Process for preparing 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridine-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

Abstract

This invention provides a process for preparing compound A, which is used to synthesize a KRAS inhibitor. [Solution] A process for preparing compound A as shown below is provided, comprising: (a) mixing a reactive compound containing 2-isopropyl-4-methylpyridine-3-amine or a salt thereof, a first base, and phosgene or a phosgene equivalent in an organic solvent to form 3-isocyanate-2-isopropyl-4-methylpyridine (compound C); (b) mixing compound C and 2,6-dichloro-5-fluoronicotinamide to form 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridine-3-yl)carbamoyl)nicotinamide (compound E); and (c) mixing compound E and a second base to form a product mixture containing compound A and the second base. A process for synthesizing AMG 510 using compound A is also provided. JPEG2026071310000032.jpg35150

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 116,703, filed on November 20, 2020, which is incorporated herein by reference in its entirety. [Background technology]

[0002] The Karsten rat sarcoma virus oncogene homolog (KRAS) is the most frequently mutated oncogene in human cancers and encodes a guanosine triphosphatase (GTPasease) that cycles between an active guanosine triphosphate (GTP)-bound state and an inactive guanosine diphosphate (GDP)-bound state, regulating signal transduction. See, for example, Simanshu DK, Nissley DV, McCormick F. "RAS proteins and their regulators in human disease" in Cell 2017;170:17-33.

[0003] KRAS mutations are often associated with resistance to targeted therapies and poor outcomes in cancer patients, yet despite more than 30 years of scientific effort, selective KRAS inhibitors have yet to be approved. For example, Nadal E, Chen G, Prensner JR, et al. “KRAS-G12C mutation is associated with poor outcome in surgically resected lung adenocarcinoma” in J Thorac Oncol 2014;9:1513-22; Massarelli E, Varella-Garcia M, Tang X, et al. “KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase “G12V and G12A KRAS mutations are associated with poor outcome in patients with metastatic colorectal cancer treated with bevacizumab”in Tumour Biol 2016;37:6823-30;Lie vre A,Bachet JB, Le Corre D, et al. “KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer in Cancer Res 2006;66:3992-5; McCormick F. “K-Ras protein as a drug target” in J Mol Med(Berl)2016;94:253-8; Jones RP, Sutton PA, Evans JP, et al.See "Specific mutations in KRAS codon 12 are associated with worse overall survival in patients with advanced and recurrent colorectal cancer" in Br J Cancer 2017;116:923-9; Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. "Drugging the undruggable RAS; mission possible?" in Nat Rev Drug Discov 2014;13:828-51; Ostrem JM, Shokat KM. "Direct small molecule inhibitors of KRAS; from structural insights to mechanism-based design" in Nat Rev Drug Discov 2016;15:771-85; Suzawa K, Offin M, Lu D, et al. "Activation of KRAS mediates resistance to targeted therapy in MET exon 14-mutant non-small cell lung cancer" in Clin Cancer Res 2019;25:1248-60; Clarke PA, Roe T, Swabey K, et al. "Dissecting mechanisms of resistance to targeted drug combination therapy in human colorectal cancer" in Oncogene 2019;38:5076-90; and Del Re M, Rofi E, Restante G, et al. "Implications of KRAS mutations in acquired resistance to treatment in NSCLC" in Oncotarget 2017;9:6630-43.

[0004] KRAS G12C mutations occur in approximately 13% of non-small cell lung cancers (NSCLCs) and 1-3% of colorectal cancers and other solid tumors. For example, Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. “Drugging the undruggable RAS; mission possible?” in Nat Rev Drug Discov 2014;13:828-51; Biernacka A, Tsongalis PD, Peterson JD, et al. “The potential utility of re-mining results of somatic mutation testing:KRAS status in lung adenocarcinoma” in Cancer Genet 2016;209:195-8;Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A. “Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer” in Pathol Res Pract 2009;205:858-62; and Ouerhani S, Elgaaied ABA. “The mutational spectrum of HRAS,KRAS,NRAS and FGFR3 genes in See "bladder cancer" in Cancer Biomark 2011-2012;10:259-66.

[0005] A mutation from glycine to cysteine ​​at position 12 favors the active form of the KRAS protein, resulting in the dominance of GTP-bound KRAS oncoplasmic protein and promoting tumor cell proliferation and survival. See, for example, Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. "K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions" in Nature 2013;503:548-51 and Kargbo RB. "Inhibitors of G12C mutant Ras proteins for the treatment of cancers" in ACS Med Chem Lett 2018;10:10-1.

[0006] This mutated cysteine ​​is located adjacent to the switch II region pocket (P2). The P2 pocket exists only when KRAS is in the inactive GDP-bound conformation. G12CThese have been used to establish covalent inhibitors of KRAS. For example, see Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. "K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions" in Nature 2013;503:548-51; Lito P, Solomon M, Li LS, Hansen R, Rosen N. "Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism" in Science 2016;351:604-8; and Patricelli MP, Janes MR, Li LS, et al. "Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state" in Cancer Discov 2016;6:316-29.

[0007] The AMG 510 interacts uniquely with the P2 pocket, KRAS G12C It is a small molecule that specifically and irreversibly inhibits other KRAS. G12C KRAS operates through a similar mechanism to that described for inhibitors. G12C It captures the KRAS in an inactive GDP-bound state. See, for example, Lito P, Solomon M, Li LS, Hansen R, Rosen N. “Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism” in Science 2016;351:604-8. In preclinical studies, AMG 510 inhibited almost all detectable phosphorylation of extracellular signal-regulated kinases (ERKs), which are major downstream effectors of KRAS, and KRAS G12CIt has been shown to induce persistent and complete tumor regression in mice with tumors. See, for example, Canon J, Rex K, Saiki AY, et al. “The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumor immunity” in Nature 2019;575:217-23.

[0008] AMG 510 has the following chemical structure: [ka] This compound has a chiral center in the atrop isomer, and in the (M) configuration (shown above), it is more active in the target protein than in the (P) configuration.

[0009] One synthetic intermediate in the synthesis of AMG 510 is compound A, whose IUPAC name is 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridine-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. [ka] Having a structure, The following structure [ka] They may exist as (P)- and (M)-atropisomers having the characteristic .

[0010] In the synthesis of AMG 510, (M)-compound A obtained from compound A is transferred to the synthesis and converted to AMG 510.

[0011] From the above perspective, there is a need for an efficient, scalable, and cost-effective process for preparing compound A. [Prior art documents] [Non-patent literature]

[0012]

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[0013] As described herein, this disclosure relates to compound A: [ka] A process for preparing, The present invention provides a process comprising: (a) mixing a reactive compound containing 2-isopropyl-4-methylpyridine-3-amine (compound B) or a salt thereof, a first base, and phosgene or a phosgene equivalent in an organic solvent to form 3-isocyanate-2-isopropyl-4-methylpyridine (compound C); (b) mixing compound C and 2,6-dichloro-5-fluoronicotinamide (compound D) to form 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridine-3-yl)carbamoyl)nicotinamide (compound E); and (c) mixing compound E and a second base to form a product mixture containing compound A.

[0014] This disclosure further provides a process for synthesizing AMG 510, which includes using compound A prepared according to the disclosed process. [Modes for carrying out the invention]

[0015] 7-Chloro-6-fluoro-1-(2-isopropyl-4-methylpyridine-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (i.e., compound A), or a salt thereof: [ka] A process for preparing is provided herein.

[0016] A disclosed process for preparing compound A or a salt thereof is (a) 2-isopropyl-4-methylpyridine-3-amine (i.e., compound B): [ka] Alternatively, a salt thereof, a first base, and a reactive compound containing phosgene or a phosgene equivalent are mixed in an organic solvent to form 3-isocyanate-2-isopropyl-4-methylpyridine (i.e., compound C): [ka] To form, (b) Compound C and 2,6-dichloro-5-fluoronicotinamide (i.e., compound D): [ka] Mix them together, 2,6-Dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridine-3-yl)carbamoyl)nicotinamide (compound E), or a salt thereof: [ka] To form, (c) Mixing compound E or a salt thereof with a second base to form a product mixture containing compound A.

[0017] The process disclosed herein for preparing compound A offers several advantages over conventional synthesis processes (such as those described in U.S. Patent No. 10,519,146, Lanman et al., J.Med.Chem. 2020;63:52-65 ("Lanman"), and International Publication Nos. 2020 / 102730, 2021 / 097207, and 2021 / 097212). For example, the conventional synthesis of compound A is: [ka] The process proceeds via an acyl isocyanate intermediate. As shown in Scheme 1 below, the conventional synthetic route for compound A involves activating compound D as an acyl isocyanate compound, then reacting it with compound B to obtain compound E, and then converting this to compound A. [ka] Scheme 1. Conventional synthesis route of compound A.

