Process for preparing 4-methyl-2-propan-2-yl-pyridine-3-carbonitrile

Abstract

Provided herein is a process for preparing compound A or a salt thereof, the process comprising mixing compound B or a salt thereof and crotonaldehyde in the presence of an acid catalyst and a solvent to form compound A. TIFF2025509217000078.tif17170

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 317,187, filed March 7, 2022, the disclosure of which is incorporated by reference herein 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;Lievre 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 (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] The glycine to cysteine ​​mutation 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] The mutated cysteine ​​is adjacent to a pocket (P2) in the switch II region that is present only in the inactive, GDP-bound conformation of KRAS. G12CIt has 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] Sotorasib (also known as AMG 510 and sold as LUMAKRAS®) inhibits KRAS by uniquely interacting with the P2 pocket. G12C This inhibitor is a small molecule that specifically and irreversibly inhibits KRAS. G12C The mechanism is similar to that described for KRAS inhibitors. G12C It traps KRAS in its 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, G12CIn mice bearing mutant tumors, AMG 510 was shown to nearly completely inhibit detectable phosphorylation of extracellular signal-regulated kinase (ERK), a key downstream effector of KRAS, and to induce durable and complete tumor regression. See, e.g., Canon J, Rex K, Saiki AY, et al. “The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity” in Nature 2019;575:217-23.

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

[0009] A synthetic intermediate in the synthesis of sotorasib is compound A, which has the IUPAC name of 4-methyl-2-propan-2-yl-pyridine-3-carbonitrile (also known as 2-isopropyl-4-methylnicotinonitrile) and the following structure: [ka]

[0010] Compound A can be converted to other compounds useful as synthetic intermediates in processes for preparing AMG 510. In view of the above, there is a need for an efficient, scalable, cost-effective method for producing compound A or a salt thereof. [Prior art documents] [Non-patent literature]

[0011] [Non-Patent Document 1] Simanshu DK, Nissley DV, McCormick F. “RAS proteins and their regulators in human disease” in Cell 2017;170:17 - 33 Non - Patent Document 2 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 Non - Patent Document 3 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 inhibitors in non - small - cell lung cancer” in Clin Cancer Res 2007;13:2890 - 6 Non - Patent Document 4 Fiala 0, Buchler T, Mohelnikova - Duchonova B, et al. “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 Non - Patent Document 5 Lievre 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 [Non-Patent Document 6] McCormick F. “K-Ras protein as a drug target” in J Mol Med (Berl)2016;94:253-8 [Non-Patent Document 7] Jones RP, Sutton PA, Evans JP, et al. “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 [Non-Patent Document 8] 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 [Non-Patent Document 9] 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 [Non-Patent Document 10] 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

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[0012] The present disclosure provides a method for preparing compound A or a salt thereof, comprising mixing compound B or a salt thereof and crotonaldehyde in a solvent and in the presence of a catalytic reagent to form compound A or a salt thereof, wherein the catalytic reagent comprises an acid catalyst, an organic catalyst, or a combination thereof. [ka] [Brief description of the drawings]

[0013] [Figure 1A] 1 shows the DSC of Compound G Form 2 isolated from the crude product. [Figure 1B] 1 shows a TGA of Compound G Form 2 isolated from the crude product. [Figure 2A] 1 shows the DSC of Compound G Form 1 isolated from the crude product. [Figure 2B] 1 shows a TGA of Compound G Form 1 isolated from the crude product. [Figure 3A] FIG. 2 shows the experimental XRPD pattern of compound G Form 2. [Figure 3B] FIG. 1 shows the experimental XRPD pattern of Compound G Form 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The present disclosure provides a method for preparing compound A or a salt thereof. Without wishing to be bound by any particular theory, the disclosed method comprises a [3+3] cycloaddition of compound B or a salt thereof and crotonaldehyde. In some embodiments, the present disclosure provides a method for preparing compound A or a salt thereof, comprising mixing compound B or a salt thereof and crotonaldehyde in a solvent and in the presence of a catalytic reagent, including an acid catalyst, an organic catalyst, or a combination thereof, to form compound A. [ka]

[0015] The disclosed methods advantageously provide compound A or a salt thereof in high yield and purity with minimal amounts of by-products, such as, for example, compound C, compound D, and compound E shown below. [ka] As described herein, compounds C-E are by-products of the disclosed method for preparing compound A or a salt thereof from compound B and crotonaldehyde. In some embodiments, the disclosed method for preparing compound A or a salt thereof provides at least one by-product selected from compound C or a salt thereof, compound D or a salt thereof, and compound E or a salt thereof. In some embodiments, the disclosed method for preparing compound A or a salt thereof provides at least one by-product comprising compound C or a salt thereof. The disclosed method for preparing compound A or a salt thereof typically provides compound A as the major product. For example, in some embodiments, the disclosed methods for preparing Compound A or a salt thereof provide a method for preparing a cycloaliphatic compound having a molecular weight of from 1.5:1 to 99:1 or more (e.g., 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45:1, 46:1, 47:1, 48:1, 49:1, 50:1, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1, 57:1, 58:1, 59:1, 60:1, 61:1, 62:1, 63:1, 64:1, 65:1, 66:1, 67:1, 68:1, 69:1, 70:1, 71:1, 72:1, 73:1, 74:1, 75:1, 76:1, 77:1, 78:1, 1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45:1, 46:1, 47:1, 48:1, 49 :1, 50:1, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1, 57:1, 58:1, 59:1, 60:1, 61:1, 62:1, 63:1, 64:1, 65:1, 66:1, 67:1, 68:1, 69:1, 70:1, 71:1, 72:1, 73:1, 74:1, 75:1, 76:1, 77:1, 7 In some embodiments, the disclosed methods for preparing compound A or a salt thereof provide compound A substantially free of compound C. As used herein, the term "substantially free" refers to having 5% or less of a reference substance present (e.g., having no more than 5, 4, 3, 2, 1%).In some embodiments, substantially free refers to having 0.5% or less of the reference material present (e.g., not having more than 0.5, 0.4, 0.3, 0.2, 0.1%). In some embodiments, substantially free refers to the reference material being undetectable. In some embodiments, the molar ratio of Compound A to Compound C is greater than 99:1. Additionally, in some embodiments, along with other embodiments, the disclosed methods for preparing Compound A or a salt thereof provide a molar ratio of Compound A to Compound C of 1.5:1 to 99:1 or more (e.g., 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45:1, 46:1, 47:1, 48 :1, 49:1, 50:1, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1, 57:1, 58:1, 59:1, 60:1, 61:1, 62:1, 63:1, 64:1, 65:1, 66:1, 67:1, 68:1, 69:1, 70:1, 71:1, 72:1, 73:1, 74:1, 75:1, 76:1, 77: In some embodiments, the disclosed methods for preparing compound A or a salt thereof provide compound A substantially free of compound D.Further, in some embodiments, the disclosed methods for preparing Compound A or a salt thereof provide a method for preparing a cycloaliphatic alcohol having a methyl group ... 1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45:1, 46:1, 47:1, 48:1, 49 :1, 50:1, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1, 57:1, 58:1, 59:1, 60:1, 61:1, 62:1, 63:1, 64:1, 65:1, 66:1, 67:1, 68:1, 69:1, 70:1, 71:1, 72:1, 73:1, 74:1, 75:1, 76:1, 77:1, 7 In some embodiments, the disclosed methods for preparing compound A or a salt thereof provide compound A substantially free of compound E.

[0016] The disclosed method is suitable for preparing compound A on a large scale, and therefore suitable for the large-scale synthesis of sotorasibe. For example, in some embodiments, compound A or a salt thereof can be prepared on a scale of at least 30 g with a yield of more than 60% and more than 90% by weight. Thus, the disclosed method for preparing compound A or a salt thereof is useful for providing a synthetic intermediate in the production of sotorasibe. As an example, compound A can be converted to compound F or a salt thereof, which can then be converted to compound G or a salt thereof, which can then be used to form sotorasibe. In some embodiments, the disclosed method provides compound G or a salt thereof on a scale of 50 g or more. [ka]

[0017] The methods disclosed herein offer several advantages over existing methods. For example, compound G is the most expensive raw material in the synthesis of sotorasibe, accounting for a calculated 42.5% of the raw material cost and 26% of the total cost of goods manufactured from the drug raw material. The disclosed methods can succinctly provide compound G from two readily available chemical building blocks in four linear steps. In contrast, some currently known synthetic routes to compound G include several more steps. For example, Verghese J, Kong CJ, Rivalti D, et al. “Increasing global access to the high-volume HIV drug nevirapine through process intensification.” Green Chemistry 19.13(2017):2986-2991 (“Verghese”) discloses a five-step synthesis of 3-amino-2-chloro-4-methylpyridine (“CAPIC”), which can then be converted to compound A in two additional steps. A comparison of currently known routes is shown below: 7 steps via the intermediate compound CAPIC disclosed in Verghese with further conversion to compound G (also referred to as compound 1 in the scheme below) disclosed in Chinese Patent Application Publication No. CN111205286 (Suzhou Institute of Drug Innovation) and PCT Publication No. WO 2021 / 123294 (Bartolome-Nebreda et al.-Janssen Pharmaceutica, NV), as well as one embodiment of the method disclosed herein (4 steps). [ka]

