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

Abstract

Provided herein is a process for preparing Compound A, comprising: (a) mixing reactive compounds including 2-isopropyl-4-methylpyridin-3-amine (Compound B), or a salt thereof, a first base, and phosgene or a phosgene equivalent in an organic solvent to form 3-isocyanato-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-methylpyridin-3-yl)carbamoyl)nicotinamide (Compound E); and (c) mixing Compound E and a second base to form a product mixture including Compound A and the second base. Also provided herein is a process for synthesizing AMG 510 (Compound A), comprising using Compound A prepared according to the disclosed process. TIFF2023550386000033.tif40170

Description

[Technical Field]

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

[0002] Kirsten rat sarcoma viral oncogene homolog (KRAS), the most frequently mutated oncogene in human cancers, encodes a guanosine triphosphatase (GTPase) that cycles between an active guanosine triphosphate (GTP)-bound state and an inactive guanosine diphosphate (GDP)-bound state to regulate signal transduction. See, e.g., 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, no selective KRAS inhibitors have yet been 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 JML, 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 (NSCLC) and 1-3% of colorectal 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 bladder cancer” in Cancer Biomark 2011-2012;10:259-66.

[0005] Mutation of glycine to cysteine ​​at position 12 favors the active form of the KRAS protein, resulting in the predominance of the GTP-bound KRAS oncoprotein and promoting tumor cell proliferation and survival. See, e.g., 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 ​​lies adjacent to a pocket (P2) in the switch II region, which is present only when KRAS is in the inactive, GDP-bound conformation. G12CThese techniques have been used to establish covalent inhibitors of K-Ras. See, e.g., 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 uniquely interacts with the P2 pocket to enhance KRAS G12C This inhibitor is a small molecule that specifically and irreversibly inhibits KRAS. G12C KRAS inhibitors are used in a similar manner to those described for KRAS inhibitors. G12C It traps KRAS in an inactive GDP-bound state. See, e.g., 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 nearly all detectable phosphorylation of extracellular signal-regulated kinase (ERK), the major downstream effector of KRAS, and inhibited KRAS. G12CIt has been shown to induce durable and complete tumor regression in tumor-bearing mice. See, e.g., Canon J, Rex K, Saiki AY, et al., "The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumor immunity," Nature 2019;575:217-23.

[0008] AMG 510 has the following chemical structure: [ka] This compound has an atropisomeric chiral center, and in the (M)-configuration (shown above) it is more active at target proteins than the (P)-configuration.

[0009] One synthetic intermediate in the synthesis of AMG 510 is compound A, which has the IUPAC name 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. [ka] having the structure The following structure [ka] It can exist as (P)- and (M)-atropisomers having the formula:

[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] In view of the above, 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, the present disclosure provides a compound A: [ka] 1. A process for preparing The process includes: (a) mixing reactive compounds including 2-isopropyl-4-methylpyridin-3-amine (Compound B), or a salt thereof, a first base, and phosgene or a phosgene equivalent in an organic solvent to form 3-isocyanato-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-methylpyridin-3-yl)carbamoyl)nicotinamide (Compound E); and (c) mixing Compound E and a second base to form a product mixture including Compound A.

[0014] The present disclosure further provides a process for synthesizing AMG 510, comprising using compound A prepared according to the disclosed process. DETAILED DESCRIPTION OF THE INVENTION

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

[0016] The disclosed process for preparing Compound A, or a salt thereof, comprises: (a) reacting 2-isopropyl-4-methylpyridin-3-amine (i.e., Compound B): [ka] or a salt thereof, a first base, and a reactive compound including phosgene or a phosgene equivalent are mixed in an organic solvent to obtain 3-isocyanato-2-isopropyl-4-methylpyridine (i.e., compound C): [ka] and forming (b) Compound C and 2,6-dichloro-5-fluoronicotinamide (i.e., Compound D): [ka] Mix the 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide (compound E), or a salt thereof: [ka] and forming (c) combining Compound E or a salt thereof and a second base to form a product mixture comprising Compound A.

[0017] The processes disclosed herein for preparing Compound A offer several advantages over conventional synthetic processes (e.g., as described in U.S. Pat. No. 10,519,146, Lanman et al., J. Med. Chem. 2020;63:52-65 ("Lanman"), and WO 2020 / 102730, WO 2021 / 097207, and WO 2021 / 097212). For example, conventional syntheses of Compound A involve preparing a compound of formula: [ka] As shown in Scheme 1 below, the conventional synthesis route to compound A involves activating compound D as an acyl isocyanate compound, which is then reacted with compound B to give compound E, which is then converted to compound A. [ka] Scheme 1. Conventional synthetic route to compound A.