[0018] In contrast, as shown in Scheme 2, the disclosed process involves compound C, in particular, an isocyanate derived from aniline: [ka] This involves the formation of a compound and, therefore advantageously, does not proceed via an acyl isocyanate intermediate. While not bound by any particular theory, by eliminating the acyl isocyanate intermediate, which acts as an electrophilic reaction site so that the acyl carbon forms an undesirable byproduct, a higher yield process is provided that does not involve distillation, complex workups, or chromatography, for example, allowing the reaction product to be isolated by direct crystallization and filtration. Specifically, a large-scale process disclosed on page 55 of International Publication No. 2020 / 102730 produces compound A ("Rac-dione") in 41% yield over two steps (steps 2 and 3) based on compound B (see also International Publication No. 2021 / 097207 (page 45) and International Publication No. 2021 / 097212 (page 49)). Lanman discloses a smaller-scale process in which compound E is used without further purification (see Step 2 on page 62 of Lanman), and compound A is produced in quantitative yield from unpurified compound E after chromatographic purification (see Step 3 on page 62 of Lanman). In contrast, the process disclosed herein, for example in Example 1, provides compound A in yields of 75% and 80% relative to compound B, avoids cumbersome distillation and work-up processes, and yields compound A in high purity (≥99.5% by HPLC) by simple crystallization and filtration. [ka] Scheme 2. Disclosed process for preparing compound A.

[0019] Other aspects of the disclosed process are also advantageous. For example, the disclosed reaction conditions for mixing compound E and a second base provide a product mixture containing compound A and a second base, and compound A is provided in higher yield and purity compared to the prior art process for forming compound A from compound E. Conventional synthesis has been complicated by the presence of tert-butyl ether impurities such as 7-(tert-butoxy)-6-fluoro-1-(2-isopropyl-4-methylpyridine-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione resulting from the undesirable reactivity of sodium tert-butoxide bases (see International Publication No. 2020 / 102730, page 55, step 3). In contrast, the process of the present disclosure can preferably be carried out by using a milder base to convert compound E to compound A. Converting compound E to compound A using milder, non-nucleophilic bases such as tetramethylguanidine and 1,8-diazabicyclo[5.4.0]undeca-7-ene, rather than sodium tert-butoxide, is advantageous in that it reduces the formation of undesirable by-products.

[0020] Furthermore, this disclosure provides a process that is particularly simple to operate, requires few unit operations (e.g., no temperature adjustment or distillation after sequentially filling reagents, no phase cut, and direct isolation of compound A from the reaction stream), and is suitable for sequential reactions in the same reaction vessel. In addition, certain starting materials can be easily purged (e.g., excess phosgene can be purged by spurging the subsurface with dry nitrogen). Moreover, in some embodiments, the disclosed process can be carried out without isolating any intermediate compounds such as compound C or compound E, and certain processes provided herein can be carried out as a “one-pot” process in a single reaction vessel.

[0021] Furthermore, the disclosed processes result in reduced environmental impacts (e.g., improved processes, or "greenness") as measured by one or more of the following:

[0022] 1) Improvement in process mass strength (PMI) such that the cumulative mass of the material used throughout the disclosed process is less than 20 kg per kg of compound A, compared to prior art processes (see steps 2 and 3 disclosed in International Publication No. 2020 / 102730, for example, having a PMI of more than 115 kg per kg of compound A), which is achieved, for example, by reducing the amount of organic solvent used by about 80% and similarly reducing the use of aqueous solvents. In some embodiments, the PMI of the processes disclosed herein is less than 115, 100, 90, 80, 70, 60, 50, 45, 40, 35, 30, 25, or 20 kg per kg of compound A.

[0023] 2) Reduction of time and energy costs by reducing the number of unit operations (no distillation, no work-up) (e.g., more than 50% fewer than the number of unit operations in a conventional synthesis process; compare steps 2 and 3 (13 unit operations) on page 55 of International Publication No. 2020 / 102730 with the processes disclosed herein, e.g., Example 1A (5 unit operations) and Example 1B (6 unit operations)) and improving the robustness of the process, which requires fewer in-process tests (IPTs) (e.g., 2, 3, 4, 5, 6, 7, or fewer IPTs), for example, a 50% reduction in the expected manufacturing cycle time, for example, by reducing the cycle time by a shorter cycle time of at least one day or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 days or more).

[0024] 3) Elimination of halogenated solvents (for example, elimination of dichloromethane in certain processes disclosed herein, e.g., the process of Example 1, on the other hand, dichloromethane is used in processes disclosed in, for example, International Publication No. 2020 / 102730 (e.g., step 2 on page 55), International Publication No. 2021 / 097207 (e.g., step 2 on page 45), and International Publication No. 2021 / 097212 (e.g., steps 1a and 1b on page 49)).

[0025] Furthermore, the disclosed process is expected to reduce manufacturing cycle time, raw material volume, and analytical testing, allowing compound A to be prepared with a reduced manufacturing cost per kilogram. In addition, the disclosed process has a reduced wide point (e.g., Vmax). For example, in some embodiments, the solvent wide point for compound A is reduced to more than 20 volumes and less than 15 volumes (L / kg) (e.g., 10 volumes). Naturally, the disclosed process allows for larger batch sizes to be carried out in less time using the same reaction vessel capacity, thereby resulting in an overall improvement in manufacturing efficiency.

[0026] In addition, the disclosed process provides compound A in high yield over three chemical reactions via two intermediates, with compound B as the starting material. In various embodiments, the overall yield of compound A is 50%, 75%, or 80% or higher compared to compound B (for example, 55%, 60%, 65%, 70%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% compared to compound B).

[0027] Furthermore, the disclosed process provides compound A with high chemical purity. In various embodiments, the chemical purity of compound A prepared according to the disclosed process is 90% or higher as measured by liquid chromatography. For example, in various embodiments, the chemical purity of compound A as measured by liquid chromatography is 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or even 99.9%.

[0028] Conversion from compound B to compound C As described herein, the disclosed process involves forming compound C by mixing compound B or a salt thereof, a first base, and a reactive compound comprising phosgene or a phosgene equivalent in an organic solvent.

[0029] Compound B may be a free base or a free salt. In some embodiments, compound B is a free base. In some embodiments, compound B exists as a preferred salt, such as a hydrochloride salt.

[0030] As used herein, “compound” (e.g., compound A, compound B, compound C, compound D, and / or compound E) means “compound” or a salt thereof unless otherwise explicitly stated.

[0031] Non-limiting exemplary conditions for converting compound B to compound C include: filling a solution of compound B (e.g., 1 equivalent) and a first base (e.g., 1 equivalent) in an anhydrous solvent (e.g., 1 volume per compound B) with a solution of the reactive compound (e.g., 1.2 equivalents) in an anhydrous solvent (e.g., 3 volumes per compound B), while maintaining a low temperature. It has been found that the reaction slows down at temperatures below -40°C, which can result in the accumulation of unreacted compound B.

[0032] While not bound by any particular theory, the conditions described herein for converting compound B to compound C exhibit high selectivity for the formation of the desired compound C, resulting in reduced amounts of by-reactants / by-products. An exemplary by-product is a symmetric urea compound derived from the self-coupling (e.g., self-condensation) of compound B having the following formula: [ka] These are some examples.

[0033] In various embodiments, the conversion from compound B to compound C is characterized by the formation of less than 5% by-products (e.g., 4% or less, 3% or less, 2% or less, or 1% by weight or less by-products). In some embodiments, the disclosed process provides the conversion from compound B to compound C while producing less than 1% symmetric urea.

[0034] First base As described herein, the conversion from compound B to compound C involves the use of a first base. The first base may be any suitable base. In various embodiments, the first base is an amine. In some embodiments, when the first base is an amine, the amine is a tertiary amine. Non-limiting examples of tertiary amines include triethylamine and N,N-diisopropylethylamine (DIPEA). In some embodiments, the tertiary amine is DIPEA.

[0035] The first base is present in an amount suitable for promoting the conversion of compound B to compound C. In various embodiments, the first base is present in an amount of 0.4 molar equivalents (equiv) or more (e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2 equivalents) relative to compound B. As used herein, the terms "molar equivalent" and "equiv" are used interchangeably unless otherwise specified. In some cases, the first base is present in an amount of 1.1 equivalents or less (e.g., 1.0 equivalent, 0.9 equivalent, or 0.8 equivalent) relative to compound B. Thus, the first base is present in any amount defined by and including the aforementioned endpoints. For example, the first base is present in amounts of 0.4 to 2 equivalents relative to compound B, or 0.4 to 1.9 equivalents, 0.5 to 1.8 equivalents, 0.6 to 1.7 equivalents, 0.7 to 1.6 equivalents, 0.8 to 1.5 equivalents, 0.9 to 1.4 equivalents, 1 to 1.3 equivalents, or 1.1 to 1.2 equivalents relative to compound B. In some embodiments, the first base is present in amounts of 0.4 to 1.1 equivalents, 0.5 to 1.0 equivalents, 0.6 to 0.9 equivalents, or 0.7 to 0.8 equivalents relative to compound B.

[0036] Reactive compounds As described herein, the conversion from compound B to compound C utilizes a reactive compound containing phosgene or a phosgene equivalent. In various embodiments, the reactive compound is phosgene. In some embodiments, the reactive compound is a phosgene equivalent. In some embodiments, when the reactive compound contains a phosgene equivalent, the phosgene equivalent is selected from trichloromethyl carbonochloride (corresponding to two phosgene equivalents), bis(trichloromethyl)carbonate (corresponding to three phosgene equivalents), di(imidazole-1-yl)methanone, or bis(2,5-dioxopyrrolidine-1-yl)carbonate. In some embodiments, the reactive compound corresponding to three phosgene equivalents is bis(trichloromethyl)carbonate. In some embodiments, it may be advantageous to convert a reactive compound containing multiple phosgene equivalents, such as three phosgene equivalents of bis(trichloromethyl)carbonate, to phosgene by treatment with a suitable base. In various embodiments, the base is an amine. In some embodiments, when the base is an amine, the amine is a tertiary amine. Non-limiting examples of tertiary amines include triethylamine and N,N-diisopropylethylamine (DIPEA). In some embodiments, the tertiary amine is DIPEA. In some embodiments, the preferred base is an additional amount of the first base. In other embodiments, the preferred base is a base different from the first base. In one embodiment, the preferred base is added as a solution in an organic solvent, as provided herein.

