Process for the preparation of 4-{8-amino-3-[(2S)-1-(buta-2-inoyl)-pyrroridine-2-yl]imidazo[1,5-a]-pyrazine-1-yl}N-(pyridine-2-yl)-benzamide

Abstract

To provide 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 used in such processes.SOLUTION: The present disclosure relates to an intermediate that is a crystalline form of a compound having the structure of Formula (VII), characterized by a reflection X-ray powder diffraction pattern that includes at least three peaks selected from a peak group including 9.9±0.2°2θ.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This disclosure relates in general to processes for the preparation of 4-{8-amino-3-[(2S)-1-(buta-2-inoyl)pyrrolidine-2-yl]imidazo[1,5-a]pyrazine-1-yl}-N-(pyridine-2-yl)-benzamide, and more particularly to improvements in large-scale processes for producing 4-{8-amino-3-[(2S)-1-(buta-2-inoyl)pyrrolidine-2-yl]imidazo[1,5-a]pyrazine-1-yl}-N-(pyridine-2-yl)benzamide and / or intermediates used in such processes. [Background technology]

[0002] 4-{8-amino-3-[(2S)-1-(buta-2-inoyl)pyrrolidine-2-yl]imidazo[1,5-a]pyrazine-1-yl}-N-(pyridine-2-yl)benzamide (also known by the international generic name acalabrutinib) is the active pharmaceutical ingredient in the drug product CALQUENCE®. In 2017, the U.S. Food and Drug Administration granted marketing authorization for CALQUENCE® for the treatment of mantle cell lymphoma in adult patients who have received at least one prior therapy. Clinical trials are underway to evaluate the use of CALQUENCE® for the treatment of further indications, including chronic lymphocytic leukemia and Waldenström macroglobulinemia.

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

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

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

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

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

[0008] As described above, this disclosure relates to improvements in large-scale processes for preparing acalabrutinib and / or intermediates used in the preparation of acalabrutinib.

[0009] In one embodiment, the present disclosure relates to a compound having the structure of formula (VIII): [ka] Or relating to a process for preparing the salt, the process is: Compounds having the structure of formula (VII): [Chemical] reacting an acid of formula (II), or a salt thereof, with 2-butynoic acid, or a salt thereof, in a reaction medium in the presence of 1-propylphosphonic anhydride and a base to form a reaction mixture comprising a compound of formula (VIII), or a salt thereof, and one or more reaction by-products; and selectively isolating from the reaction mixture the compound of formula (VIII), or a salt thereof, with respect to the one or more reaction by-products.

[0010] In another aspect, the present disclosure relates to a process for preparing a compound having the structure of formula (VII): [Chemical] or a salt thereof, the process comprising: reacting a compound having the structure of formula (V): [Chemical] or a salt thereof, with a compound having the structure of formula (VI): [Chemical] <000009​​​​​​​​​​​​​​​​​​​​​ [ka] Or contact the salt thereof with an acidic medium under conditions sufficient to deprotect the compound of formula (IV) and form a reaction mixture containing the compound of formula (VI), or its salt, and a benzyl halide byproduct; and The method includes isolating a compound of formula (VI), or a salt thereof, from a reaction mixture under conditions sufficient to substantially avoid the formation of aminal impurities.

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

[0013] In another aspect, the present disclosure relates to a compound having the structure of formula (IV): [ka] The process for preparing the sulfate of is, Compounds having the structure of formula (III): [ka] Alternatively, contacting the salt thereof with an amination agent in a reaction medium to form a reaction mixture containing the compound of formula (IV); Forming sulfates of compounds of formula (IV); and This includes isolating sulfates.

[0014] In another aspect, the present disclosure relates to a compound having the structure of formula (III): [ka] Or relating to a process for preparing the salt, the process is: Compounds having the structure of formula (I): [ka] Alternatively, a salt thereof may be brought into contact with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound of formula (II): [ka] or forming a salt thereof; and Compounds having the structure of formula (III) obtained by brominating a compound of formula (II), or a salt thereof, with a brominating agent: [ka] or including bringing forth the salt; The temperature of the reaction medium is controlled during the contact step in a manner sufficient to maintain a chiral purity of at least about 80% with respect to the compound of formula (II) or its salt.

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

[0016] In another aspect, the present disclosure relates to a compound having the structure of formula (VII): [ka] Regarding the crystal form, The crystal form is, A reflected X-ray powder diffraction pattern including 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 It is characterized by a reflected X-ray powder diffraction pattern selected from a reflected X-ray powder diffraction pattern that includes at least three peaks selected from the group consisting of 7.4±0.2°2θ, 11.7±0.2°2θ, 12.5±0.2°2θ, 22.3±0.2°2θ, and 21.6±0.2°2θ.

[0017] In another aspect, the present disclosure relates to a compound having the structure of formula (VII): [ka] Regarding the crystal form, The crystalline morphology is characterized by a reflection X-ray powder 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.

[0018] In one embodiment, the present disclosure relates to a compound having the structure of formula (IV): [ka] This relates to crystalline sulfates. [Brief explanation of the drawing]

[0019] [Figure 1] The X-ray powder diffraction (PXRD) patterns, measured in reflectance mode, are shown from a sample of crystalline sulfate of (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazine-3-yl)-1-pyrrolidinecarboxylate benzyl, which has a stoichiometric ratio of approximately one sulfate molecule and one bisulfate molecule for all three free base molecules. [Figure 2]The X-ray powder diffraction (PXRD) pattern measured in reflection mode from a type II crystalline sample of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]-imidazo[1,5-a]pyrazine-1-yl}-N-(2-pyridinyl)benzamide is shown. [Figure 3] The X-ray powder diffraction (PXRD) pattern measured in reflection mode from a type 3 crystalline sample of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]-imidazo[1,5-a]pyrazine-1-yl}-N-(2-pyridinyl)benzamide is shown. [Figure 4] The image shows the X-ray powder diffraction (PXRD) pattern measured in reflection mode from a C-type crystalline sample of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]-imidazo[1,5-a]pyrazine-1-yl}-N-(2-pyridinyl)benzamide. [Modes for carrying out the invention]

[0020] This description discloses the invention using examples, and any person skilled in the art may also carry out the invention, which includes preparing and using the disclosed salts, substances, or compositions, and performing any of the disclosed methods or processes. The scope of the patentable invention is defined by the claims and may include other examples that a person skilled in the art would notice. Such other examples are intended to be within the claims if they have elements that are not different from the verbatim wording of the claims, or if they have equivalent elements that are not substantially different from the verbatim wording of the claims.

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

[0022] When a range of numbers is enumerated, each number within that range is explicitly considered with the same degree of precision. For example, for the range 6–9, the numbers 7 and 8 are considered in addition to 6 and 9, and for the range 6.0–7.0, 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. Similarly, all enumerated ratios also include all sub-ratios that fall within the broader ratio.

[0023] The singular forms "a," "an," and "the" refer to multiple objects unless the context explicitly indicates otherwise.

[0024] The term "approximately" generally refers to a range of numbers that a person skilled in the art would consider equivalent to (i.e., having the same function or result as) the listed values. Often, the term "approximately" may include numbers rounded to the nearest significant figure.

[0025] Unless otherwise required by context, the terms “comprise,” “comprises,” and “comprising” are used with full understanding that they are to be interpreted comprehensively, not exclusively, and that the applicant intends each of these terms to be interpreted in this way when interpreting the present patent, which includes the following claims.

[0026] The term "sulfate (2:3)" refers to a sulfate having a stoichiometric ratio of approximately 2:3 sulfate to free base, containing one sulfate molecule and one bisulfate molecule for every three free base molecules.

[0027] When the term "crystalline purity" is used in relation to the crystalline form of a compound, it refers to the percentage of the crystalline form of the compound in the referenced composition relative to other crystalline or amorphous forms.

[0028] The abbreviations used throughout this disclosure have the meanings set forth in Table 1 below.

[0029] [Table 1]

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

[0031] [Table 2]

[0032] [Table 3]

[0033] [Table 4]

[0034] This disclosure also discusses the crystalline forms of specific compounds listed in Table 2 and includes X-ray powder diffraction patterns characterizing such crystalline forms. It is known in the art that X-ray powder diffraction patterns with one or more measurement errors may be obtained depending on the measurement conditions (apparatus, sample preparation, or the machine used). In particular, it is generally known that the intensity of the X-ray powder diffraction pattern may vary depending on the measurement conditions and sample preparation. For example, a person skilled in the field of X-ray powder diffraction will understand that the relative intensity of the peaks may vary depending on the orientation of the sample being tested and the type and settings of the instrument being used. A person skilled in the art will also understand that the position of the reflection may be affected by the exact height at which the sample is positioned in the diffractometer and the zero calibration of the diffractometer. The surface flatness of the sample may also have some effect. Therefore, those skilled in the art will recognize that the diffraction pattern data presented herein should not be interpreted as absolute, and that any crystal form that yields substantially the same powder diffraction pattern as disclosed herein falls within the scope of this disclosure (for further information, see Jenkins, R & Snyder, RL, "Introduction to X-Ray Powder Diffractometry," John Wiley & Sons, 1996).

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

[0036] III. Clinical Trial Supply Process Scheme 3 below illustrates the process subsequently developed to manufacture a supply of acalabrutinib for clinical trials. The individual steps of Scheme 3 will be discussed in more detail throughout this disclosure. Scheme 3 [ka]

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

[0038] More specifically, the process in Scheme 3 has several limitations, including the following: (1) Racemization of the chiral center during the process of producing compound (II) was difficult to control and resulted in the failure of several batches. (2) Some environmentally undesirable solvents are used in some of the processes. (3) One of the more problematic solvents used is dichloromethane. In addition to environmental concerns, the use of dichloromethane in processes involving amines has further drawbacks, as it generates aminal impurities from the reaction of the amine with dichloromethane, which can sometimes even lead to batch failure. During the process of producing compound (VI), for example, methylene cross-linked dimers may be formed. Furthermore, acid-based liquid chromatography analysis used in connection with the process of producing compound (VI) failed to detect aminal impurities. (4) The use of a combination of N,N-dimethylformamide and thionyl chloride to produce compound (V) may potentially lead to the formation of toxic dimethylcarbamoyl chloride. (5) The coupling reaction in the step to produce compound (VII) is prone to stalling. The addition of more palladium catalyst increases the burden on the removal step in the final step to produce acalabrutinib, which already requires excessive repeated cycles with silica-based scavengers. (6) Isolation of compound (VII) by filtration is difficult and unsuitable for large-scale production. It requires the use of two pressure filters and multiple manual releases of the product as a wet paste for a 50 kg scale, and is limited to cases where the time disadvantage is significant. (7) Multiple batch failures occurred through various different modes of failure due to acylation that produces acalabrutinib. (8) Isolation of acalabrutinib using distillation precipitation does not allow control over the particle properties of the isolated product.

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

[0040] Preparation of V.(2S)-2-(8-chloroimidazo[1,5-a]pyrazine-3-yl)pyrrolidine-1-carboxylate benzyl (compound II) This disclosure relates in part to a process for preparing (2S)-2-(8-chloroimidazo[1,5-a]pyrrolidine-1-carboxylate benzyl (compound II) or a salt thereof from (2S)-2-[(3-chloropyrazine-2-yl)methylcarbamoyl]pyrrolidine-1-carboxylate benzyl (compound II) or a salt thereof. Scheme 5 below illustrates the general process: Scheme 5 [ka]

[0041] The cyclization of compound (I) to form the imidazole ring present in compound (II) is advantageous because it provides stability to the chiral center of the subsequent intermediate used in the production of acalabrutinib. However, the clinical trial supply process presents a problem because the uncyclized compound (I) readily racemizes under the acidic conditions of the cyclization reaction. Unwanted racemization is difficult to control and has led to the failure of multiple batches. The use of nitrogen sweeping to remove the generated hydrochloric acid limits the resulting chiral reduction to some extent, but the degree of chiral reduction remains highly variable.

[0042] The clinical trial supply process utilized a reaction temperature of approximately 80°C with approximately 0.2 molar equivalents of N,N-dimethylformamide catalyst packing. It has now been shown that increasing the N,N-dimethylformamide packing (e.g., to approximately 0.6 molar equivalents) and decreasing the reaction temperature (e.g., to approximately 40°C) limits the observed chiral decomposition and consistently results in the formation of chiral, pure compound (II). A lower amount of N,N-dimethylformamide catalyst packing used in the clinical trial supply process results in a reaction rate requiring a higher temperature for reaction completion, subsequently causing the observed chiral decomposition. In contrast, the increased N,N-dimethylformamide catalyst packing in the improved process results in a faster reaction rate, allowing the reaction to be carried out at a lower temperature that suppresses racemization. Chiral decomposition is reduced, chiral integrity is maintained, and therefore the yield is improved.

[0043] Therefore, in one embodiment, the present disclosure relates to a compound having the structure of formula (II): [ka] Or relating to a process for preparing the salt, the process is: Compounds having the structure of formula (I): [ka] Or, the method involves contacting a salt thereof with a cyclizing agent in a reaction medium in the presence of a catalyst to form a compound of formula (II) or a salt thereof; The temperature of the reaction medium is controlled during the contact step in a manner sufficient to maintain a chiral purity of at least about 80% with respect to the compound of formula (II) or its salt.

[0044] As described above, proper control of the reaction temperature during the cyclization reaction is important for maintaining the desired chiral purity of the product. Generally, the temperature of the reaction medium is controlled during the cyclization reaction in a manner sufficient to maintain at least about 85% chiral purity with respect to the compound of formula (II) or its salt. In one embodiment, the temperature of the reaction medium is controlled during the contact step in a manner sufficient to maintain at least about 90% chiral purity with respect to the compound of formula (II) or its salt. In another embodiment, the temperature of the reaction medium is controlled during the contact step in a manner sufficient to maintain at least about 95% chiral purity with respect to the compound of formula (II) or its salt. In yet another embodiment, the temperature of the reaction medium is controlled during the contact step in a manner sufficient to maintain at least about 99% chiral purity with respect to the compound of formula (II) or its salt.

[0045] Maintaining the reaction medium at a temperature below approximately 80°C during the contact process generally improves the chiral purity of the compound of formula (II) or its salt. In one embodiment, the reaction medium is maintained at a temperature below approximately 70°C during the contact process. In another embodiment, the reaction medium is maintained at a temperature below approximately 60°C during the contact process. In yet another embodiment, the reaction medium is maintained at a temperature below approximately 50°C during the contact process. In yet another embodiment, the reaction medium is maintained at a temperature between approximately 30°C and approximately 50°C during the contact process. In yet another embodiment, the reaction medium is maintained at a temperature of approximately 40°C during the contact process.