[0018] PCT Publication No. WO 2021 / 097207 (Corbett and Caille-Amgen Inc.) discloses methods for preparing Compound A, Compound F, and Compound G. For example, see Schemes A1-A3 on pp. 63-67 shown below. Here, Compound A is Compound 35 in Schemes A2 and A3, Compound F is Compound 36 in Scheme A2, and Compound G is Compound 2A in Schemes A1-A3. Scheme A1 below provides a procedure for the synthesis of 2-isopropyl-4-methylpyridin-3-amine. Scheme A2 below provides a procedure for the synthesis of 2-isopropyl-4-methylpyridin-3-amine. Scheme A3 below provides a synthetic route for aniline via 2-isopropyl-4-methylnicotinonitrile. Scheme A1. [ka] Scheme A2. [ka] Scheme A3. [ka]

[0019] In particular, the synthesis of compound 2A shown in Scheme A1 uses isoprenylboronic acid ester in step 1 and precious metal palladium catalyst in steps 1 and 2, which are all high-cost materials, making the cost of producing compound 2A higher. In addition, step 1 in Scheme A1 uses dimethoxyethane as a reaction solvent and dichloromethane as a solvent in the work-up of step 1. In addition, the hydrogenation reaction in step 2 of Scheme A1 requires specialized equipment capable of operating at high pressure for the hydrogenation reaction. Similarly, the synthesis of compound 2A shown in Scheme A2 of PCT Publication No. WO 2021 / 097207 uses dichloromethane in the extractive work-up in multiple steps (steps 1 and 2). In addition, step 2 of Scheme A2 uses DMF-DMA (suspected reproductive hazard) to promote the methylation reaction, and step 3 of Scheme A2 uses corrosive sulfuric acid (85%) for functional group interconversion in step 3. Furthermore, the synthesis of compound 2A shown in Scheme A3 uses expensive chiral catalysts and is not suitable for large scale. Furthermore, many of the products in Scheme A3 are purified using chromatography and / or work-up steps with halogenated solvents (e.g., dichloromethane).

[0020] The methods disclosed in PCT Publication No. WO 2021 / 097207 are characterized by the use of high-cost reagents (e.g., isopropenyl boronic esters and palladium catalysts); harmful solvents (e.g., halogenated hydrocarbon solvents and carcinogenic solvents); chromatographic isolation; aqueous work-up; corrosive acids (e.g., sulfuric acid); and / or specialized reaction equipment capable of operating under high pressure (e.g., hydrogenation). In comparison, the methods disclosed herein offer several advantages, including: using inexpensive raw materials without the use of precious metal catalysts; avoiding the use of halogenated or harmful hydrocarbon solvents (i.e., dichloromethane or dimethoxyethane); avoiding aqueous work-up and chromatography; using basic nitrile hydrolysis to form compound F; and being carried out using standard reaction equipment that does not require high pressure operation. Thus, the disclosed methods result in reduced environmental impact (e.g., improved process "greenness"), for example, as measured by a reduction in halogenated solvents. For example, in some embodiments, the disclosed methods include the following steps to provide compound G or a salt thereof: [ka]

[0021] Compounds A~G As described herein, compound A is 4-methyl-2-propan-2-yl-pyridine-3-carbonitrile of the formula [ka] and salts thereof. As used herein, Compound A may also be referred to as 2-isopropyl-4-methylnicotinonitrile or "4-Me-nicotinonitrile" or "nicotinonitrile".

[0022] As described herein, Compound B has the formula: 3-amino-4-methylpent-2-enenitrile ("enaminonitrile"). [ka] and salts thereof. As will be appreciated, compound B may exist as a mixture of (Z / E) stereoisomers, as represented by the formula: [ka] (Z)-Compound B (E)-Compound B As used herein, "compound B" and its various expressions herein are used interchangeably to refer to a (Z / E) mixture unless otherwise specified. In some embodiments, compound B has a (Z / E) ratio of 3:1.

[0023] Compound B can be prepared using any suitable method. An exemplary synthesis of compound B is described in Monatshefte für Chemie (1999), 130(3), 441-450. For example, in some embodiments, compound B is prepared by n-butyllithium mediated heterodimerization of two different nitriles under cryogenic conditions, and purified by Kugelrohr vacuum distillation as a stereoisomeric mixture (Z / E ratio of 3:1).

[0024] As described herein, crotonaldehyde is a compound of the formula [ka] It refers to crotonaldehyde, β-methylacrolein, 2-butenal, or propylenealdehyde, also known herein as "enal". As will be understood, crotonaldehyde can exist as a mixture of (E / Z) stereoisomers (e.g., (2E)-but-2-enal). As used herein, "crotonaldehyde" and its various expressions are used interchangeably to refer to the (E / Z) mixture, unless otherwise specified.

[0025] Compound C is 2-isopropyl-6-methylnicotinonitrile ("6-Me-nicotinonitrile") of the formula [ka] and salts thereof. Without wishing to be bound by any particular theory, it is understood that compound C is a positional isomer of compound A formed by certain methods described herein.

[0026] Compound D refers to a compound of the following formula: [ka] Without wishing to be bound by any particular theory, it is believed that compound D is formed (reversibly) as a dynamic reaction intermediate during the disclosed method for preparing compound A. Compound D has a molecular weight (m / z) [M+H] of 273. + has.

[0027] Compound E refers to a compound of the following formula: [ka] Without wishing to be bound by any particular theory, it is believed that compound D is formed as a by-product in the disclosed method for preparing compound A. Compound E has a molecular weight (m / z) [M+H] of 323. + has.

[0028] Compound F has the formula: 2-isopropyl-4-methylnicotinamide ("nicotinamide"). [ka] and its salts.

[0029] Compound G has the formula: 2-isopropyl-4-methylpyridin-3-amine ("aniline") [ka] , its salts, and hydrates thereof. In some embodiments, the disclosed methods provide a hydrate of compound G (e.g., a hemihydrate).

[0030] The compounds disclosed herein may be used as salts. As used herein, "salt" includes, for example, acid addition salts. Salts include inorganic or organic acid addition salts. Non-limiting exemplary acid addition salts include, for example, salts with inorganic acids (e.g., hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfonate, nitrate) and salts with organic acids (e.g., malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, alkanoate, such as acetate, trifluoroacetate, and HOOC-(CH2) n -COOH (wherein n is 0 to 4).

[0031] As used herein, the term hydrate refers to a chemical compound formed by the interaction of water and a compound, including, for example, hemihydrate, monohydrate, dihydrate, trihydrate, etc. The term "monohydrate" refers to a compound or a salt thereof having about one associated water molecule. Those skilled in the art will recognize that the exact number of associated water molecules may vary slightly at any given time due to changes in temperature, pressure, and other environmental influences. All slight variations in the number of associated water molecules are intended to be within the scope of this disclosure. The term "dihydrate" refers to a compound or a salt thereof having about two associated water molecules. Those skilled in the art will recognize that the exact number of associated water molecules may vary slightly at any given time due to changes in temperature, pressure, and other environmental influences. All slight variations in the number of associated water molecules are intended to be within the scope of this disclosure.

[0032] Catalytic Reagents The methods disclosed herein include using a catalytic reagent. The catalytic reagent includes any suitable catalyst capable of catalyzing the reaction of compound B or a salt thereof and crotonaldehyde to form compound A. In some embodiments, the catalytic reagent includes an acid catalyst, an organic catalyst, or a combination thereof. In some embodiments, the catalytic reagent includes an acid catalyst. In some embodiments, the catalytic reagent includes an organic catalyst. As described herein, the catalytic reagent includes a suitable amount of an acid catalyst and / or an organic catalyst.

[0033] Acid Catalyst In some embodiments, the disclosed method includes mixing compound B or a salt thereof and crotonaldehyde in the presence of an acid catalyst. In some embodiments, the acid catalyst includes a Bronsted-Lowry acid. Suitable non-limiting examples of Bronsted-Lowry acids include, for example, anhydrous hydrochloric acid, benzoic acid, sulfonic acids (e.g., methanesulfonic acid (MsOH) and trifluoromethanesulfonic acid (triflic acid, TfOH)), and combinations thereof.

[0034] In some embodiments, the acid catalyst comprises a Lewis acid. Suitable non-limiting examples of Lewis acids include, for example, metal halides, triflates (trifluoromethanesulfonate, CF3SO3 - , OTF - ), boron-containing compounds (e.g., boron etherates, BF3SMe2, BF3NEt, BCl3, BBr3), and combinations thereof.

[0035] As used herein, "halide" refers to bromide, chloride, iodide, and fluoride.

[0036] Exemplary suitable metal halides include, for example, aluminum(III) chloride (AlCl), copper(II) chloride (CuCl), iron(III) chloride (FeCl), and zinc(II) bromide (ZnBr). In some embodiments, the metal halide is iron(III) chloride (FeCl) or any hydrate thereof (e.g., monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, etc.). In some embodiments, the metal halide is iron(III) chloride. In some embodiments, the metal halide is iron(III) chloride hexahydrate.