[0037] The reactive compound is present in an amount suitable for promoting the conversion of compound B to compound C. For example, in some embodiments, the reactive compound, such as phosgene or a phosgene equivalent, is present in an amount of 1.0 equivalent or more (e.g., 1.2 equivalents based on compound B) relative to compound B. In other embodiments, the reactive compound, such as a reactive compound corresponding to two phosgene equivalents, is present in an amount of 0.5 equivalents or more (e.g., 0.6 equivalents based on compound B) relative to compound B. In yet another embodiment, the reactive compound, such as a reactive compound corresponding to three phosgene equivalents, is present in an amount of 0.3 equivalents or more (e.g., 0.4 equivalents based on compound B) relative to compound B. Or, in addition, the reactive compound is present in an amount of 1.8 equivalents or less (e.g., 1.5 equivalents based on compound B) relative to compound B. Thus, the reactive compound is present in any amount defined by and including the aforementioned endpoints. For example, the reactive compound is present in an amount of 1.0 to 1.8 equivalents relative to compound B, or in an amount of 1.2 to 1.5 equivalents relative to compound B. In some embodiments, if the reactive compound contains phosgene, a slightly excess amount of phosgene is used (e.g., 1.2 equivalents relative to compound B).

[0038] In various embodiments, if the reactive compound contains phosgene, residual phosgene can be removed from the reaction mixture using any suitable method. In various embodiments, residual phosgene is removed from the reaction mixture by sparging below the surface with dry nitrogen.

[0039] Reaction temperature The reaction temperature is controlled during the conversion from compound B to compound C. In some embodiments, compound B, the first base, and the reactive compound are mixed while maintaining the reaction temperature at room temperature (e.g., 15–25°C).

[0040] In some embodiments, compound B, the first base, and the reactive compound are mixed while maintaining a reaction temperature below 0°C. In various embodiments, compound B, the first base, and the reactive compound are mixed while maintaining a reaction temperature of -35°C to 0°C (e.g., -30°C, -25°C, -20°C, -15°C, -10°C, or -5°C) during the period before heating to room temperature. For example, in some embodiments, the reduced reaction temperature is maintained for a period of at least 15 minutes before heating to 25°C.

[0041] Organic solvents The organic solvent may be any suitable organic solvent. In some embodiments, the organic solvent is selected from the group consisting of dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methyl tert-butyl ether, cyclopentyl methyl ether, toluene, and combinations thereof. In various embodiments, with respect to the above or other embodiments below, the organic solvent is a polar organic solvent. In some embodiments, with respect to the above or other embodiments below, the organic solvent is a polar aprotic solvent. Non-limiting examples of polar aprotic organic solvents include, for example, haloalkanes (e.g., dichloromethane, dichloroethane), dioxane (e.g., 1,4-dioxane), dimethoxyethane, N-methylpyrrolidone, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide, and propylene carbonate. In various embodiments, the organic solvent is an anhydrous. In some embodiments, the organic solvent includes solvents selected from the group consisting of acetonitrile, dichloromethane, dichloroethane, dimethoxyethane, isopropyl acetate, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and combinations thereof. In some cases, the organic solvent includes solvents selected from the group consisting of 2-methyltetrahydrofuran, toluene, acetonitrile, NMP, DMSO, sulfolane, and combinations thereof. In some cases, the organic solvent includes acetonitrile. In some more specific cases, the organic solvent includes anhydrous acetonitrile. In some embodiments, the solvent is a non-halogenated solvent such as acetonitrile, rather than a halogenated solvent such as dichloromethane.

[0042] Conversion from compound C to compound E As described herein, the disclosed process for preparing compound A includes converting compound C to compound E by mixing compound C with compound D.

[0043] Non-limiting exemplary conditions for converting compound C to compound E include mixing compound C as a solid, or optionally by a 0.5 volume solvent rinse to facilitate the addition of compound D, with a slightly excess of compound D (e.g., 1.1 equivalents), and heating the mixture overnight (e.g., 12-16 hours), or heating until compound C is completely converted to E as determined, for example by HPLC (e.g., above 25°C, e.g., 60-80°C or 80°C). In one embodiment, the reaction proceeds, for example, a) extracting the sample, b) quenching with methanol, and c) the methanol adduct (i.e., methyl carbamate of compound B): [ka] This can be monitored by analysis. In some embodiments, compound E or a salt thereof can be isolated by filtration, rinsed with a solvent (e.g., acetonitrile), and dried under nitrogen to obtain compound E or a salt thereof. In various embodiments, when compound E is isolated, compound E is formed in a yield of 85% or more relative to compound B (e.g., 86%, 87%, 88%, 89%, 90%, 91%, 92% or more relative to compound B). In some embodiments, the yield of compound E is 85% to 92% relative to compound B. In some embodiments, the yield of compound E is 86% relative to B.

[0044] The disclosed process for converting compound C to compound E advantageously maximizes the conversion of compound C. For example, in various embodiments, less than 0.2% of compound C remains after the conversion from compound C to compound E is complete.

[0045] The mixing of compound C and compound D is carried out at a preferred temperature. In some embodiments, with respect to the above or other embodiments below, the mixing of compound C with compound D is carried out at a temperature from room temperature to 120°C (e.g., 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, or 115°C, or 25-60°C, 50-120°C, 60-100°C, or 50-90°C), and in various embodiments, the mixing of compound C with compound D is carried out at a temperature of 60°C or higher (e.g., 61°C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C, 68°C, 69°C, or 70°C or higher). Alternatively, the mixing of compound C and compound D may be carried out at a temperature of 80°C or less (e.g., 79°C, 78°C, 77°C, 76°C, 75°C, 74°C, 73°C, 72°C, or 71°C or less). Thus, the mixing of compound C with compound D may be carried out at a temperature defined by and including any of the aforementioned endpoints, for example, 15-120°C, 20-115°C, 25-110°C, 30-105°C, 35-100°C, 40-95°C, 45-90°C, 50-85°C, 55-80°C, 60-80°C, 61-79°C, 62-78°C, 63-77°C, 64-76°C, 65-75°C, 66-74°C, 67-73°C, 68-72°C, or 69-71°C.

[0046] A suitable amount of compound D is used. Typically, at least 1 equivalent of compound D is used. In various embodiments, a slightly excess amount of compound D (e.g., 1.1 equivalents) is used relative to the amount of compound B. This slight excess is based on the starting amount of compound B, as compound C is obtained immediately after being formed from compound B, without isolation or calculation, and is reacted with compound D. In various embodiments, 1.1 equivalents of compound D (relative to compound B) are mixed with compound C to form compound E.

[0047] In some embodiments, the disclosed process further includes drying Compound D before using it in the reaction. In embodiments where Compound D is dried, Compound D is dried to a moisture content of less than 200 ppm before mixing with Compound C. In some embodiments, Compound D is dried to have a moisture content of 190 ppm or less, such as 180 ppm or less, 170 ppm or less, 160 ppm or less, 150 ppm or less, 140 ppm or less, 130 ppm or less, 120 ppm or less, 110 ppm or less, 100 ppm or less, 90 ppm or less, 80 ppm or less, 70 ppm or less, 60 ppm or less, 50 ppm or less, 40 ppm or less, 30 ppm or less, 20 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, 1 ppm or less, or 0 ppm.

[0048] Conversion of Compound E to Compound A As described herein, the disclosed process for preparing Compound A includes converting Compound E to Compound A by mixing Compound E and a second base to form a product mixture comprising Compound A and the second base.

[0049] As shown in Scheme 3, Compound E can be kinetically reacted via at least two different pathways, namely a substitution reaction pathway (SNAr) (having a reaction rate of k SNAr ), and a fragmentation pathway (having a reaction rate of k Frag ). It is the SNAr pathway that provides Compound A, and it is the fragmentation pathway that results in undesirable side products.

Chemical formula

[0050] Without being bound by any particular theory, this k SNAr / k FragThe selectivity is expected to increase with dielectric constant and decrease with increasing reaction temperature. It is desirable that the process of this disclosure exhibits high selectivity for the SNAr pathway.

[0051] Non-limiting exemplary conditions for converting compound E to compound A include: cooling a mixture of compound E or a salt thereof in a solvent (e.g., acetonitrile) to below 25°C or below 17°C (e.g., -5 to 25°C, -5 to 20°C, -5 to 15°C, -5 to 10°C, -5 to 5°C, -5 to 0°C, 0 to 25°C, 0 to 20°C, 0 to 15°C, 0 to 10°C, 5 to 25°C, 5 to 20°C, 5 to 15°C, 5 to 10°C, 12 to 20°C, 20°C), and adding an excess of the second base (e.g., 2 to 10 equivalents) while maintaining the reaction mixture at a temperature of 12 to 20°C, e.g., 15 to 17°C, 17°C, or 20°C, during and after the addition of the second base. After adding the second base, the reaction mixture was stirred at a temperature of 12–20°C, e.g., 15–17°C, for 24 hours, or until complete, as demonstrated by HPLC. In some cases, compound E or its salt is present in a solution containing a solvent (e.g., DMSO) for mixing with TMG. Using a solution of compound E or its salt in a solvent (e.g., DMSO) allows for faster reaction times, reduced impurities, and / or higher yields.

