0789] Example 105. The method according to Example 103, wherein at least about 50 kg of the compound of formula (VI) are loaded into the batch reaction.

[0790] Example 106. The method according to Example 103, wherein at least about 75 kilograms of the compound of formula (VI) is loaded into the batch reaction.

[0791] Example 107. The method according to Example 103, wherein at least about 100 kilograms of the compound of formula (VI) is loaded into the batch reaction.

[0792] Example 108. The method according to any one of Examples 73 to 107, wherein the reducing step comprises separating the reaction mixture into an aqueous waste phase and an organic phase comprising the compound of formula (VII).

[0793] Example 109. The method according to Example 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 providing a substantially anhydrous mixture.

[0794] Example 110. The method according to Example 109, wherein the method further comprises washing the organic phase with water before distillation.

[0795] Example 111. The method according to any one of Examples 109 or 110, wherein the organic phase is treated with a silica scavenger before distillation.

[0796] Example 112. The method according to any one of Examples 109 to 111, wherein the organic phase is treated with a silica scavenger for a period of at least two hours before distillation.

[0797] Example 113. The method according to Example 111 or 112, wherein the silica scavenger comprises propanethiol-functionalized silica.

[0798] Example 114. The method according to Example 111 or 112, wherein the silica scavenger comprises QuadraSil TM MP.

[0799] Example 115. The method according to any one of Examples 111 to 114, wherein the method further comprises removing the silica scavenger from the organic phase before distillation.

[0800] Example 116. The method according to any one of Examples 111 to 114, wherein the method further comprises removing the silica scavenger from the organic phase by filtration before distillation.

[0801] Example 117. The method as described in Example 115 or 116, wherein the method further comprises washing the organic phase with an aqueous brine solution after removing the catalyst and before distillation.

[0802] Example 118. The method as described in any one of Examples 109 to 117, wherein the reducing step comprises:

[0803] Separating the reaction mixture into an aqueous waste phase and an organic phase comprising a compound of formula (VII);

[0804] Washing the organic phase with water;

[0805] Treating the organic phase with a silica scavenger;

[0806] Removing the silica scavenger from the organic phase;

[0807] Washing the organic phase with an aqueous brine solution; and

[0808] Distilling the organic phase under conditions sufficient to reduce the amount of water present in the organic phase.

[0809] Example 119. The method as described in any one of Examples 109 to 118, wherein the organic phase is distilled by vacuum distillation.

[0810] Example 120. The method as described in any one of Examples 109 to 118, wherein the organic phase is distilled by continuous horizontal vacuum distillation.

[0811] Example 121. The method as described in any one of Examples 109 to 120, wherein the organic phase is distilled at a temperature not exceeding about 60 °C.

[0812] Example 122. The method as described in any one of Examples 109 to 120, wherein the organic phase is distilled at a temperature from about 50 °C to about 60 °C.

[0813] Example 123. The method as described in any one of Examples 109 to 122, wherein the organic phase comprises an alcohol.

[0814] Example 124. The method as described in Example 123, wherein the organic phase is supplemented with an alcohol during the distillation step.

[0815] Example 125. The method as described in any one of Examples 109 to 122, wherein the organic phase comprises 2-butanol.

[0816] Example 126. The method as described in Example 125, wherein the organic phase is supplemented with 2-butanol during the distillation step.

[0817] Example 127. The method according to any one of Examples 73 to 126, wherein the substantially anhydrous mixture comprises less than about 5% by weight of water.

[0818] Example 128. The method according to any one of Examples 73 to 126, wherein the substantially anhydrous mixture comprises less than about 3% by weight of water.

[0819] Example 129. The method according to any one of Examples 73 to 128, wherein the separation step comprises crystallizing the compound of formula (VII) from the substantially anhydrous mixture.

[0820] Example 130. The method according to Example 129, wherein the substantially anhydrous mixture is seeded with a crystalline form of the compound of formula (VII).

[0821] Example 131. The method according to Example 129 or 130, wherein after the start of crystallization, the substantially anhydrous mixture is maintained at a temperature of at least about 70 °C for a period of at least two hours.

[0822] Example 132. The method according to Example 129 or 130, wherein after the start of crystallization, the substantially anhydrous mixture is maintained at a temperature of at least about 70 °C for a period of at least two hours and then cooled to crystallize the compound of formula (VII).

[0823] Example 133. The method according to any one of Examples 73 to 132, wherein the stoichiometric method yield of the compound of formula (VII) is at least about 50%.

[0824] Example 134. The method according to any one of Examples 73 to 132, wherein the stoichiometric method yield of the compound of formula (VII) is at least about 65%.

[0825] Example 135. The method according to any one of Examples 73 to 132, wherein the stoichiometric method yield of the compound of formula (VII) is at least about 75%.

[0826] Example 136. A method for preparing a compound having the structure of formula (VI):

[0827]

[0828] or a salt thereof, wherein the method comprises:

[0829] reacting a compound of formula (IV):

[0830]

[0831] or a salt thereof, is contacted with an acidic medium under conditions sufficient to deprotect a compound of formula (IV) and form a reaction mixture comprising a compound of formula (VI), or a salt thereof, and a benzyl halide by-product;

[0832] at least a portion of the benzyl halide by-product is removed from the reaction mixture; and

[0833] the compound of formula (VI), or a salt thereof, is separated from the reaction mixture under conditions sufficient to substantially avoid the formation of acetalamine impurities.