[0037] Exemplary suitable triflates include, for example, metal triflates and silyl triflates. In some embodiments, the triflates are selected from the group consisting of TMSOTf, Al(OTf)3, Bi(OTf)3, Cu(OTf)2, Sc(OTf)3, In(OTf)3, La(OTf)3, Yb(OTf)3, Zn(OTf)2, and combinations thereof. Exemplary silyl triflates include trimethylsilyl triflate (TMSOTf), tert-butyldimethylsilyl triflate (TBSOTf), and triisopropylsilyl triflate (TIPSOTf).

[0038] Exemplary suitable boron-containing compounds include, for example, BF3SMe2, BF3NEt, BCl3, BBr3BF3·2CH3COOH, BF3·2H2O, and BF3·nPrOH.

[0039] Exemplary suitable boron etherates include, for example, boron trifluoroetherate (BF3Et2O), BF3THF, and BF3OMe2.

[0040] The acid catalyst is present in any suitable amount. If there is too little acid catalyst present, the process may not proceed at a suitable reaction rate or efficiency. In contrast, if there is too much acid catalyst present, the process may be less cost-effective or produce a higher amount of undesirable by-products. In some embodiments, the acid catalyst is present at 5 mol % or more based on compound B (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 mol % or more based on compound B). Alternatively, or in addition, in some embodiments, the acid catalyst is present at 100 mol % or less based on Compound B (e.g., 100, 99, 98, 97, 96, 95, 94, 93, 92, 91, 90, 89, 88, 87, 86, 85, 84, 83, 82, 81, 80, 79, 78, 77, 76, 75, 74, 73, 72, 71, 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, or 51 mol % or less based on Compound B). Thus, the acid catalyst may be present in an amount between and including any of the aforementioned values ​​(e.g., 5-100, 6-99, 7-98, 8-97, 9-96, 10-95, 11-94, 12-93, 13-92, 14-91, 15-90, 5-50, 5-40, 5-30, 5-20 mol %, etc., based on compound B). In some embodiments, the acid catalyst is present in an amount of 5-75 mol % based on compound B. In some embodiments, the acid catalyst is present in an amount of 5-50 mol % based on compound B. In some embodiments, the acid catalyst is present in an amount of 5-20 mol % based on compound B. In some embodiments, the acid catalyst is present at 10 mol % based on compound B.

[0041] organic catalyst In some embodiments, along with other embodiments described above or below, the catalytic reagent comprises an organic catalyst. In some embodiments, the organic catalyst comprises an amine or a salt thereof. In some embodiments, the amine comprises an amino acid (e.g., proline or β-alanine) or a salt thereof. In some embodiments, the amine or a salt thereof is a secondary amine or a salt thereof. In some embodiments, the secondary amine or a salt thereof is selected from the group consisting of dialkylamines, heterocyclic amines, and combinations thereof. As used herein, the term "dialkylamine" refers to an amine substituted with two alkyl groups, e.g., a compound of formula NHR'R'', where each of R' and R'' is independently an alkyl group as described herein. The term "heterocyclic amine" refers to a monocyclic or polycyclic ring (saturated, partially saturated, or unsaturated) containing 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) members of which 1 to 4 (e.g., 1, 2, 3, or 4) ring atoms are heteroatoms selected from N, O, and S, where at least one heteroatom is a basic N.

[0042] The term "alkyl" as used herein refers to a saturated straight or branched chain hydrocarbon. In some embodiments, the alkyl group is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, sec-butyl, tert-butyl, isopentyl, n-pentyl, neopentyl, sec-pentyl, 3-pentyl, sec-isopentyl, active pentyl, isohexyl, n-hexyl, sec-hexyl, neohexyl, and tert-hexyl.

[0043] In some embodiments, the secondary amine comprises a chiral amine. In some embodiments, the secondary amine comprises an achiral amine.

[0044] In some embodiments, the amine is β-alanine or a salt thereof, in some embodiments, the amine is a secondary amine or a salt thereof selected from the group consisting of benzylmethylamine, diisopropylamine, D,L-proline, L-proline, prolinol, morpholine, piperidine, pyrrolidine, and combinations thereof.

[0045] In some embodiments, the organic catalyst comprises pyrrolidine or a salt thereof. Exemplary pyrrolidine salts include, for example, pyrrolidine hydrochloride, pyrrolidine hexafluorophosphate, pyrrolidine benzoate, pyrrolidine mesylate, pyrrolidine fluoroborate, pyrrolidine hydrochloride, pyrrolidine trifluoroacetate, pyrrolidine acetate, and combinations thereof. In some embodiments, the organic catalyst comprises pyrrolidine hydrochloride.

[0046] In some embodiments, the organocatalyst is [ka] and combinations thereof.

[0047] In some embodiments, the organocatalyst is [ka] and combinations thereof.

[0048] In some embodiments, the organocatalyst is [ka] and combinations thereof.

[0049] When present, the organic catalyst is present in any suitable amount. If too little organic catalyst is present, the process may not proceed with suitable reaction rate or efficiency. In contrast, if too much organic catalyst is present, the process may be less cost-effective or result in higher amounts of undesired by-products. In some embodiments, the organic catalyst is present in an amount of 5 mol % or more based on compound B (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 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, 100, 101, 102, 103, 104, 105, 106, 107, 1 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 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 mol % or more). Alternatively, or in addition, in some embodiments, the organic catalyst is present in an amount of 200 mol % or less based on compound B (e.g., 200, 199, 198, 197, 196, 195, 194, 193, 192, 191, 190, 189, 188, 187, 186, 185, 184, 183, 182, 181, 180, 179, 178, 177, 176, 175, 174, 173, 172, 171, 170, 169, 168, 167, 166, 165, 164, 163, 162, 161, 160, 159, 158, 157, 1 56, 155, 154, 153, 152, 151, 150, 149, 148, 147, 146, 145, 144, 143, 142, 141, 140, 139, 138, 137, 136, 135, 134, 133, 132, 131, 130, 129, 128, 127, 126, 125, 124, 123, 122, 121, 120, 119, 118, 117, 116, 115, 114, 113, 112, 111, 110, 109, 108, 107, 106, 105, 104, 103, 102, or 101 mol % or less).Thus, the organic catalyst may be present in an amount between and including any of the aforementioned values ​​(e.g., 5-200, 10-200, 6-99, 7-98, 8-97, 9-96, 10-95, 11-94, 12-93, 13-92, 14-91, 15-90, 5-50, 5-40, 5-30, 5-20, 10-50, 10-40, 10-30, or 10-20 mol %, etc., based on compound B). In some embodiments, the organic catalyst is present in an amount of 5-200 mol % based on compound B. In some embodiments, the organic catalyst is present in an amount of 5-150 mol % based on compound B. In some embodiments, the organic catalyst is present in an amount of 5-100 mol % based on compound B. In some embodiments, the organic catalyst is present in an amount of 5-75 mol % based on compound B. In some embodiments, the organic catalyst is present in an amount of 5-50 mol % based on compound B. In some embodiments, the organic catalyst is present in an amount of 5 mol % based on compound B. In some embodiments, the organic catalyst is present in an amount of 10 mol % based on compound B. In some embodiments, the organic catalyst is present in an amount of 50 mol % based on compound B.

[0050] solvent The disclosed method is carried out in a suitable solvent. In some embodiments, the solvent comprises a polar aprotic solvent, such as acetone, acetonitrile, dichloromethane, dimethylformamide (DMF), dimethylpropylene urea, dimethyl sulfoxide (DMSO), ethyl acetate, hexamethylphosphoric triamide, or tetrahydrofuran (THF). In some embodiments, the solvent comprises a polar protic solvent, such as formic acid, n-butanol, isopropanol, nitromethane, ethanol, methanol, acetic acid, or water. In some embodiments, the solvent comprises a polar aprotic solvent, a polar protic solvent, or a combination thereof. In some embodiments, in conjunction with other embodiments above or below, the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, acetic acid, acetonitrile, acetone, cyclopentyl methyl ether, ethyl acetate, methyl isobutyl ketone, isopropyl acetate, tetrahydrofuran, methyl tert-butyl ether, N-methylpyrrolidone, dimethyl sulfoxide, dimethylformamide, toluene, n-heptane, and combinations thereof. In some embodiments, the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, acetic acid, acetonitrile, dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, and combinations thereof. In some embodiments, the solvent is selected from the group consisting of cyclopentyl methyl ether, ethyl acetate, acetonitrile, tetrahydrofuran, and combinations thereof. In some embodiments, the solvent comprises acetonitrile.

[0051] The solvent is present in a suitable amount. If too little solvent is present, the reactants may not be able to mix in a suitable manner to facilitate reaction or processing of the reaction mixture. In contrast, if the amount of solvent is too high, the concentration of the reactants may be too dilute for suitable reaction, or processing of the reaction may be unnecessarily cumbersome, or may have high energy requirements to remove the solvent.

[0052] By way of example, in the disclosed methods for compound A, the solvent is present in an amount of 5 volumes to 40 volumes (L / kg) based on compound B (e.g., 10-35 volumes, 15-30 volumes, or 20-25 volumes of solvent based on compound B). As used herein, "volume" refers to liters of solvent per kilogram of compound B. In some embodiments, the solvent is present in an amount of 10 volumes (L / kg) based on compound B.