[0046] The catalyst may include any suitable catalyst, in particular a catalyst selected from the group consisting of N,N-dimethylformamide and N-methylformanilide. In one embodiment, the catalyst includes N,N-dimethylformamide. In another embodiment, the catalyst includes N-methylformanilide. As described above, the amount of catalyst packed into the reaction medium can also affect the chiral purity of the product. Generally, at least about 0.1 molar equivalents of catalyst per unit of the compound of formula (I) or its salt are packed into the reaction medium. In one embodiment, at least about 0.4 molar equivalents of catalyst per unit of the compound of formula (I) or its salt are packed into the reaction medium. In a further embodiment, at least about 0.6 molar equivalents of catalyst per unit of the compound of formula (I) or its salt are packed into the reaction medium. In a further embodiment, about 0.1 to about 1.0 molar equivalents of catalyst per unit of the compound of formula (I) or its salt are packed into the reaction medium. In a further embodiment, about 0.4 to about 1.0 molar equivalents of catalyst relative to the compound of formula (I) or its salt are packed into the reaction medium. In a further embodiment, the catalyst comprises N,N-dimethylformamide, and about 0.1 to about 1.0 molar equivalents of catalyst relative to the compound of formula (I) or its salt are packed into the reaction medium. In a further embodiment, the catalyst comprises N,N-dimethylformamide, and about 0.4 to about 1.0 molar equivalents of catalyst relative to the compound of formula (I) or its salt are packed into the reaction medium. In a further embodiment, the catalyst comprises N,N-dimethylformamide, and about 0.6 molar equivalents of catalyst relative to the compound of formula (I) or its salt are packed into the reaction medium.

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

[0048] The reaction medium may be any suitable reaction medium, in particular, comprising at least one solvent selected from the group consisting of aromatic hydrocarbons, chlorinated hydrocarbons, ethers, and nitriles. In one embodiment, the reaction medium comprises at least one compound selected from the group consisting of acetonitrile, butyronitrile, dichloromethane, toluene, anisole, tetrahydrofuran, and 2-methyltetrahydrofuran. In another embodiment, the reaction medium comprises acetonitrile. The volume of the reaction medium is generally about 2 liters to about 20 liters of reaction medium per kilogram of the compound of formula (I) or its salt filled into the reaction medium. In one embodiment, 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 filled into the reaction medium.

[0049] The contact process is generally carried out as a batch reaction, particularly when at least about 50 kilograms of the compound of formula (I) or a salt thereof is loaded into the batch reaction. In one embodiment, at least about 100 kilograms of the compound of formula (I) or a salt thereof is loaded into the batch reaction. In another embodiment, at least about 200 kilograms of the compound of formula (I) or a salt thereof is loaded into the batch reaction. In yet another embodiment, at least about 300 kilograms of the compound of formula (I) or a salt thereof is loaded into the batch reaction.

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

[0051] In another representative embodiment, the present disclosure relates to a compound having the structure of formula (II): [ka] Or relating to a process for preparing the salt, the process is: Compounds having the structure of formula (I): [ka] Alternatively, this may involve contacting a salt thereof with phosphorus oxychloride in a reaction medium in the presence of a catalyst to form a compound of formula (II) or a salt thereof; The reaction medium is maintained at a temperature of less than approximately 80°C during the contact process; At least about 0.4 molar equivalents of the catalyst, relative to the compound of formula (I) or its salt, are packed into the reaction medium; The chiral purity of the compound of formula (II), or its salt, is at least about 80%.

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

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

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

[0055] Therefore, in one embodiment, the present disclosure relates to a compound having the structure of formula (III): [ka] Or relating to a process for preparing the salt, the process is: Compounds having the structure of formula (I): [ka] Alternatively, a salt thereof may be brought into contact with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound of formula (II): [ka] or forming a salt thereof; and Compounds having the structure of formula (III) obtained by brominating a compound of formula (II), or a salt thereof, with a brominating agent: [ka] or including bringing forth the salt; The temperature of the reaction medium is controlled during the contact step in a manner sufficient to maintain a chiral purity of at least about 80% with respect to the compound of formula (II) or its salt.

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

[0057] When a compound of formula (II), or a salt thereof, is isolated from a reaction mixture and subsequently contacted with a brominating agent in a brominating medium, the brominating medium may contain any suitable brominating medium, in particular at least one solvent selected from the group consisting of chlorinated hydrocarbons and polar aprotic solvents. In one embodiment, the brominating medium contains at least one solvent selected from the group consisting of N,N-dimethylformamide, N-methylpyrrolidinone, N-butylpyrrolidinone, dimethyl sulfoxide, dimethylacetamide, and dichloromethane. In another embodiment, the brominating medium contains N,N-dimethylformamide. In yet another embodiment, the brominating medium contains N-methylpyrrolidinone.

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

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

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

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

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

[0063] In another representative embodiment, the present disclosure relates to a compound having the structure of formula (III): [ka] Or relating to a process for preparing the salt, the process is: Compounds having the structure of formula (I): [ka] Alternatively, a salt thereof may be contacted with phosphorus oxychloride in a reaction medium in the presence of a catalyst to obtain the compound of formula (II): [ka] or forming a salt thereof; and Compounds having the structure of formula (III) are obtained by brominating a compound of formula (II), or a salt thereof, with N-bromosuccinimide: [ka] or including bringing forth the salt; The reaction medium is maintained at a temperature of less than approximately 80°C during the contact process; At least about 0.4 molar equivalents of the catalyst, relative to the compound of formula (I) or its salt, are packed into the reaction medium; The chiral purity of the compound of formula (II), or its salt, is at least about 80%.

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

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

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

[0067] As reflected in Scheme 9 above, compound (III), or a salt thereof, can be aminated with an amination agent (e.g., ammonia, ammonium hydroxide, etc.) to obtain compound (IV), which can optionally be converted to a salt, in particular a sulfate of compound (IV), as will be discussed further below. Since the amination reaction may result in the presence of residual ammonia, it may be advantageous to reduce the amount of residual ammonia present before the formation of the salt of compound (IV) (e.g., by distillation of the crude compound (IV) product), especially if a sulfate of compound (IV) is desired. If residual ammonia present with compound (IV) is sufficiently removed when the sulfate is produced, inorganic ammonium sulfate may be produced in addition to the sulfate of compound (IV), which may hinder the determination of the exact stoichiometry of the sulfate produced. From a regulatory standpoint, understanding the exact stoichiometry of the sulfate produced may be necessary (e.g., if the sulfate is a registered starting material for regulatory purposes).

[0068] Therefore, in one embodiment, the present disclosure relates to a compound having the structure of formula (IV): [ka] The process for preparing the sulfate of is, Compounds having the structure of formula (III): [ka] Alternatively, contacting the salt thereof with an amination agent in a reaction medium to form a reaction mixture containing the compound of formula (IV); Forming sulfates of compounds of formula (IV); and This includes isolating sulfates.

[0069] Generally, sulfates of compounds having the structure of formula (IV) have a stoichiometric ratio of one sulfate molecule and one bisulfate molecule for every three free base molecules. In one embodiment, the sulfate is a crystalline salt. In another embodiment, the crystalline sulfate is characterized by a reflectance X-ray powder diffraction pattern containing at least three peaks selected from the group consisting of 7.7±0.2°2θ, 10.6±0.2°2θ, 11.1±0.2°2θ, 12.6±0.2°2θ, and 13.5±0.2°2θ. In another embodiment, 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.

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

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

[0072] The reaction medium may contain any suitable reaction medium, in particular at least one solvent selected from the group consisting of alkyl hydrocarbons, aromatic hydrocarbons, chloride hydrocarbons, aromatic heterocyclic compounds, alcohols, ethers, and dipolar aprotic solvents. In one embodiment, the reaction medium contains at least one compound selected from the group consisting of methanol, ethanol, propanol, butanol, pentanol, N-methylpyrrolidinone, and N,N-dimethylformamide. In another embodiment, the reaction medium contains an aliphatic alcohol. In another embodiment, the reaction medium contains butanol. In another embodiment, the reaction medium contains 2-butanol. The volume of the reaction medium is generally about 1.5 liters to about 40 liters of reaction medium per kilogram of the compound of formula (III) or its salt filled into the reaction medium. In one embodiment, the volume of the reaction medium is about 2.0 liters to about 30 liters of reaction medium per kilogram of the compound of formula (III) or its salt filled into the reaction medium.

[0073] During the contact process, the reaction medium is generally maintained at a temperature above 70°C. In one embodiment, the reaction medium is maintained at a temperature above 90°C during the contact process. In another embodiment, the reaction medium is maintained at a temperature of approximately 50°C to approximately 100°C during the contact process. In yet another embodiment, the reaction medium is maintained at a temperature of approximately 60°C to approximately 95°C during the contact process.

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

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

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

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

[0078] In another representative embodiment, the present disclosure relates to a compound having the structure of formula (IV): [ka] The process for preparing the sulfate of is, Compounds having the structure of formula (III): [ka] Alternatively, contacting the salt thereof with an amination agent in a reaction medium to form a reaction mixture containing the compound of formula (IV); To isolate the compound of formula (IV) from the reaction mixture as a free base; Contacting a free base with sulfuric acid to form a sulfate of the compound of formula (IV); and Including the isolation of sulfates; Sulfates have a stoichiometric ratio of one sulfate molecule and one bisulfate molecule for every three free base molecules.

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

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

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

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

[0083] Therefore, in one embodiment, the present disclosure relates to a compound having the structure of formula (V): [ka] The present invention relates to a process for preparing a salt thereof, the process comprising contacting 4-carboxyphenylboronic acid, or a salt thereof, with thionyl chloride and a catalyst in a reaction medium containing an organic solvent to form an acyl chloride intermediate, and subsequently contacting it in situ with 2-aminopyridine to form a reaction mixture containing the compound of formula (V), or a salt thereof. In one embodiment, the process further comprises isolating the compound of formula (V), or a salt thereof, from the reaction mixture.

[0084] Generally, the reaction medium is filled with 2-aminopyridine in a molar excess relative to 4-carboxyphenylboronic acid or its salt. In one embodiment, about 1.5 to about 5 molar equivalents of 2-aminopyridine relative to 4-carboxyphenylboronic acid or its salt is filled into the reaction medium. In another embodiment, about 1.5 to about 3.5 molar equivalents of 2-aminopyridine relative to 4-carboxyphenylboronic acid or its salt is filled into the reaction medium. In yet another embodiment, about 2 molar equivalents of 2-aminopyridine relative to 4-carboxyphenylboronic acid or its salt is filled into the reaction medium.

[0085] Generally, the reaction medium is filled with thionyl chloride in a molar excess relative to 4-carboxyphenylboronic acid or its salt. In one embodiment, 4-carboxyphenylboronic acid or its salt is contacted with about 2 to about 5 molar equivalents of thionyl chloride relative to 4-carboxyphenylboronic acid or its salt. In another embodiment, 4-carboxyphenylboronic acid or its salt is contacted with about 2 to about 3.5 molar equivalents of thionyl chloride relative to 4-carboxyphenylboronic acid or its salt. In yet another embodiment, 4-carboxyphenylboronic acid or its salt is contacted with about 2.75 molar equivalents of thionyl chloride relative to 4-carboxyphenylboronic acid or its salt.

[0086] The catalyst may include any suitable catalyst, in particular a catalyst selected from the group consisting of tetrabutylammonium chloride and N-methylformanilide. In one embodiment, the catalyst comprises tetrabutylammonium chloride. In another embodiment, the catalyst comprises N-methylformanilide. In yet another embodiment, the catalyst does not contain N,N-dimethylformamide. Generally, about 0.01 to about 0.1 molar equivalents of the catalyst relative to 4-carboxyphenylboronic acid or a salt thereof are packed into the reaction medium.

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

[0088] The reaction medium is generally maintained at a temperature of approximately 50°C to 90°C during the contact process. In one embodiment, the reaction medium is maintained at a temperature of approximately 60°C to 80°C during the contact process.

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

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

[0091] In another representative embodiment, the present disclosure relates to a compound having the structure of formula (V): [ka] The present invention relates to a process for preparing a salt thereof, comprising contacting 4-carboxyphenylboronic acid or a salt thereof with thionyl chloride and a catalyst in a reaction medium containing an organic solvent to form an acyl chloride intermediate, and subsequently contacting it in situ with 2-aminopyridine to form a reaction mixture containing a compound of formula (V) or a salt thereof; neither the reaction medium nor the catalyst contains N,N-dimethylformamide.

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

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

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

[0095] Initial developmental efforts to avoid aggressive acidic conditions by utilizing hydrogenation to deprotect compound (IV) or its salt and yield compound (VI) or its salt did not yield good results due to the presence of an unstable bromide on the imidazole ring. Further developmental efforts faced challenges including the generation and / or removal of several impurities.

[0096] Firstly, the deprotection reaction produces benzyl halides (e.g., benzyl chloride), which may potentially react further with compound (VI) or its salt, to form compound (IX): [ka] This generates an N-benzyl impurity having the following structure.

[0097] Secondly, the use of dichloromethane in the deprotection reaction involves compound (X): [ka] This can generate aminal impurities having the following structure.

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

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

[0100] Therefore, in one embodiment, the present disclosure relates to a compound having the structure of formula (VI): [ka] Or relating to a process for preparing the salt, the process is: Compound of formula (IV): [ka] Or, contact the salt thereof with an acidic medium under conditions sufficient to deprotect the compound of formula (IV) or its salt, and to form a reaction mixture containing the compound of formula (VI) or its salt, and a benzyl halide byproduct; To remove at least a portion of the benzyl halogen by-products from the reaction mixture; and The method includes isolating a compound of formula (VI), or a salt thereof, from a reaction mixture under conditions sufficient to substantially avoid the formation of aminal impurities.

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

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

[0103] In one embodiment, the acidic medium is an aqueous acidic medium. The aqueous acidic medium generally contains at least about 10 molar equivalents of acid relative to mineral acids, particularly hydrochloric acid, and the compound of formula (IV) or its salt. In one embodiment, the aqueous acidic medium contains about 10 to about 40 molar equivalents of acid relative to the compound of formula (IV) or its salt. In another embodiment, the aqueous acidic medium contains about 10 to about 25 molar equivalents of acid relative to the compound of formula (IV) or its salt. The volume of the aqueous reaction medium is generally about 2 to about 10 liters of aqueous reaction medium per kilogram of the compound of formula (IV) or its salt filled into the acidic medium. In one embodiment, the volume of the aqueous reaction medium is about 3 to about 4 liters of aqueous reaction medium per kilogram of the compound of formula (IV) or its salt filled into the aqueous reaction medium. During the contact process, the aqueous reaction medium is generally maintained at a temperature of about 25°C to about 70°C. In one embodiment, the aqueous reaction medium is maintained at a temperature of approximately 40°C to 50°C during the contact process.

[0104] In another embodiment, the process includes removing at least a portion of the benzyl halide by-product from the reaction mixture; raising the pH of the resulting reaction mixture to a basic pH to form a basic reaction medium containing 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.