[0018] In contrast, as shown in Scheme 2, the disclosed process specifically targets the isocyanate derived from aniline, compound C: [ka] and thus advantageously does not proceed via an acyl isocyanate intermediate compound. Without being bound by theory, eliminating the acyl isocyanate intermediate compound, where the acyl carbon acts as an electrophilic reactive site to form undesired by-products, provides a higher-yielding process that allows the reaction product to be isolated by direct crystallization and filtration, for example, without distillation, complicated workup, or chromatography. Specifically, the large-scale process disclosed on page 55 of WO 2020 / 102730 produces compound A ("Rac-dione") in 41% yield over two steps (steps 2 and 3) based on compound B (see also WO 2021 / 097207 (page 45) and WO 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 crude compound E after chromatographic purification (see step 3 on page 62 of Lanman). In contrast, the processes disclosed herein, e.g., Example 1, provide compound A in 75% and 80% yield based on compound B, avoid cumbersome distillation and workup processes, and provide highly pure (>99.5% by HPLC) compound A by simple crystallization and filtration. [ka] Scheme 2. Disclosed process for preparing compound A.

[0019] Other aspects of the disclosed processes are also advantageous. For example, the disclosed reaction conditions for combining compound E and a second base provide a product mixture containing compound A and a second base, with compound A being provided in higher yield and purity compared to prior art processes for forming compound A from compound E. Previous syntheses have been complicated by the presence of tert-butyl ether impurities, such as 7-(tert-butoxy)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, resulting from the undesired reactivity of sodium tert-butoxide base (see WO 2020 / 102730, page 55, step 3). In contrast, the disclosed processes can be desirably carried out by using a milder base to convert compound E to compound A. The conversion of compound E to compound A using a milder, non-nucleophilic base, such as tetramethylguanidine and 1,8-diazabicyclo[5.4.0]undec-7-ene, rather than sodium tert-butoxide, advantageously reduces the formation of undesired by-products.

[0020] Additionally, the present disclosure provides a process that is particularly operationally simple, requires few unit operations (e.g., no temperature adjustment or distillation after sequential reagent charging, no phase cut, and direct isolation of Compound A from the reaction stream), and is suitable for sequential reactions in the same reaction vessel. Additionally, certain starting materials can be easily purged (e.g., excess phosgene can be purged by subsurface sparging with dry nitrogen). Furthermore, in some embodiments, the disclosed process can be carried out without isolating any intermediate compounds, such as Compound C or Compound E, allowing certain processes provided herein to be carried out in a single reaction vessel as a "one-pot" process.

[0021] Additionally, the disclosed processes result in reduced environmental impact (eg, improved process "greenness") as measured by one or more of the following:

[0022] 1) Improved process mass intensity (PMI), where the cumulative mass of materials used throughout the disclosed process is less than 20 kg per kg of Compound A, compared to prior art processes (see, e.g., steps 2 and 3 disclosed in WO2020 / 102730, which have a PMI of greater than 115 kg per kg of Compound A), 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) Reductions in time and energy costs, e.g., an expected 50% reduction in manufacturing cycle time, e.g., by requiring fewer unit operations (no distillation, no workup) (e.g., more than 50% fewer than the unit operations of conventional synthetic processes; compare steps 2 and 3 (13 unit operations) on page 55 of WO 2020 / 102730 with processes disclosed herein, e.g., Example 1A (5 unit operations) and Example 1B (6 unit operations)), and by improving process robustness, requiring fewer in-process tests (IPT) (e.g., 2, 3, 4, 5, 6, 7, or fewer IPT), e.g., a shorter cycle time of at least 1 day or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 days or more).

[0024] 3) Elimination of halogenated solvents (e.g., elimination of dichloromethane in certain processes disclosed herein, e.g., the process of Example 1, whereas dichloromethane is used in processes disclosed, for example, in WO 2020 / 102730 (e.g., step 2 on page 55), WO 2021 / 097207 (e.g., step 2 on page 45), and WO 2021 / 097212 (e.g., steps 1a and 1b on page 49)).

[0025] Furthermore, using the disclosed processes, Compound A can be prepared at a reduced cost per kilogram of production due to potential reductions in manufacturing cycle time, raw material quantities, and analytical testing. In addition, the disclosed processes have a reduced wide point (e.g., Vmax). By way of example, in some embodiments, the solvent wide point is reduced to greater than 20 volumes to less than 15 volumes (L / kg) (e.g., 10 volumes) for Compound A. Naturally, the disclosed processes allow for larger batch sizes to be run in a shorter time using the same reactor capacity, thereby improving overall manufacturing efficiency.

[0026] Additionally, the disclosed process provides high yields of Compound A over three chemical reactions, via two intermediates, based on Compound B as the starting material. In various embodiments, the overall yield of Compound A is 50% or greater, 75% or greater, or 80% or greater relative to Compound B (e.g., 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% yield relative to Compound B).

[0027] Additionally, the disclosed processes provide high chemical purity of Compound A. In various embodiments, Compound A prepared according to the disclosed processes has a chemical purity of 90% or greater, as measured by liquid chromatography. For example, in various embodiments, Compound A has a chemical purity of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or even 99.9%, as measured by liquid chromatography.

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

[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 is present as a suitable salt, for example, the hydrochloride salt.