[0834] Example 137. The method according to Example 136, wherein the separation step comprises:

[0835] at least a portion of the benzyl halide by-product is removed from the reaction mixture;

[0836] the pH of the resulting reaction mixture is increased to a basic pH to form a basic reaction medium comprising a compound of formula (VI), or a salt thereof; and

[0837] the compound of formula (VI), or a salt thereof, is separated from the basic reaction mixture.

[0838] Example 138. The method according to Example 136, wherein the separation step comprises:

[0839] at least a portion of the benzyl halide by-product is extracted from the reaction mixture into a waste organic phase;

[0840] the pH of the resulting reaction mixture is increased to a basic pH to form a basic reaction medium comprising a compound of formula (VI), or a salt thereof;

[0841] the compound of formula (VI), or a salt thereof, is extracted from the basic reaction medium into a product organic phase; and

[0842] the compound of formula (VI), or a salt thereof, is separated from the product organic phase.

[0843] Example 139. The method according to any one of Examples 136 to 138, wherein the acidic medium is an aqueous acidic medium.

[0844] Example 140. The method according to any one of Examples 136 to 139, wherein a sulfate salt of the compound of formula (IV) is contacted with the acidic medium.

[0845] Example 141. The method according to any one of Examples 136 to 140, wherein the acidic medium comprises an inorganic acid.

[0846] Example 142. The method according to any one of Examples 136 to 140, wherein the acidic medium comprises hydrochloric acid.

[0847] Example 143. The method according to any one of Examples 136 to 142, wherein the acidic medium comprises at least about 10 molar equivalents of acid relative to the compound of formula (IV), or a salt thereof.

[0848] Example 144. The method according to any one of Examples 136 to 142, wherein the acidic medium comprises from about 10 to about 40 molar equivalents of acid relative to the compound of formula (IV), or a salt thereof.

[0849] Example 145. The method according to any one of Examples 136 to 142, wherein the acidic medium comprises from about 10 to about 25 molar equivalents of acid relative to the compound of formula (IV), or a salt thereof.

[0850] Example 146. The method according to any one of Examples 136 to 145, wherein the volume of the acidic medium is from about 2 liters to about 10 liters of acidic medium per kilogram of the compound of formula (IV), or a salt thereof, loaded into the acidic medium.

[0851] Example 147. The method according to any one of Examples 136 to 145, wherein the volume of the acidic medium is from about 3 liters to about 4 liters of acidic medium per kilogram of the compound of formula (IV), or a salt thereof, loaded into the acidic medium.

[0852] Example 148. The method according to any one of Examples 136 to 147, wherein during the contacting step, the acidic medium is maintained at a temperature from about 25 °C to about 70 °C.

[0853] Example 149. The method according to any one of Examples 136 to 147, wherein during the contacting step, the acidic medium is maintained at a temperature from about 40 °C to about 50 °C.

[0854] Example 150. The method according to any one of Examples 136 to 149, wherein the contacting step is carried out as a batch reaction.

[0855] Example 151. The method according to Example 150, wherein at least about 50 kg of the compound of formula (IV) is loaded into the batch reaction.

[0856] Example 152. The method according to Example 150, wherein at least about 100 kg of the compound of formula (IV) is loaded into the batch reaction.

[0857] Example 153. The method according to Example 150, wherein at least about 200 kg of the compound of formula (IV) is loaded into the batch reaction.

[0858] Example 154. The method according to Example 150, wherein at least about 300 kg of the compound of formula (IV) is loaded into the batch reaction.

[0859] Example 155. The method according to any one of Examples 136 to 154, wherein the method comprises selectively extracting at least a portion of the benzyl halide by-product into a waste organic phase from the reaction mixture relative to the compound of formula (VI) prior to the separation step.

[0860] Example 156. The method according to Example 155, wherein at least about 80 wt% of the benzyl halide by-product compound present in the reaction mixture is extracted into the waste organic phase.

[0861] Example 157. The method according to Example 155, wherein less than about 20 wt% of the compound of formula (VI) present in the reaction mixture is extracted into the waste organic phase.

[0862] Example 158. The method according to Example 155, wherein at least about 80 wt% of the benzyl halide by-product compound present in the reaction mixture and less than about 20 wt% of the compound of formula (VI) present in the reaction mixture are extracted into the waste organic phase.

[0863] Example 159. The method according to Example 155, wherein at least about 90 wt% of the benzyl halide by-product compound present in the reaction mixture and less than about 10 wt% of the compound of formula (VI) present in the reaction mixture are extracted into the waste organic phase.

[0864] Example 160. The method according to Example 155, wherein at least about 95 wt% of the benzyl halide by-product compound present in the reaction mixture and less than about 5 wt% of the compound of formula (VI) present in the reaction mixture are extracted into the waste organic phase.

[0865] Example 161. The method according to any one of Examples 155 to 160, wherein the waste organic phase comprises at least one solvent selected from the group consisting of alkyl hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons, and ethers.

[0866] Example 162. The method according to any one of Examples 155 to 160, wherein the discarded organic phase comprises at least one compound selected from the group consisting of pentane, hexane, heptane, octane, nonane, toluene, dichloromethane, methyl tert-butyl ether, and 2-methyltetrahydrofuran.

[0867] Example 163. The method according to any one of Examples 155 to 160, wherein the discarded organic phase comprises heptane.

[0868] Example 164. The method according to any one of Examples 155 to 163, wherein the method further comprises:

[0869] increasing the pH of the reaction mixture after the extraction of the benzyl halide by-product to form a basic reaction medium comprising the compound of formula (VI), or a salt thereof; and

[0870] extracting the compound of formula (VI), or a salt thereof, from the basic reaction medium into a product organic phase.