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

[0106] The organic phase to be discarded generally contains at least one solvent selected from the group consisting of alkyl hydrocarbons, aromatic hydrocarbons, chloride hydrocarbons, and ethers. In another embodiment, the organic phase to be discarded contains 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 yet another embodiment, the organic phase to be discarded contains heptane.

[0107] In further embodiments, the process includes raising the pH of the reaction mixture after extraction of benzyl halide byproducts to form a basic reaction medium containing the compound of formula (VI) or a salt thereof; and extracting the compound of formula (VI) or a salt thereof from the basic reaction medium into the product organic phase. In one embodiment, the process includes extracting at least some of the benzyl halide byproducts from the reaction mixture into a discarded organic phase; raising the pH of the resulting reaction mixture to a basic pH (e.g., by adding sodium hydroxide) to form a basic reaction medium containing the compound of formula (VI) or a salt thereof; extracting the compound of formula (VI) or a salt thereof from the basic reaction medium into the product organic phase; and isolating the compound of formula (VI) or a salt thereof from the product organic phase. The pH of the basic reaction mixture is generally raised to at least about 8.0. In one embodiment, the pH of the basic reaction mixture is raised to at least about 10.0.

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

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

[0110] The compound of formula (VI), or a salt thereof, can be isolated from the reaction mixture by any suitable means, in particular by crystallizing the compound of formula (VI), or a salt thereof, from the reaction mixture. In one embodiment, the isolation step includes seeding the reaction mixture with the compound of formula (VI), or a salt thereof, in crystalline form to promote crystallization. In another embodiment, the isolation step includes seeding the reaction mixture with at least about 0.005 relative weight of the compound of formula (VI), or a salt thereof, in crystalline form to promote crystallization. In yet another embodiment, the isolation step includes seeding the reaction mixture with at least about 0.01 relative weight of the compound of formula (VI), or a salt thereof, in crystalline form to promote crystallization. In yet another embodiment, the isolation step includes seeding the reaction mixture with at least about 0.005 to about 0.02 relative weight of the compound of formula (VI), or a salt thereof, in crystalline form to promote crystallization. It may also be advantageous to fill the reaction mixture with a poor solvent to promote crystallization. In one embodiment, the poor solvent is heptane.

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

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

[0113] In another representative embodiment, the present disclosure relates to a compound having the structure of formula (VI): [ka] Or relating to a process for preparing the salt, the process is: Compound of formula (IV): [ka] Or, contact the salt thereof with an acidic medium under conditions sufficient to deprotect the compound of formula (IV) or its salt, and to form a reaction mixture containing the compound of formula (VI) or its salt, and a benzyl halide byproduct; Selectively extracting at least a portion of the benzyl halogen by-products from the reaction mixture into an organic phase discarded for the compound of formula (VI) or its salt; Raise the pH of the resulting reaction mixture to a pH above approximately 7.0 to form a basic reaction mixture; Selective extraction of at least a portion of the compound of formula (VI), or a salt thereof, from a basic reaction mixture into the product organic phase; and The method includes distilling the product organic phase under conditions sufficient to reduce the amount of water present in the product organic phase, thereby forming a distilled organic phase containing the compound of formula (VI) or a salt thereof.

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

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

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

[0117] The process utilizes the Suzuki reaction to couple compound (V) and compound (VI) to produce compound (VII). The clinical trial supply process performed the Suzuki coupling in an aqueous 2-butanol medium. Crude compound (VII) crystallized from the aqueous 2-butanol medium in crystalline form (then identified as the type II crystalline form of compound (VII)), which proved extremely difficult to filter from the medium even on a 50 kg scale. The type II crystalline form of compound (VII) was isolated as a viscous, clay-like product, which required oven drying to remove the large amount of water that adhered to a wet paste upon release from the filter.

[0118] Attempts to improve the filterability of the crystallized compound (VII) led to the discovery of two additional crystalline forms of compound (VII), called the type 3 crystalline form and the type C crystalline form. The type 2 crystalline form has an ultrafine needle-like form and is thought to be the hemi-butanol solvate-hydrate. The type 3 crystalline form has a needle-like form and is thought to be the butanol solvate. The type C crystalline form is an anhydrous form with an improved form that yields larger crystals. It has been found that crystallization of compound (VII) from a non-aqueous medium (generally less than 5% by weight of water) can produce the type 3 crystalline form and / or the type C crystalline form. Both crystalline forms penetrate faster than the type 2 crystalline form, but the type C crystalline form also penetrates faster than the type 3 crystalline form. Therefore, further attempts have focused on reducing or substantially removing any water present before the initial isolation of compound (VII) (e.g., by distillation) in order to reproducibly isolate compound (VII) as the type C crystalline form.

[0119] Removal of water prior to the isolation of compound (VII) typically resulted in the C-type crystalline form, although occasional batches still crystallized with an inconsistent amount of the present type III crystalline form. Further investigation determined that the C-type crystalline form is a thermodynamic form at temperatures above approximately 75°C. At this temperature, any present type III crystalline form generally converts to the C-type crystalline form within a relatively short period. By incorporating temperature cycling before the isolation of compound (VII), the C-type crystalline form can always be generated as a thermodynamic form. The conversion from the C-type crystalline form to the type III crystalline form can occur when cooling to below 75°C (especially in the presence of residual water), but this conversion is sufficiently slow that cooling and filtration can be performed without significant conversion to the type III crystalline form.

[0120] Furthermore, it was found to be advantageous to move the silica scavenging treatment from the final step for generating acalabrutinib from compound (VII) (as used in the clinical trial supply process) to the main step for generating compound (VII). This change in the sequencing of the silica scavenging treatment results in a better balance between efficient palladium removal and loss of product yield (to the scavenging agent).

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

[0122] Therefore, in one embodiment, the present disclosure relates to a compound having the structure of formula (VII): [ka] Or relating to a process for preparing the salt, the process is: Compounds having the structure of formula (V): [ka] or a salt thereof, a compound having the structure of formula (VI): [ka] Alternatively, contact the salt thereof with a base and a palladium catalyst in an aqueous reaction medium containing an organic solvent to form a reaction mixture containing the compound of formula (VII); To reduce the amount of water present in the reaction mixture to form a substantially anhydrous mixture containing the compound of formula (VII) or a salt thereof; and This involves isolating a compound of formula (VII), or a salt thereof, from a substantially anhydrous mixture.

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

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

[0125] In another embodiment, the aqueous reaction medium further comprises an alkali metal halide. In one embodiment, the aqueous reaction medium comprises an alkali metal iodide. In another embodiment, the aqueous reaction medium comprises potassium iodide. Generally, the aqueous reaction medium is filled with at least about 0.1 molar equivalents of alkali metal halide relative to the compound of formula (VI) or its salt. In one embodiment, the aqueous reaction medium is generally filled with about 0.1 to about 1.0 molar equivalents of alkali metal halide relative to the compound of formula (VI) or its salt. In one embodiment, the aqueous reaction medium is filled with about 0.1 to about 1.0 molar equivalents of potassium iodide relative to the compound of formula (VI) or its salt. In another embodiment, the aqueous reaction medium is filled with about 0.2 to about 0.4 molar equivalents of potassium iodide relative to the compound of formula (VI) or its salt.

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

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

[0128] The palladium catalyst may be any suitable palladium catalyst, particularly bis(tert-butyldicyclohexylphosphine)dichloropalladium(II). Generally, about 0.002 to about 0.05 molar equivalents of the palladium catalyst relative to the compound of formula (VI) or its salt are packed into the aqueous reaction medium. In one embodiment, about 0.007 to about 0.013 molar equivalents of the palladium catalyst relative to the compound of formula (VI) or its salt are packed into the aqueous reaction medium.

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

[0130] The volume of the aqueous reaction medium is generally about 10 to 20 liters of aqueous reaction medium per kilogram of the compound of formula (VI) or its salt packed into the aqueous reaction medium. In one embodiment, the volume ratio of water to organic solvent in the aqueous reaction medium is about 1:3 to 3:1. During the contact process, the aqueous reaction medium is generally maintained at a temperature of about 50°C to 100°C. In one embodiment, the aqueous reaction medium is maintained at a temperature of about 70°C to 90°C during the contact process.

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

[0132] In further embodiments, the organic phase is treated with a silica scavenger before distillation. In one embodiment, the organic phase is treated with a silica scavenger for at least two hours before distillation. The silica scavenger generally includes propanethol-functionalized silica. In one embodiment, the silica scavenger includes QuadraSil® MP. The process may further include removing the silica scavenger from the organic phase before distillation. In one embodiment, the silica scavenger is removed from the organic phase by filtration before distillation. In another embodiment, the process further includes washing the organic phase with an aqueous salt solution after catalyst removal and before distillation.

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

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

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

[0136] The isolation step generally involves crystallizing the compound of formula (VII) as a C-type crystalline form from a substantially anhydrous mixture. To ensure that the product crystallizes as a 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 during which the substantially anhydrous mixture is maintained at a temperature (or temperature range) of at least about 70°C before cooling begins will depend on the temperature (or temperature range) chosen. Higher temperatures generally require shorter retention periods to convert any existing non-C-type crystalline forms to the C-type crystalline form. However, the temperature chosen should not result in the decomposition of the compound of formula (VII) or exceed the boiling point of the substantially anhydrous mixture. Furthermore, stirring the substantially anhydrous mixture during the retention period and / or seeding the substantially anhydrous mixture in the C-type crystalline form may be advantageous in further reducing the duration of any required retention period. Therefore, in various embodiments, the substantially anhydrous mixture is maintained at a selected temperature (or range of temperatures) for a certain period after the start of crystallization and before the start of cooling, and the temperature (or range of temperatures) and the selected period are sufficient to obtain a substantially C-type crystalline form of the compound of formula (VII) upon cooling of the substantially anhydrous mixture.

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

[0138] In another embodiment, the selected temperature is high enough so that no further holding period is required before cooling begins. In another embodiment, the holding period before cooling is at least about 15 minutes. In another embodiment, the holding period before cooling is at least about 30 minutes. In another embodiment, the holding period before cooling is at least about 1 hour. In another embodiment, the holding period before cooling is at least about 1.5 hours. In another embodiment, the holding period before cooling is at least about 2 hours.

[0139] In one embodiment, the temperature is at least about 75°C and the holding period before cooling is at least about 2 hours. In another embodiment, the temperature is at least about 80°C and the holding period is at least about 1.5 hours. In another embodiment, the temperature is at least about 85°C and the holding period is at least about 1 hour. In another embodiment, the temperature is at least about 90°C and the holding period is at least about 15 minutes. In another embodiment, the temperature is at least about 90°C and the holding period is not required. In another embodiment, the temperature is about 75°C to about 105°C and the holding period is about 15 minutes to about 3 hours. In another embodiment, the temperature is about 80°C to about 105°C and the holding period is about 15 minutes to about 3 hours. In another embodiment, the temperature is about 85°C to about 105°C and the holding period is about 15 minutes to about 3 hours. In another embodiment, the temperature is about 90°C to about 105°C and the holding period is about 5 minutes to about 2 hours. In another embodiment, the temperature is approximately 90°C to 105°C, and no further holding period is required before cooling.

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

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

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

[0143] In another representative embodiment, the present disclosure relates to a process for preparing a compound having the structure of formula (VII):

Chemical formula

Chemical formula

Chemical formula

[0144] In one embodiment, the process further comprises washing the organic phase with water prior to the treatment step. In another embodiment, the process further comprises washing the organic phase with an aqueous salt solution after the removal step and prior to the distillation step. In another embodiment, 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 embodiment, the substantially anhydrous mixture is held at a temperature above 75 °C until any crystalline liquid present is substantially converted to the C-type crystal form prior to isolating the compound of formula (VII) from the substantially anhydrous mixture.

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

Chemical formula

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

[0147] Compound (VII) reacts with 2-butic acid in the presence of a coupling agent to produce acalabrutinib. This coupling step is difficult to manipulate in the clinical trial supply process. The addition of a small excess of 2-butic acid to compound (VII) in dichloromethane produced a relatively viscous mixture containing the tetrolate salt of compound (VII), which was difficult to stir. Subsequent addition of triethylamine to the viscous mixture did not significantly improve the viscosity. However, the addition of triethylamine before 2-butic acid avoided the formation of the tetrolate salt of compound (VII), resulting in a relatively thin, stirable slurry. However, the subsequent addition of a coupling agent (e.g., 1-propylphosphonic anhydride) to the resulting slurry was difficult to control, and there was a narrow range of control in the process to meet the quality criteria for the acalabrutinib product. Insufficient addition of 1-propylphosphonic anhydride does not consume all of the starting material (i.e., compound (VII)), while excessive addition results in impurities with the structure of compound (XIV): [ka] This led to the formation of [something].

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

[0149] The obstacles associated with the removal of the two impurities were found to be overcome using a sequential extraction technique. Acalabrutinib is selectively extracted from the reaction mixture to an aqueous phase having a first acidic pH (e.g., pH 1.8–2.2) for compound (XIV) impurity, and the reaction mixture containing compound (XIV) impurity is discarded. Next, the pH of the aqueous phase containing acalabrutinib is adjusted to a second pH (e.g., pH 4.5–5.0), and acalabrutinib is selectively extracted from the aqueous phase to an organic phase for compound (VII) impurity, and the aqueous phase containing compound (VII) impurity is discarded. Since the sequential extraction technique results in the efficient removal of unwanted impurities from the final product, the addition of 1-propylphosphonic anhydride does not require the same strict control as in the clinical trial supply process, and the addition of 1-propylphosphonic anhydride is more robust.

[0150] Another problem encountered in the clinical trial supply process involved solvent exchange from dichloromethane to ethanol, which utilized multiple "put-and-take" distillation cycles. The acalabrutinib product consistently became oily or rubbery before finally crystallizing. The kinetics of acalabrutinib crystallization from ethanol were found to be remarkably slow. The point at which the oil crystallized could not be controlled, and the crystallized acalabrutinib was accompanied by an undesirable amount of crystallization solvent. Consequently, the encapsulation of dichloromethane in the acalabrutinib crystal lattice was a concern in the clinical trial supply process. A more controlled procedure is now being developed that utilizes a continuous level of vacuum distillation (e.g., 18-20 rel. vol., 50°C) to maintain acalabrutinib in solution throughout the distillation process (even when the dichloromethane solvent is completely replaced with ethanol) and to avoid the oiliness problem. Once distillation is complete, seeding with crystalline acalabrutinib and maintaining the seeded solution at a suitable temperature (e.g., 50°C) results in controlled crystallization, allowing the acalabrutinib product to be isolated with consistent particle characteristics. Crystallization further purifies the acalabrutinib product, particularly against any excess acylated by-products present.