[0053] temperature The disclosed method for preparing compound A or its salt is carried out at a suitable temperature. If the temperature is too low, the reaction may not proceed at a sufficient rate. In contrast, if the temperature is too high, the reaction may not be stable or may produce a larger amount of undesirable by-products. In some embodiments, the disclosed methods are performed at a temperature of 0° C. or higher (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75° C. or higher). Alternatively, or in addition, the disclosed methods can include heating the catalyst at temperatures below 150° C. (e.g., 150, 149, 148, 147, 146, 145, 144, 143, 142, 141, 140, 139, 138, 137, 136, 135, 134, 133, 132, 131, 130, 129, 128, 127, 126, 125, 124, 123, 122, 121, 120, 119, 118, , 117, 116, 115, 114, 113, 112, 111, 110, 109, 108, 107, 106, 105, 104, 103, 102, 101, 100, 99, 98, 97, 96, 95, 94, 93, 92, 91, 90, 89, 88, 87, 86, 85, 84, 83, 82, 81, 80, 79, 78, 77, or 76°C or less). Thus, the disclosed methods can be carried out at any temperature between and including any of the aforementioned values ​​(e.g., 0-150, 1-149, 2-148, 3-147, 4-146, 5-145, 6-144, 7-143, 8-142, 9-141, 10-140°C, etc.). In some embodiments, the mixing of compound B and crotonaldehyde is carried out at a temperature of 0-150°C (e.g., 20-110°C, 40-80°C, or 50-70°C). In some embodiments, the mixing of compound B and crotonaldehyde is carried out at 60°C.

[0054] stoichiometry The disclosed methods for preparing compound A or a salt thereof include mixing compound B or a salt thereof with a suitable amount of crotonaldehyde. In some embodiments, the crotonaldehyde is present in a molar excess relative to compound B. In some embodiments, crotonaldehyde is present in an amount of 1.1 to 5 molar equivalents relative to compound B (e.g., 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0 molar equivalents relative to compound B). In some embodiments, crotonaldehyde is present in an amount of 1.1 to 5 molar equivalents relative to compound B. In some embodiments, crotonaldehyde is present in 1.5 to 2.5 molar equivalents relative to Compound B. In some embodiments, crotonaldehyde is present in 2 molar equivalents relative to Compound B.

[0055] yield The disclosed method provides compound A or a salt thereof in a suitable yield. In some embodiments, the yield of compound A or a salt thereof is 10% to 90% based on compound B (e.g., a yield of 15 to 90%, 20 to 90%, 25 to 90%, 30 to 90%, 35 to 90%, 40 to 90%, 45 to 90%, 50 to 90%, 55 to 95%, 60 to 95%, 65 to 95%, 70 to 95%, 75 to 95%, 80 to 95%, or 90 to 95% based on compound B). In some embodiments, the yield of compound A is 50-75% (e.g., 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75%) based on compound B. In some embodiments, the yield of compound A is 55-65%. In some embodiments, the yield of compound A is at least 50% (e.g., at least 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95%). In some embodiments, compound A is obtained in an assay yield (e.g., HPLC) of 68-75% and an isolated yield (e.g., column chromatography) of 40-53%. In some embodiments, Compound A has a purity of at least 60% (e.g., at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 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%) by HPLC.

[0056] Compound A can be isolated in any suitable form or technique. In some embodiments, compound A is isolated as a crystalline salt or free base. In some embodiments, compound A is isolated as a free base. In some embodiments, compound A is isolated using purification filtration and / or distillation (e.g., vacuum distillation).

[0057] Use of Compound A in the Preparation of Compounds F, G, and Sotorasib In some embodiments, as well as other embodiments described above or below, the disclosed methods further include converting compound A, or a salt thereof, to another compound useful for preparing sotorasib (e.g., compound F, or a salt thereof, or compound G, or a salt thereof).

[0058] In some embodiments, along with other embodiments above or below, the disclosed methods for preparing compound A or a salt thereof include converting compound A or a salt thereof to compound F or compound G in a single reaction vessel, whereby reaction conditions as described below, e.g., heating compound A or a salt thereof or mixing compound F or a salt thereof with an oxidizing agent and a base, are carried out without isolating compound F or a salt thereof.

[0059] Compound F: Compound A or a salt thereof can be converted to compound F or a salt thereof under any suitable conditions. In some embodiments, the disclosed methods for preparing compound A or a salt thereof further comprise heating compound A or a salt thereof in the presence of an acid or a base to a temperature of at least 30° C. to form compound F or a salt thereof. In some embodiments, the disclosed methods result in the formation of compound F as a free base.

[0060] In embodiments involving converting compound A to compound F, compound A or a salt thereof can be heated to a temperature of 65° C. or greater (e.g., 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, or 85° C. or greater). Alternatively, or in addition, compound A or a salt thereof can be heated to a temperature of 105° C. or less (e.g., 105, 104, 103, 102, 101, 100, 99, 98, 97, 96, 95, 94, 93, 92, 91, 90, 89, 88, 87, or 86° C. or less). Thus, compound A may be heated to any temperature between and including the aforementioned values ​​(e.g., 65-105°C, 66-104°C, 67-103°C, 68-102°C, 69-101°C, 70-100°C, 90-100°C, 90-95°C, etc.). In some embodiments, compound A or a salt thereof is heated to a temperature of 90°C in embodiments involving converting compound A to compound F. In some embodiments, compound A or a salt thereof is heated to a temperature of 92°C in embodiments involving converting compound A to compound F. In some embodiments, compound A or a salt thereof is heated to a temperature of 100°C in embodiments involving converting compound A to compound F.

[0061] In some embodiments, when compound A is heated in the presence of an acid, the acid is selected from the group consisting of sulfuric acid, hydrochloric acid, phosphoric acid, and combinations thereof. In some embodiments, the acid comprises sulfuric acid.

[0062] In some embodiments, when compound A is heated in the presence of a base. In some embodiments, the base comprises a metal hydroxide. Exemplary suitable metal hydroxides include, for example, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide, and combinations thereof. In some embodiments, the metal hydroxide is sodium hydroxide.

[0063] Compound G: In some embodiments, the disclosed methods further include converting compound F, or a salt thereof, to compound G, or a salt thereof. In some embodiments, the disclosed methods further include converting compound F, or a salt thereof, to compound G. In these embodiments, compound G, or a salt thereof, is prepared by combining compound F, or a salt thereof, with an oxidizing agent and a base to form compound G, or a salt thereof.

[0064] In some embodiments, the oxidizing agent is selected from the group consisting of sodium hypochlorite, sodium hypobromite, N-bromosuccinimide, lead tetraacetate, and combinations thereof, hi some embodiments, the oxidizing agent comprises sodium hypochlorite.

[0065] In some embodiments, the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, 1,8-diazabicyclo[5.4.0]undec-7-ene, and combinations thereof. In some embodiments, the base comprises sodium hydroxide.

[0066] In some embodiments, compound G or a salt thereof produced from the disclosed methods is crystalline. Without wishing to be bound by any particular theory, it is believed that compound G or a salt thereof produced from the disclosed methods may exist in various crystalline forms (e.g., Form 1 and Form 2).

[0067] The crystalline form of Compound G may be analyzed using any suitable technique. For example, in some embodiments, the crystalline form of Compound G is assessed using one or more of the following techniques: differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction, single crystal X-ray diffraction (SCXRD), and / or Karl Fischer titration.

[0068] In some embodiments, Compound G or a salt thereof comprises crystalline Compound G Anhydrous Form 1. In some embodiments, Compound G Anhydrous Form 1 is characterized by an X-ray powder diffraction (XRPD, CuKα radiation (1.54 Å)) pattern including peaks at 7.17, 8.59, 11.44, 12.76, 13.62, 14.17, 15.34, 17.69, 20.25, 24.05, 24.34, 25.56, 29.85, 30.12, 31.38, and 34.37 (±0.2° 2θ). In some embodiments, Compound G Anhydrous Form 1 is characterized by an (XRPD, CuKα radiation (1.54 Å)) pattern including peaks (±0.2° 2θ) at 7.17, 8.57, 12.74, 13.61, 21.53, 24.35, 29.85, and 34.99. In some embodiments, Compound G Anhydrous Form 1 is characterized by a crystalline structure having the following properties when measured at 100 degrees Kelvin (i.e., −173° C.):

[0069] [Table 1]

[0070] In some embodiments, compound G is characterized by a unit cell having the following unit cell dimensions, as measured at -173°C: a=13.0 Å; b=8.2 Å; c=24.9 Å; α=90°; γ=90°; and β=101.7°.

[0071] In some embodiments, Compound G Anhydrous Form 1 is characterized by a crystalline structure having the following properties when measured at room temperature (i.e., 23° C.):

[0072] [Table 2]

[0073] In some embodiments, compound G is characterized by a unit cell having the following unit cell dimensions, as measured at 23° C.: a=13.9 Å; b=8.4 Å; c=25.4 Å; α=90°; γ=90°; and β=103.1°.