[0030] As used herein, "compound" (e.g., Compound A, Compound B, Compound C, Compound D, and / or Compound E) refers to "the compound" or a salt thereof, unless expressly stated otherwise.

[0031] Non-limiting exemplary conditions for converting compound B to compound C include the following: 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) is charged to 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 reduced temperature. It has been found that temperatures below -40°C can slow the reaction and result in the accumulation of unreacted compound B.

[0032] Without being bound by any particular theory, the conditions described herein for converting compound B to compound C are highly selective for the formation of the desired compound C and result in reduced amounts of side reactants / by-products. Exemplary by-products include symmetrical urea compounds derived from the self-coupling (e.g., self-condensation) of compound B having the formula: [ka] Examples include:

[0033] In various embodiments, the conversion of 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% or less by weight by-products). In some embodiments, the disclosed processes provide for the conversion of compound B to compound C while producing less than 1% symmetrical urea.

[0034] First base As described herein, the conversion of compound B to compound C includes using a first base. The first base can 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 to facilitate the conversion of compound B to compound C. In various embodiments, the first base is present in 0.4 molar equivalents (equiv) or more based on compound B (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 based on compound B). As used herein, the terms "molar equivalent" and "equivalent" are used interchangeably unless otherwise specified. In some cases, the first base is present in 1.1 equivalents or less based on compound B (e.g., 1.0 equivalent, 0.9 equivalent, or 0.8 equivalents based on 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 0.4 to 2 equivalents based on 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 based on compound B. In some embodiments, the first base is present in 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 based on compound B.

[0036] reactive compounds As described herein, the conversion of compound B to compound C utilizes a reactive compound comprising 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 comprises a phosgene equivalent, the phosgene equivalent is selected from trichloromethyl carbonochloridate (equivalent to two phosgene equivalents), bis(trichloromethyl)carbonate (equivalent to three phosgene equivalents), di(imidazol-1-yl)methanone, or bis(2,5-dioxopyrrolidin-1-yl)carbonate. In some embodiments, the reactive compound equivalent to three phosgene equivalents is bis(trichloromethyl)carbonate. In some embodiments, it may be advantageous to convert a reactive compound comprising multiple phosgene equivalents, for example, 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 suitable base is an additional amount of the first base. In other embodiments, the suitable base is a different base from the first base. In one embodiment, the suitable base is added as a solution in an organic solvent, as provided herein.

[0037] The reactive compound is present in an amount suitable to facilitate the conversion of compound B to compound C. For example, in some embodiments, the reactive compound, e.g., phosgene or a phosgene equivalent, is present in 1.0 equivalent or more based on compound B (e.g., 1.2 equivalents based on compound B). In other embodiments, the reactive compound, e.g., a reactive compound corresponding to two phosgene equivalents, is present in 0.5 equivalents or more based on compound B (e.g., 0.6 equivalents based on compound B). In another embodiment, the reactive compound, e.g., a reactive compound corresponding to three phosgene equivalents, is present in 0.3 equivalents or more based on compound B (e.g., 0.4 equivalents based on compound B). Alternatively, or in addition, the reactive compound is present in 1.8 equivalents or less based on compound B (e.g., 1.5 equivalents based on compound B). Thus, the reactive compound is present in any amount defined by and inclusive of the aforementioned endpoints. For example, the reactive compound is present in an amount of 1.0 to 1.8 equivalents based on compound B, or in an amount of 1.2 to 1.5 equivalents based on compound B. In some embodiments, when the reactive compound includes phosgene, a slight excess of phosgene is used (e.g., 1.2 equivalents relative to compound B).

[0038] In various embodiments, when the reactive compound includes phosgene, any suitable method can be used to remove residual phosgene from the reaction mixture, hi various embodiments, residual phosgene is removed from the reaction mixture by subsurface sparging with dry nitrogen.

[0039] Reaction temperature The reaction temperature is controlled during the conversion of compound B to compound C. In some embodiments, compound B, a first base, and a 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 combined while maintaining a reaction temperature below 0° C. In various embodiments, compound B, the first base, and the reactive compound are combined while maintaining a reaction temperature between −35° C. and 0° C. (e.g., −30° C., −25° C., −20° C., −15° C., −10° C., or −5° C.), for example, for a period before warming to room temperature. For example, in some embodiments, the reduced reaction temperature is maintained for a period of at least 15 minutes before warming 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, as with other embodiments above or below, the organic solvent is a polar organic solvent. In some embodiments, as with other embodiments above or 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), dioxanes (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 anhydrous. In some embodiments, the organic solvent comprises a solvent 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 comprises a solvent selected from the group consisting of 2-methyltetrahydrofuran, toluene, acetonitrile, NMP, DMSO, sulfolane, and combinations thereof. In some cases, the organic solvent comprises acetonitrile. In some more particular cases, the organic solvent comprises 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 of Compound C to Compound E As described herein, the disclosed process for preparing compound A involves 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, either as a solid or, optionally, with a 0.5 volume solvent rinse to facilitate the addition of compound D, with a slight excess of compound D (e.g., 1.1 equivalents), and heating the mixture overnight (e.g., 12-16 hours) or until complete conversion of compound C to E (e.g., above 25°C, e.g., 60-80°C or 80°C) as determined, for example, by HPLC. In one embodiment, the reaction progress can be monitored by, for example, a) extracting a sample, b) quenching with methanol, and c) isolating the methanol adduct (i.e., the methyl carbamate of compound B): [ka] The yield of compound E can be monitored by analyzing for . 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 greater relative to compound B (e.g., 86%, 87%, 88%, 89%, 90%, 91%, 92% or greater relative to compound B). In some embodiments, the yield of compound E is 85%-92% relative to compound B. In some embodiments, the yield of compound E is 86% relative to B.