[0151] Thus, in one embodiment, the present disclosure relates to a process for preparing a compound having the structure of formula (VIII): [Chemical formula] or a salt thereof, the process comprising contacting a compound having the structure of formula (VII): with 2-butynoic acid, or a salt thereof, in a reaction medium in the presence of 1-propylphosphonic anhydride and a base to form a reaction mixture comprising the compound of formula (VIII) and one or more reaction by-products; and<{ [Chemical formula] selectively isolating the compound of formula (VIII), or a salt thereof, from the reaction mixture with respect to the one or more by-products. As described above, the order of addition with respect to the process can have an impact. Generally, the contacting step comprises adding the compound of formula (VII), or a salt thereof, and the base to the reaction medium; adding 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 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.

[0152]

[0153] In another embodiment, the present disclosure relates to a process for preparing a compound having the structure of formula (VIII): [Chemical formula] or a salt thereof, the process comprising contacting a compound having the structure of formula (VII): [Chemical formula] ​Alternatively, contact the salt thereof with 2-butic acid or a salt thereof in a reaction medium in the presence of 1-propylphosphonic anhydride and a base to form a reaction mixture containing the compound of formula (VIII) or a salt thereof; an unreacted compound of formula (VII) or a salt thereof; and a reaction byproduct (the reaction byproduct being a compound having the structure of formula (XIV): [ka] or including its salt); and This method involves selectively isolating a compound of formula (VIII) or a salt thereof from a reaction mixture with respect to a compound of formula (VII) or a salt thereof, and a compound of formula (XIV) or a salt thereof.

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

[0155] In another embodiment, the present disclosure relates to a compound having the structure of formula (VIII): [ka] Or relating to a process for preparing the salt, the process is: Compounds having the structure of formula (VII): [ka] Alternatively, contact the salt thereof with 2-butic acid or a salt thereof in a reaction medium in the presence of 1-propylphosphonic anhydride and a base to form a reaction mixture containing the compound of formula (VIII) or a salt thereof; an unreacted compound of formula (VII) or a salt thereof; and a reaction byproduct (the reaction byproduct being a compound having the structure of formula (XIV): [ka] or including its salt); Extracting at least a portion of the compound of formula (VIII), or its salt, from the reaction mixture into the aqueous phase (the compound of formula (VIII), or its salt, is selectively extracted into the aqueous phase relative to the compound of formula (XIV), or its salt); Adjusting the pH of the aqueous phase; and This includes extracting at least a portion of the compound of formula (VIII), or a salt thereof, from the aqueous phase into the organic phase (the compound of formula (VIII), or a salt thereof, is selectively extracted into the organic phase relative to the compound of formula (VII), or a salt thereof).

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

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

[0158] In general, the reaction medium is generally filled with at least about 0.3 molar equivalents of 1-propylphosphonic anhydride relative to the compound of formula (VII). In one embodiment, the reaction medium is generally filled with at least about 0.5 molar equivalents of 1-propylphosphonic anhydride relative to the compound of formula (VII). In another embodiment, the reaction medium is generally filled with at least about 1.0 molar equivalent of 1-propylphosphonic anhydride relative to the compound of formula (VII). In another embodiment, the reaction medium is generally filled with about 0.3 to about 3.0 molar equivalents of 1-propylphosphonic anhydride relative to the compound of formula (VII). In another embodiment, the reaction medium is generally filled with about 0.5 to about 2.0 molar equivalents of 1-propylphosphonic anhydride relative to the compound of formula (VII). In another embodiment, the reaction medium is generally filled with about 0.7 to about 1.5 molar equivalents of 1-propylphosphonic anhydride relative to the compound of formula (VII). In another embodiment, the reaction medium is filled with approximately 1.0 to 1.2 molar equivalents of 1-propylphosphonic anhydride relative to the compound of formula (VII).

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

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

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

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

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

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

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

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

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

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

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

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

[0171] In another representative embodiment, the present disclosure relates to a compound having the structure of formula (VIII): [ka] Or relating to a process for preparing the salt, the process is: Compounds having the structure of formula (VII): [ka] Alternatively, a salt thereof may be contacted with 2-butic acid or a salt thereof in a reaction medium in the presence of 1-propylphosphonic anhydride and a base to form a reaction mixture containing the compound of formula (VIII), an unreacted compound of formula (VII), and a reaction byproduct (the reaction byproduct being a compound having the structure of formula (XIV): [ka] or including its salt); Extracting at least a portion of the compound of formula (VIII), or a salt thereof, from the reaction mixture into an aqueous phase having a pH of about 1.8 to about 2.2 (the compound of formula (VIII) is selectively extracted into the aqueous phase relative to the compound of formula (XIV)); Adjust the pH of the aqueous phase to approximately 4.5 to approximately 5.0; and This method involves extracting at least a portion of the compound of formula (VIII), or a salt thereof, from the aqueous phase into the organic phase (the compound of formula (VIII) is selectively extracted into the organic phase compared to the compound of formula (VII)).

[0172] In one embodiment, the contact step includes adding the compound of formula (VII) and a base to a reaction medium; adding 2-butyric acid to the reaction medium containing the compound of formula (VII) and a base; and adding 1-propylphosphonic anhydride to the reaction medium containing the compound of formula (VII), 2-butyric acid, and a base. In another embodiment, the reaction mixture is washed with water, and the washed reaction mixture is separated into an aqueous phase and a discarded phase, and the compound of formula (VIII) is selectively extracted into the aqueous phase. In another embodiment, the organic phase contains an organic phase solvent, and the process further includes replacing the organic phase solvent with a substitution solvent to form a crystalline mixture containing the compound of formula (VIII). In another embodiment, the process further includes isolating the compound of formula (VIII) from the crystalline mixture. In another embodiment, the crystalline mixture is seeded with the compound of formula (VIII) in crystalline form and maintained at a temperature above about 40°C for at least about 5 hours after the start of crystallization.

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

[0174] XIII. Additional Embodiments By combining various embodiments of the individual processes described above, further embodiments of the overall process for the preparation of acalabrutinib can be provided. The embodiments described below are representative embodiments that further illustrate the overall process. They are intended to illustrate the overall process, but are not limiting.

[0175] In one embodiment, a compound having the structure of formula (VIII): [ka] Or the salt is, Compounds having the structure of formula (VII): [ka] Alternatively, contacting a salt thereof with 2-butic acid or a salt thereof in a reaction medium in the presence of 1-propylphosphonic anhydride and a base to form a reaction mixture containing the compound of formula (VIII) and one or more reaction byproducts; and Prepared by a process comprising selectively isolating a compound of formula (VIII), or a salt thereof, from a reaction mixture with respect to one or more by-products; A compound having the structure of formula (VII), or a salt thereof, Compounds having the structure of formula (V): [ka] or a salt thereof, a compound having the structure of formula (VI): [ka] Alternatively, contact the salt thereof with a base and a palladium catalyst in an aqueous reaction medium containing an organic solvent to form a reaction mixture containing the compound of formula (VII); To reduce the amount of water present in the reaction mixture to form a substantially anhydrous mixture containing the compound of formula (VII) or a salt thereof; and It is prepared by a process that involves isolating the compound of formula (VII), or a salt thereof, from a substantially anhydrous mixture.

[0176] In another embodiment, a compound having the structure of formula (VIII): [ka] Or the salt is, Compounds having the structure of formula (VII): [ka] Alternatively, contact the salt thereof with 2-butyric acid or a salt thereof in a reaction medium in the presence of a coupling agent and a base to form a reaction mixture containing the compound of formula (VIII) or a salt thereof; an unreacted compound of formula (VII) or a salt thereof; and a reaction byproduct (the reaction byproduct being a compound having the structure of formula (XIV): [ka] or including its salt); Extracting at least a portion of the compound of formula (VIII), or its salt, from the reaction mixture into the aqueous phase (the compound of formula (VIII), or its salt, is selectively extracted into the aqueous phase relative to the compound of formula (XIV), or its salt); Adjusting the pH of the aqueous phase; and Prepared by a process comprising extracting at least a portion of the compound of formula (VIII), or a salt thereof, from the aqueous phase into the organic phase (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); A compound having the structure of formula (VII), or a salt thereof, Compounds having the structure of formula (V): [ka] or a salt thereof, a compound having the structure of formula (VI): [ka] Alternatively, contacting the salt thereof with an aqueous reaction medium containing an organic solvent in the presence of a base and a palladium catalyst to form a reaction mixture containing the compound of formula (VII) or a salt thereof; To reduce the amount of water present in the reaction mixture to form a substantially anhydrous mixture containing the compound of formula (VII) or a salt thereof; and It is prepared by a process that involves isolating the compound of formula (VII), or a salt thereof, from a substantially anhydrous mixture.

[0177] In another embodiment, the process further, Compound of formula (IV): [ka] Or, contact the salt thereof with an acidic medium under conditions sufficient to deprotect the compound of formula (IV) or its salt, and to form a reaction mixture containing the compound of formula (VI) or its salt, and a benzyl halide byproduct; To remove at least a portion of the benzyl halogen by-products from the reaction mixture; and The process includes preparing a compound having the structure of formula (VI), or a salt thereof, by isolating the compound of formula (VI), or a salt thereof, from a reaction mixture under conditions sufficient to substantially avoid the formation of aminal impurities.

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

[0179] In another embodiment, the process further involves a compound having the structure of formula (III): [ka] Alternatively, contacting the salt thereof with an amination agent in a reaction medium to form a reaction mixture containing the compound of formula (IV); Forming sulfates of compounds of formula (IV); and The process includes preparing a compound having the structure of formula (IV), or a salt thereof, by a process that includes isolating a sulfate.

[0180] In another embodiment, the process further involves a compound having the structure of formula (I): [ka] Alternatively, a salt thereof may be brought into contact with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound of formula (II): [ka] or forming a salt thereof; and Compounds having the structure of formula (III) obtained by brominating a compound of formula (II), or a salt thereof, with a brominating agent: [ka] The process includes preparing a compound having the structure of formula (III), or a salt thereof, by a process that also includes obtaining a salt thereof; The temperature of the reaction medium is controlled during the contact step in a manner sufficient to maintain a chiral purity of at least about 80% with respect to the compound of formula (II) or its salt.

[0181] In another embodiment, the present disclosure relates to a compound having the structure of formula (VIII): [ka] Or relating to a process for preparing the salt, the process is: Compounds having the structure of formula (V): [ka] or a salt thereof, a compound having the structure of formula (VI): [ka] Alternatively, a salt thereof may be brought into contact with a compound having the structure of formula (VII) in an aqueous reaction medium containing an organic solvent in the presence of a base and a palladium catalyst: [ka] or forming a reaction mixture containing the salt thereof; Reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture containing the compound of formula (VII) or a salt thereof; Isolating the compound of formula (VII), or a salt thereof, from a substantially anhydrous mixture; and This includes converting a compound of formula (VII), or a salt thereof, to a compound of formula (VIII), or a salt thereof.

[0182] In another embodiment, the present disclosure relates to a compound having the structure of formula (VIII): [ka] Or relating to a process for preparing the salt, the process is: Compounds having the structure of formula (IV): [ka] or a salt thereof, a compound of formula (IV), or a deprotected salt thereof, having the structure of formula (VI): [ka] Or contact with an acidic medium under conditions sufficient to form a reaction mixture containing the salt thereof and a benzyl halogen by-product; Removal of at least a portion of the benzyl halogen by-product from the reaction mixture; To isolate the compound of formula (VI), or a salt thereof, from the reaction mixture under conditions sufficient to substantially avoid the formation of aminal impurities; and This includes converting a compound of formula (VI), or a salt thereof, to a compound of formula (VIII), or a salt thereof.

[0183] In another embodiment, the present disclosure relates to a compound having the structure of formula (VIII): [ka] Or relating to a process for preparing the salt, the process is: Compounds having the structure of formula (III): [ka] Alternatively, by contacting a salt thereof with an amination agent in a reaction medium, a compound having the structure of formula (IV) is obtained: [ka] Form a reaction mixture containing the following: Formation of a sulfate of the compound of formula (IV); Isolating sulfates; and This includes converting a sulfate into a compound of formula (VIII) or a salt thereof.

[0184] In another embodiment, the present disclosure relates to a compound having the structure of formula (VIII): [ka] Or relating to a process for preparing the salt, the process is: Compounds having the structure of formula (I): [ka] Alternatively, a salt thereof may be brought into contact with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound of formula (II): [ka] or forming a salt thereof; Compounds having the structure of formula (III) obtained by brominating a compound of formula (II), or a salt thereof, with a brominating agent: [ka] or bringing forth the salt; and This includes converting a compound of formula (III), or a salt thereof, to a compound of formula (VIII), or a salt thereof; The temperature of the reaction medium is controlled during the contact step in a manner sufficient to maintain a chiral purity of at least about 80% with respect to the compound of formula (II) or its salt.

[0185] In another embodiment, the present disclosure relates to a compound having the structure of formula (VIII): [ka] Or relating to a process for preparing the salt, the process is: Compounds having the structure of formula (I): [ka] Alternatively, a salt thereof may be brought into contact with a cyclizing agent in the presence of a catalyst in a reaction medium to obtain a compound having the structure of formula (II): [ka] or forming a salt thereof; and This includes converting a compound of formula (II), or a salt thereof, to a compound of formula (VIII), or a salt thereof; The temperature of the reaction medium is controlled during the contact step in a manner sufficient to maintain a chiral purity of at least about 80% with respect to the compound of formula (II) or its salt.

[0186] Overall, the improved large-scale process has reduced batch failures and results in high-quality acalabrutinib that can be consistently produced from compound (I) on large scale with yields exceeding 32%. [Examples]

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

[0188] Next, the product was extracted twice from the mixture with dichloromethane (905 kg, 5.0 rel. wt.). The combined organic extract was then washed with a solution of sodium bicarbonate (114.4 kg) in water (1139 L), followed by a solution of sodium chloride (75 kg) in water (376 L), filtered through Celite (18 kg), then filtered through silica (40 kg), and the silica filtrate was washed twice with dichloromethane (909 kg). The solvent was removed by vacuum distillation while maintaining a temperature below 40°C to approximately 1.0 rel. vol. N-methylpyrrolidone (819 kg, 4.6 rel. wt.) was added to dissolve the mixture, and then N-bromosuccinimide (77.3 kg, approximately 1.1 mol. eq.) was gradually added, stirring at 20°C to 30°C after each change until the reaction was considered complete. Next, the mixture was added to a solution of sodium bicarbonate (21.8 kg) in water (1092 L), and the product was subsequently extracted with dichloromethane (1500 kg, 8.4 rel. wt.), followed by dichloromethane (907 kg, 5.1 rel. wt.). The organic phases were combined and washed three times with water (682 L), followed by eight more washes with water (382 L). The organic solution was concentrated to approximately 1.0 rel. vol., concentrated from heptane (191 kg, 1.1 rel. vol.), and then crystallized by adding heptane (191 kg, 1.1 rel. vol.). The mixture was filtered and dried to obtain the solid (2S)-2-(1-bromo-8-chloroimidazo[1,5-a]pyrazine-3-yl)pyrrolidine-1-carboxylate benzyl (compound (III), 152.2 kg, 75.6%). Enantiomer excess rate = 97.8%.