[0074] Form 2 In some embodiments, Compound G or a salt thereof comprises crystalline Compound G hemihydrate Form 2. In some embodiments, Compound G hemihydrate Form 2 is characterized by an X-ray powder diffraction (XRPD, CuKα radiation (1.54 Å)) pattern including peaks (±0.2° 2θ) at 10.82, 11.76, 14.07, 15.26, 16.02, 17.78, 20.79, 21.73, 22.27, 23.62, 24.78, 26.03, 29.2 30.04, 31.09, 32.22, 36.76, 40.39, and 41.44. In some embodiments, Compound G hemihydrate Form 2 is characterized by an X-ray powder diffraction (XRPD, CuKα radiation (1.54 Å)) pattern containing peaks at 10.82, 21.73, 30.04, 32.22, and 40.39 (±0.2° 2θ). In some embodiments, Compound G hemihydrate Form 2 is characterized by a crystalline structure having the following properties when measured at 100 degrees Kelvin (i.e., −173° C.):

[0075] [Table 3]

[0076] In some embodiments, compound G is characterized by a unit cell having the following unit cell dimensions, as measured at -173°C: a=11.5 Å; b=9.8 Å; c=8.1 Å; α=90°; γ=90°; and β=90°.

[0077] In some embodiments, Compound G hemihydrate Form 2 is characterized by a crystalline structure having the following properties when measured at room temperature (i.e., 23° C.):

[0078] [Table 4]

[0079] In some embodiments, compound G is characterized by a unit cell having the following unit cell dimensions, as measured at 23° C.: a=8.2 Å; b=9.9 Å; c=11.6 Å; α=90°; γ=90°; and β=90°.

[0080] It is understood that the SCXRD test can be performed at 100K and the XRPD can be performed at room temperature.

[0081] Sotorastic: In some embodiments, the disclosed methods further include using any one of Compound A, Compound F, and Compound G, or a salt of any of the above, prepared to form sotorasib, e.g., as described in PCT Publication Nos. WO 2021 / 097207 A1 and WO 2018 / 217651 A1 (both of which are incorporated by reference in their entireties for all purposes).

[0082] In some embodiments, the disclosed methods further include forming sotorasib or any sotorasib intermediate using any one of Compound A, Compound F, and Compound G, or a salt of any of the foregoing, as described in any of the syntheses of sotorasib provided herein.

[0083] The following intermediate compounds of sotorasib are representative of the present disclosure and are not intended to be construed as limiting the scope of the present invention. Compound A, Compound F, and / or Compound G or a salt of any of the above may be used in the following synthetic routes to obtain any intermediate, any group of intermediates, and / or sotorasib itself provided below.

[0084] The synthesis of sotorasibe and several related intermediates is described in U.S. Patent Application Serial No. 15 / 984,855, filed May 21, 2018 (U.S. Patent Application Publication No. 2018 / 0334454, November 22, 2018), which claims priority to and benefit of U.S. Provisional Patent Application Serial No. 62 / 509,629, filed May 22, 2017, both of which are incorporated herein by reference in their entirety for all purposes. The synthetic routes provided in U.S. Patent Application Serial No. 15 / 984,855 are provided below. As disclosed elsewhere herein, Compound A, Compound F, and / or Compound G or a salt of any of the above may be used and / or implemented in the following synthetic routes to obtain any intermediate, any group of intermediates (e.g., any one or more of intermediates A1, A2, A3, A4, A5, and / or A6) provided herein, and / or sotorasibe itself. [ka] As will be understood in light of the present disclosure, Compound A, Compound F, and / or Compound G, or a salt of any of the foregoing, may be used and / or practiced in some embodiments of the processes for preparing intermediates A2, A3, A4, A5, A6, sotorasib, and / or any one or more of combinations thereof. Such methods may include any combination of steps disclosed herein, for example, the manufacturing methods recited in the following combinations of steps (including any reagents required in any one or more steps): Compound B → Compound A → Compound G + A1 → A2; Compound G + A1 → A2 → A3; Compound B → Compound A → Compound G + A1 → A2 → A3 → A4 → A5 → A6; Compound B → Compound A → Compound G + A1 → A2 → A3 → A4 → A5 → A6 → sotorasib; Compound B → Compound A → Compound G + A1 → sotorasib; Compound B → Compound A → Compound G + A1 → A2 → A5 → A6 → sotorasib; or any other variation of the combination of steps disclosed in the above scheme (e.g., omission or inclusion of any of the steps provided above).

[0085] Another synthesis of sotorasib and some related intermediates is described in International Application No. PCT / US19 / 61815, filed November 15, 2019 (PCT Publication No. WO 2020 / 102730, May 22, 2020), which claims priority to and the benefit of U.S. Provisional Application No. 62 / 768,802, filed November 16, 2018, both of which are incorporated herein by reference in their entireties for all purposes. The synthetic routes provided in International Application No. PCT / US19 / 61815 are provided below. As disclosed elsewhere herein, Compound A, Compound F, and / or Compound G or a salt of any of the above may be used and / or implemented in the following synthetic pathways to provide any intermediate, any group of intermediates provided below (e.g., any one or more of intermediates B3, B4, B5, B6, B7, B8, and / or combinations thereof) and / or sotorasib itself. As will be appreciated, Compound A, Compound F, and / or Compound G or a salt of any of the above may be implemented in a synthetic pathway with one or more of B1 and / or B2 to provide, for example, B3 or any intermediate, any group of intermediates provided below (e.g., any one or more of intermediates B3, B4, B5, B6, B7, and / or B8) and / or sotorasib itself. [ka] As will be understood in light of the present disclosure, Compound A, Compound F, and / or Compound G, or a salt of any of the above, may be used and / or practiced in some embodiments of the process for producing any one or more of intermediates B3, B4, B5, B6, B7, B8, sotorasib, and / or combinations thereof. Such methods may include any combination of steps disclosed herein, for example, the manufacturing methods recited in the following combinations of steps (including any reagents required in any one or more steps): Compound B → Compound A → Compound G + B2 → B3; Compound G + B2 → B3 → B4; Compound B → Compound A → Compound G + B2 → B3 → B4 → B5 → B6 → B7; Compound B → Compound A → Compound G + B2 → B3 → B4 → B5 → B6 → B7 → B8 → Sotorasib; Compound B → Compound A → Compound G + B2 → Sotorasib; Compound B → Compound A → Compound G + B2 → B3 → B7 → B8 → Sotorasib; or any other variation of the combination of steps disclosed in the above scheme (e.g., omission or inclusion of any of the steps provided above).

[0086] Another synthesis of sotorasib and related intermediates is described in International Application No. PCT / US2020 / 060421, filed November 13, 2020 (PCT Publication No. WO 2021 / 097212, May 20, 2021), which claims priority to and the benefit of U.S. Provisional Application No. 62 / 935,502, filed November 14, 2019, both of which are incorporated herein by reference in their entireties for all purposes. The synthetic routes provided in International Application No. PCT / US2020 / 060421 are provided below. As disclosed elsewhere herein, Compound A, Compound F, and / or Compound G or a salt of any of the above may be used and / or implemented in the following synthetic pathways to provide any intermediate, any group of intermediates provided below (e.g., any one or more of intermediates C3, C4, C5, C6, C7, C8, C9, and / or combinations thereof) and / or sotorasib itself. As will be appreciated, Compound A, Compound F, and / or Compound G or a salt of any of the above may be implemented in a synthetic pathway with one or more of C1 and / or C2 to provide, for example, C3 or any intermediate, any group of intermediates provided below (e.g., any one or more of intermediates C3, C4, C5, C6, C7, C8, and / or C9) and / or sotorasib itself. [ka] As will be understood in light of the present disclosure, Compound A, Compound F, and / or Compound G, or a salt of any of the above, may be used and / or practiced in some embodiments of the process for producing any one or more of intermediates C3, C4, C5, C6, C7, C8, C9, sotorasib, and / or combinations thereof. Such methods may include any combination of steps disclosed herein, for example, the manufacturing methods recited in the following combinations of steps (including any reagents required in any one or more steps): Compound B → Compound A → Compound G + C2 → C3; Compound G + C2 → C3 → C4; Compound B → Compound A → Compound G + C2 → C3 → C4 → C5 → C6 → C7; Compound B → Compound A → Compound G + C2 → C3 → C4 → C5 → C6 → C7 → C8 → C9 → Sotorasib; Compound B → Compound A → Compound G + C2 → Sotorasib; Compound B → Compound A → Compound G + C2 → C3 → C7 → C8 → Sotorasib; Compound A → Compound G + C2 → C3 → C9 → Sotorasib; or any other variation of the combination of steps disclosed in the above scheme (e.g., omission or inclusion of any of the steps provided above).