[0052] Second base The second base is any suitable base. In some embodiments, the second base includes 1,5,7-triazabicyclo(4.4.0)deca-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo(4.4.0)deca-5-ene (MTBD), 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,1,3,3-tetramethylguanidine (TMG), or a combination thereof. In one embodiment, the second base is TMG. In another embodiment, the second base is DBU.

[0053] The second base is present in an appropriate amount. In some embodiments, with respect to the embodiments described above or below, the second base is present in 2 equivalents or more (e.g., 2.5, 3, 3.5, 4, 4.5, or 5 or more equivalents). Or, in addition, the second base is present in 10 equivalents or less (e.g., 9, 8.5, 8, 7.5, 7, 6.5, 6, or 5.5 or less equivalents). Thus, the second base can be present in an amount determined by any of the aforementioned values, for example, 2 to 10 equivalents, 2.5 to 9.5 equivalents, 3 to 9 equivalents, 3.5 to 8.5 equivalents, 4 to 8 equivalents, 4.5 to 7.5 equivalents, 4.5 to 6.5 equivalents, 5 to 7 equivalents, or 5.5 to 6.5 equivalents. In one embodiment, the second base may be present in 4.5 equivalents. In another embodiment, the second base may be present in an amount of 6.0 equivalents.

[0054] In embodiments in which compound E is treated to reduce impurities (for example, when compound E is isolated), compound A can be obtained from compound E using two or more equivalents of a second base (e.g., 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or three or more equivalents). While not bound by any particular theory, it is believed that reducing the amount of impurities in the reaction mixture used to convert compound E to compound A can reduce the amount of second base used for the conversion. In various embodiments, with respect to the above or other embodiments described below, the second base is present in amounts of 4.5 equivalents or more relative to compound E, for example, 4.6 equivalents, 4.7 equivalents, 4.8 equivalents, 4.9 equivalents, 5.0 equivalents, 5.1 equivalents, 5.2 equivalents, 5.3 equivalents, 5.4 equivalents, or 5.5 equivalents or more relative to compound E. Alternatively, the second base may be present in amounts of 6.5 equivalents or less relative to compound E, for example, 6.4 equivalents, 6.3, 6.2, 6.1, 6.0, 5.9, 5.8, 5.7, or 5.6 equivalents relative to compound E. Thus, in various embodiments, the second base may be present in amounts defined by and including either of the two aforementioned endpoints, for example, 2 to 10 equivalents, 2.5 to 9.5 equivalents, 3 to 9 equivalents, 3.5 to 8.5 equivalents, 4 to 8 equivalents, 4.5 to 7.5 equivalents, 4.5 to 6.5 equivalents, 5 to 7 equivalents, or 5.5 to 6.5 equivalents of the second base. Furthermore, in some embodiments, the second base is present in amounts of 4.5–6.5 equivalents, 4.6–6.4 equivalents, 4.7–6.3 equivalents, 4.8–6.2 equivalents, 4.9–6.1 equivalents, 5.0–6.0 equivalents, 5.1–5.9 equivalents, 5.2–5.8 equivalents, 5.3–5.7 equivalents, or 5.4–5.6 equivalents relative to compound E. In some embodiments, the second base is present in amounts of 4.8–5.2 equivalents relative to compound E.

[0055] In some embodiments, the second base is added to compound E while maintaining a temperature of 25°C or lower (e.g., 24°C, 23°C, 22°C, 21°C, 20°C, 19°C, 18°C, 17°C, 16°C, or 15°C or lower, or 12-20°C). In some embodiments, the second base is added to compound E while maintaining a temperature of 15-17°C. In various embodiments, the temperature is adjusted to 15-17°C after the second base has been added at a temperature of 25°C or lower (e.g., 12-20°C).

[0056] In some embodiments, the conversion from compound E to compound A is carried out in a suitable solvent. Exemplary solvents for converting compound E to compound A include dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidine, 2-methyltetrahydrofuran, tetrahydrofuran, and acetonitrile. In some embodiments, the conversion from compound E to compound A is carried out in a solvent containing DMSO. The solvent is present in an appropriate amount (e.g., 4 volumes). In some embodiments, the conversion from compound E to compound A is carried out in a solvent containing acetonitrile. In one embodiment, the solvent is an anhydrous, such as anhydrous acetonitrile.

[0057] As used herein, “volume” of a liquid (e.g., solvent) refers to the amount of solvent (mL) per unit mass (g) of solid. For example, adding 21 mL of solvent to 7 g of solid is equivalent to adding “3 volumes” of solvent.

[0058] As described herein, the conversion from compound E to compound A is advantageously unaffected by the presence of alcohols. For example, the presence of alcohols such as n-butanol, isobutanol, sec-butanol, tert-butanol, propanol, isopropanol, ethanol, methanol, or combinations thereof does not substantially affect the conversion from compound E to compound A.

[0059] In some embodiments, the disclosed process further includes crystallizing compound A from the product mixture. In various embodiments, compound A is crystallized from the product mixture by adding an aqueous solution of an acid. Suitable acids for crystallizing compound A include, for example, phosphoric acid, citric acid, sulfuric acid, tartaric acid, and hydrochloric acid. In some embodiments, 6M phosphoric acid is used to crystallize compound A from the product mixture. In some embodiments, 6M phosphoric acid is used to crystallize compound A from the product mixture at a temperature of 20°C or less, and the crystallized compound A is isolated by filtration. In some embodiments, 6M phosphoric acid is used to crystallize compound A from the product mixture at a temperature of 25°C or less, and the crystallized compound A is isolated by filtration. In some embodiments, 4.5M phosphoric acid is used to crystallize compound A from the product mixture at a temperature of 20°C or less, and the crystallized compound A is isolated by filtration.

[0060] In some embodiments, when compound A is crystallized, the process may further include isolating the crystallized compound A. In some embodiments, the crystallized compound A is isolated by filtration.

[0061] From compound A to compound F Compound F can be synthesized using compound A prepared by the process disclosed herein, for example, in a manner similar to that disclosed in U.S. Patent No. 10,519,146. Therefore, in some embodiments, the disclosed process for preparing compound A further includes using compound A to synthesize compound F, its pharmaceutically acceptable salts, atropisomers, or pharmaceutically acceptable salts of atropisomers. [ka]