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

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

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

[0192] [Table 5]

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

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

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

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

[0197] Example 5: Preparation of the sulfate (2:3) of (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazine-3-yl)-1-pyrrolidinecarboxylate benzyl (compound (IV)) [ka] The synthesis described in Example 4 assumed that the final product would have a 1:1 ratio of free base to salt, but the assay and mass balance did not match. Therefore, the synthesis was further modified as follows to obtain a final product with a defined stoichiometry that could meet the regulatory requirements for characterizing the intermediate used in the preparation of the registered active ingredient. The presence of inorganic ammonium sulfate in the product of Example 4 hindered the accurate determination of the sulfate stoichiometry. The modified process below removes residual ammonia before the formation of the sulfate, substantially eliminating this problem.

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

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

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

[0201] [Table 6]

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

[0203] The stoichiometry was confirmed to consist of three molecules of (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazine-3-yl)-1-pyrrolidinecarboxylate benzyl, one sulfate, and one bisulfate. Crystal structure analysis also identified one molecule of water per three molecules of (2S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazine-3-yl)-1-pyrrolidinecarboxylate benzyl, but further diffraction and thermal analysis indicate that this may be variable without substantially affecting the overall structure and salt stoichiometry.

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

[0205] [Table 7]

[0206] Characteristic peaks related to this crystal morphology are those at 7.7, 10.6, 11.1, 12.6, 13.5, 17.4, 18.0, 18.9, 19.2, and 21.9±0.2°2θ, particularly those at 7.7, 10.6, 11.1, 12.6, and 13.5±0.2°2θ.

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

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

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

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

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

[0212] Example 11: Preparation of [4-(2-pyridylcarbamoyl)phenyl]boronic acid (compound (V)) [ka] The synthesis described in Example 10 was further modified to identify suitable substitution solvents for N,N-dimethylformamide that reduce the potential formation of undesirable by-products, particularly dimethylcarbamoyl chloride.

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

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

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

[0216] Next, water (727 L, 15 rel. vol.) was slowly added, and the mixture was cooled to approximately 20°C, after which it was filtered and washed with water. The filtration and washing cycles were very slow. During the process, two filters and multiple releases were required, and it usually took 3-4 days to complete. X-ray powder diffraction of the material isolated in this filtration step yielded a diffractogram consistent with that of Figure 2 (i.e., type 2). The water-moistened product was further dried by refluxing in heptane (964 L) for 29 hours under Dean-Stark conditions, followed by filtration and drying under vacuum at 45°C to obtain the yellow crystalline solid 4-{8-amino-3-[(2S)-2-pyrrolidinyl]-imidazo[1,5-a]pyrazine-1-yl}-N-(2-pyridinyl)benzamide (compound (VII), 61.6 kg, 81.5%).

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

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

[0219] The solid 4-{8-amino-3-[(2S)-2-pyrrolidinyl]-imidazo[1,5-a]pyrazine-1-yl}-N-(2-pyridinyl)benzamide (compound (VII), 40.6 kg, 1.0 mol. eq.) was purified by forming a slurry in 1 M potassium carbonate aqueous solution (162.4 L, 4.0 rel. vol.) to remove impurities from 4-[8-amino-3-[(2S)-pyrrolidinyl-2-yl]imidazo[1 After removing [5-a]pyrazine-1-yl]benzoic acid (compound (XII)), the mixture was filtered and washed with water (81.2 L, 2.0 rel. vol.), followed by heptane (81.2 L, 2.0 rel. vol.) to obtain the yellow crystal 4-{8-amino-3-[(2S)-2-pyrrolidinyl]-imidazo[1,5-a]pyrazine-1-yl}-N-(2-pyridinyl)benzamide (compound (VII), 39.7 kg, 98%). In addition to the impurity of 4-[8-amino-3-[(2S)-pyrrolidine-2-yl]imidazo[1,5-a]pyrazine-1-yl]benzoic acid (compound (XII)), another impurity, 4-[8-amino-3-[(2S)-1-[4-[8-amino-3-[(2S)-pyrrolidine-2-yl]imidazo[1,5-a]pyrazine-1-yl]benzoyl]pyrrolidine-2-yl]imidazo[1,5-a]pyrazine-1-yl]-N-(2-pyridyl)benzamide (compound (XIII)) was observed and was not removed by this reprocessing.

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

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

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

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

[0224] Analysis of Type B2 crystal morphology Samples of type II crystalline 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazine-1-yl}-N-(2-pyridinyl)benzamide (compound (VII)) were analyzed by X-ray powder diffraction. The resulting X-ray diffraction patterns are shown in Figure 2, along with the selected peaks and relative intensities reported in Table 6 below.

[0225] [Table 8]

[0226] The type II 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 at 5.0, 5.7, 7.2, 9.9, and / or 11.2 ± 0.2° 2θ. As mentioned above, the product isolated from the first filtration of Example 12 corresponds to the type II crystalline form.

[0227] Analysis of C.3 type crystal morphology Samples of the type 3 crystalline 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazine-1-yl}-N-(2-pyridinyl)benzamide (compound (VII)) produced by slurrying type 2 in pure butanol for 7 days under ambient conditions were analyzed by X-ray powder diffraction. The resulting X-ray diffraction patterns are shown in Figure 3, along with the selected peaks and relative intensities reported in Table 7 below.

[0228] [Table 9]

[0229] The Type 3 crystal morphology 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 at 7.4, 11.7, 12.5, 22.3, and / or 21.6±0.2°2θ.

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

[0231] [Table 10]

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

[0233] Example 16: Preparation of 4-{8-amino-3-[(2S)-1-(buta-2-inoyl)pyrrolidine-2-yl]imidazo[1,5-a]pyrazine-1-yl}-N-(pyridine-2-yl)benzamide (compound (VIII)) [ka] 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazine-1-yl}-N-(2-pyridinyl)-benzamide (compound (VII), 70 kg, 1.0 mol.eq.) and 2-butyric acid (17.5 kg, 1.2 mol.eq.) were mixed in dichloromethane (1537 kg, 22 rel. vol.) to obtain a viscous slurry. After adding triethylamine (44.5 kg, 2.5 mol.eq.), 1-propylphosphonic anhydride (T3P) (approximately 111.4 kg, 1.0 mol.eq.) was added (a further constant amount of T3P was added in small amounts until the reaction was considered complete). The resulting organic solution was washed twice with water (525 kg, 7.5 rel. vol.), and then concentrated to approximately 2-3 rel. vol. Water (700 kg, 10.0 rel. vol.) was added, and the mixture was then acidified with a 6 M hydrochloric acid aqueous solution to approximately pH 2. The organic phase was then separated and discarded. The aqueous layer (containing the product) was washed three times with 2-methyltetrahydrofuran (478 kg, 8.0 rel. vol.), followed by two more washes with 2-methyltetrahydrofuran (180 kg, 3.0 rel. vol.). Dichloromethane (742 kg, 8.0 rel. vol.) was added to the aqueous phase, and the mixture was adjusted to a pH of 7.0-8.5 with triethylamine (variable amount) to extract the product into the organic phase. The organic phase was separated, washed twice with water (350 kg, 5.0 rel. vol.), then filtered through carbon, and subsequently treated repeatedly with Quadrasil-MP (17.5 kg, 0.25 rel. wt.), with the spent scavenger clumps washed with methanol each time until the palladium specifications were met. The filtrate was concentrated to 5 rel. vol. Ethanol (276 kg, 5 rel. vol.) was added and concentrated to 5 rel. vol., and this procedure was repeated two more times. Next, the mixture was heated to 50°C, cooled to 20°C, and filtered. The product was washed twice with ethanol (55 kg, 1.0 rel. vol.), then the wet clumps were returned to the container and dissolved in methanol (831 kg, 15 rel. vol.) at 60°C. The filtrate was concentrated to 5 rel. vol. Ethanol (276 kg, 5 rel. vol.) was added and concentrated to 5 rel. vol., and this procedure was repeated once.Next, the mixture was heated to 50°C, cooled to 20°C, and filtered. The product was washed twice with ethanol (55 kg, 1.0 rel. vol.), and then dried under vacuum at 50°C to obtain acalabrutinib (compound VIII, 52.2 kg, 64%) as a white crystalline solid.

[0234] Example 17: Preparation of 4-{8-amino-3-[(2S)-1-(buta-2-inoyl)pyrrolidine-2-yl]imidazo[1,5-a]pyrazine-1-yl}-N-(pyridine-2-yl)benzamide (compound (VIII)) [ka] The synthesis described in Example 16 was further modified to yield a product with sufficient purity, in particular, allowing for greater flexibility in operating conditions. Among other advantages, the modified synthesis offers improvements in the removal of certain impurities.

[0235] 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazine-1-yl}-N-(2-pyridinyl)-benzamide (compound (VII), 131.7 kg, 1.0 mol.eq.) was prepared as a slurry in dichloromethane (955 L, 7.25 rel. vol.) and triethylamine (90.1 kg, 2.7 mol.eq.). After adding 2-butic acid (33.3 kg, 1.2 mol.eq.) in dichloromethane (263.4 L, 2.0 rel. vol.), 1-propylphosphonic anhydride (T3P) (50% w / w solution in dichloromethane, 209.8 kg, 1.0 mol.eq.) was added. The resulting organic solution was washed twice with water (658.5 L, 5.0 rel. vol.), followed by the addition of water (1317 L, 10.0 rel. vol.). Next, the mixture was acidified to approximately pH 2.2 using a 6 M hydrochloric acid aqueous solution, followed by the addition of a 2 M hydrochloric acid aqueous solution to reach a pH of 1.8–2.2. The organic phase was then separated and discarded. Dichloromethane (1317 L, 10.0 rel. vol.) was added to the aqueous phase, and the mixture was adjusted to pH 4.5–5.0 with triethylamine. The organic phase was separated, and the aqueous phase was re-extracted with dichloromethane (527 L, 4.0 rel. vol.). The combined dichloromethane extract was screened, and the organic phase was concentrated to approximately 5.0 rel. vol. Ethanol (1712 L, 13.0 rel. vol.) was added, and the mixture was distilled while maintaining a constant volume (18.0 rel. vol.) by adding ethanol (1580 L, 12.0 rel. vol.) (approximately 360 mbar). A portion of the crystallized 4-{8-amino-3-[(2S)-1-(buta-2-inoyl)pyrrolidine-2-yl]imidazo[1,5-a]pyrazine-1-yl}-N-(pyridine-2-yl)benzamide (compound (VIII), 1.32 kg, 0.01 rel. wt.) 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 rel. vol.) and then dried under vacuum at 50°C to obtain acalabrutinib (compound VIII, 113.6 kg, 74%) as a white crystalline solid.

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

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

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

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

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

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

[0242] The organic phase was concentrated under vacuum at 40 °C to 45 °C (to about 5.0 rel.vol.), and the mixture was heated to 60 °C. After stirring for 15 minutes to obtain a solution, the mixture was cooled to 50 °C. Methyl tert-butyl ether (1.6 L, 4.4 rel.vol.) was added dropwise to the mixture until a suspension was observed. The mixture was cooled to 5 °C to 10 °C for 3 hours and stirred for 12 hours. It was filtered, and the wet mass was 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 stereoisomers in solution, and the resonances are cited only for the major stereoisomer. 1 H NMR (500 MHz, DMSO-d6) δ 1.75 - 1.85 (m, 2H), 1.87 - 1.93 (m, 1H), 2.12 - 2.21 (m, 1H), 3.34 - 3.40 (m, 1H), 3.42 - 3.​​​​​​​​​​​​​​​​​​​​​​ Or, contacting a salt thereof with 2-butic acid or a salt thereof in a reaction medium in the presence of 1-propylphosphonic anhydride and a base to form a reaction mixture containing the compound of formula (VIII) or a salt thereof, and one or more reaction byproducts; and This method involves selectively isolating a compound of formula (VIII) or a salt thereof from a reaction mixture for one or more reaction by-products.

[0244] Embodiment 2. The contact process is, Adding the compound of formula (VII), or a salt thereof, and a base to the reaction medium; Adding 2-butyric acid, or a salt thereof, to a reaction medium containing the compound of formula (VII), or a salt thereof, and a base; and The process of Embodiment 1, comprising adding 1-propylphosphonic anhydride to a reaction medium comprising a compound of formula (VII) or a salt thereof; 2-butyric acid or a salt thereof; and a base.

[0245] Embodiment 3. The process is Compounds having the structure of formula (VII): [ka] Alternatively, contact the salt thereof with 2-butic acid or a salt thereof in a reaction medium in the presence of 1-propylphosphonic anhydride and a base to form a reaction mixture containing the compound of formula (VIII) or a salt thereof; an unreacted compound of formula (VII) or a salt thereof; and a reaction byproduct (the reaction byproduct being a compound having the structure of formula (XIV): [ka] or including its salt); and The process of Embodiment 1 or 2, comprising selectively isolating a compound of formula (VIII) or a salt thereof from a reaction mixture with respect to a compound of formula (VII) or a salt thereof, and a compound of formula (XIV) or a salt thereof.

[0246] Embodiment 4. The process is Compounds having the structure of formula (VII): [ka] Alternatively, contact the salt thereof with 2-butic acid or a salt thereof in a reaction medium in the presence of 1-propylphosphonic anhydride and a base to form a reaction mixture containing the compound of formula (VIII) or a salt thereof; an unreacted compound of formula (VII) or a salt thereof; and a reaction byproduct (the reaction byproduct being a compound having the structure of formula (XIV): [ka] or including its salt); Extracting at least a portion of the compound of formula (VIII), or its salt, from the reaction mixture into the aqueous phase (the compound of formula (VIII), or its salt, is selectively extracted into the aqueous phase relative to the compound of formula (XIV), or its salt); Adjusting the pH of the aqueous phase; and The process of Embodiment 1 or 2, comprising extracting at least a portion of the compound of formula (VIII), or a salt thereof, from the aqueous phase into the organic phase (the compound of formula (VIII), or a salt thereof, is selectively extracted into the organic phase relative to the compound of formula (VII), or a salt thereof).

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

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

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

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

[0251] Embodiment 9. Any of the processes of Embodiments 4 to 8, wherein the process further comprises isolating the compound of formula (VIII) from the organic phase from which the compound of formula (VIII) has been selectively extracted.

[0252] Embodiment 10. A process according to any of Embodiments 4 to 9, wherein the aqueous phase contains more than approximately 75 area percent of the compound of formula (VIII), as measured by high-performance liquid chromatography at the completion of aqueous phase extraction.