[0871] Example 165. The method according to Example 164, wherein the pH of the basic reaction mixture is at least about 8.0.

[0872] Example 166. The method according to Example 164, wherein the pH of the basic reaction mixture is at least about 10.0.

[0873] Example 167. The method according to any one of Examples 164 to 166, wherein the product organic phase comprises at least one solvent selected from the group consisting of alkyl hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons, and ethers.

[0874] Example 168. The method according to any one of Examples 164 to 166, wherein the product organic phase comprises at least one compound selected from the group consisting of dichloromethane, 2-methyltetrahydrofuran, and anisole.

[0875] Example 169. The method according to any one of Examples 164 to 166, wherein the product organic phase comprises 2-methyltetrahydrofuran.

[0876] Example 170. The method according to any one of Examples 164 to 169, wherein the method further comprises washing the product organic phase with water.

[0877] Example 171. The method according to any one of Examples 164 to 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.

[0878] Example 172. The method according to Example 171, wherein the product organic phase comprises 2-methyltetrahydrofuran and additional 2-methyltetrahydrofuran is loaded into the product organic phase during the distillation step.

[0879] Example 173. The method according to Example 171 or 172, wherein the product organic phase is distilled at atmospheric pressure.

[0880] Example 174. The method according to any one of Examples 136 to 173, wherein the separation step comprises crystallizing the compound of formula (VI).

[0881] Example 175. The method according to Example 174, wherein the separation step further comprises seeding with a crystalline form of the compound of formula (VI) to facilitate crystallization.

[0882] Example 176. The method according to Example 174, wherein the separation step comprises seeding with at least about 0.0005 relative weight of a crystalline form of the compound of formula (VI) to facilitate crystallization.

[0883] Example 177. The method according to Example 174, wherein the separation step comprises seeding with at least about 0.001 relative weight of a crystalline form of the compound of formula (VI) to facilitate crystallization.

[0884] Example 178. The method according to any one of Examples 175 to 177, wherein the method further comprises loading an anti-solvent to facilitate crystallization.

[0885] Example 179. The method according to Example 178, wherein the anti-solvent is heptane.

[0886] Example 180. The method according to Example 136, wherein the separation step comprises:

[0887] selectively extracting at least a portion of the benzyl halide by-product from the reaction mixture into a waste organic phase relative to the compound of formula (VI);

[0888] increasing the pH of the resulting reaction mixture to a pH greater than about 7.0 to form a basic reaction mixture;

[0889] selectively pre-extracting at least a portion of the compound of formula (VI) from the basic reaction mixture into a product organic phase; and

[0890] 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 (VI).

[0891] Example 181. The method according to Example 180, wherein the method further comprises crystallizing the compound of formula (VI) from the distilled organic phase.

[0892] Example 182. The method according to any one of Examples 136 to 181, wherein the acetalamine impurity comprises a compound having the structure of formula (X):

[0893]

[0894] or a salt thereof.

[0895] Example 183. The method according to any one of Examples 136 to 182, wherein the separated compound of formula (VI), or a salt thereof, comprises less than 5% by weight of acetalamine impurities.

[0896] Example 184. The method according to any one of Examples 136 to 182, wherein the separated compound of formula (VI), or a salt thereof, comprises less than 3% by weight of acetalamine impurities.

[0897] Example 185. The method according to any one of Examples 136 to 182, wherein the separated compound of formula (VI), or a salt thereof, comprises less than 1% by weight of acetalamine impurities.

[0898] Example 186. The method according to any one of Examples 136 to 185, wherein the stoichiometric method yield of the compound of formula (VI) is at least about 50%.

[0899] Example 187. The method according to any one of Examples 136 to 185, wherein the stoichiometric method yield of the compound of formula (VI) is at least about 65%.

[0900] Example 188. The method according to any one of Examples 136 to 185, wherein the stoichiometric method yield of the compound of formula (VI) is at least about 80%.

[0901] Example 189. A method for preparing a compound having the structure of formula (V):

[0902]

[0903] 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, and then 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.

[0904] Example 190. The method according to Example 189, wherein the method further comprises separating a compound of formula (V), or a salt thereof, from the reaction mixture.

[0905] Example 191. The method according to Example 189 or 190, wherein the catalyst comprises tetrabutylammonium chloride.

[0906] Example 192. The method according to Example 189 or 190, wherein the catalyst comprises N-methyltoluidine.

[0907] Example 193. The method according to Example 189 or 190, wherein the catalyst does not comprise N,N-dimethylformamide.

[0908] Example 194. The method according to any one of Examples 189 to 193, wherein the reaction medium does not comprise N,N-dimethylformamide.

[0909] Example 195. The method according to any one of Examples 189 to 194, wherein the organic solvent comprises at least one solvent selected from the group consisting of aromatic hydrocarbons, aromatic heterocycles, and nitriles.

[0910] Example 196. The method according to any one of Examples 189 to 194, wherein the organic solvent comprises a compound selected from the group consisting of toluene, acetonitrile, and pyridine.

[0911] Example 197. The method according to any one of Examples 189 to 194, wherein the organic solvent comprises toluene.

[0912] Example 198. The method according to any one of Examples 189 to 197, wherein the volume of the reaction medium is from about 3 liters to about 30 liters of reaction medium per kilogram of 4-carboxyphenylboronic acid, or a salt thereof, loaded into the reaction medium.

[0913] Example 199. The method according to any one of Examples 189 to 197, wherein the volume of the reaction medium is from about 5 liters to about 15 liters of reaction medium per kilogram of 4-carboxyphenylboronic acid, or a salt thereof, loaded into the reaction medium.