[0087] Another synthesis of sotorasibe and related intermediates is described in International Application No. PCT / US2021 / 060048, filed November 19, 2021 (PCT Publication No. WO 2022 / 109242, May 27, 2022), which claims priority and benefit of U.S. Provisional Application No. 63 / 116,703, filed November 20, 2020, both of which are incorporated herein by reference in their entirety for all purposes. The synthetic pathways provided in International Application No. PCT / US2021 / 060048 are provided below. As disclosed elsewhere herein, Compound A, Compound F, and / or Compound G or any salt of the above may be used and / or performed in the following synthetic pathways to obtain any intermediate provided below, any intermediate group (e.g., D1) and / or sotorasibe itself. As will be appreciated, Compound A, Compound F, and / or Compound G or a salt of any of the above, along with one or more of A1, A2, A3, A4, A5, A6, B2, B3, B4, B5, B6, B7, B8, C1, C3, C4, C5, C6, C7, C8, and / or C9, may be implemented in the synthetic pathways shown below and / or above to, for example, obtain sotorasibe or any other intermediate disclosed herein. As will be appreciated in light of the present disclosure, Compound A, Compound F, and / or Compound G or a salt of any of the above may be used and / or implemented in some embodiments of the manufacturing methods to obtain any one or more of intermediates A1, A2, A3, A4, A5, A6, B2, B3, B4, B5, B6, B7, B8, C1, C3, C4, C5, C6, C7, C8, C9, sotorasibe, and / or combinations thereof. Such methods may include any combination of the steps (or omit any combination of the steps) disclosed herein. [ka]

[0088] As used herein, "intermediate" compounds include structures produced by the described synthetic procedures prior to obtaining the final desired compound, whether isolated or produced in situ and not isolated. These intermediates are included within the scope of the present disclosure. Exemplary embodiments of such intermediate compounds are described elsewhere herein.

[0089] Embodiment 1. Compound A or a salt thereof [ka] A method for preparing mixing compound B or a salt thereof and crotonaldehyde in a solvent and in the presence of a catalytic reagent to form compound A or a salt thereof; The method, wherein the catalytic reagent comprises an acid catalyst, an organic catalyst, or a combination thereof. [ka]

[0090] 2. The method of embodiment 1, wherein the acid catalyst comprises Bronsted-Lowry acid.

[0091] 3. The method of embodiment 2, wherein the Bronsted-Lowry acid is triflic acid (TfOH).

[0092] 4. The method of embodiment 1, wherein the acid catalyst comprises a Lewis acid.

[0093] 5. The method of embodiment 4, wherein the Lewis acid comprises a metal halide, a triflate, a boron etherate, or a combination thereof.

[0094] 6. The method of embodiment 5, wherein the metal halide is selected from the group consisting of AlCl3, CuCl2, FeCl3, ZnBr2, and combinations thereof.

[0095] 7. The method of embodiment 6, wherein the metal halide is FeCl3.

[0096] 8. The method of any one of embodiments 5-7, wherein the triflate is selected from the group consisting of metal triflates, silyl triflates, and combinations thereof.

[0097] 9. The method of embodiment 8, wherein the metal triflate is selected from the group consisting of Al(OTf)3, Bi(OTf)3, Cu(OTf)2, Sc(OTf)3, In(OTf)3, La(OTf)3, Yb(OTf)3, Zn(OTf)2, and combinations thereof.

[0098] 10. The method of embodiment 8, wherein the triflate is a silyl triflate.

[0099] 11. The method of embodiment 8 or 10, wherein the silyl triflate is TMSOTf.

[0100] 12. The method of any one of embodiments 5 to 11, wherein the boron etherate is BF3Et2O.

[0101] 13. The method of any one of the preceding embodiments, wherein the acid catalyst is present in an amount of 5 to 75 mol % based on compound B.

[0102] 14. The method of any one of the preceding embodiments, wherein the acid catalyst is present in an amount of 5 to 50 mol % based on compound B.

[0103] 15. The method of any one of the preceding embodiments, wherein the acid catalyst is present in an amount of 5 to 20 mol % based on compound B.

[0104] 16. The method of any one of the preceding embodiments, wherein the acid catalyst is present in an amount of 50 mol % based on compound B.

[0105] 17. The method of any one of the preceding embodiments, wherein the organic catalyst comprises an amine or a salt thereof.

[0106] 18. The method of embodiment 17, wherein the amine comprises an amino acid or a salt thereof.

[0107] 19. The method of embodiment 17 or 18, wherein the amine comprises a secondary amine or a salt thereof.

[0108] 20. The method of embodiment 19, wherein the secondary amine or salt thereof is a dialkylamine, a heterocyclic amine, or a combination thereof.

[0109] 21. The method of embodiment 19 or 20, wherein the secondary amine or its salt is selected from the group consisting of benzylmethylamine, diisopropylamine, β-alanine, D,L-proline, L-proline, prolinol, morpholine, piperidine, pyrrolidine, and combinations thereof.

[0110] 22. The method of any one of the preceding embodiments, wherein the organic catalyst comprises pyrrolidine or a salt thereof.

[0111] 23. The method of embodiment 22, wherein the pyrrolidine salt is selected from the group consisting of pyrrolidine hexafluorophosphate, pyrrolidine benzoate, pyrrolidine mesylate, pyrrolidine fluoroborate, pyrrolidine hydrochloride, pyrrolidine trifluoroacetate, pyrrolidine acetate, and combinations thereof.

[0112] 24. The method of any one of the preceding embodiments, wherein the organic catalyst comprises pyrrolidine hydrochloride.

[0113] 25. An organic catalyst is [ka] and combinations thereof.

[0114] 26. The method of any one of the preceding embodiments, wherein the organic catalyst is present in an amount of 5 to 200 mol % based on compound B.

[0115] 27. The method of any one of the preceding embodiments, wherein the organic catalyst is present in an amount of 5 to 150 mol % based on compound B.

[0116] 28. The method of any one of the preceding embodiments, wherein the organic catalyst is present in an amount of 5 to 100 mol % based on compound B.

[0117] 29. The method of any one of the preceding embodiments, wherein the organic catalyst is present in an amount of 5 to 75 mol % based on compound B.

[0118] 30. The method of any one of the preceding embodiments, wherein the organic catalyst is present in an amount of 5 to 50 mol % based on compound B.

[0119] 31. The method of any one of the preceding embodiments, wherein the organic catalyst is present in an amount of 10 mol % based on compound B.

[0120] 32. The method of any one of the preceding embodiments, wherein the solvent comprises a polar aprotic solvent.

[0121] 33. The method of any one of the preceding embodiments, wherein the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, acetic acid, acetonitrile, acetone, cyclopentyl methyl ether, ethyl acetate, methyl isobutyl ketone, isopropyl acetate, tetrahydrofuran, methyl tert-butyl ether, N-methylpyrrolidone, dimethylsulfoxide, dimethylformamide, toluene, n-heptane, and combinations thereof.

[0122] 34. The method of any one of the preceding embodiments, wherein the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, acetic acid, acetonitrile, dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, and combinations thereof.

[0123] 35. The method of any one of the preceding embodiments, wherein the solvent is selected from the group consisting of cyclopentyl methyl ether, ethyl acetate, acetonitrile, tetrahydrofuran, and combinations thereof.

[0124] 36. The method of any one of the preceding embodiments, wherein the solvent comprises acetonitrile.

[0125] 37. The method of any one of the preceding embodiments, wherein the solvent is present in an amount of 5 volumes to 40 volumes based on compound B (L / kg).

[0126] 38. The method of any one of the preceding embodiments, wherein the solvent is present in an amount of 10 volumes (L / kg) based on compound B.

[0127] 39. The method of any one of the preceding embodiments, wherein the mixing is carried out at a temperature between 0°C and 150°C.

[0128] 40. The method of embodiment 39, wherein the temperature is between 20°C and 110°C.

[0129] 41. The method of embodiment 39, wherein the temperature is between 40°C and 80°C.

[0130] 42. The method of embodiment 39, wherein the temperature is between 50°C and 70°C.

[0131] 43. The method of embodiment 39, wherein the temperature is 60°C.

[0132] 44. The method of any one of the preceding embodiments, wherein crotonaldehyde is present in molar excess relative to compound B.

[0133] 45. The method of any one of the preceding embodiments, wherein crotonaldehyde is present in an amount of 1.1 to 5 molar equivalents relative to compound B.

[0134] 46. ​​The method of any one of the preceding embodiments, wherein crotonaldehyde is present in 2 molar equivalents relative to compound B.

[0135] 47. Compound A is compound D [ka] 47. The method of any one of embodiments 1 to 46, wherein the method is substantially free of:

[0136] 48. Compound A is compound E [ka] 48. The method of any one of embodiments 1 to 47, wherein the method is substantially free of

[0137] 49. Compound A is a compound C [ka] 50. The method of any one of the preceding embodiments, wherein the method is substantially free of:

[0138] 50. The method comprises: [ka] The method of any one of the preceding embodiments, wherein compound A is provided in a molar ratio of from 1.5:1 to 99:1 or more.

[0139] 51. The method of embodiment 50, wherein the molar ratio of compound A to compound C is greater than 99:1.

[0140] 52. The method of any one of embodiments 1 to 51, wherein the yield of compound A is 10% to 90% based on compound B.

[0141] 53. The method of any one of embodiments 1-52, wherein the yield of compound A is 50% to 75% based on compound B.

[0142] 54. The method of any one of the preceding embodiments, further comprising combining pyrrolidine and hydrochloric acid in a second solvent to form pyrrolidine hydrochloride.