[0062] Embodiment 1. Compound A: [ka] A process for preparing, (a) Mixing a reactive compound containing 2-isopropyl-4-methylpyridine-3-amine (compound B) or a salt thereof, a first base, and phosgene or a phosgene equivalent in an organic solvent to form 3-isocyanate-2-isopropyl-4-methylpyridine (compound C), (b) Mixing compound C and 2,6-dichloro-5-fluoronicotinamide (compound D) to form 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridine-3-yl)carbamoyl)nicotinamide (compound E), (c) A process comprising mixing compound E and a second base to form a product mixture containing compound A. 2. The process according to Embodiment 1, wherein step (a) includes adding compound B, or a salt thereof, and a first base to solution X containing a reactive compound and an organic solvent. 3. The process according to Embodiment 2, wherein in step (a), compound B or a salt thereof and the first base are added as solution Y containing compound B or a salt thereof, the first base and an organic solvent to form solution A. 4. The process according to Embodiment 2 or Embodiment 3, wherein the solution X before the addition of compound B or a salt thereof and the first base further comprises an additional amount of the first base. 5. The process according to Embodiment 4, wherein solution X prior to the addition of compound B or a salt thereof and the first base is prepared by adding an additional amount of the first base to the solution containing the reactive compound and the organic solvent. 6. The process according to Embodiment 5, wherein an additional amount of the first base is added as a solution containing the additional amount of the first base and an organic solvent. 7. The process according to Embodiment 2 or 3, wherein the temperature of solution X is maintained at a maximum temperature of 0°C. 8. The process according to any one of embodiments 2 to 6, wherein the temperature of solution X is maintained at a temperature of -10°C to 0°C. 9. The process according to any one of embodiments 2 to 6, wherein the temperature of solution X is maintained at a temperature of -7°C to -3°C. 10. The process according to any one of Embodiments 2 to 6, wherein the temperature of solution X is maintained at -5°C. 11. The process according to any one of Embodiments 1 to 3, wherein step (a) includes mixing at a temperature of -35°C to 0°C for at least 15 minutes, and then warming to 25°C. 12. The process according to any one of Embodiments 1 to 11, wherein compound B is a free base. 13. The process according to any one of Embodiments 1 to 12, wherein the first base is an amine. 14. The process according to Embodiment 13, wherein the amine is a tertiary amine. 15. The process according to Embodiment 14, wherein the tertiary amine is N,N-diisopropylethylamine. 16. The process according to any one of Embodiments 1 to 3, wherein the first base is present in an amount of 0.8 to 1.2 molar equivalents with respect to compound B. 17. The process according to any one of Embodiments 1 to 3, wherein the first base is present in an amount of 0.9 to 1.1 molar equivalents with respect to compound B. 18. The process according to any one of Embodiments 1 to 3, wherein the first base is present in an amount of 1.0 molar equivalent with respect to compound B. 19. The process according to Embodiment 4, wherein the additional amount of the first base in solution X before the addition of compound B or its salt and the first base is present in an amount of 0.01 to 0.02 molar equivalents based on compound B. 20. The process according to Embodiment 4, wherein the additional amount of the first base in solution X before the addition of compound B or a salt thereof, is present in an amount of 0.0175 molar equivalents based on compound B. 21. The process according to any one of Embodiments 1 to 20, wherein the reactive compound is phosgene. 22. The process according to any one of Embodiments 1 to 20, wherein the reactive compound is a phosgene equivalent. 23. The process according to Embodiment 22, wherein the phosgene equivalent is trichloromethyl carbonochloride, bis(trichloromethyl) carbonate, di(imidazole-1-yl)methanone, or bis(2,5-dioxopyrrolidine-1-yl) carbonate. 24. The process according to Embodiment 23, wherein the phosgene equivalent is bis(trichloromethyl) carbonate. 25. The process according to any one of Embodiments 1 to 22, wherein the reactive compound is present in an amount of 1.0 to 1.8 molar equivalents based on compound B. 26. The process according to any one of Embodiments 1 to 22, wherein the reactive compound is present in an amount of 1.0 to 1.4 molar equivalents relative to compound B. 27. The process according to any one of Embodiments 1 to 22, wherein the reactive compound is present in an amount of 1.2 molar equivalents based on compound B. 28. The process according to any one of Embodiments 1 to 22, wherein the reactive compound is present in an amount of 1.1 molar equivalents relative to compound B. 29. The process according to Embodiment 24, wherein bis(trichloromethyl) carbonate is present in an amount of 0.3 to 0.6 molar equivalents based on compound B. 30. The process according to Embodiment 24, wherein bis(trichloromethyl) carbonate is present in an amount of 0.4 molar equivalents based on compound B. 31. The process according to Embodiment 24, wherein bis(trichloromethyl) carbonate is present in an amount of 0.37 molar equivalents based on compound B. 32. The process according to any one of Embodiments 1 to 31, wherein the organic solvent in step (a) is a polar organic solvent and optionally an anhydrous solvent. 33. The process according to Embodiment 32, wherein the polar organic solvent comprises anhydrous acetonitrile. 34. The process according to any one of Embodiments 1 to 31, wherein the organic solvent comprises a solvent selected from the group consisting of 2-methyltetrahydrofuran, toluene, acetonitrile, NMP, DMSO, and sulfolane. 35. The process according to any one of embodiments 1 to 32 and 34, wherein step (b) is performed at a temperature of 60°C to 100°C. 36. The process according to any one of Embodiments 1 to 34, wherein step (b) is performed at a temperature of 60°C to 80°C. 37. The process according to any one of Embodiments 1 to 34, wherein step (b) is performed at a temperature of 70°C to 80°C. 38. The process according to any one of Embodiments 1 to 34, wherein step (b) is performed at a temperature of 75°C to 80°C. 39. The process according to any one of Embodiments 1 to 34, wherein step (b) is performed at 80°C. 40. The process according to any one of Embodiments 1 to 39, wherein compound D is present in an amount of 0.9 to 1.3 molar equivalents relative to compound B. 41. The process according to any one of Embodiments 1 to 39, wherein compound D is present in an amount of 1.0 to 1.2 molar equivalents relative to compound B. 42. The process according to any one of Embodiments 1 to 39, wherein compound D is present in an amount of 1.1 molar equivalents relative to compound B. 43. The process according to any one of Embodiments 1 to 42, further comprising drying compound D to a moisture content of less than 200 ppm before performing step (b). 44. The process according to any one of Embodiments 1 to 19, wherein step (c) includes adding a second base to compound E while maintaining a temperature of 25°C or lower. 45. The process according to Embodiment 44, wherein the temperature is maintained at 12°C to 20°C. 46. ​​The process according to Embodiment 44 or 45, wherein the temperature is adjusted to 15°C to 50°C after the addition of the second base. 47. The process according to Embodiment 44 or 45, wherein the temperature is adjusted to 12°C to 17°C after the addition of the second base. 48. The process according to Embodiment 44 or 45, wherein the temperature is adjusted to 20°C after the addition of the second base. 49. The process according to any one of Embodiments 1 to 48, wherein the second base comprises 1,5,7-triazabicyclo(4.4.0)deca-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo(4.4.0)deca-5-ene (MTBD), 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,1,3,3-tetramethylguanidine (TMG), or a combination thereof. 50. The process according to any one of Embodiments 1 to 49, wherein the second base comprises TMG. 51. The process according to any one of Embodiments 1 to 49, wherein the second base comprises DBU. 52. The process according to any one of Embodiments 1 to 51, wherein the second base is present in an amount of 2 to 10 molar equivalents with respect to compound B. 53. The process according to any one of Embodiments 1 to 51, wherein the second base is present in an amount of 4 to 7 molar equivalents with respect to compound B. 54. The process according to any one of Embodiments 1 to 51, wherein the second base is present in an amount of 4.5 to 6.5 molar equivalents with respect to compound B. 55. The process according to any one of Embodiments 1 to 51, wherein the second base is present in an amount of 5.5 to 6.5 molar equivalents with respect to compound B. 56. The process according to any one of Embodiments 1 to 51, wherein the second base is present in an amount of 5.8 to 6.2 molar equivalents with respect to compound B. 57. The process according to any one of Embodiments 1 to 51, wherein the second base is present in an amount of 6.0 molar equivalents with respect to compound B. 58. The process according to any one of Embodiments 1 to 51, wherein the second base is present in an amount of 4.0 to 5.0 molar equivalents with respect to compound B. 59. The process according to any one of Embodiments 1 to 51, wherein the second base is present in an amount of 4.3 to 4.7 molar equivalents with respect to compound B. 60. The process according to any one of Embodiments 1 to 51, wherein the second base is present in an amount of 4.5 molar equivalents with respect to compound B. 61. The process according to any one of Embodiments 1 to 60, further comprising crystallizing compound A from the product mixture by adding an aqueous solution of acid. 62. The process according to Embodiment 61, wherein the acid is present in an amount of 3.0 to 7.0 molar equivalents based on compound B. 63. The process according to Embodiment 61, wherein the acid is present in an amount of 5.5 to 6.5 molar equivalents based on compound B. 64. The process according to Embodiment 61, wherein the acid is present in an amount of 5.8 to 6.2 molar equivalents based on compound B. 65. The process according to Embodiment 61, wherein the acid is present in an amount of 6.0 molar equivalents based on compound B. 66. The process according to Embodiment 61, wherein the acid is present in an amount of 4.0 to 5.0 molar equivalents based on compound B. 67. The process according to Embodiment 61, wherein the acid is present in an amount of 4.3 to 4.7 molar equivalents based on compound B. 68. The process according to Embodiment 61, wherein the acid is present in an amount of 4.5 molar equivalents based on compound B. 69. The process according to any one of embodiments 61 to 68, wherein the acid is phosphoric acid. 70. The process according to Embodiment 69, wherein the aqueous solution contains 3 to 6 moles of phosphoric acid. 71. The process according to Embodiment 69, wherein the aqueous solution contains 6 moles of phosphoric acid. 72. The process according to Embodiment 69, wherein the aqueous solution contains 4 to 5 moles of phosphoric acid. 73. The process according to Embodiment 69, wherein the aqueous solution contains 4.3 to 4.7 moles of phosphoric acid. 74. The process according to Embodiment 69, wherein the aqueous solution contains 4.5 moles of phosphoric acid. 75. The process according to any one of embodiments 61 to 74, further comprising isolating the crystallized compound A by filtration. 76. The process according to any one of Embodiments 1 to 75, wherein compound C or compound E, or any combination thereof, is not isolated before the subsequent reaction. 77. Compound F: [ka] The process according to any one of Embodiments 1 to 76, further comprising using compound A to synthesize a pharmaceutically acceptable salt, atrop isomer, or a pharmaceutically acceptable salt of the atrop isomer.