[0914] Example 200. The method according to any one of Examples 189 to 199, wherein during the contacting step, the reaction medium is maintained at a temperature from about 50 °C to about 90 °C.

[0915] Example 201. The method according to any one of Examples 189 to 199, wherein during the contacting step, the reaction medium is maintained at a temperature from about 60 °C to about 80 °C.

[0916] Example 202. The method according to any one of Examples 189 to 201, wherein the contacting step is carried out as a batch reaction.

[0917] Example 203. The method according to 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.

[0918] Example 204. The method according to 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.

[0919] Example 205. The method according to 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.

[0920] Example 206. The method according to any one of Examples 189 to 205, wherein about 1.5 to about 5 molar equivalents of 2-aminopyridine are loaded into the reaction medium relative to 4-carboxyphenylboronic acid, or a salt thereof.

[0921] Example 207. The method according to any one of Examples 189 to 205, wherein about 1.5 to about 3.5 molar equivalents of 2-aminopyridine are loaded into the reaction medium relative to 4-carboxyphenylboronic acid, or a salt thereof.

[0922] Example 208. The method according to any one of Examples 189 to 205, wherein about 2 molar equivalents of 2-aminopyridine are loaded into the reaction medium relative to 4-carboxyphenylboronic acid, or a salt thereof.

[0923] Example 209. The method according to any one of Examples 189 to 208, wherein the stoichiometric method yield of the compound having the formula (V) is at least about 50%.

[0924] Example 210. The method according to any one of Examples 189 to 208, wherein the stoichiometric method yield of the compound having the formula (V) is at least about 70%.

[0925] Example 211. A crystalline sulfate of a compound having the structure of formula (IV):

[0926]

[0927] Example 212. The crystalline sulfate as described in Example 211, wherein the crystalline sulfate has a stoichiometric ratio of one sulfate molecule and one bisulfate molecule to three free base molecules.

[0928] Example 213. The crystalline sulfate as described in Example 211 or 212, wherein the crystalline sulfate is characterized by a powder X-ray 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.

[0929] Example 214. A method for preparing a sulfate of a compound having the structure of formula (IV):

[0930]

[0931] wherein the method comprises:

[0932] contacting a compound having the structure of formula (III)

[0933]

[0934] 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);

[0935] forming a sulfate of the compound having the structure of formula (IV); and

[0936] isolating the sulfate.

[0937] Example 215. The method as described in Example 214, wherein the sulfate has a stoichiometric ratio of one sulfate molecule and one bisulfate molecule to three free base molecules.

[0938] Example 216. The method as described in Example 214 or 215, wherein the method comprises separating the compound having the structure of formula (IV) as a free base from the reaction mixture before the forming step.

[0939] Example 217. The method as described in Example 214 or 215, wherein the method comprises:

[0940] separating the compound having the structure of formula (IV) as a free base from the reaction medium;

[0941] contacting the free base with sulfuric acid to form the sulfate; and

[0942] isolating the sulfate.

[0943] Example 218. The method according to Example 214 or 215, wherein the method comprises:

[0944] washing the reaction mixture to reduce the amount of ammonia present in the reaction mixture;

[0945] separating the compound of formula (IV) as a free base from the washed reaction medium;

[0946] contacting the free base with sulfuric acid to form the sulfate; and

[0947] separating the sulfate.

[0948] Example 219. The method according to Example 214 or 215, wherein the method comprises:

[0949] washing the reaction mixture with a brine solution;

[0950] distilling the washed reaction mixture to reduce the amount of ammonia present in the washed reaction mixture;

[0951] separating the compound of formula (IV) as a free base from the distilled reaction medium;

[0952] contacting the free base with sulfuric acid to form the sulfate; and

[0953] separating the sulfate.

[0954] Example 220. The method according to any one of Examples 214 to 219, wherein the method further comprises separating the sulfate by filtration.

[0955] Example 221. The method according to any one of Examples 214 to 220, wherein the aminating agent is ammonia.

[0956] Example 222. The method according to any one of Examples 214 to 220, wherein the aminating agent is ammonium hydroxide.

[0957] Example 223. The method according to 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.

[0958] Example 224. The method according to 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.

[0959] Example 225. The method according to any one of Examples 214 to 221, wherein the reaction medium comprises a fatty alcohol.

[0960] Example 226. The method according to any one of Examples 214 to 221, wherein the reaction medium comprises butanol.

[0961] Example 227. The method according to any one of Examples 214 to 221, wherein the reaction medium comprises 2-butanol.

[0962] Example 228. The method according to any one of Examples 214 to 227, wherein during the contacting step, the reaction medium is maintained at a temperature higher than 70 °C.

[0963] Example 229. The method according to any one of Examples 214 to 227, wherein during the contacting step, the reaction medium is maintained at a temperature higher than 90 °C.

[0964] Example 230. The method according to any one of Examples 214 to 227, wherein during the contacting step, the reaction medium is maintained at a temperature from about 50 °C to about 100 °C.

[0965] Example 231. The method according to any one of Examples 214 to 227, wherein during the contacting step, the reaction medium is maintained at a temperature from about 60 °C to about 95 °C.

[0966] Example 232. The method according to any one of Examples 214 to 231, wherein the volume of the reaction medium is from about 1.5 liters to about 40 liters of reaction medium per kilogram of the compound of formula (III), or a salt thereof, loaded into the reaction medium.

[0967] Example 233. The method according to any one of Examples 214 to 231, wherein the volume of the reaction medium is from about 2.0 liters to about 30 liters of reaction medium per kilogram of the compound of formula (III), or a salt thereof, loaded into the reaction medium.