[0143] 55. The method of any one of the preceding embodiments, further comprising heating compound A, or a salt thereof, to a temperature of at least 30° C. in the presence of an acid or a base to form compound F, or a salt thereof. [ka]

[0144] 56. The method of embodiment 55, wherein compound A or a salt thereof is heated to a temperature of 65°C to 110°C.

[0145] 57. The method of embodiment 55 or 56, wherein the temperature is 100°C.

[0146] 58. The method of any one of embodiments 55-57, wherein the acid is selected from the group consisting of sulfuric acid, hydrochloric acid, phosphoric acid, and combinations thereof.

[0147] 59. The method of any one of embodiments 55-58, wherein the acid comprises sulfuric acid.

[0148] 60. The method of any one of embodiments 55-57, wherein the base comprises a metal hydroxide.

[0149] 61. The method of any one of embodiments 55-57 and 60, wherein the base is a metal hydroxide.

[0150] 62. The method of embodiment 60 or 61, wherein the metal hydroxide is sodium hydroxide.

[0151] 63. The method of any one of the preceding embodiments, further comprising combining compound F with an oxidizing agent and a base to form compound G. [ka]

[0152] 64. The method of embodiment 63, wherein the oxidizing agent is selected from the group consisting of sodium hypochlorite, sodium hypobromite, N-bromosuccinimide, lead tetraacetate, and combinations thereof.

[0153] 65. The method of embodiment 63 or 64, wherein the oxidizing agent comprises sodium hypochlorite.

[0154] 66. The method of any one of embodiments 63-65, wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, 1,8-diazabicyclo[5.4.0]undec-7-ene, and combinations thereof.

[0155] 67. The method of any one of embodiments 63-66, wherein the base comprises sodium hydroxide.

[0156] 68. The method according to any one of embodiments 55 to 67, wherein the heating according to any one of embodiments 55 to 67 and the mixing according to any one of embodiments 63 to 67 are carried out in a single reaction vessel.

[0157] 69. The method of any one of embodiments 1-68, further comprising forming sotorasib using any one of compound A or a salt thereof, compound B or a salt thereof, compound F or a salt thereof, and compound G or a salt thereof.

[0158] 70. The method of any one of embodiments 1-54, further comprising using compound A or a salt thereof to form compound F or a salt thereof.

[0159] 71. The method of any one of embodiments 55-62, further comprising using compound F, or a salt thereof, to form compound G, or a salt thereof.

[0160] 72. The method of embodiment 71, wherein compound G is crystalline and characterized by an X-ray powder diffraction (XRPD, CuKα radiation (1.54 Å)) pattern comprising peaks (±0.2° 2θ) at 7.17, 8.59, 11.44, 12.76, 13.62, 14.17, 15.34, 17.69, 20.25, 24.05, 24.34, 25.56, 29.85, 30.12, 31.38, and 34.37.

[0161] 73. The method of embodiment 72, wherein compound G is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.17, 8.57, 12.74, 13.61, 21.53, 24.35, 29.85, and 34.99 (±0.2° 2θ).

[0162] 74. The method of embodiment 72 or 73, wherein compound G is anhydrous.

[0163] 75. The method of any one of embodiments 72-74, wherein compound G is characterized by a unit cell having the following unit cell dimensions, measured at -173°C: a=13.0 Å; b=8.2 Å; c=24.9 Å; α=90°; γ=90°; and β=101.7°.

[0164] 76. The method of any one of embodiments 72-74, wherein compound G is characterized by a unit cell having the following unit cell dimensions, measured at 23°C: a=13.9 Å; b=8.4 Å; c=25.4 Å; α=90°; γ=90°; and β=103.1°.

[0165] 77. The method of embodiment 71, wherein compound G is crystalline and characterized by an X-ray powder diffraction (XRPD, CuKα radiation (1.54 Å)) pattern comprising peaks (±0.2° 2θ) at 10.82, 11.76, 14.07, 15.26, 16.02, 17.78, 20.79, 21.73, 22.27, 23.62, 24.78, 26.03, 29.2 30.04, 31.09, 32.22, 36.76, 40.39 and 41.44.

[0166] 78. The method of embodiment 77, wherein compound G is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 10.82, 21.73, 30.04, 32.22, and 40.39 (±0.2° 2θ).

[0167] 79. The method of embodiment 77 or 78, wherein compound G is a hemihydrate.

[0168] 80. The method of any one of embodiments 77-79, wherein compound G is characterized by a unit cell having the following unit cell dimensions, measured at -173°C: a=11.5 Å; b=9.8 Å; c=8.1 Å; α=90°; γ=90°; and β=90°.

[0169] 81. The method of any one of embodiments 75-77, wherein compound G is characterized by a unit cell having the following unit cell dimensions, measured at 23°C: a=8.2 Å; b=9.9 Å; c=11.6 Å; α=90°; γ=90°; and β=90°. EXAMPLES

[0170] The following examples further illustrate the disclosed methods but, of course, should not be construed as in any way limiting their scope.

[0171] The following abbreviations are used herein: NMR refers to nuclear magnetic resonance; rt refers to room temperature; EOR refers to end of reaction; LC refers to liquid chromatography; Jorgensen's catalyst refers to (2R)-2-[diphenyl[(trimethylsilyl)oxy]methyl]pyrrolidine unless otherwise specified; LCAP refers to liquid chromatography area percentage.

[0172] General Experimental Information General reagent information. Pyrrolidine, anhydrous hydrogen chloride solution (3M in cyclopentyl methyl ether), iron(III) chloride (anhydrous, powder, ≧99.99% on a trace metals basis) and anhydrous acetonitrile (MeCN) were purchased from Sigma Aldrich and used as received. Pyrrolidine hydrochloride was freshly prepared prior to the cyclization reaction. 1,2,4,5-Tetrachloro-3-nitrobenzene (TCNB) was used as an internal standard for NMR quantitative analysis in reaction optimization. All other reagents and solvents were obtained from various commercial suppliers and used as received.

[0173] General procedure for the synthesis of compound A. A reaction vessel (e.g., screw-cap scintillation vial (Chemglass, 20.0 mL, catalog number CG-4912-05)) was charged with a magnetic stir bar (Biotage, oval, part number 353930), a source of NH3 (1.0 equiv.) or a Bronsted acid (1.0 equiv.), or iron(III) chloride (29.4 mg, 0.18 mmol, 0.1 equiv.), or an organic catalyst (free base or salt, according to the stoichiometry shown in the table) and toluene or acetonitrile (2 mL). The catalyst solution was stirred at room temperature for 10 minutes. To the catalyst solution was added crotonaldehyde (3.63 mmol, 2.0 equiv.) and compound B (1.81 mmol, 1 equiv.). The vessel was closed (e.g., the vial was capped) and the reaction mixture was stirred at the temperature shown for the reaction time shown. Work-up: The reaction mixture was then cooled to room temperature and neutralized with 6N NaOH (i.e., stoichiometric amount equal to the acid catalyst). The solution was stirred for 5 min and transferred to a 25 mL round-bottom flask. The organic layer was separated from the aqueous layer and concentrated under reduced pressure. Results analysis: The resulting residue was passed through a short silica pad and concentrated under reduced pressure to give a quantitative yield. 1 The compounds were analyzed by 1 H NMR (i.e., as determined by the weights of the internal standards and reaction aliquots and their respective proton integral ratios) and regioselectivity (i.e., as determined by the proton integral ratios). 1H NMR(500MHz,CDCl3)δ 8.57(d,J=5.1Hz,1H),7.11(d,J=5.1Hz,1H),3.55(spt,J=6.8Hz,1H),2.55(s,3H),1.35(d,J =6.8Hz,6H). 13 C NMR(126MHz,CDCl3)δ 169.9,151.6,151.4,122.2,115.8,108.9,34.6,21.7(2C),20.5.IR(neat,cm -1 ):2968,2931,2223,1578,1563,1469,1408,1380,1361,1334,1106,933,833,431.HRMS(DART-TOF)m / z:[M+H] + C 10 H 13 Calculated value for N2: 161.1073; measured value: 161.1074.

[0174] Procedure for the synthesis of compound C: Compound B (1.66 mmol, 1 equiv.), 3-oxobutanal (3.32 mmol, 2.0 equiv.) as the sodium salt, and anhydrous 1,4-dioxane (1.0 mL) were added to a reaction vessel (e.g., 25 mL round-bottom flask) equipped with a condenser and a magnetic stir bar (Biotage, egg-shaped, part number 353930). The solution was cooled to 0° C. before adding hydrogen chloride solution (0.82 mL, 4.0 M, dioxane). The reaction mixture was heated to 110° C. and stirred overnight. Workup: The reaction mixture was then cooled to room temperature and neutralized with 6N NaOH (i.e., stoichiometric amount equal to the acid catalyst). The solution was stirred for 5 min and transferred to a 25 mL round-bottom flask. The organic layer was separated from the aqueous layer and concentrated under reduced pressure. Compound C was purified by Biotage Isolera™ Spektra Systems using ACI™ (5% ethyl acetate in heptane) in 15% isolated yield as a yellow oil. 1 H NMR(500MHz,CDCl3)δ 7.77(d,J=7.9Hz,1H),7.08(d,J=7.9Hz,1H),3.52(spt,J=6.9Hz,1H),2.62(s,3H),1.36(d,J=6.9Hz,6H) 13C NMR(126MHz,CDCl3)δ 169.1,162.3,140.1,120.3,117.2,104.5,34.5,24.9(2C),21.5.