[0253] Embodiment 11. A process according to any of Embodiments 4 to 9, wherein the aqueous phase contains less than about 2.0 area % of the compound of formula (XIV), as measured by high-performance liquid chromatography at the completion of aqueous phase extraction.

[0254] Embodiment 12. Any process of Embodiments 4 to 9, wherein the aqueous phase contains more than about 75 area percent of the compound of formula (VIII) and less than about 2.0 area percent of the compound of formula (XIV), as measured by high-performance liquid chromatography at the completion of aqueous phase extraction.

[0255] Embodiment 13. A process according to any of Embodiments 4 to 12, wherein the organic phase contains at least about 75 area % of the compound of formula (VIII), as measured by high-performance liquid chromatography upon completion of organic phase extraction.

[0256] Embodiment 14. Any process of Embodiments 4 to 12, wherein the organic phase contains less than about 2.0 area % of the compound of formula (VII), as measured by high-performance liquid chromatography at the completion of organic phase extraction.

[0257] Embodiment 15. A process according to any of Embodiments 4 to 12, wherein the organic phase contains at least about 75 area % of the compound of formula (VIII) and less than about 2.0 area % of the compound of formula (VII), as measured by high-performance liquid chromatography at the completion of organic phase extraction.

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

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

[0260] Embodiment 18. Any process of Embodiments 4 to 15, wherein the aqueous phase has a pH greater than approximately 4.0 during the organic phase extraction step.

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

[0262] Embodiment 20. A process according to any of Embodiments 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.

[0263] Embodiment 21. A process according to any of Embodiments 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.

[0264] Embodiment 22. Any process of Embodiments 4 to 19, wherein the reaction medium comprises dichloromethane.

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

[0266] Embodiment 24. Any of the processes of Embodiments 4 to 22, wherein the base comprises triethylamine.

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

[0268] Embodiment 26. Any process of Embodiments 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.

[0269] Embodiment 27. A process according to any of Embodiments 4 to 24, wherein the organic phase contains dichloromethane.

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

[0271] Embodiment 29. Any process of Embodiments 4 to 27, wherein the compound of formula (VII) is contacted with about 1.0 to about 1.3 molar equivalents of 2-butyric acid relative to the compound of formula (VII).

[0272] Embodiment 30. A process according to any of Embodiments 4 to 27, wherein the compound of formula (VII) is contacted with about 1.2 molar equivalents of 2-butyric acid relative to the compound of formula (VII).

[0273] Embodiment 31. Any process of Embodiments 4 to 30, wherein about 0.3 to about 3.0 molar equivalents of 1-propylphosphonic anhydride relative to the compound of formula (VII) are packed into the reaction medium.

[0274] Embodiment 32. Any process of Embodiments 4 to 30, wherein about 0.5 to about 2.0 molar equivalents of 1-propylphosphonic anhydride relative to the compound of formula (VII) are packed into the reaction medium.

[0275] Embodiment 33. Any process of Embodiments 4 to 30, wherein about 0.7 to about 1.5 molar equivalents of 1-propylphosphonic anhydride relative to the compound of formula (VII) are packed into the reaction medium.

[0276] Embodiment 34. Any process of Embodiments 4 to 30, wherein about 1.0 to about 1.2 molar equivalents of 1-propylphosphonic anhydride relative to the compound of formula (VII) are packed into the reaction medium.

[0277] Embodiment 35. Any process from Embodiments 4 to 34, wherein about 1.0 to about 10.0 molar equivalents of base relative to the compound of formula (VII) are packed into the reaction medium.

[0278] Embodiment 36. Any of the processes of Embodiments 4 to 34, wherein about 2.0 to about 5.0 molar equivalents of base relative to the compound of formula (VII) are packed into the reaction medium.

[0279] Embodiment 37. Any process from Embodiments 4 to 34, wherein about 2.4 to about 3.0 molar equivalents of base relative to the compound of formula (VII) are packed into the reaction medium.

[0280] Embodiment 38. The process of Embodiments 4 to 37, wherein the reaction medium is maintained at a temperature of approximately 10°C to approximately 30°C during the contact step.

[0281] Embodiment 39. Any process of Embodiments 4 to 38, wherein the volume of the reaction medium is about 5 liters to about 20 liters of reaction medium per kilogram of compound of formula (VII) filled into the reaction medium.

[0282] Embodiment 40. Any process of Embodiments 4 to 39, wherein the contact step is performed as a batch reaction.

[0283] Embodiment 41. The process of Embodiment 40, wherein at least about 25 kilograms of the compound of formula (VII) are packed into a batch reaction.

[0284] Embodiment 42. The process of Embodiment 40, wherein at least about 50 kilograms of the compound of formula (VII) are packed into a batch reaction.

[0285] Embodiment 43. The process of Embodiment 40, wherein at least about 75 kilograms of the compound of formula (VII) are packed into a batch reaction.

[0286] Embodiment 44. The process of Embodiment 40, wherein at least about 100 kilograms of the compound of formula (VII) are packed into a batch reaction.

[0287] Embodiment 45. A process according to any of Embodiments 4 to 44, wherein the compound of formula (VIII) is isolated from the organic phase by crystallization.

[0288] Embodiment 46. A process according to any of Embodiments 4 to 44, wherein the organic phase comprises an organic phase solvent, and the process further comprises replacing the organic phase solvent with a substitution solvent to form a crystalline mixture containing a compound of formula (VIII).

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

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

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

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

[0293] Embodiment 51. A process according to any of Embodiments 48 to 50, wherein the crystalline form is anhydrous crystalline form.

[0294] Embodiment 52. Any process of Embodiments 46 to 51, wherein the organic phase solvent includes a polar solvent.

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

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

[0297] Embodiment 55. Any process of Embodiments 46 to 51, wherein the organic phase solvent contains dichloromethane.

[0298] Embodiment 56. Any process of Embodiments 46 to 55, wherein the substitution solvent contains an alcohol.

[0299] Embodiment 57. Any process of Embodiments 46 to 55, wherein the substitution solvent contains ethanol.

[0300] Embodiment 58. Any process of Embodiments 46 to 51, wherein the organic phase solvent includes a polar solvent and the substitution solvent includes an alcohol.

[0301] Embodiment 59. Any process of Embodiments 46 to 51, wherein the organic phase solvent contains dichloromethane and the substitution solvent contains ethanol.

[0302] Embodiment 60. Any process of Embodiments 46 to 51, wherein the organic phase solvent has a boiling point lower than the boiling point of the substitution solvent.

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

[0304] Embodiment 62. Any process of Embodiments 46 to 61, wherein the organic phase solvent is replaced with a substituted solvent by continuous level distillation.

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

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

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

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

[0309] Embodiment 67. Any process of Embodiments 62 to 66, wherein continuous-level vacuum distillation is performed at a temperature not exceeding approximately 60°C.

[0310] Embodiment 68. A process according to any of Embodiments 46 to 67, wherein the crystallized mixture is seeded in the crystalline form of the compound of formula (VIII), and maintained at a temperature above about 40°C for at least about 5 hours after seeding.

[0311] Embodiment 69. Any process of Embodiments 46 to 68, wherein the crystallized mixture is cooled to a temperature of about 20°C for at least 5 hours before isolating the compound of formula (VIII).

[0312] Embodiment 70. A process according to any of Embodiments 1 to 69, wherein the stoichiometric process yield of the compound of formula (VIII) is at least about 50%.

[0313] Embodiment 71. A process according to any of Embodiments 1 to 69, wherein the stoichiometric process yield of the compound of formula (VIII) is at least about 60%.

[0314] Embodiment 72. Compound having the structure of formula (VII): [ka] It is a crystalline form of, A crystal morphology characterized by a reflection X-ray powder diffraction pattern containing at least three peaks selected from the group consisting of 9.9±0.2°2θ, 11.1±0.2°2θ, 12.8±0.2°2θ, 14.1±0.2°2θ, and 19.0±0.2°2θ.

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

[0316] Embodiment 74. The process of Embodiment 73, wherein the isolation step includes filtering a substantially anhydrous mixture.

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

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

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

[0320] Embodiment 78. A process according to any one of Embodiments 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.

[0321] Embodiment 79. A process according to any of Embodiments 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.

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

[0323] Embodiment 81. A process according to any of Embodiments 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, tributylamine, diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, methyldicyclohexylamine, and potassium phosphate.

[0324] Embodiment 82. A process according to any of Embodiments 73 to 80, wherein the base comprises triethylamine.

[0325] Embodiment 83. Any of the processes of Embodiments 73 to 80, wherein the base comprises potassium carbonate.

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

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

[0328] Embodiment 86. Any process of Embodiments 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).

[0329] Embodiment 87. Any process of Embodiments 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).

[0330] Embodiment 88. Any process of Embodiments 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).

[0331] Embodiment 89. A process according to any of Embodiments 77 to 88, wherein about 0.1 to about 1.0 molar equivalents of potassium iodide relative to the compound of formula (VI) are packed into an aqueous reaction medium.

[0332] Embodiment 90. A process according to any of Embodiments 77 to 88, wherein about 0.2 to about 0.4 molar equivalents of potassium iodide relative to the compound of formula (VI) are packed into an aqueous reaction medium.

[0333] Embodiment 91. A process according to any of Embodiments 73 to 90, wherein about 0.5 to about 10 molar equivalents of a base relative to the compound of formula (VI) are packed into an aqueous reaction medium.

[0334] Embodiment 92. Any process of Embodiments 73 to 90, wherein the base comprises triethylamine, and about 0.5 to about 10 molar equivalents of triethylamine relative to the compound of formula (VI) are packed into the aqueous reaction medium.

[0335] Embodiment 93. Any process of Embodiments 73 to 90, wherein the base comprises triethylamine, and about 1.0 to about 2.0 molar equivalents of triethylamine relative to the compound of formula (VI) are packed into the aqueous reaction medium.

[0336] Embodiment 94. Any process of Embodiments 73 to 90, wherein the base contains potassium carbonate, and about 0.5 to about 10.0 molar equivalents of potassium carbonate relative to the compound of formula (VI) are packed into the aqueous reaction medium.

[0337] Embodiment 95. Any process of Embodiments 73 to 90, wherein the base contains potassium carbonate, and about 2.0 to about 3.0 molar equivalents of potassium carbonate relative to the compound of formula (VI) are packed into the aqueous reaction medium.

[0338] Embodiment 96. Any process of Embodiments 73 to 90, wherein the base contains potassium carbonate, and about 2.3 to about 2.7 molar equivalents of potassium carbonate relative to the compound of formula (VI) are packed into the aqueous reaction medium.

[0339] Embodiment 97. A process according to any of Embodiments 73 to 96, wherein about 0.002 to about 0.05 molar equivalents of a palladium catalyst relative to the compound of formula (VI) are packed into an aqueous reaction medium.

[0340] Embodiment 98. A process according to any of Embodiments 73 to 96, wherein about 0.007 to about 0.013 molar equivalents of a palladium catalyst relative to the compound of formula (VI) are packed into an aqueous reaction medium.

[0341] Embodiment 99. Any process of Embodiments 73 to 98, wherein the aqueous reaction medium is maintained at a temperature of approximately 50°C to approximately 100°C during the contact step.

[0342] Embodiment 100. Any process of Embodiments 73 to 98, wherein the aqueous reaction medium is maintained at a temperature of approximately 70°C to approximately 90°C during the contact step.

[0343] Embodiment 101. A process according to any of Embodiments 73 to 100, wherein the volume of the aqueous reaction medium is about 10 liters to about 20 liters of aqueous reaction medium per kilogram of compound of formula (VI) filled into the aqueous reaction medium.

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

[0345] Embodiment 103. A process of any of Embodiments 73 to 101, wherein the contact step is performed as a batch reaction.

[0346] Embodiment 104. The process of Embodiment 103, wherein at least about 25 kilograms of the compound of formula (VI) are packed into the batch reaction.

[0347] Embodiment 105. The process of Embodiment 103, wherein at least about 50 kilograms of the compound of formula (VI) are packed into a batch reaction.

[0348] Embodiment 106. The process of Embodiment 103, wherein at least about 75 kilograms of the compound of formula (VI) are packed into the batch reaction.

[0349] Embodiment 107. The process of Embodiment 103, wherein at least about 100 kilograms of the compound of formula (VI) are packed into a batch reaction.

[0350] Embodiment 108. The reduction step is a process of any of Embodiments 73 to 107, comprising separating the reaction mixture into an aqueous waste phase and an organic phase containing the compound of formula (VII).

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

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

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

[0354] Embodiment 112. Any process of Embodiments 109 to 111, wherein the organic phase is treated with a silica scavenger before distillation for at least 2 hours.

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

[0356] Embodiment 114. The process of Embodiment 111 or 112, wherein the silica scavenging agent comprises QuadraSil® MP.

[0357] Embodiment 115. Any of the processes of Embodiments 111 to 114, wherein the process further includes removing the silica scavenger from the organic phase before distillation.

[0358] Embodiment 116. Any of the processes of Embodiments 111 to 114, wherein the process further includes removing the silica scavenger from the organic phase by filtration before distillation.

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

[0360] Embodiment 118. The process of reducing is The reaction mixture is separated into an aqueous phase to be discarded and an organic phase containing the compound of formula (VII); Wash the organic phase with water; Treating the organic phase with a silica scavenger; Removal of silica scavengers from the organic phase; Washing the organic phase with an aqueous salt solution; and A process according to any of embodiments 109 to 117, comprising distilling an organic phase under conditions sufficient to reduce the amount of water present in the organic phase.

[0361] Embodiment 119. Any process from Embodiments 109 to 118, wherein the organic phase is distilled by vacuum distillation.

[0362] Embodiment 120. Any process from Embodiments 109 to 118, wherein the organic phase is distilled by continuous vacuum distillation.

[0363] Embodiment 121. Any process from Embodiments 109 to 120, wherein the organic phase is distilled at a temperature not exceeding approximately 60°C.

[0364] Embodiment 122. Any process from Embodiments 109 to 120, wherein the organic phase is distilled at a temperature of approximately 50°C to approximately 60°C.

[0365] Embodiment 123. Any process of Embodiments 109 to 122, wherein the organic phase includes an alcohol.

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

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

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

[0369] Embodiment 127. Any process of Embodiments 73 to 126, wherein the substantially anhydrous mixture contains less than about 5% by weight of water.

[0370] Embodiment 128. Any process of Embodiments 73 to 126, wherein the substantially anhydrous mixture contains less than about 3% by weight of water.

[0371] Embodiment 129. Any process of Embodiments 73 to 128, wherein the isolation step includes crystallizing a compound of formula (VII) from a substantially anhydrous mixture.

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

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

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

[0375] Embodiment 133. A process according to any of Embodiments 73 to 132, wherein the stoichiometric process yield of the compound of formula (VII) is at least about 50%.