[0968] Example 234. The method according to any one of Examples 214 to 233, wherein the contacting step is carried out as a batch reaction.

[0969] Example 235. The method according to Example 234, wherein at least about 50 kg of the compound of formula (III) is loaded into the batch reaction.

[0970] Example 236. The method according to Example 234, wherein at least about 100 kg of the compound of formula (III) is loaded into the batch reaction.

[0971] Example 237. The method according to Example 234, wherein at least about 200 kg of the compound of formula (III) is loaded into the batch reaction.

[0972] Example 238. The method according to Example 234, wherein at least about 300 kg of the compound of formula (III) is loaded into the batch reaction.

[0973] Example 239. The method according to any one of Examples 214 to 238, wherein the forming step comprises contacting a compound of formula (IV) with sulfuric acid to form a sulfate mixture comprising the sulfate.

[0974] Example 240. The method according to Example 239, wherein the compound of formula (IV) is contacted with at least about 0.5 molar equivalent of sulfuric acid relative to the compound of formula (III).

[0975] Example 241. The method according to Example 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).

[0976] Example 242. The method according to any one of Examples 214 to 241, wherein the stoichiometric method yield of the sulfate of formula (IV) is at least about 50%.

[0977] Example 243. The method according to any one of Examples 214 to 241, wherein the stoichiometric method yield of the sulfate of formula (IV) is at least about 65%.

[0978] Example 244. The method according to any one of Examples 214 to 241, wherein the stoichiometric method yield of the sulfate of formula (IV) is at least about 80%.

[0979] Example 245. A method for preparing a compound having the structure of formula (II):

[0980]

[0981] or a salt thereof, wherein the method comprises:

[0982] contacting a compound having the structure of formula (I)

[0983]

[0984] or a salt thereof, with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound of formula (II), or a salt thereof;

[0985] Wherein during the contacting step, the temperature of the reaction medium is controlled in a manner sufficient to maintain at least about 80% chiral purity of the compound of formula (II), or a salt thereof.

[0986] Example 246. The method according to Example 245, wherein the cyclizing agent comprises phosphorus oxychloride.

[0987] Example 247. The method according to Example 245 or 246, wherein the catalyst comprises a catalyst selected from the group consisting of N,N-dimethylformamide and N-methyltoluidine.

[0988] Example 248. The method according to Example 245 or 246, wherein the catalyst comprises N,N-dimethylformamide.

[0989] Example 249. The method according to any one of Examples 245 to 248, wherein the reaction medium comprises at least one solvent selected from the group consisting of aromatic hydrocarbons, chlorinated hydrocarbons, ethers, and nitriles.

[0990] Example 250. The method according to any one of Examples 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.

[0991] Example 251. The method according to any one of Examples 245 to 248, wherein the reaction medium comprises acetonitrile.

[0992] Example 252. The method according to any one of Examples 245 to 251, wherein the compound of formula (I) or a 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 a salt thereof.

[0993] Example 253. The method according to any one of Examples 245 to 251, wherein the compound of formula (I) or a salt thereof is contacted with about 1.5 to about 2.5 molar equivalents of the cyclizing agent, relative to the compound of formula (I) or a salt thereof.

[0994] Example 254. The method according to any one of Examples 245 to 251, wherein the compound of formula (I) or a salt thereof is contacted with about 2.0 molar equivalents of the cyclizing agent, relative to the compound of formula (I) or a salt thereof.

[0995] Example 255. The method according to any one of Examples 245 to 254, wherein at least about 0.1 molar equivalent of the catalyst is loaded into the reaction medium, relative to the compound of formula (I) or a salt thereof.

[0996] Example 256. The method according to any one of Examples 245 to 254, wherein from about 0.1 to about 1.0 molar equivalent of the catalyst is loaded into the reaction medium relative to the compound of formula (I) or a salt thereof.

[0997] Example 257. The method according to any one of Examples 245 to 254, wherein at least about 0.4 molar equivalent of the catalyst is loaded into the reaction medium relative to the compound of formula (I) or a salt thereof.

[0998] Example 258. The method according to any one of Examples 245 to 254, wherein from about 0.4 to about 1.0 molar equivalent of the catalyst is loaded into the reaction medium relative to the compound of formula (I) or a salt thereof.

[0999] Example 259. The method according to any one of Examples 245 to 254, wherein the catalyst comprises N,N-dimethylformamide, and at least about 0.1 molar equivalent of the catalyst is loaded into the reaction medium relative to the compound of formula (I) or a salt thereof.

[1000] Example 260. The method according to any one of Examples 245 to 254, wherein the catalyst comprises N,N-dimethylformamide, and from about 0.1 to about 1.0 molar equivalent of the catalyst is loaded into the reaction medium relative to the compound of formula (I), or a salt thereof.

[1001] Example 261. The method according to any one of Examples 245 to 254, wherein the catalyst comprises N,N-dimethylformamide, and at least about 0.4 molar equivalent of the catalyst is loaded into the reaction medium relative to the compound of formula (I) or a salt thereof.

[1002] Example 262. The method according to any one of Examples 245 to 254, wherein the catalyst comprises N,N-dimethylformamide, and from about 0.4 to about 1.0 molar equivalent of the catalyst is loaded into the reaction medium relative to the compound of formula (I) or a salt thereof.

[1003] Example 263. The method according to any one of Examples 245 to 254, wherein the catalyst comprises N,N-dimethylformamide, and at least about 0.6 molar equivalent of the catalyst is loaded into the reaction medium relative to the compound of formula (I) or a salt thereof.