[0063] Furthermore, the following set of alternative embodiments are provided herein: 1. Compound A: [ka] A process for preparing, (a) Mixing a reactive compound containing 2-isopropyl-4-methylpyridine-3-amine (compound B) or a salt thereof, a first base, and phosgene or a phosgene equivalent in an organic solvent to form 3-isocyanate-2-isopropyl-4-methylpyridine (compound C), (b) Mixing compound C and 2,6-dichloro-5-fluoronicotinamide (compound D) to form 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridine-3-yl)carbamoyl)nicotinamide (compound E), (c) A process comprising mixing compound E and a second base to form a product mixture containing compound A and the second base. 2. The process according to Embodiment 1, wherein step (a) comprises adding compound B, or a salt thereof, and the first base to a solution of the reactive compound and an organic solvent. 3. The process according to Embodiment 2, wherein compound A, or a salt thereof, and the first base are added to a solution of the reactive compound while maintaining a maximum temperature of 0°C. 4. The process according to any one of Embodiments 1 to 3, wherein step (a) includes mixing at a temperature of -35°C to 0°C for at least 15 minutes, and then warming to 25°C. 5. The process according to any one of Embodiments 1 to 4, wherein compound A is a free base. 6. The process according to any one of Embodiments 1 to 5, wherein the first base is an amine. 7. The process according to Embodiment 6, wherein the amine is a tertiary amine. 8. The process according to Embodiment 7, wherein the tertiary amine is N,N-diisopropylethylamine. 9. The process according to any one of Embodiments 1 to 8, wherein the first base is present in an amount of 0.4 to 1.1 molar equivalents with respect to compound B. 10. The process according to any one of Embodiments 1 to 9, wherein the reactive compound is phosgene. 11. The process according to any one of Embodiments 1 to 9, wherein the reactive compound is a phosgene equivalent. 12. The process according to Embodiment 11, wherein the phosgene equivalent is trichloromethyl carbonochloride, bis(trichloromethyl) carbonate, di(imidazole-1-yl)methanone, or bis(2,5-dioxopyrrolidine-1-yl) carbonate. 13. The process according to Embodiment 12, wherein the phosgene equivalent is bis(trichloromethyl) carbonate. 14. The process according to any one of Embodiments 1 to 13, wherein the reactive compound is present in an amount of 0.3 to 0.6 molar equivalents relative to compound B. 15. The process according to any one of Embodiments 1 to 14, wherein the organic solvent in step (a) is a polar organic solvent and optionally an anhydrous solvent. 16. The process according to Embodiment 15, wherein the polar organic solvent comprises anhydrous acetonitrile. 17. The process according to any one of Embodiments 1 to 14, wherein the organic solvent comprises a solvent selected from the group consisting of 2-methyltetrahydrofuran, toluene, acetonitrile, NMP, DMSO, and sulfolane. 18. The process according to any one of claims 1 to 17, wherein step (b) is performed at a temperature of 60°C to 80°C. 19. The process according to any one of Embodiments 1 to 18, further comprising drying compound D to a moisture content of less than 200 ppm before performing step (b). 20. The process according to any one of Embodiments 1 to 19, wherein step (c) includes adding a second base to compound E while maintaining a temperature of 25°C or lower. 21. The process according to Embodiment 20, wherein the temperature is maintained at 12°C to 20°C. 22. The process according to Embodiment 20 or 21, wherein the temperature is adjusted to 15°C to 50°C after the addition of the second base. 23. The process according to any one of Embodiments 1 to 22, wherein the second base comprises 1,5,7-triazabicyclo(4.4.0)deca-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo(4.4.0)deca-5-ene (MTBD), 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,1,3,3-tetramethylguanidine (TMG), or a combination thereof. 24. The process according to Embodiment 23, wherein the second base comprises TMG. 25. The process according to any one of Embodiments 1 to 24, wherein the second base is present in an amount of 2 to 10 molar equivalents with respect to compound E. 26. The process according to any one of Embodiments 1 to 25, wherein the second base is present in an amount of 4.5 to 6.5 molar equivalents with respect to compound E. 27. The process according to Embodiment 26, wherein the second base is present in a molar equivalent of 4.8 to 5.2 with respect to compound E. 28. The process according to any one of Embodiments 1 to 27, wherein step (c) is carried out in dimethyl sulfoxide (DMSO). 29. The process according to any one of Embodiments 1 to 25, further comprising crystallizing compound A from the product mixture by adding an aqueous solution of acid. 30. The process according to Embodiment 29, wherein the acid is phosphoric acid. 31. The process according to Embodiment 30, wherein the aqueous solution contains 6 moles of phosphoric acid. 32. The process according to any one of embodiments 29 to 31, further comprising isolating the crystallized compound A by filtration. 33. The process according to any one of Embodiments 1 to 32, wherein compound C, compound D, compound E, or any combination thereof is not isolated before the subsequent reaction. 34. The process according to Embodiment 33, wherein the organic solvent comprises acetonitrile. 35. The process according to any one of Embodiments 1 to 32, wherein compound E is isolated before step c). 36.Compound F: [ka] The process according to any one of Embodiments 1 to 35, further comprising using compound A to synthesize a pharmaceutically acceptable salt, atrop isomer, or a pharmaceutically acceptable salt of the atrop isomer. [Examples]

[0064] The following examples further illustrate the formulation and process of the disclosed tablets, but should not be construed as limiting their scope in any way.

[0065] In this specification, the following abbreviations are used: HPLC means high-performance liquid chromatography, IPC means in-process control, UV means ultraviolet light, ACN means acetonitrile, DBU means 1,8-diazabicyclo[5.4.0]undeca-7-ene, MeTHF means 2-methyltetrahydrofuran, NMP means N-methyl-2-pyrrolidone, DMSO means dimethyl sulfoxide, DMA means dimethylacetamide, DMF means dimethylformamide, TOL means toluene, TMG means tetramethylguanidine, DIPEA means diisopropylethylamine, EOR means end of reaction, and ε means dielectric constant.

[0066] HPLC method High-performance liquid chromatography (HPLC) was used to determine the completion of the reaction and to identify the reaction products. The following are non-limiting exemplary procedures for preparing the in-process control (IPC) samples used herein: The reaction mixture was quenched with anhydrous methanol (1:1) in a nitrogen-purged flask, and an aliquot (e.g., 250 μL) of the quenched reaction mixture was transferred to a 5 mL nitrogen-purged volumetric flask pre-filled with anhydrous methanol and thoroughly mixed.

[0067] The samples were analyzed using HPLC. Non-limiting, exemplary HPLC conditions used herein include the following conditions listed in Tables 1A and 1B.

[0068] [Table 1]

[0069] [Table 2]

[0070] Example 1 Example 1A: The reactor was packed with triphosgene (0.4 equivalents) and anhydrous acetonitrile (solvent, 3.0 L / kg relative to compound B). The contents of the reactor were stirred until homogenized and cooled to -5°C. A solution of compound B (1.0 equivalent) and N,N-diisopropylethylamine (1.0 equivalent) in anhydrous acetonitrile (1.0 L / kg) was added to the phosgene solution over 1 hour while maintaining the internal temperature at ≤0°C. This batch was stirred at 0°C for 15 minutes and then heated to 25°C. Compound C was formed by the reaction of compound B with triphosgene, but this compound was not isolated. Subsurface sparging with dry N2 was performed at 25°C for several minutes to remove residual phosgene, and the vapor was exhausted into a scrubber containing aqueous ammonia solution. Compound D (1.1 equivalents) was packed as a solid, and the contents of the reactor were heated and stirred at 80°C until compound C was completely converted to compound E as determined by HPLC. The reaction mixture was cooled to ≤12°C. Compound E was not isolated. Tetramethylguanidine (TMG) (6.0 equivalents) was added while maintaining the batch temperature at ≤17°C. The reaction mixture was stirred at 15°C until compound E was completely converted to compound A, as determined by HPLC. Aqueous phosphoric acid (6M) (6.0 equivalents) was added at a temperature below 25°C. The resulting slurry was filtered and washed with 1:4 acetonitrile:water (v / v) (3 × 3 L / kg) to remove the liquid. The product was dried under a nitrogen stream at ambient temperature until it reached a constant weight. Typically, the above procedure yields compound A in 75% yield relative to the starting amount of compound B, with a purity of ≥99.5% as determined by HPLC (room temperature: 15.1 min under the conditions shown in Table 1B above, injection volume 2 μL).

[0071] Example 1B: Anhydrous acetonitrile (solvent, 3.0 L / kg relative to compound B) was packed into the reactor, and the contents of the reactor were cooled to -5°C. Next, triphosgene (0.366 equivalents) was packed into the reactor, and the contents were stirred at -5°C for 15 minutes. Anhydrous acetonitrile (solvent, 0.1 L / kg relative to compound B) solution of N,N-diisopropylethylamine (0.0175 equivalents) was packed into the reactor, and the contents were stirred at -5°C for 1.5 hours. Anhydrous acetonitrile (solvent, 1.0 L / kg relative to compound B) solution of compound B (1.0 equivalent) and N,N-diisopropylethylamine (1.0 equivalent) was added to the phosgene solution by subsurface addition over 4 hours while maintaining the internal batch temperature at -5°C. This batch was stirred at 0°C for 15 minutes, and then warmed to 25°C. Compound C was formed by the reaction of compound B with triphosgene, but this compound was not isolated. Compound D (1.1 equivalents) was packed as a solid, and the contents of the reactor were heated and stirred at 80°C until compound C was completely converted to compound E as determined by HPLC. The reaction mixture was cooled to 20°C. Compound E was not isolated. 1,8-Diazabicyclo[5.4.0]undeca-7-ene (DBU) (4.5 equivalents) was added while maintaining the batch temperature at 20°C. The reaction mixture was stirred at 20°C until compound E was completely converted to compound A as determined by HPLC. Aqueous phosphoric acid (4.5 M) (4.5 equivalents) was added at a temperature of 20°C. The resulting product slurry was filtered and washed with 30:70 acetonitrile:water (v / v) (3 × 3 L / kg) to remove the liquid. The product was dried under a nitrogen stream at ambient temperature until it reached a constant weight. Typically, the above procedure yields compound A in 80% yield relative to the starting amount of compound B, with a purity of ≥99.5% as measured by HPLC (room temperature: 15.1 minutes under the conditions shown in Table 1B above, injection volume 2 μL).