[0376] Embodiment 134. A process according to any of Embodiments 73 to 132, wherein the stoichiometric process yield of the compound of formula (VII) is at least about 65%.

[0377] Embodiment 135. A process according to any of Embodiments 73 to 132, wherein the stoichiometric process yield of the compound of formula (VII) is at least about 75%.

[0378] Embodiment 136. Compound having the structure of formula (VI): [ka] or a process for preparing the salt thereof, the process is Compound of formula (IV): [ka] Alternatively, contact the salt thereof with an acidic medium under conditions sufficient to deprotect the compound of formula (IV) and form a reaction mixture containing the compound of formula (VI), or its salt, and a benzyl halide byproduct; To remove at least a portion of the benzyl halogen by-products from the reaction mixture; and A process comprising isolating a compound of formula (VI), or a salt thereof, from a reaction mixture under conditions sufficient to substantially avoid the formation of aminal impurities.

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

[0380] Embodiment 138. The isolation step is, Extracting at least a portion of the benzyl halogen by-products from the reaction mixture into a discarded organic phase; Raise the pH of the resulting reaction mixture to a basic pH to form a basic reaction medium containing the compound of formula (VI) or its salt; Extracting the compound of formula (VI), or a salt thereof, from a basic reaction medium into the product organic phase; and The process of Embodiment 136, comprising isolating a compound of formula (VI) or a salt thereof from the product organic phase.

[0381] Embodiment 139. Any process of Embodiments 136 to 138, wherein the acidic medium is an aqueous acidic medium.

[0382] Embodiment 140. A process according to any of Embodiments 136 to 139, wherein a sulfate of the compound of formula (IV) is brought into contact with an acidic medium.

[0383] Embodiment 141. Any process of Embodiments 136 to 140, wherein the acidic medium contains a mineral acid.

[0384] Embodiment 142. Any process of Embodiments 136 to 140, wherein the acidic medium contains hydrochloric acid.

[0385] Embodiment 143. Any process of Embodiments 136 to 142, wherein the acidic medium contains at least about 10 molar equivalents of acid relative to the compound of formula (IV) or a salt thereof.

[0386] Embodiment 144. Any process of Embodiments 136 to 142, wherein the acidic medium contains about 10 to about 40 molar equivalents of acid relative to the compound of formula (IV) or a salt thereof.

[0387] Embodiment 145. Any process of Embodiments 136 to 142, wherein the acidic medium contains about 10 to about 25 molar equivalents of acid relative to the compound of formula (IV) or a salt thereof.

[0388] Embodiment 146. Any process of Embodiments 136 to 145, wherein the volume of the acidic medium is about 2 to 10 liters of acidic medium per kilogram of compound of formula (IV) or its salt filled into the acidic medium.

[0389] Embodiment 147. Any process of Embodiments 136 to 145, wherein the volume of the acidic medium is about 3 to 4 liters of acidic medium per kilogram of compound of formula (IV) or its salt filled into the acidic medium.

[0390] Embodiment 148. Any process of Embodiments 136 to 147, wherein the acidic medium is maintained at a temperature of approximately 25°C to approximately 70°C during the contact step.

[0391] Embodiment 149. Any process of Embodiments 136 to 147, wherein the acidic medium is maintained at a temperature of approximately 40°C to approximately 50°C during the contact step.

[0392] Embodiment 150. Any of the processes from Embodiments 136 to 149, wherein the contact step is performed as a batch reaction.

[0393] Embodiment 151. The process of Embodiment 150, wherein at least about 50 kilograms of the compound of formula (IV) are packed into a batch reaction.

[0394] Embodiment 152. The process of Embodiment 150, wherein at least about 100 kilograms of the compound of formula (IV) are packed into a batch reaction.

[0395] Embodiment 153. The process of Embodiment 150, wherein at least about 200 kilograms of the compound of formula (IV) are packed into a batch reaction.

[0396] Embodiment 154. The process of Embodiment 150, wherein at least about 300 kilograms of the compound of formula (IV) are packed into a batch reaction.

[0397] Embodiment 155. Any of the processes of Embodiments 136 to 154, wherein the process includes selectively extracting at least a portion of the benzyl halide by-products from the reaction mixture into an organic phase that is discarded relative to the compound of formula (VI) prior to the isolation step.

[0398] Embodiment 156. The process of Embodiment 155, wherein at least about 80% by weight of the benzyl halogen by-product compound present in the reaction mixture is extracted into the organic phase to be discarded.

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

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

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

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

[0403] Embodiment 161. A process according to any of Embodiments 155 to 160, wherein the organic phase to be discarded comprises at least one solvent selected from the group consisting of alkyl hydrocarbons, aromatic hydrocarbons, chloride hydrocarbons, and ethers.

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

[0405] Embodiment 163. A process according to any of Embodiments 155 to 160, wherein the organic phase to be discarded contains heptane.

[0406] Embodiment 164. The process further, After extraction of the benzyl halogen byproduct, raise the pH of the reaction mixture to form a basic reaction medium containing the compound of formula (VI) or a salt thereof; and A process according to any of Embodiments 155 to 163, comprising extracting a compound of formula (VI) or a salt thereof from a basic reaction medium into the product organic phase.

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

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

[0409] Embodiment 167. A process according to any of Embodiments 164 to 166, wherein the product organic phase comprises at least one solvent selected from the group consisting of alkyl hydrocarbons, aromatic hydrocarbons, chloride hydrocarbons, and ethers.

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

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

[0412] Embodiment 170. Any of the processes of Embodiments 164 to 169, wherein the process further includes washing the product organic phase with water.

[0413] Embodiment 171. Any of the processes of Embodiments 164 to 170, wherein the process further includes distilling the product organic phase under conditions sufficient to reduce the amount of water present in the product organic phase.

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

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

[0416] Embodiment 174. Any process of Embodiments 136 to 173, wherein the isolation step includes crystallizing the compound of formula (VI).

[0417] Embodiment 175. The process of Embodiment 174, wherein the isolation step further includes seeding the compound of formula (VI) in a crystalline form to promote crystallization.

[0418] Embodiment 176. The process of Embodiment 174, wherein the isolation step includes seeding in a crystalline form of the compound of formula (VI) at least about 0.0005 relative weight to promote crystallization.

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

[0420] Embodiment 178. Any of the processes of Embodiments 175 to 177, wherein the process further includes filling with a poor solvent to promote crystallization.

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

[0422] Embodiment 180. The isolation step is, Selectively extracting at least a portion of the benzyl halogen by-product from the reaction mixture into an organic phase discarded for the compound of formula (VI); Raise the pH of the resulting reaction mixture to a pH above approximately 7.0 to form a basic reaction mixture; Selective extraction of at least a portion of the compound of formula (VI) from the basic reaction mixture into the product organic phase; and The process of Embodiment 136, comprising distilling the product organic phase under conditions sufficient to reduce the amount of water present in the product organic phase to form a distilled organic phase containing the compound of formula (VI).

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

[0424] Embodiment 182. The aminal impurity is a compound having the structure of formula (X): [ka] A process according to any of embodiments 136 to 181, or a process comprising the salt thereof.

[0425] Embodiment 183. Any process of Embodiments 136 to 182, wherein the isolated compound of formula (VI), or a salt thereof, contains less than 5% by weight of aminal impurities.

[0426] Embodiment 184. Any process of Embodiments 136 to 182, wherein the isolated compound of formula (VI), or a salt thereof, contains less than 3% by weight of aminal impurities.

[0427] Embodiment 185. Any process of Embodiments 136 to 182, wherein the isolated compound of formula (VI), or a salt thereof, contains less than 1% by weight of an aminal impurity.

[0428] Embodiment 186. Any process of Embodiments 136 to 185, wherein the stoichiometric process yield of the compound of formula (VI) is at least about 50%.

[0429] Embodiment 187. A process according to any of Embodiments 136 to 185, wherein the stoichiometric process yield of the compound of formula (VI) is at least about 65%.

[0430] Embodiment 188. Any process of Embodiments 136 to 185, wherein the stoichiometric process yield of the compound of formula (VI) is at least about 80%.

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

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

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

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

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

[0436] Embodiment 194. Any process of Embodiments 189 to 193, wherein the reaction medium does not contain N,N-dimethylformamide.

[0437] Embodiment 195. Any process of Embodiments 189 to 194, wherein the organic solvent comprises at least one solvent selected from the group consisting of aromatic hydrocarbons, aromatic heterocyclic compounds, and nitriles.

[0438] Embodiment 196. Any process of Embodiments 189 to 194, wherein the organic solvent comprises a compound selected from the group consisting of toluene, acetonitrile, and pyridine.

[0439] Embodiment 197. Any process of Embodiments 189 to 194, wherein the organic solvent contains toluene.

[0440] Embodiment 198. Any process of Embodiments 189 to 197, wherein the volume of the reaction medium is about 3 liters to about 30 liters of reaction medium per kilogram of 4-carboxyphenyl-boronic acid or its salt filled into the reaction medium.

[0441] Embodiment 199. Any process of Embodiments 189 to 197, wherein the volume of the reaction medium is about 5 liters to about 15 liters of reaction medium per kilogram of 4-carboxyphenyl-boronic acid or its salt filled into the reaction medium.

[0442] Embodiment 200. Any process of Embodiments 189 to 199, wherein the reaction medium is maintained at a temperature of approximately 50°C to approximately 90°C during the contact step.

[0443] Embodiment 201. Any process of Embodiments 189 to 199, wherein the reaction medium is maintained at a temperature of approximately 60°C to approximately 80°C during the contact step.

[0444] Embodiment 202. A process of any of Embodiments 189 to 201, wherein the contact step is performed as a batch reaction.

[0445] Embodiment 203. Any process of Embodiments 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.

[0446] Embodiment 204. A process according to any of Embodiments 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.

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

[0448] Embodiment 206. A process according to any of Embodiments 189 to 205, wherein about 1.5 to 5 molar equivalents of 2-aminopyridine relative to 4-carboxyphenylboronic acid or a salt thereof are packed into the reaction medium.

[0449] Embodiment 207. A process according to any of Embodiments 189 to 205, wherein about 1.5 to 3.5 molar equivalents of 2-aminopyridine relative to 4-carboxyphenylboronic acid or a salt thereof are packed into the reaction medium.

[0450] Embodiment 208. A process according to any of Embodiments 189 to 205, wherein about 2 molar equivalents of 2-aminopyridine are packed into the reaction medium relative to 4-carboxyphenylboronic acid or a salt thereof.

[0451] Embodiment 209. A process according to any of Embodiments 189 to 208, wherein the stoichiometric process yield of the compound of formula (V) is at least about 50%.

[0452] Embodiment 210. A process according to any of Embodiments 189-208, wherein the stoichiometric process yield of the compound of formula (V) is at least about 70%.

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

[0454] Embodiment 212. The crystalline sulfate of Embodiment 211, wherein the crystalline sulfate has a stoichiometric ratio of one sulfate molecule and one bisulfate molecule for every three free base molecules.

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

[0456] Embodiment 214. Compound having the structure of formula (IV): [ka] A process for preparing a sulfate of, the process is Compounds having the structure of formula (III): [ka] Alternatively, contacting the salt thereof with an amination agent in a reaction medium to form a reaction mixture containing the compound of formula (IV); Forming sulfates of compounds of formula (IV); and A process that includes isolating sulfates.

[0457] Embodiment 215. The process of Embodiment 214, wherein the sulfate has a stoichiometric ratio of one sulfate molecule and one bisulfate molecule for every three free base molecules.

[0458] Embodiment 216. The process of Embodiment 214 or 215, wherein the process includes isolating the compound of formula (IV) from the reaction mixture as a free base before the formation step.

[0459] Embodiment 217. The process is, Isolating the compound of formula (IV) from the reaction medium as a free base; Contacting a free base with sulfuric acid to form a sulfate; and A process of Embodiment 214 or 215, comprising isolating the sulfate.

[0460] Embodiment 218. The process is, Washing the reaction mixture to reduce the amount of ammonia present in the reaction mixture; Isolating the compound of formula (IV) from the reaction medium after washing with free base; Contacting a free base with sulfuric acid to form a sulfate; and A process of Embodiment 214 or 215, comprising isolating the sulfate.

[0461] Embodiment 219. The process is, Wash the reaction mixture with a saline solution; Distilling the washed reaction mixture to reduce the amount of ammonia present in the washed reaction mixture; Isolating the compound of formula (IV) from the reaction medium distilled as a free base; Contacting a free base with sulfuric acid to form a sulfate; and A process of Embodiment 214 or 215, comprising isolating the sulfate.

[0462] Embodiment 220. Any of the processes of Embodiments 214 to 219, wherein the process further includes isolating the sulfate by filtration.

[0463] Embodiment 221. Any process of Embodiments 214 to 220, wherein the amination agent is ammonia.

[0464] Embodiment 222. Any of the processes of Embodiments 214 to 220, wherein the amination agent is ammonium hydroxide.

[0465] Embodiment 223. Any process of Embodiments 214 to 221, wherein the reaction medium comprises at least one solvent selected from the group consisting of alkyl hydrocarbons, aromatic hydrocarbons, chloride hydrocarbons, aromatic heterocyclic compounds, alcohols, ethers, and dipolar aprotic solvents.

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

[0467] Embodiment 225. Any process of Embodiments 214 to 221, wherein the reaction medium comprises an aliphatic alcohol.

[0468] Embodiment 226. Any process of Embodiments 214 to 221, wherein the reaction medium comprises butanol.

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

[0470] Embodiment 228. Any process of Embodiments 214 to 227, wherein the reaction medium is maintained at a temperature above 70°C during the contact step.

[0471] Embodiment 229. Any process of Embodiments 214 to 227, wherein the reaction medium is maintained at a temperature above 90°C during the contact step.

[0472] Embodiment 230. Any process of Embodiments 214 to 227, wherein the reaction medium is maintained at a temperature of approximately 50°C to approximately 100°C during the contact step.

[0473] Embodiment 231. Any process of Embodiments 214 to 227, wherein the reaction medium is maintained at a temperature of approximately 60°C to approximately 95°C during the contact step.

[0474] Embodiment 232. Any process of Embodiments 214 to 231, wherein the volume of the reaction medium is about 1.5 liters to about 40 liters of reaction medium per kilogram of the compound of formula (III) or its salt filled in the reaction medium.

[0475] Embodiment 233. Any process of Embodiments 214 to 231, wherein the volume of the reaction medium is about 2.0 liters to about 30 liters of reaction medium per kilogram of the compound of formula (III) or its salt filled in the reaction medium.

[0476] Embodiment 234. Any of the processes in Embodiments 214 to 233, wherein the contact step is performed as a batch reaction.

[0477] Embodiment 235. The process of Embodiment 234, wherein at least about 50 kilograms of the compound of formula (III) are packed into the batch reaction.