[1004] Example 264. The method according to any one of Examples 245 to 254, wherein the catalyst comprises N,N-dimethylformamide, and about 0.6 molar equivalents of the catalyst are loaded into the reaction medium relative to the compound of formula (I) or a salt thereof.

[1005] Example 265. The method according to any one of Examples 245 to 264, wherein during the contacting step, the temperature of the reaction medium is controlled in a manner sufficient to maintain at least about 90% chiral purity of the compound of formula (II) or a salt thereof.

[1006] Example 266. The method according to any one of Examples 245 to 264, wherein during the contacting step, the temperature of the reaction medium is controlled in a manner sufficient to maintain at least about 95% chiral purity of the compound of formula (II) or a salt thereof.

[1007] Example 267. The method according to any one of Examples 245 to 266, wherein during the contacting step, the reaction medium is maintained at a temperature of less than about 80 °C.

[1008] Example 268. The method according to any one of Examples 245 to 266, wherein during the contacting step, the reaction medium is maintained at a temperature of less than about 50 °C.

[1009] Example 269. The method according to any one of Examples 245 to 266, wherein during the contacting step, the reaction medium is maintained at a temperature from about 30 °C to about 50 °C.

[1010] Example 270. The method according to any one of Examples 245 to 269, wherein during the contacting step, the reaction medium is maintained at a temperature of about 40 °C.

[1011] Example 271. The method according to any one of Examples 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 a salt thereof loaded into the reaction medium.

[1012] Example 272. The method according to any one of Examples 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 a salt thereof loaded into the reaction medium.

[1013] Example 273. The method according to any one of Examples 245 to 272, wherein the contacting step is carried out as a batch reaction.

[1014] Example 274. The method according to Example 273, wherein at least about 50 kg of the compound of formula (I) is loaded into the batch reaction.

[1015] Example 275. The method according to Example 273, wherein at least about 100 kg of the compound of formula (I) is loaded into the batch reaction.

[1016] Example 276. The method according to Example 273, wherein at least about 200 kg of the compound of formula (I) is loaded into the batch reaction.

[1017] Example 277. The method according to Example 273, wherein at least about 300 kg of the compound of formula (I) is loaded into the batch reaction.

[1018] Example 278. The method according to any one of Examples 245 to 277, wherein the stoichiometric method yield of the compound of formula (II) is at least about 50%.

[1019] Example 279. The method according to any one of Examples 245 to 277, wherein the stoichiometric method yield of the compound of formula (II) is at least about 65%.

[1020] Example 280. The method according to any one of Examples 245 to 277, wherein the stoichiometric method yield of the compound of formula (II) is at least about 80%.

[1021] Example 281. A method for preparing a compound having the structure of formula (III):

[1022]

[1023] or a salt thereof, wherein the method comprises:

[1024] contacting a compound having the structure of formula (I)

[1025]

[1026] or a salt thereof, with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound having formula (II);

[1027]

[1028] or a salt thereof; and

[1029] brominating the compound of formula (II), or a salt thereof, with a brominating agent to provide a compound having the structure of formula (III):

[1030]

[1031] or a salt thereof;

[1032] wherein during the contacting step, the temperature of the reaction medium is controlled in a manner sufficient to maintain at least about 80% chiral purity of the compound of formula (II) or a salt thereof.

[1033] Example 282. The method according to Example 281, wherein the brominating agent comprises N-bromosuccinimide.

[1034] Example 283. The method according to Example 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.

[1035] Example 284. The method according to any one of Examples 281 to 283, wherein the compound of formula (II) or a salt thereof is separated from the reaction medium before the bromination step.

[1036] Example 285. The method according to Example 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 chlorinated hydrocarbons and polar aprotic solvents.

[1037] Example 286. The method according to Example 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-methylpyrrolidone, N-butylpyrrolidone, dimethyl sulfoxide, dimethylacetamide, and dichloromethane.

[1038] Example 287. The method according to Example 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.

[1039] Example 288. The method according to Example 284, wherein the compound of formula (II) or a salt thereof is contacted with the brominating agent in a bromination medium comprising N-methylpyrrolidone.

[1040] Example 289. The method according to any one of Examples 284 to 288, wherein during the bromination step, the bromination medium is maintained at a temperature from about 5 °C to about 40 °C.

[1041] Example 290. The method according to any one of Examples 284 to 288, wherein during the bromination step, the bromination medium is maintained at a temperature of about 20 °C.

[1042] Example 291. The method according to any one of Examples 284 to 290, wherein the bromination step is carried out as a batch reaction.

[1043] Example 292. The method according to Example 291, wherein at least about 50 kg of the compound of formula (II) is loaded into the batch reaction.

[1044] Example 293. The method according to Example 291, wherein at least about 100 kg of the compound of formula (II) is loaded into the batch reaction.

[1045] Example 294. The method according to Example 291, wherein at least about 200 kg of the compound of formula (II) is loaded into the batch reaction.

[1046] Example 295. The method according to Example 291, wherein at least about 300 kg of the compound of formula (II) is loaded into the batch reaction.

[1047] Example 296. The method according to any one of Examples 284 to 295, wherein the method comprises separating the compound of formula (III) or a salt thereof from the bromination medium.

[1048] Example 297. The method according to Example 296, wherein an aqueous solution is added to the bromination medium to separate the compound of formula (III) or a salt thereof.

[1049] Example 298. The method according to Example 296, wherein an aqueous solution having a basic pH is added to the bromination medium to separate the compound of formula (III) or a salt thereof.