[0072] Example 2 An equimolar mixture of compound B and N,N-diisopropylethylamine base, dissolved in anhydrous acetonitrile, was slowly added to a slightly excess amount of triphosgene dissolved in anhydrous acetonitrile, while maintaining the internal temperature below 0°C. The resulting suspension of compound C as hydrochloride was warmed to 25°C, and excess phosgene was purged by sparging below the surface with nitrogen. Compound C was then mixed with a slightly excess amount of compound D and heated at near reflux temperature (approximately 80°C). After several hours of clean coupling reaction, the product, compound E, crystallized as urea hydrochloride during the reaction at 80°C. Cyclization from compound E to compound A was carried out in the presence of excess tetramethylguanidine (TMG) as a base, either as a through-process or by isolating the intermediate of compound E. Compound A was crystallized by adding aqueous phosphoric acid at 20°C and isolated as a colorless crystalline substance in high yield (75-80% relative to the starting amount of compound B) and high purity (99.5% by HPLC).

[0073] Example 3 A dry 100 mL reactor was packed with triphosgene (5.53 g, 18.64 mmol, 0.4 equivalents) and anhydrous acetonitrile (21 mL, 3.0 volumes per compound B). Optionally, the reactor was rinsed with 0.5 volumes of acetonitrile. The mixture was stirred until homogenized and cooled to -5°C. The triphosgene solution in acetonitrile was shown to gradually release dissolved phosgene upon standing. This process occurred almost instantaneously in the presence of a catalytic base (e.g., 0.1 equivalents of DIPEA). Excessive headspace spurging was avoided to maintain accurate phosgene stoichiometry.

[0074] Alternatively, phosgene (55.9 mmol, 1.2 equivalents) was dissolved in pre-cooled acetonitrile (0 to -35°C). A solution of compound B (7.0 g, 46.6 mmol, 1.0 equivalent) and N,N-diisopropylethylamine (8.13 mL, 46.6 mmol, 1.0 equivalent) in anhydrous acetonitrile (7.0 mL, 1 volume per compound B) was added to the phosgene solution over a period of less than 1 hour while maintaining the internal temperature at 0°C.

[0075] The hydrochloride salt of compound C was crystallized from the reaction mixture that formed the slurry. This batch was stirred below 0°C for 15 minutes and then heated to 25°C. Since excess phosgene inhibits the reaction of compound D with compound C, the residual phosgene was removed by subsurface sparging with dry nitrogen at 25°C for 15 minutes.

[0076] The water content of compound D was analyzed before proceeding. If the water level exceeded 200 ppm, compound D was azeotropically distilled until the water level was 200 ppm or less. Compound D (10.71 g, 51.23 mmol, 1.1 equivalents) was packed as a solid (optionally rinsed with 0.5 volume of acetonitrile), and the mixture was heated overnight at 80°C until the reaction mixture became homogeneous at 60°C. The completion of the reaction was monitored using an assay for conversion from compound C (the sample was removed, quenched with methanol, and analyzed for the methanol adduct of compound C). Compound E, as a hydrochloride salt, crystallized to form a slurry.

[0077] At this stage, compound E hydrochloride was isolated by filtration, rinsed with acetonitrile, and dried under nitrogen to obtain analytically pure compound E hydrochloride in a yield of approximately 86%, although less than 0.5% of compound C remained. The reaction mixture was cooled to below 12°C. Tetramethylguanidine (32 g, 279 mmol, 6.0 equivalents) was added dropwise at below 17°C. The reaction mixture was stirred at 15°C for no more than 24 hours, resulting in cyclization and the formation of compound A.

[0078] An alternative process for forming compound A was as follows: compound E, as a hydrochloride salt, was reacted with 5.0 equivalents of TMG in 3 volumes of DMSO at 15°C. The conversion from compound E to compound A occurred more rapidly in DMSO (several hours) and produced fewer by-products (reduced fragmentation into by-products such as aniline compound B and amide compound D). The resulting formation of compound A proceeded with a high assay yield (approximately 98%) relative to the starting compound E.

[0079] Compound A was crystallized by adding 6M aqueous phosphoric acid (46 mL, 279 mmol, 6.0 equivalents) at around room temperature and allowing the reaction to proceed. At the time of phosphoric acid addition, the pH of the reaction mixture was 3.7.

[0080] Compound A was isolated by filtration through a frit funnel of moderate porosity. The wet residue was slurry-washed with, for example, 2:8 acetonitrile:water (v / v). This wet residue was dried under nitrogen / vacuum at room temperature until it reached a constant weight, yielding compound A from compound B in a yield of 75% and a purity of over 99% (i.e., 99.5%) as measured by chromatography.

[0081] Example 4 Various parameters for converting compound B to compound E were investigated, including the amount of organic solvent, the amount of the first base, the addition of acid, and the removal of salt (e.g., filtration).

[0082] The reaction was carried out using 100 mg of compound B. In summary, a solution of compound B was prepared in the solvent as described. 0.4 equivalents of triphosgene in 10 volumes of solvent were added to compound B at room temperature and stirred for 45 minutes. To each solution, a solution of compound D in 10 volumes of solvent was added at 60°C for 20 hours (at room temperature for DCM). In experiments involving the addition of acid, 4 M hydrochloric acid was added as a 10% solution in dioxane. The reaction mixture was diluted with methanol and analyzed.

[0083] The results of this evaluation are summarized in Table 2.

[0084] [Table 3]

[0085] As demonstrated by the results in Table 2, the reactions using MeTHF and toluene as solvents yielded compound E of good purity in good yields. Furthermore, favorable results were obtained when 2 equivalents of the first base and / or salt were not filtered. In particular, good results were obtained in Examples 4K, 4L, 4S, and 4T, where the solvent was MeTHF or toluene, 2 equivalents of the first base, and the salt were not filtered. Furthermore, the addition of 10% HCl / dioxane (e.g., 4K and 4S) resulted in improved yields.

[0086] Example 5 Various parameters (e.g., second base, amount of second base, solvent, and temperature) are evaluated to determine the relative k of the conversion from compound E to compound A. SNAr / k Frag Selectivity (compound A:compound D) was investigated. [ka]

[0087] In summary, after filling each reaction vessel with compound E, DBU or TMG in 5 volumes of solvent shown in Table 3 was added at either 73°C or 35°C. The reaction was monitored by liquid chromatography. The results are summarized in Table 3.

[0088] [Table 4]

[0089] As demonstrated by the results in Table 3, the reaction using TMG as the second base yielded favorable results. Furthermore, the reaction using NMP, ACN, DMSO, and sulfolane also yielded favorable results.

[0090] The effect of the dielectric constant (ε) of the solvent was also investigated. 4.0 equivalents of TMG in 1.3 volumes of solvent were added over 10 minutes to a solution of compound E (3.0 g) in 3 volumes of solvent (DMSO, DMA, DMF). The reaction temperature was maintained below 27°C during the addition. The results are summarized in Table 4.

[0091] [Table 5]

[0092] The amount of product representing the fragmentation product (i.e., compound D) was similar in all solvents (approximately 0.3 A% or 2.5 mol%) at the end of TMG addition, indicating that the fragmentation pathway / product is not affected by dielectric constant. Furthermore, the small amount of compound E remaining at the end of reaction (EOR) indicates that compound E was efficiently converted to compound A.

[0093] Example 6 As shown in the results of the following scheme, using DBU for the conversion from compound E to compound A results in a higher LCAP conversion to compound A. When TMG is used as the base in the reaction, a major impurity (trapping of compound C by TMG) ​​is observed. [ka]

[0094] As shown in the results of the following scheme, using DBU in the process resulted in a crude mixture at the end of the reaction with a high LCAP to compound A and an increased yield of 75–80%. [ka]

[0095] All references cited herein, including publications, patent applications, and patents, are incorporated herein by reference to the same degree as each reference is incorporated by reference to the entirety of this specification, as if each reference were incorporated by reference to the entirety of this specification.

[0096] The use of the terms “one (a),” “one (an),” and “it,” and similar reference subjects in relation to the description of the present invention (particularly in relation to the following claims), should be construed as encompassing both singular and plural unless otherwise indicated herein or unless explicitly stated otherwise. The terms “include,” “have,” “include,” and “contain,” should be construed as open-ended terms (i.e., “include, but not limited to”) unless otherwise specified herein. The descriptions of value ranges herein are intended merely as a concise way of referring individually to each distinct value that falls within that range, unless otherwise indicated herein, and each distinct value is incorporated herein as if it were individually enumerated herein. All methods described herein may be performed in any suitable order unless otherwise indicated herein or unless explicitly stated otherwise. The use of any examples or illustrative words provided herein (e.g., “etc.”) is intended merely to further illustrate the present invention and, unless otherwise asserted, does not impose any limitation on the scope of the present invention. Nothing in this specification should be construed as indicating that any non-claimed element is essential to the implementation of the invention.

Claims

1. Compound A: 【Chemistry 1】 A process for preparing, (a) Mixing a reactive compound containing 2-isopropyl-4-methylpyridine-3-amine (compound B), or a salt thereof, a first base, and phosgene or a phosgene equivalent in an organic solvent to form 3-isocyanate-2-isopropyl-4-methylpyridine (compound C), (b) Mixing compound C and 2,6-dichloro-5-fluoronicotinamide (compound D) to form 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridine-3-yl)carbamoyl)nicotinamide (compound E), (c) A process comprising mixing compound E and a second base to form a product mixture containing compound A.

2. The process according to claim 1, wherein step (a) includes adding compound B, or a salt thereof, and the first base to solution X containing the reactive compound and the organic solvent.

3. The process according to claim 2, wherein in step (a), the compound B or a salt thereof and the first base are added as a solution Y containing the compound B or a salt thereof, the first base and the organic solvent to form solution A.