[0044] The disclosed processes for converting compound C to compound E advantageously maximize the conversion of compound C. For example, in various embodiments, less than 0.2% of compound C remains upon completion of the conversion of compound C to compound E.

[0045] The mixing of Compound C and Compound D is carried out at a suitable temperature. In some embodiments, as with other embodiments above or below, the mixing of Compound C with Compound D is carried out at a temperature between room temperature and 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 or additionally, compound C and compound D are mixed at a temperature of 80°C or lower (e.g., 79°C, 78°C, 77°C, 76°C, 75°C, 74°C, 73°C, 72°C, or 71°C or lower). Thus, compound C is mixed with compound D at a temperature defined by and including any of the aforementioned endpoints, e.g., 15 to 120°C, 20 to 115°C, 25 to 110°C, 30 to 105°C, 35 to 100°C, 40 to 95°C, 45 to 90°C, 50 to 85°C, 55 to 80°C, 60 to 80°C, 61 to 79°C, 62 to 78°C, 63 to 77°C, 64 to 76°C, 65 to 75°C, 66 to 74°C, 67 to 73°C, 68 to 72°C, or 69 to 71°C.

[0046] A suitable amount of compound D is used. Typically, at least 1 equivalent or more of compound D is used. In various embodiments, a slight excess of compound D (e.g., 1.1 equivalents) relative to the amount of compound B is used. This slight excess is based on the starting amount of compound B, because compound C is not isolated or calculated, but is obtained immediately after formation from compound B and 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 water content of less than 200 ppm before mixing with compound C. In some embodiments, compound D is dried to have a water content of 190 ppm or less, e.g., 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 combining 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 synthesized via at least two different pathways: the substitution reaction pathway (SNAr) (k SNAr ) and fragmentation pathways (k Frag ) to provide compound A, and a fragmentation pathway to provide undesired side reactants. [ka] Scheme 3. Kinetic pathway for the reaction of compound E.

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

[0051] Non-limiting exemplary conditions for converting compound E to compound A include the following: cooling a mixture of compound E or a salt thereof in a solvent (e.g., acetonitrile) to 25°C or below or 17°C or below (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 the addition of the second base, the reaction mixture is stirred at a temperature of 12-20°C, e.g., 15-17°C, for 24 hours, or until complete, e.g., as evidenced by HPLC. In some cases, Compound E or a salt thereof is in solution with a solvent (e.g., DMSO) for mixing with TMG. Using a solution of Compound E or a salt thereof in a solvent (e.g., DMSO) can result in faster reaction times, fewer impurities, and / or higher yields.

[0052] Second base The second base can be any suitable base. In some embodiments, the second base comprises 1,5,7-triazabicyclo(4.4.0)dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo(4.4.0)dec-5-ene (MTBD), 1,8-diazabicyclo[5.4.0]undec-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 comprises TMG. In another embodiment, the second base comprises DBU.

[0053] The second base is present in an appropriate amount. In some embodiments, as with the above or below embodiments, the second base is present in 2 or more equivalents (e.g., 2.5, 3, 3.5, 4, 4.5, or 5 or more equivalents). Alternatively or additionally, the second base is present in 10 or less equivalents (e.g., 9.5, 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 defined by any of the foregoing 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 of the second base. In one embodiment, the second base can be present in 4.5 equivalents. In another embodiment, the second base may be present at 6.0 equivalents.

[0054] In embodiments in which compound E has been treated to reduce impurities (e.g., when isolating compound E), compound A can be obtained from compound E using 2 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 3 or more equivalents). Without being bound by theory, it is believed that reducing the amount of impurities in the reaction mixture for converting compound E to compound A can allow for a smaller amount of second base to be used in the conversion. In various embodiments, and in relation to other embodiments described above or below, the second base is present in 4.5 or more equivalents based on compound E, e.g., 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, or 5.5 or more equivalents based on compound E. Alternatively or additionally, the second base is present in 6.5 equivalents or less based on compound E, e.g., 6.4, 6.3, 6.2, 6.1, 6.0, 5.9, 5.8, 5.7, or 5.6 equivalents or less based on compound E. Thus, in various embodiments, the second base is present in an amount defined by and including either of the two foregoing endpoints, e.g., 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. Further, in some embodiments, the second base is present in 4.5 to 6.5 equivalents, 4.6 to 6.4 equivalents, 4.7 to 6.3 equivalents, 4.8 to 6.2 equivalents, 4.9 to 6.1 equivalents, 5.0 to 6.0 equivalents, 5.1 to 5.9 equivalents, 5.2 to 5.8 equivalents, 5.3 to 5.7 equivalents, or 5.4 to 5.6 equivalents based on compound E. In some embodiments, the second base is present in 4.8 to 5.2 equivalents based on compound E.