[1050] Example 299. The method according to Example 296, wherein an aqueous sodium bicarbonate solution is added to the bromination mixture to separate the compound of formula (III) or a salt thereof.

[1051] Example 300. The method according to Example 299, wherein the sodium bicarbonate solution is about 1 wt% to 10 wt% sodium bicarbonate.

[1052] Example 301. The method according to Example 299, wherein the sodium bicarbonate solution is about 2 wt% sodium bicarbonate.

[1053] Example 302. The method according to any one of Examples 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 separating the compound of formula (II) or a salt thereof from the reaction mixture.

[1054] Example 303. The method according to any one of Examples 281 to 302, wherein the stoichiometric method yield of the compound having formula (III) is at least about 50%.

[1055] Example 304. The method according to any one of Examples 281 to 302, wherein the stoichiometric method yield of the compound having formula (III) is at least about 65%.

[1056] Example 305. The method according to any one of Examples 281 to 302, wherein the stoichiometric method yield of the compound having formula (III) is at least about 80%.

[1057] Example 306. The method according to Example 1, wherein the compound having formula (VII), or a salt thereof, is prepared by a method comprising:

[1058] contacting a compound having the structure of formula (V)

[1059]

[1060] or a salt thereof, with a compound having the structure of formula (VI):

[1061]

[1062] or a 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 the compound having formula (VII), or a salt thereof;

[1063] reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising the compound having formula (VII), or a salt thereof; and

[1064] separating the compound having formula (VII), or a salt thereof, from the substantially anhydrous mixture.

[1065] Example 307. The method according to Example 306, wherein the compound having formula (VI), or a salt thereof, is prepared by a method comprising:

[1066] contacting a compound having formula (IV):

[1067]

[1068] or a salt thereof, with an acidic medium under conditions sufficient to deprotect the compound having formula (IV), or a salt thereof, and forming a reaction mixture comprising the compound having formula (VI), or a salt thereof, and a benzyl halide byproduct; and

[1069] The compound of formula (VI), or a salt thereof, is separated from the reaction mixture under conditions sufficient to substantially avoid the formation of acetalamine impurities.

[1070] Example 308. The method according to Example 306, wherein the compound of formula (V), or a salt thereof, is prepared by a method comprising contacting 4-carboxyphenylboronic acid, or a salt thereof, with thionyl chloride and a catalyst in a reaction medium comprising an organic solvent to form an acyl chloride intermediate, and then 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.

[1071] Example 309. The method according to Example 306, wherein:

[1072] The compound of formula (VI), or a salt thereof, is prepared by a method comprising:

[1073] Contacting a compound of formula (IV):

[1074]

[1075] or a salt thereof, with an acidic medium under conditions sufficient to deprotect the compound of formula (IV), or a salt thereof, and form a reaction mixture comprising a compound of formula (VI), or a salt thereof, and a benzyl halide by-product; and

[1076] Separating the compound of formula (VI), or a salt thereof, from the reaction mixture under conditions sufficient to substantially avoid the formation of acetalamine impurities; and

[1077] The compound of formula (V), or a salt thereof, is prepared by a method comprising contacting 4-carboxyphenylboronic acid, or a salt thereof, with thionyl chloride and a catalyst in a reaction medium comprising an organic solvent to form an acyl chloride, and then contacting the acyl chloride in situ with 2-aminopyridine to form a reaction mixture comprising the compound of formula (V), or a salt thereof.

[1078] Example 310. The method according to any one of Examples 306 to 309, wherein the compound of formula (IV), or a salt thereof, is a sulfate; and the sulfate is prepared by a method comprising:

[1079] Contacting a compound of formula (III)

[1080]

[1081] or a salt thereof, with an aminating agent in a reaction medium to form a reaction mixture comprising the compound of formula (IV);

[1082] Forming a sulfate of the compound of formula (IV); and

[1083] Separate the sulfate.

[1084] Example 311. The method according to Example 310, wherein the compound of formula (III), or a salt thereof, is prepared by a method comprising:

[1085] Contacting a compound having the structure of formula (I)

[1086]

[1087] 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);

[1088]

[1089] or a salt thereof; and

[1090] Brominating the compound of formula (II), or a salt thereof, with a brominating agent to provide a compound having the structure of formula (III), or a salt thereof;

[1091] 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.

[1092] Example 312. A method for preparing a compound having the structure of formula (VIII):

[1093]

[1094] or a salt thereof, wherein the method comprises:

[1095] Contacting a compound having the structure of formula (V)

[1096]

[1097] or a salt thereof, with a compound having the structure of formula (VI):

[1098]

[1099] 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):

[1100]

[1101] or a salt thereof;

[1102] Reduce 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;

[1103] Isolate a compound of formula (VII), or a salt thereof, from the substantially anhydrous mixture; and

[1104] Convert a compound of formula (VII), or a salt thereof, to a compound of formula (VIII).

[1105] Example 313. A method for preparing a compound having the structure of formula (VIII):

[1106]

[1107] or a salt thereof, wherein the method comprises:

[1108] Contacting a compound having the structure of formula (IV)

[1109]

[1110] 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 having the structure of formula (VI):

[1111]

[1112] or a salt thereof, and a benzyl halide by-product;

[1113] Isolating a compound of formula (VI), or a salt thereof, from the reaction mixture under conditions sufficient to substantially avoid the formation of acetalamine impurities; and

[1114] Converting a compound of formula (VI), or a salt thereof, to a compound of formula (VIII), or a salt thereof.