[0478] Embodiment 236. The process of Embodiment 234, wherein at least about 100 kilograms of the compound of formula (III) are packed into the batch reaction.

[0479] Embodiment 237. The process of Embodiment 234, wherein at least about 200 kilograms of the compound of formula (III) are packed into a batch reaction.

[0480] Embodiment 238. The process of Embodiment 234, wherein at least about 300 kilograms of the compound of formula (III) are packed into the batch reaction.

[0481] Embodiment 239. Any process of Embodiments 214 to 238, wherein the forming step includes contacting a compound of formula (IV) with sulfuric acid to form a sulfate mixture containing a sulfate.

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

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

[0484] Embodiment 242. Any process of Embodiments 214 to 241, wherein the stoichiometric process yield of the sulfate of formula (IV) is at least about 50%.

[0485] Embodiment 243. Any process of Embodiments 214 to 241, wherein the stoichiometric process yield of the sulfate of formula (IV) is at least about 65%.

[0486] Embodiment 244. Any process of Embodiments 214 to 241, wherein the stoichiometric process yield of the sulfate of formula (IV) is at least about 80%.

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

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

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

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

[0491] Embodiment 249. Any process of Embodiments 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.

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

[0493] Embodiment 251. Any process of Embodiments 245 to 248, wherein the reaction medium comprises acetonitrile.

[0494] Embodiment 252. A process according to any of Embodiments 245 to 251, wherein a compound of formula (I), or a salt thereof, is contacted with a cyclizing agent in an amount of about 0.7 to about 10 molar equivalents relative to the compound of formula (I), or a salt thereof.

[0495] Embodiment 253. A process according to any of Embodiments 245 to 251, wherein a compound of formula (I), or a salt thereof, is contacted with a cyclizing agent in an amount of about 1.5 to about 2.5 molar equivalents relative to the compound of formula (I), or a salt thereof.

[0496] Embodiment 254. Any process of Embodiments 245 to 251, wherein a compound of formula (I), or a salt thereof, is contacted with a cyclizing agent in an amount of about 2.0 molar equivalents relative to the compound of formula (I), or a salt thereof.

[0497] Embodiment 255. A process according to any of Embodiments 245 to 254, wherein at least about 0.1 molar equivalents of a catalyst relative to the compound of formula (I) or a salt thereof are packed into the reaction medium.

[0498] Embodiment 256. Any process of Embodiments 245 to 254, wherein about 0.1 to about 1.0 molar equivalent of a catalyst relative to the compound of formula (I) or a salt thereof is packed into the reaction medium.

[0499] Embodiment 257. A process according to any of Embodiments 245 to 254, wherein at least about 0.4 molar equivalents of a catalyst relative to the compound of formula (I) or a salt thereof are packed into the reaction medium.

[0500] Embodiment 258. Any process of Embodiments 245 to 254, wherein about 0.4 to about 1.0 molar equivalent of a catalyst relative to the compound of formula (I) or a salt thereof is packed into the reaction medium.

[0501] Embodiment 259. Any process of Embodiments 245 to 254, wherein the catalyst comprises N,N-dimethylformamide, and at least about 0.1 molar equivalents of the catalyst relative to the compound of formula (I) or a salt thereof are packed into the reaction medium.

[0502] Embodiment 260. Any process of Embodiments 245 to 254, wherein the catalyst comprises N,N-dimethylformamide, and the catalyst is packed into the reaction medium in an amount of about 0.1 to about 1.0 molar equivalents relative to the compound of formula (I) or a salt thereof.

[0503] Embodiment 261. Any process of Embodiments 245 to 254, wherein the catalyst comprises N,N-dimethylformamide, and at least about 0.4 molar equivalents of the catalyst relative to a compound of formula (I) or a salt thereof are packed into the reaction medium.

[0504] Embodiment 262. Any process of Embodiments 245 to 254, wherein the catalyst comprises N,N-dimethylformamide, and about 0.4 to about 1.0 molar equivalents of the catalyst relative to the compound of formula (I) or a salt thereof are packed into the reaction medium.

[0505] Embodiment 263. Any process of Embodiments 245 to 254, wherein the catalyst comprises N,N-dimethylformamide, and at least about 0.6 molar equivalents of the catalyst relative to the compound of formula (I) or a salt thereof are packed into the reaction medium.

[0506] Embodiment 264. Any process of Embodiments 245 to 254, wherein the catalyst comprises N,N-dimethylformamide, and about 0.6 molar equivalents of the catalyst relative to the compound of formula (I) or a salt thereof are packed into the reaction medium.

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

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

[0509] Embodiment 267. Any process of Embodiments 245 to 266, wherein the reaction medium is maintained at a temperature of less than approximately 80°C during the contact step.

[0510] Embodiment 268. Any process of Embodiments 245 to 266, wherein the reaction medium is maintained at a temperature of less than approximately 50°C during the contact step.

[0511] Embodiment 269. Any process of Embodiments 245 to 266, wherein the reaction medium is maintained at a temperature of approximately 30°C to approximately 50°C during the contact step.

[0512] Embodiment 270. Any process of Embodiments 245 to 269, wherein the reaction medium is maintained at a temperature of approximately 40°C during the contact step.

[0513] Embodiment 271. Any process of Embodiments 245 to 270, wherein the volume of the reaction medium is about 2 liters to about 20 liters of reaction medium per kilogram of the compound of formula (I) or its salt filled in the reaction medium.

[0514] Embodiment 272. Any process of Embodiments 245 to 270, wherein the volume of the reaction medium is about 3 liters to about 10 liters of reaction medium per kilogram of the compound of formula (I) or its salt filled in the reaction medium.

[0515] Embodiment 273. Any of the processes in Embodiments 245 to 272, wherein the contact step is performed as a batch reaction.

[0516] Embodiment 274. The process of Embodiment 273, wherein at least about 50 kilograms of the compound of formula (I) are packed into the batch reaction.

[0517] Embodiment 275. The process of Embodiment 273, wherein at least about 100 kilograms of the compound of formula (I) are packed into a batch reaction.

[0518] Embodiment 276. The process of Embodiment 273, wherein at least about 200 kilograms of the compound of formula (I) are packed into a batch reaction.

[0519] Embodiment 277. The process of Embodiment 273, wherein at least about 300 kilograms of the compound of formula (I) are packed into a batch reaction.

[0520] Embodiment 278. A process according to any of Embodiments 245 to 277, wherein the stoichiometric process yield of the compound of formula (II) is at least about 50%.

[0521] Embodiment 279. A process according to any of Embodiments 245 to 277, wherein the stoichiometric process yield of the compound of formula (II) is at least about 65%.

[0522] Embodiment 280. A process according to any of Embodiments 245 to 277, wherein the stoichiometric process yield of the compound of formula (II) is at least about 80%.

[0523] Embodiment 281. Compound having the structure of formula (III): [ka] or a process for preparing the salt thereof, the process is Compounds having the structure of formula (I): [ka] Alternatively, a salt thereof may be brought into contact with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound of formula (II): [ka] or forming a salt thereof; and Compounds having the structure of formula (III) obtained by brominating a compound of formula (II), or a salt thereof, with a brominating agent: [ka] or including bringing forth the salt; A process in which the temperature of the reaction medium is controlled during the contact step in a manner sufficient to maintain at least about 80% chiral purity with respect to the compound of formula (II) or its salt.

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

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

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

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

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

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

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

[0531] Embodiment 289. Any process of Embodiments 284 to 288, wherein the bromination medium is maintained at a temperature of approximately 5°C to approximately 40°C during the bromination process.

[0532] Embodiment 290. Any process of Embodiments 284 to 288, wherein the bromination medium is maintained at a temperature of approximately 20°C during the bromination process.

[0533] Embodiment 291. Any of the processes of Embodiments 284 to 290, wherein the bromination step is performed as a batch reaction.

[0534] Embodiment 292. The process of Embodiment 291, wherein at least about 50 kilograms of the compound of formula (II) are packed into the batch reaction.

[0535] Embodiment 293. The process of Embodiment 291, wherein at least about 100 kilograms of the compound of formula (II) are packed into the batch reaction.

[0536] Embodiment 294. The process of Embodiment 291, wherein at least about 200 kilograms of the compound of formula (II) are packed into the batch reaction.

[0537] Embodiment 295. The process of Embodiment 291, wherein at least about 300 kilograms of the compound of formula (II) are packed into the batch reaction.

[0538] Embodiment 296. Any of the processes of Embodiments 284 to 295, wherein the process includes isolating a compound of formula (III) or a salt thereof from a brominating medium.

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

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

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

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

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

[0544] Embodiment 302. Any process of Embodiments 281 to 283, wherein the compound of formula (III), or a salt thereof, is prepared from the compound of formula (II), or a salt thereof, without isolating the compound of formula (II), or a salt thereof, from the reaction mixture.

[0545] Embodiment 303. A process according to any of Embodiments 281 to 302, wherein the stoichiometric process yield of the compound of formula (III) is at least about 50%.

[0546] Embodiment 304. A process according to any of Embodiments 281 to 302, wherein the stoichiometric process yield of the compound of formula (III) is at least about 65%.

[0547] Embodiment 305. A process according to any of Embodiments 281 to 302, wherein the stoichiometric process yield of the compound of formula (III) is at least about 80%.

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

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

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

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

[0552] Embodiment 310. The compound of formula (IV), or a salt thereof, is a sulfate; and the sulfate is, Compounds having the structure of formula (III): [ka] Alternatively, contacting the salt thereof with an amination agent in a reaction medium to form a reaction mixture containing the compound of formula (IV); Forming sulfates of compounds of formula (IV); and A process according to any of embodiments 306 to 309, which is prepared by a process that includes isolating a sulfate.

[0553] Embodiment 311. A compound of formula (III), or a salt thereof, Compounds having the structure of formula (I): [ka] Alternatively, a salt thereof may be brought into contact with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound of formula (II): [ka] or forming a salt thereof; and Prepared by a process comprising brominating a compound of formula (II), or a salt thereof, with a brominating agent to obtain a compound having the structure of formula (III), or a salt thereof; The process of Embodiment 310, wherein the temperature of the reaction medium is controlled during the contact step in a manner sufficient to maintain at least about 80% chiral purity with respect to the compound of formula (II) or its salt.

[0554] Embodiment 312. Compound having the structure of formula (VIII): [ka] or a process for preparing the salt thereof, the process is Compounds having the structure of formula (V): [ka] or a salt thereof, a compound having the structure of formula (VI): [ka] Alternatively, a salt thereof may be brought into contact with a compound having the structure of formula (VII) in an aqueous reaction medium containing an organic solvent in the presence of a base and a palladium catalyst: [ka] or forming a reaction mixture containing the salt thereof; Reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture containing the compound of formula (VII) or a salt thereof; Isolating the compound of formula (VII), or a salt thereof, from a substantially anhydrous mixture; and A process comprising converting a compound of formula (VII), or a salt thereof, to a compound of formula (VIII).

[0555] Embodiment 313. Compound having the structure of formula (VIII): [ka] or a process for preparing the salt thereof, the process is Compounds having the structure of formula (IV): [ka] Or a salt thereof, which deprotects the compound of formula (IV) and has the structure of formula (VI): [ka] Or contact with an acidic medium under conditions sufficient to form a reaction mixture containing the salt thereof and a benzyl halogen by-product; Isolating the compound of formula (VI), or a salt thereof, from the reaction mixture under conditions sufficient to substantially avoid the formation of aminal impurities; and A process comprising converting a compound of formula (VI), or a salt thereof, to a compound of formula (VIII), or a salt thereof.

[0556] Embodiment 314. Compound having the structure of formula (VIII): [ka] or a process for preparing the salt thereof, the process is Compounds having the structure of formula (III): [ka] Alternatively, by contacting a salt thereof with an amination agent in a reaction medium, a compound having the structure of formula (IV) is obtained: [ka] Forming a reaction mixture containing, Formation of a sulfate of the compound of formula (IV); Isolating sulfates; and A process comprising converting a sulfate into a compound of formula (VIII) or a salt thereof.

[0557] Embodiment 315. Compound having the structure of formula (VIII): [ka] or a process for preparing the salt thereof, the process is Compounds having the structure of formula (I): [ka] Alternatively, a salt thereof may be brought into contact with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound of formula (II): [ka] or forming a salt thereof; Compounds having the structure of formula (III) obtained by brominating a compound of formula (II), or a salt thereof, with a brominating agent: [ka] or bringing forth the salt; and This includes converting a compound of formula (III), or a salt thereof, to a compound of formula (VIII), or a salt thereof; A process in which the temperature of the reaction medium is controlled during the contact step in a manner sufficient to maintain at least about 80% chiral purity with respect to the compound of formula (II) or its salt.

[0558] All references (patents and non-patents) cited above are incorporated into this patent application by reference. The discussions in these references are intended only to summarize the claims made by their authors. No endorsement is made that any reference (or any part of any reference) constitutes relevant prior art (or any prior art). The applicant reserves the right to challenge the accuracy and validity of the cited references. Furthermore, the present invention encompasses the following aspects. 1. Compounds having the structure of formula (VIII): [ka] or a process for preparing the salt thereof, wherein the process is Compounds having the structure of formula (VII): [ka] Alternatively, contacting a salt thereof with 2-butic acid or a salt thereof in a reaction medium in the presence of 1-propylphosphonic anhydride and a base to form a reaction mixture containing the compound of formula (VIII) or a salt thereof, and one or more reaction byproducts; and A process comprising selectively isolating the compound of formula (VIII), or a salt thereof, from the reaction mixture with respect to one or more reaction by-products. 2. The contact process is, Adding the compound of formula (VII), or a salt thereof, and the base to the reaction medium; Adding the 2-butic acid or a salt thereof to the reaction medium containing the compound of formula (VII) or a salt thereof, and the base; and The process according to claim 1, comprising adding the 1-propylphosphonic anhydride to the reaction medium comprising the compound of formula (VII) or a salt thereof; 2-butyric acid or a salt thereof; and the base. 3. The process described above is Compounds having the structure of formula (VII):

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Claims

1. Compounds having the structure of formula (VII): 【Chemistry 1】 It is a crystal of, The aforementioned crystal, Reflected X-ray powder diffraction pattern containing at least three peaks selected from the group consisting of 9.9±0.2°2θ, 11.1±0.2°2θ, 12.8±0.2°2θ, 14.1±0.2°2θ, and 19.0±0.2°2θ. A crystal characterized by...

2. The crystal according to claim 1, characterized by a reflected X-ray powder diffraction pattern having peaks at 9.9±0.2°2θ, 11.1±0.2°2θ, 12.8±0.2°2θ, 14.1±0.2°2θ, and 19.0±0.2°2θ.

3. The crystal according to claim 1, characterized by a reflected X-ray powder diffraction pattern having peaks at 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.

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