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

[0056] In some embodiments, the conversion of 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 of compound E to compound A is carried out in a solvent comprising DMSO. The solvent is present in an appropriate amount (e.g., 4 volumes). In some embodiments, the conversion of compound E to compound A is carried out in a solvent comprising acetonitrile. In one embodiment, the solvent is anhydrous, such as anhydrous acetonitrile.

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

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

[0059] In some embodiments, the disclosed process further comprises 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, 6 M phosphoric acid is used to crystallize compound A from the product mixture. In some embodiments, 6 M 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, 6 M 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, 4.5 M 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 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] Compound A to Compound F Compound A prepared by the processes disclosed herein can be used to synthesize compound F in a manner similar to that disclosed, for example, in U.S. Patent No. 10,519,146. Thus, in some embodiments, the disclosed processes for preparing compound A further include using compound A to synthesize compound F, a pharmaceutically acceptable salt, an atropisomer thereof, or a pharmaceutically acceptable salt of the atropisomer. [ka]

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

[0063] Additionally, the following set of alternative embodiments are provided herein: 1. Compound A: [ka] 1. A process for preparing (a) mixing reactive compounds including 2-isopropyl-4-methylpyridin-3-amine (compound B) or a salt thereof, a first base, and phosgene or a phosgene equivalent in an organic solvent to form 3-isocyanato-2-isopropyl-4-methylpyridine (compound C); (b) combining Compound C and 2,6-dichloro-5-fluoronicotinamide (Compound D) to form 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide (Compound E); (c) combining Compound E and a second base to form a product mixture comprising Compound A and a second base. 2. The process of embodiment 1, wherein step (a) comprises adding compound B, or a salt thereof, and a first base to a solution of the reactive compound and an organic solvent. 3. The process of embodiment 2, wherein compound A, or a salt thereof, and the first base are added to a solution of the reactive compounds while maintaining a temperature of at most 0° C. 4. The process of any one of embodiments 1 to 3, wherein step (a) comprises mixing for at least 15 minutes at a temperature of -35°C to 0°C, followed by warming to 25°C. 5. The process of any one of embodiments 1-4, wherein compound A is a free base. 6. The process of any one of embodiments 1 to 5, wherein the first base is an amine. 7. The process of embodiment 6, wherein the amine is a tertiary amine. 8. The process of embodiment 7, wherein the tertiary amine is N,N-diisopropylethylamine. 9. The process of any one of embodiments 1 to 8, wherein the first base is present in an amount of 0.4 to 1.1 molar equivalents based on compound B. 10. The process of any one of embodiments 1 to 9, wherein the reactive compound is phosgene. 11. The process of any one of embodiments 1 to 9, wherein the reactive compound is a phosgene equivalent. 12. The process of embodiment 11, wherein the phosgene equivalent is trichloromethyl carbonochloridate, bis(trichloromethyl)carbonate, di(imidazol-1-yl)methanone, or bis(2,5-dioxopyrrolidin-1-yl)carbonate. 13. The process of embodiment 12, wherein the phosgene equivalent is bis(trichloromethyl)carbonate. 14. The process of any one of embodiments 1 to 13, wherein the reactive compound is present in an amount of 0.3 to 0.6 molar equivalents, based on compound B. 15. The process of any one of embodiments 1 to 14, wherein the organic solvent in step (a) is a polar organic solvent, optionally anhydrous. 16. The process of embodiment 15, wherein the polar organic solvent comprises anhydrous acetonitrile. 17. The process of any one of embodiments 1-14, wherein the organic solvent comprises a solvent selected from the group consisting of 2-methyltetrahydrofuran, toluene, acetonitrile, NMP, DMSO, and sulfolane. 18. The process of any one of claims 1 to 17, wherein step (b) is carried out at a temperature of 60°C to 80°C. 19. The process of any one of embodiments 1-18, further comprising drying compound D to a moisture content of less than 200 ppm before carrying out step (b). 20. The process of any one of embodiments 1-19, wherein step (c) comprises adding a second base to compound E while maintaining a temperature of 25° C. or less. 21. The process of embodiment 20, wherein the temperature is maintained at 12°C to 20°C. 22. The process of embodiment 20 or 21, wherein after adding the second base, the temperature is adjusted to 15°C to 50°C. 23. The process of any one of embodiments 1 to 22, wherein the second base comprises 1,5,7-triazabicyclo(4.4.0)dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo(4.4.0)dec-5-ene (MTBD), 1,8-diazabicyclo[5.4.0]undec-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 of embodiment 23, wherein the second base comprises TMG. 25. The process of any one of embodiments 1-24, wherein the second base is present in 2 to 10 molar equivalents based on compound E. 26. The process of any one of embodiments 1-25, wherein the second base is present in 4.5 to 6.5 molar equivalents based on compound E. 27. The process of embodiment 26, wherein the second base is present in an amount of 4.8 to 5.2 molar equivalents based on compound E. 28. The process of any one of embodiments 1-27, wherein step (c) is carried out in dimethyl sulfoxide (DMSO). 29. The process of any one of embodiments 1-25, further comprising crystallizing compound A from the product mixture by adding an aqueous solution of an acid. 30. The process of embodiment 29, wherein the acid is phosphoric acid. 31. The process of embodiment 30, wherein the aqueous solution comprises 6 molar phosphoric acid. 32. The process of any one of embodiments 29-31, further comprising isolating the crystallized Compound A by filtration. 33. The process of any one of embodiments 1-32, wherein compound C, compound D, compound E, or any combination thereof, is not isolated prior to subsequent reaction. 34. The process of embodiment 33, wherein the organic solvent comprises acetonitrile. 35. The process according to any one of embodiments 1-32, wherein compound E is isolated before step c). 36.Compound F: [ka] 36. The process of any one of embodiments 1-35, further comprising using compound A to synthesize a pharmaceutically acceptable salt thereof, an atropisomer, or a pharmaceutically acceptable salt of an atropisomer. [Example]