[1115] Example 314. A method for preparing a compound having the structure of formula (VIII):

[1116]

[1117] or a salt thereof, wherein the method comprises:

[1118] Contacting a compound having the structure of formula (III)

[1119]

[1120] 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):

[1121]

[1122] Form a sulfate of the compound of formula (IV);

[1123] Isolate the sulfate; and

[1124] Convert the sulfate to a compound of formula (VIII), or a salt thereof.

[1125] Example 315. A method for preparing a compound having the structure of formula (VIII):

[1126]

[1127] or a salt thereof, wherein the method comprises:

[1128] Contact a compound having the structure of formula (I)

[1129]

[1130] or a salt thereof, with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound of formula (II);

[1131]

[1132] or a salt thereof;

[1133] Brominate the compound of formula (II), or a salt thereof, with a brominating agent to provide a compound having the structure of formula (III):

[1134]

[1135] or a salt thereof; and

[1136] Convert the compound of formula (III), or a salt thereof, to a compound of formula (VIII), or a salt thereof;

[1137] wherein during the contacting step, the temperature of the reaction medium is controlled in a manner sufficient to maintain at least about 80% chiral purity of the compound of formula (II), or a salt thereof.

[1138] ***********

[1139] All of the above references (patent and non-patent) are incorporated herein by reference. The discussion of these references is intended only to outline the assertions made by their authors. No admission is made that any reference (or any part of any reference) is relevant prior art (or is prior art). The applicant reserves the right to challenge the accuracy and relevance of the cited references.

Claims

1. A method for preparing a compound of formula (VIII) or a salt thereof: wherein the method comprises: contacting a compound of formula (VII) 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 the compound of formula (VIII) or a salt thereof, the unreacted compound of formula (VII) or a salt thereof, and reaction by-products; wherein the reaction by-products comprise a compound of formula (XIV): or a salt thereof; extracting 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; adjusting the pH of the aqueous phase; and extracting 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; wherein the aqueous phase has a pH from 1.8 to 2.2 during the aqueous phase extraction step; and the aqueous phase has a pH from 4.5 to 5.0 or from 7.0 to 8.5 during the organic phase extraction step.

2. The method according to claim 1, wherein the aqueous phase has a pH from 1.8 to 2.2 during the aqueous phase extraction step; and the aqueous phase has a pH from 4.5 to 5.0 during the organic phase extraction step.

3. The method according to claim 2, wherein the contacting step comprises: adding the compound of formula (VII) or a salt thereof and the base to the reaction medium; adding the 2-butynoic 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-butynoic acid or a salt thereof; and the base.

4. The method according to claim 2 or 3, wherein the method further comprises separating the compound of formula (VIII) from the organic phase into which the compound of formula (VIII) has been selectively extracted.

5. The method according to claim 2 or 3, wherein after completion of the aqueous phase extraction, as measured by high performance liquid chromatography, the aqueous phase comprises greater than 75 area % of the compound of formula (VIII) and less than 2.0 area % of the compound of formula (XIV).

6. The method according to claim 2 or 3, wherein after completion of the organic phase extraction, as measured by high performance liquid chromatography, the organic phase comprises greater than 75 area % of the compound of formula (VIII) and less than 2.0 area % of the compound of formula (VII).

7. The method according to claim 2 or 3, wherein the base comprises a compound selected from the group consisting of: triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.

8. The method according to claim 7, wherein the base comprises triethylamine.

9. The method according to claim 2 or 3, wherein the reaction medium comprises a solvent selected from the group consisting of: dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, tert-amyl alcohol, acetone, methyl isobutyl ketone, 2-butanol, methyl ethyl ketone, acetonitrile, and ethyl acetate.

10. The method according to claim 9, wherein the reaction medium comprises dichloromethane.

11. The method according to claim 2 or 3, wherein the organic phase comprises a compound selected from: dichloromethane, methyltetrahydrofuran, 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.

12. The method according to claim 11, wherein the organic phase comprises dichloromethane.

13. The method according to claim 2 or 3, wherein the compound of formula (VII) is contacted with 0.5 to 5.0 molar equivalents of 2-butyric acid relative to the compound of formula (VII).

14. The method according to claim 2 or 3, wherein 0.3 to 3.0 molar equivalents of 1-propylphosphonic anhydride are loaded into the reaction medium relative to the compound of formula (VII).

15. The method according to claim 2 or 3, wherein 1.0 to 10.0 molar equivalents of the base are loaded into the reaction medium relative to the compound of formula (VII).

16. The method according to claim 2 or 3, wherein during the contacting step, the reaction medium is maintained at a temperature from 10 °C to 30 °C.

17. The method according to claim 2 or 3, 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 crystalline mixture comprising the compound of formula (VIII).

18. The method according to claim 17, wherein: the organic phase solvent is replaced with the replacement solvent by continuous horizontal vacuum distillation; and the continuous horizontal vacuum distillation is carried out at a temperature not exceeding 60 °C.

19. The method according to claim 18, wherein the replacement solvent comprises an alcohol.

20. The method according to claim 18, wherein the replacement solvent comprises ethanol.

21. The method according to claim 17, wherein the organic phase solvent comprises dichloromethane and the replacement solvent comprises ethanol.

22. The method according to claim 17, wherein after crystallization begins, the crystalline mixture is maintained at a temperature greater than 40 °C for five hours.

23. The method according to claim 22, wherein before separating the compound of formula (VIII), the crystalline mixture is cooled to a temperature of 20 °C over a five-hour period.

24. The method according to claim 2 or 3, wherein the compound having the structure of formula (VII) is prepared by a method comprising separating the compound in crystalline form, wherein the crystalline form is characterized by a powder X-ray diffraction pattern comprising 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.

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