4. The process according to claim 2 or 3, wherein the solution X prior to the addition of compound B or a salt thereof and the first base further comprises an additional amount of the first base.

5. The process according to claim 4, wherein the solution X prior to the addition of compound B or a salt thereof and the first base is prepared by adding the additional amount of the first base to the solution containing the reactive compound and the organic solvent.

6. The process according to claim 5, wherein the additional amount of the first base is added as a solution containing the additional amount of the first base and the organic solvent.

7. The process according to claim 2 or 3, wherein the temperature of the solution X is maintained at a maximum temperature of 0°C.

8. The process according to any one of claims 2 to 6, wherein the temperature of the solution X is maintained at a temperature of -10°C to 0°C.

9. The process according to any one of claims 2 to 6, wherein the temperature of the solution X is maintained at a temperature of -7°C to -3°C.

10. The process according to any one of claims 2 to 6, wherein the temperature of the solution X is maintained at a temperature of -5°C.

11. The process according to any one of claims 1 to 3, wherein step (a) includes mixing at a temperature of -35°C to 0°C for at least 15 minutes, and then warming to 25°C.

12. The process according to any one of claims 1 to 11, wherein compound B is a free base.

13. The process according to any one of claims 1 to 12, wherein the first base is an amine.

14. The process according to claim 13, wherein the amine is a tertiary amine.

15. The process according to claim 14, wherein the tertiary amine is N,N-diisopropylethylamine.

16. The process according to any one of claims 1 to 3, wherein the first base is present in an amount of 0.8 to 1.2 molar equivalents based on compound B.

17. The process according to any one of claims 1 to 3, wherein the first base is present in an amount of 0.9 to 1.1 molar equivalents based on compound B.

18. The process according to any one of claims 1 to 3, wherein the first base is present in an amount of 1.0 molar equivalent with reference to compound B.

19. The process according to claim 4, wherein the compound B, or a salt thereof, and the additional amount of the first base in the solution X before the addition of the first base are present in an amount of 0.01 to 0.02 molar equivalents based on compound B.

20. The process according to claim 4, wherein compound B, or a salt thereof, and the additional amount of the first base in solution X before the addition of the first base are present in an amount of 0.0175 molar equivalents based on compound B.

21. The process according to any one of claims 1 to 20, wherein the reactive compound is phosgene.

22. The process according to any one of claims 1 to 20, wherein the reactive compound is a phosgene equivalent.

23. The process according to claim 22, wherein the phosgene equivalent is trichloromethyl carbonochloride, bis(trichloromethyl) carbonate, di(imidazole-1-yl)methanone, or bis(2,5-dioxopyrrolidine-1-yl) carbonate.

24. The process according to claim 23, wherein the phosgene equivalent is bis(trichloromethyl) carbonate.

25. The process according to any one of claims 1 to 22, wherein the reactive compound is present in an amount of 1.0 to 1.8 molar equivalents based on compound B.

26. The process according to any one of claims 1 to 22, wherein the reactive compound is present in an amount of 1.0 to 1.4 molar equivalents based on compound B.

27. The process according to any one of claims 1 to 22, wherein the reactive compound is present in an amount of 1.2 molar equivalents based on compound B.

28. The process according to any one of claims 1 to 22, wherein the reactive compound is present in an amount of 1.1 molar equivalents based on compound B.

29. The process according to claim 24, wherein the bis(trichloromethyl) carbonate is present in an amount of 0.3 to 0.6 molar equivalents based on compound B.

30. The process according to claim 24, wherein the bis(trichloromethyl) carbonate is present in an amount of 0.4 molar equivalents based on compound B.

31. The process according to claim 24, wherein the bis(trichloromethyl) carbonate is present in an amount of 0.37 molar equivalents based on compound B.

32. The process according to any one of claims 1 to 31, wherein the organic solvent in step (a) is a polar organic solvent and optionally an anhydrous solvent.

33. The process according to claim 32, wherein the polar organic solvent includes anhydrous acetonitrile.

34. The process according to any one of claims 1 to 31, wherein the organic solvent comprises a solvent selected from the group consisting of 2-methyltetrahydrofuran, toluene, acetonitrile, NMP, DMSO, and sulfolane.

35. The process according to any one of claims 1 to 32 or 34, wherein step (b) is performed at a temperature of 60°C to 100°C.

36. The process according to any one of claims 1 to 34, wherein step (b) is performed at a temperature of 60°C to 80°C.

37. The process according to any one of claims 1 to 34, wherein step (b) is performed at a temperature of 70°C to 80°C.

38. The process according to any one of claims 1 to 34, wherein step (b) is performed at a temperature of 75°C to 80°C.

39. The process according to any one of claims 1 to 34, wherein step (b) is performed at 80°C.

40. The process according to any one of claims 1 to 39, wherein compound D is present in an amount of 0.9 to 1.3 molar equivalents based on compound B.

41. The process according to any one of claims 1 to 39, wherein compound D is present in an amount of 1.0 to 1.2 molar equivalents based on compound B.

42. The process according to any one of claims 1 to 39, wherein compound D is present in an amount of 1.1 molar equivalents based on compound B.

43. The process according to any one of claims 1 to 42, further comprising drying compound D to a moisture content of less than 200 ppm before performing step (b).

44. The process according to any one of claims 1 to 19, wherein step (c) includes adding the second base to compound E while maintaining a temperature of 25°C or lower.

45. The process according to claim 44, wherein the temperature is maintained at 12°C to 20°C.

46. The process according to claim 44 or 45, wherein the temperature is adjusted to 15°C to 50°C after the addition of the second base.

47. The process according to claim 44 or 45, wherein the temperature is adjusted to 12°C to 17°C after the addition of the second base.

48. The process according to claim 44 or 45, wherein the temperature is adjusted to 20°C after the addition of the second base.

49. The process according to any one of claims 1 to 48, wherein the second base comprises 1,5,7-triazabicyclo(4.4.0)deca-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo(4.4.0)deca-5-ene (MTBD), 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,1,3,3-tetramethylguanidine (TMG), or a combination thereof.

50. The process according to any one of claims 1 to 49, wherein the second base comprises TMG.

51. The process according to any one of claims 1 to 49, wherein the second base comprises DBU.

52. The process according to any one of claims 1 to 51, wherein the second base is present in an amount of 2 to 10 molar equivalents with reference to compound B.

53. The process according to any one of claims 1 to 51, wherein the second base is present in an amount of 4 to 7 molar equivalents with reference to compound B.

54. The process according to any one of claims 1 to 51, wherein the second base is present in an amount of 4.5 to 6.5 molar equivalents based on compound B.

55. The process according to any one of claims 1 to 51, wherein the second base is present in an amount of 5.5 to 6.5 molar equivalents based on compound B.

56. The process according to any one of claims 1 to 51, wherein the second base is present in an amount of 5.8 to 6.2 molar equivalents with reference to compound B.

57. The process according to any one of claims 1 to 51, wherein the second base is present in an amount of 6.0 molar equivalents with reference to compound B.

58. The process according to any one of claims 1 to 51, wherein the second base is present in an amount of 4.0 to 5.0 molar equivalents with respect to compound B.

59. The process according to any one of claims 1 to 51, wherein the second base is present in an amount of 4.3 to 4.7 molar equivalents with reference to compound B.

60. The process according to any one of claims 1 to 51, wherein the second base is present in an amount of 4.5 molar equivalents with reference to compound B.

61. The process according to any one of claims 1 to 60, further comprising crystallizing compound A from the resulting mixture by adding an aqueous solution of acid.

62. The process according to claim 61, wherein the acid is present in an amount of 3.0 to 7.0 molar equivalents based on compound B.

63. The process according to claim 61, wherein the acid is present in an amount of 5.5 to 6.5 molar equivalents based on compound B.

64. The process according to claim 61, wherein the acid is present in an amount of 5.8 to 6.2 molar equivalents based on compound B.

65. The process according to claim 61, wherein the acid is present in an amount of 6.0 molar equivalents based on compound B.

66. The process according to claim 61, wherein the acid is present in an amount of 4.0 to 5.0 molar equivalents based on compound B.

67. The process according to claim 61, wherein the acid is present in an amount of 4.3 to 4.7 molar equivalents based on compound B.

68. The process according to claim 61, wherein the acid is present in an amount of 4.5 molar equivalents based on compound B.

69. The process according to any one of claims 61 to 68, wherein the acid is phosphoric acid.

70. The process according to claim 69, wherein the aqueous solution contains 3 to 6 moles of phosphoric acid.

71. The process according to claim 69, wherein the aqueous solution contains 6 moles of phosphoric acid.

72. The process according to claim 69, wherein the aqueous solution contains 4 to 5 moles of phosphoric acid.

73. The process according to claim 69, wherein the aqueous solution contains 4.3 to 4.7 moles of phosphoric acid.

74. The process according to claim 69, wherein the aqueous solution contains 4.5 moles of phosphoric acid.

75. The process according to any one of claims 61 to 74, further comprising isolating the crystallized compound A by filtration.

76. The process according to any one of claims 1 to 75, wherein compound C or compound E, or any combination thereof, is not isolated before the subsequent reaction.

77. Compound F: 【Chemistry 2】 The process according to any one of claims 1 to 76, further comprising using compound A to synthesize a pharmaceutically acceptable salt, atrop isomer, or a pharmaceutically acceptable salt of the atrop isomer.

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