[0064] The following examples further illustrate the disclosed tablet formulations and processes but, of course, should not be construed as in any way limiting their scope.

[0065] The following abbreviations are used herein: HPLC means high performance liquid chromatography, IPC means in-process control, UV means ultraviolet, ACN means acetonitrile, DBU means 1,8-diazabicyclo[5.4.0]undec-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 reaction completion and identify the reaction products. A non-limiting exemplary procedure for preparing the in-process control (IPC) samples used herein is as follows: 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 mixed thoroughly.

[0067] 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: A reactor was charged with triphosgene (0.4 equiv.) and anhydrous acetonitrile (solvent, 3.0 L / kg relative to compound B). The contents of the reactor were stirred until homogeneous and cooled to -5 °C. A solution of compound B (1.0 equiv.) and N,N-diisopropylethylamine (1.0 equiv.) in anhydrous acetonitrile (1.0 L / kg) was added to the phosgene solution over 1 h, maintaining the internal temperature at ≤0 °C. The batch was stirred at 0 °C for 15 min and then warmed to 25 °C. The reaction of compound B with triphosgene formed compound C, which was not isolated. Subsurface sparging with dry N2 was performed for several minutes at 25 °C to remove residual phosgene, and the vapors were vented to a scrubber containing aqueous ammonia. Compound D (1.1 equiv.) was charged as a solid, and the contents of the reactor were heated and stirred at 80 °C until complete conversion of compound C to compound E was achieved, as determined by HPLC. The reaction mixture was cooled to ≤12 °C. Compound E was not isolated. Tetramethylguanidine (TMG) (6.0 equiv.) was added while maintaining the batch temperature at ≦17°C. The reaction mixture was stirred at 15°C until complete conversion of Compound E to Compound A was achieved, as determined by HPLC. Aqueous phosphoric acid (6 M) (6.0 equiv.) was added at a temperature below 25°C. The resulting product slurry was filtered, washed with 1:4 acetonitrile:water (v / v) (3×3 L / kg), and deliquified. The product was dried to constant weight under a stream of nitrogen at ambient temperature. Typically, the above procedure afforded Compound A in 75% yield, based on the starting amount of Compound B, with a purity of ≧99.5% by HPLC (room temperature, 15.1 min, 2 μL injection volume under the conditions shown in Table 1B above).

[0071] Example 1B: The reactor was charged with anhydrous acetonitrile (solvent, 3.0 L / kg relative to compound B) and the contents of the reactor were cooled to -5°C. Triphosgene (0.366 equivalents) was then charged to the reactor and the contents were stirred at -5°C for 15 minutes. A solution of N,N-diisopropylethylamine (0.0175 equivalents) in anhydrous acetonitrile (solvent, 0.1 L / kg relative to compound B) was charged to the reactor and the contents were stirred at -5°C for 1.5 hours. A solution of compound B (1.0 equivalents) and N,N-diisopropylethylamine (1.0 equivalents) in anhydrous acetonitrile (solvent, 1.0 L / kg relative to compound B) was added by subsurface addition to the phosgene solution over 4 hours while maintaining the internal batch temperature at -5°C. The 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 charged as a solid, and the reactor contents were heated and stirred at 80°C until complete conversion of Compound C to Compound E was achieved, as determined by HPLC. The reaction mixture was cooled to 20°C. Compound E was not isolated. 1,8-diazabicyclo[5.4.0]undec-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 complete conversion of Compound E to Compound A was achieved, 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, washed with 30:70 acetonitrile:water (v / v) (3 x 3 L / kg), and deliquored. The product was dried under a stream of nitrogen at ambient temperature to constant weight. Typically, the above procedure afforded Compound A in 80% yield based on the starting amount of Compound B, with a purity of ≥99.5% by HPLC (room temperature: 15.1 min, 2 μL injection volume under the conditions shown in Table 1B above).

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

[0073] Example 3 A dry 100 mL reactor was charged with triphosgene (5.53 g, 18.64 mmol, 0.4 equiv.) and anhydrous acetonitrile (21 mL, 3.0 volumes per compound B). Optionally, rinse with 0.5 volumes of acetonitrile. Stir until homogeneous and cool to -5°C. A solution of triphosgene in acetonitrile has been shown to slowly liberate dissolved phosgene upon standing. This process occurred nearly instantaneously in the presence of catalytic base (e.g., 0.1 equiv. DIPEA). Excessive sparging of the headspace was avoided to ensure accurate phosgene stoichiometry was maintained.

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

[0075] The hydrochloride salt of Compound C crystallized from the reaction mixture, which formed a slurry. The batch was stirred below 0° C. for 15 minutes and then warmed to 25° C. Because excess phosgene inhibits the reaction of Compound D with Compound C, a subsurface sparge with dry nitrogen was performed for 15 minutes at 25° C. to remove residual phosgene.

[0076] Compound D was analyzed for water content before proceeding. If the water level was above 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 equiv.) was charged as a solid (optionally rinsing with 0.5 volumes of acetonitrile) and the mixture was heated at 80° C. overnight; the reaction mixture became homogeneous once the temperature reached 60° C. An assay for conversion from compound C (a sample was removed, quenched with methanol, and analyzed for the methanol adduct of compound C) was used to monitor completion of the reaction. Compound E, as the 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 give analytically pure compound E as its hydrochloride salt in approximately 86% yield, with less than 0.5% of compound C remaining. The reaction mixture was cooled to below 12°C. Tetramethylguanidine (32 g, 279 mmol, 6.0 equiv.) was added dropwise at below 17°C. The reaction mixture was stirred at 15°C for up to 24 hours, which resulted in cyclization to form compound A.

[0078] An alternative process for forming Compound A was as follows: Compound E as the hydrochloride salt in 3 volumes of DMSO was reacted with 5.0 equivalents of TMG at 15° C. The conversion of Compound E to Compound A occurred at a faster rate (several hours) in DMSO with fewer side products (reduced fragmentation to side products such as aniline Compound B and amide Compound D). The resulting production of Compound A proceeded in high assay yield (approximately 98%) based on the starting Compound E.

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

[0080] Compound A was isolated by filtration through a medium porosity fritted funnel. The wet cake was slurry washed with, for example, 2:8 acetonitrile:water (v / v). The wet cake was dried under nitrogen / vacuum at room temperature to a constant weight, affording Compound A from Compound B in 75% yield and greater than 99% (i.e., 99.5%) purity, as determined by chromatography.

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

[0082] Reactions were performed using 100 mg of compound B. Briefly, solutions of compound B were prepared in the solvent indicated. Triphosgene (0.4 equivalents) in solvent (10 volumes) was added to compound B at room temperature and stirred for 45 minutes. To each solution, a solution of compound D (1 equivalent) in solvent (10 volumes) was added at 60°C for 20 hours (room temperature for DCM). For experiments involving the addition of acid, 4 M hydrochloric acid was added as a 10% solution in dioxane. The reaction mixtures were diluted with methanol and analyzed.

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

[0084] [Table 3]

[0085] As evidenced by the results in Table 2, reactions carried out using MeTHF and toluene as solvents afforded Compound E in good yields of good purity. Furthermore, reactions in which two equivalents of the first base and / or salt were not filtered out produced favorable results. In particular, Examples 4K, 4L, 4S, and 4T, in which the solvent was MeTHF or toluene, two equivalents of the first base, and the salt was not filtered, produced favorable results. 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 for the conversion of compound E to compound A. SNAr / k Frag The selectivity (compound A:compound D) was investigated. [ka]

[0087] Briefly, after each reactor was charged with Compound E, DBU or TMG in 5 volumes of the solvent indicated in Table 3 was added at either 73° C. or 35° C. The reactions were monitored by liquid chromatography. The results are summarized in Table 3.

[0088] [Table 4]

[0089] As evidenced by the results in Table 3, reactions performed using TMG as the second base gave good results. Additionally, reactions performed using NMP, ACN, DMSO, and sulfolane gave good results.

[0090] The effect of the dielectric constant (ε) of the solvent was also investigated. TMG (4.0 equiv.) in 1.3 volumes of solvent was added over 10 min 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 the dielectric constant. Furthermore, the low amount of compound E remaining at the end of reaction (EOR) indicates the efficient conversion of compound E to compound A.

[0093] Example 6 As shown in the results in the following scheme, the use of DBU in the conversion of compound E to compound A results in a high 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 in the following scheme, the use of 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, including publications, patent applications, and patents, cited in this specification are herein incorporated by reference to the same extent as if each individual reference was individually and specifically indicated to be incorporated by reference and set forth in its entirety herein.

[0096] The use of the terms "a," "an," and "the," and similar referents in describing the present invention (particularly with reference to the claims that follow) should be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprise," "have," "include," and "contain" should be construed as open-ended terms (i.e., meaning "including, but not limited to"), unless otherwise indicated. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any examples or exemplary language (e.g., "such as") provided herein is intended merely to further clarify the invention and does not pose a limitation on the scope of the invention unless otherwise asserted. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

Claims

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

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

3. 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 a solution X.

4. 4. The process of claim 2 or claim 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. 5. The process of claim 4, wherein the solution X before 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 a solution containing the reactive compound and the organic solvent.

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

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

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

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

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

11. 4. The process of any one of claims 1 to 3, wherein step (a) comprises mixing for at least 15 minutes at a temperature of -35°C to 0°C, followed by warming to 25°C.

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

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

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

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

16. 4. The process of claim 1, wherein the first base is present in an amount of 0.8 to 1.2 molar equivalents based on Compound B.

17. 4. The process of claim 1, wherein the first base is present in an amount of 0.9 to 1.1 molar equivalents based on compound B.

18. 4. The process of claim 1, wherein the first base is present in 1.0 molar equivalent based on Compound B.

19. 5. The process of claim 4, wherein the additional amount of the first base in Solution X prior to the addition of Compound B, or a salt thereof, and the first base is present in an amount of 0.01 to 0.02 molar equivalents based on Compound B.

20. 5. The process of claim 4, wherein the additional amount of the first base in Solution X prior to the addition of Compound B, or a salt thereof, and the first base is present in an amount of 0.0175 molar equivalents, based on Compound B.

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

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

23. 23. The process of claim 22, wherein the phosgene equivalent is trichloromethyl carbonochloridate, bis(trichloromethyl)carbonate, di(imidazol-1-yl)methanone, or bis(2,5-dioxopyrrolidin-1-yl)carbonate.

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

25. 23. The process of 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. 23. The process of 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. 23. The process of any one of claims 1 to 22, wherein the reactive compound is present in 1.2 molar equivalents based on compound B.

28. 23. The process of 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. 25. The process of 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. 25. The process of claim 24, wherein the bis(trichloromethyl)carbonate is present in an amount of 0.4 molar equivalents based on Compound B.

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

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

33. 33. The process of claim 32, wherein the polar organic solvent comprises anhydrous acetonitrile.

34. 32. The process of 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 of any one of claims 1 to 32 and 34, wherein step (b) is carried out at a temperature of from 60°C to 100°C.

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

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

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

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

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

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

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

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

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

45. 45. The process of claim 44, wherein the temperature is maintained between 12°C and 20°C.

46. 46. ​​The process of claim 44 or 45, wherein after adding the second base, the temperature is adjusted to between 15°C and 50°C.

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

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

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

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

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

52. 52. The process of any one of claims 1 to 51, wherein the second base is present in 2 to 10 molar equivalents based on compound B.

53. 52. The process of any one of claims 1 to 51, wherein the second base is present in 4 to 7 molar equivalents based on Compound B.

54. 52. The process of 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. 52. The process of any one of claims 1 to 51, wherein the second base is present in 5.5 to 6.5 molar equivalents based on Compound B.

56. 52. The process of any one of claims 1 to 51, wherein the second base is present in an amount of 5.8 to 6.2 molar equivalents based on Compound B.

57. 52. The process of any one of claims 1 to 51, wherein the second base is present in 6.0 molar equivalents based on Compound B.

58. 52. The process of any one of claims 1 to 51, wherein the second base is present in 4.0 to 5.0 molar equivalents based on Compound B.

59. 52. The process of any one of claims 1 to 51, wherein the second base is present in an amount of 4.3 to 4.7 molar equivalents based on Compound B.

60. 52. The process of any one of claims 1 to 51, wherein the second base is present in 4.5 molar equivalents based on Compound B.

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

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

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

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

65. 62. The process of claim 61, wherein the acid is present in 6.0 molar equivalents based on Compound B.

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

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

68. 62. The process of claim 61, wherein the acid is present in 4.5 molar equivalents based on Compound B.

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

70. 70. The process of claim 69, wherein the aqueous solution comprises 3 to 6 molar phosphoric acid.

71. 70. The process of claim 69, wherein the aqueous solution comprises 6 molar phosphoric acid.

72. 70. The process of claim 69, wherein the aqueous solution comprises 4 to 5 molar phosphoric acid.

73. 70. The process of claim 69, wherein the aqueous solution comprises 4.3 to 4.7 molar phosphoric acid.

74. 70. The process of claim 69, wherein the aqueous solution comprises 4.5 molar phosphoric acid.

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

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

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

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