[0175] Procedure for synthesizing compound D: A reaction vessel (e.g., 50 mL round bottom flask) was charged with a magnetic stir bar (Biotage, egg-shaped, part number 353930), iron(III) chloride (29.4 mg, 0.18 mmol, 0.1 equiv), pyrrolidine hydrochloride (0.5 equiv) and acetonitrile (2.0 mL). To the catalyst solution was added crotonaldehyde (3.63 mmol, 2.0 equiv) and compound B (1.81 mmol, 1 equiv). The reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure. Compound D was purified by Biotage Isolera™ Spektra Systems using ACI™ (5-20% ethyl acetate in heptane) in 14% isolated yield as a yellow solid. 1 H NMR(600MHz,acetonitrile-d3)δ 5.11(br s,2H),4.97(br s,1H),3.87-3.97(m,1H),3.01(td,J=6.95,13.94Hz,1H),2.93(spt,J=7.03Hz,1H),2.42-2.49(m,1H), 1.78(ddd,J=5.38,8.83,13.03Hz,1H),1.49(td,J=4.10,13.01Hz,1H),1.15(td,J=7.43,13.29Hz,15H). 13 C NMR (151 MHz, acetonitrile-d3) δ 20.77 (s, 1C) 22.22 (s, 1C) 28.30 (s, 1C) 33.57 (s, 1C) 34.20 (s, 1C) 34.53 (s, 1C) 45.06 (s, 1C) 76.76 (s, 1C) 78.97 (s, 1C) 121.49 (s, 1C) 123.17 (s, 1C) 162.40 (s, 1C) 166.04 (s, 1C). HRMS (DART-TOF) m / z: [M+H] + C 16 H 25 Calculated value for N4 273.2074; observed value 273.2074.

[0176] Procedure for synthesizing compound E: A reaction vessel (e.g., screw cap scintillation vial (Chemglass, 20.0 mL, catalog number CG-4912-05)) was charged with a magnetic stir bar (Biotage, oval, part number 353930), pyrrolidine hydrochloride (0.5 equiv.), and dimethylsulfoxide (20.0 mL). To the catalyst solution was added crotonaldehyde (3.63 mmol, 2.0 equiv.) and compound B (1.81 mmol, 1 equiv.). The reaction mixture was stirred at 60° C. for 12 hours. Workup: The reaction mixture was then cooled to room temperature and neutralized with 6N NaOH (i.e., stoichiometric amount equal to the acid catalyst). The solution was stirred for 5 minutes and transferred to a 250 mL separatory funnel. 100 mL of water was added to the funnel to aid in phase separation. Ethyl acetate was used to extract the organic contents from the aqueous layer. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. Compound E was purified by Biotage Isolera™ Spektra Systems using ACI™ (5-20% ethyl acetate in heptane) in 10% isolated yield as a yellow solid. 1 H NMR (600 MHz, acetonitrile-d3) δ 8.42 (s, 1H), 5.42 (br s, 1H), 4.68-4.78 (m, 1H), 3.48 (spt, J = 6.74 Hz, 1H), 3.06 (spt, J = 7.01 Hz, 1H), 2.52 (s, 3H), 2.16-2.24 (m, 1H), 1.79-1.87 (m, 1H), 1.60-1.68 (m, 1H), 1.29 (dd, J = 3.74, 6.71 Hz, 6H), 1.23 (d, J = 7.02 Hz, 3H), 1.17 (d, J = 7.10 Hz, 3H), 1.12-1.15 (m, 3H). 13C NMR(151MHz,acetonitrile-d3)δ 17.54(s,1C)20.68(s,1C)20.94(s,1C)21.26(s,1C)22.04(s,1C)22.17(s,1C)26.49(s,1C)33.63(s,1C)35.25(s,1C)35.44(s,1C)48.3 5(s,1C)77.40(s,1C)110.19(s,1C)117.25(s,1C)122.37(s,1C)136.00(s,1C)149.28(s,1C)151.20(s,1C)162.58(s,1C)169.20(s,1C).

[0177] General purification information. All work-up and purification procedures were performed using reagent grade solvents. Organic solutions were concentrated under reduced pressure using a Buchi rotary evaporator. Unless otherwise indicated, compounds were purified by flash column chromatography using 40-63 μm silica gel (SiliCycle SiliaFlash® F60) or using Biotage Isolera™ Spektra Systems with ACI™.

[0178] General analytical information. All substrates and products were 1 H NMR, 13 Characterized by C NMR, IR spectroscopy, elemental analysis or HRMS and melting point analysis (if solid). 1 H and 13 C NMR spectra were recorded using a 100-position SampleXpress sample exchanger ( 1 H, 600MHz; 13 C, 151 MHz) with a Bruker 600 MHz (Avance-600), 5 mm BBFO z-gradient probe ( 1 H, 500MHz; 13 C, 126 MHz) with a Bruker 500 MHz (Avance-500), a Bruker 400 MHz (Avance III-400) with a 25-position SampleXpress sample changer, or a Bruker 400 MHz (Avance-400) instrument ( 1 H, 400MHz;13 All 600 MHz NMR data were collected on samples dissolved in acetonitrile-d3, where 1 H is referenced to the residual solvent peak at 1.96 ppm; 13 C refers to the solvent signal at 1.39 ppm. All 1 H NMR data are reported in δ units, parts per million (ppm), and were measured relative to the residual proton signal in deuterated solvents at 7.26 ppm (CDCl3). All 13 C NMR spectrum, 1 H decoupled and reported in ppm relative to the solvent signal at 77.16 ppm (CDCl3). Data are reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, dd=doublet of doublets, t=triplet, td=triplet of doublets, q=quartet, quin=quintet, sep=septet, m=multiplet, br=broad singlet), coupling constant J (Hz), and integral. 1 The integrals of aromatic proton signals in 1 H NMR can be used to monitor reaction yields and selectivity using 1,2,4,5-tetrachloro-3-nitrobenzene (TCNB) as an internal standard.

[0179] IR spectra were recorded on a Thermo Scientific Nicolet iS5 FT-IR spectrometer (iD5 ATR, Diamond) and the absorption frequencies (cm -1 High-resolution mass spectra were recorded on a ThermoFischer Q-Exactive.

[0180] The products were also analyzed using high performance liquid chromatography (HPLC). Exemplary HPLC conditions for the analysis include the following:

[0181] In some of the following examples, reaction yields and purity were determined using quantitative HPLC using the methods described in Table 1. The method (34 min) was used to determine the yield of compound A (t r =16.446 min), Compound D(t r= 17.125 min), and compound E (t r = 24.496 min). The HPLC method used a binary mobile phase containing 20 mM ammonium formate in water (mobile phase A) and acetonitrile (mobile phase B). Samples were diluted with 50% (v / v) acetonitrile in water.

[0182] [Table 5]

[0183] The retention times (RT) and corresponding peak areas of compounds A, D, and E were used to assess the yield and product distribution.

[0184] Differential Scanning Calorimetry (DSC) Analysis: DSC data are collected using a TA Instruments Q200 DSC. Approximately 2-8 mg of sample was placed in a Tzero sealed alodine treated aluminum pan, sealed with a Tzero sealed lid, equilibrated at 25° C. for 5 minutes, and scanned from approximately 25° C. to 80-100° C. at a rate of approximately 10° C. / min under a nitrogen purge of approximately 50 mL / min.

[0185] Thermogravimetric Analysis (TGA): TGA measurements are recorded using a TA Q500 instrument. Approximately 10-20 mg of sample was added to a pre-tared TGA aluminum pan. TGA runs were performed by equilibrating the sample at 25°C for 5 minutes at a heating rate of approximately 10°C / min over a temperature range of approximately 25°C to 80-100°C while purging with nitrogen at a flow rate of approximately 60 mL / min.

[0186] X-ray powder diffraction (XRPD) analysis: XRPD data were obtained using a PANalytical X'Pert PRO diffractometer. Samples were scanned at ambient temperature (20-23 °C) in continuous mode from 5 to 45° (2θ) with a step size of 0.0334° at 45 kV and 40 mA using CuKα radiation (1.54 Å). The incident beam path included 0.02 Radsolar slits, a 15 mm mask, a 4° fixed anti-scatter slit, and a programmable divergence slit. The diffracted beam included 0.02 Radsolar slits, a programmable anti-scatter slit, and a 0.02 mm nickel filter. Samples were prepared in a low background sample holder and mounted on a rotation stage with a rotation time of 2 seconds.

[0187] Single Crystal X-ray Diffraction (SCXRD) Analysis: Preparation of single crystals for Form 1 Compound G and Form 2 Compound G: Single crystals of Form 1 Compound G were obtained by drying a sample of Form 2 under reduced pressure at 40° C. for 4 days. A sample of Form 2 was suspended in 1:9 MeCN:H2O and used for SCXRD analysis.

[0188] SCXRD data collection for form 2: A colorless irregularly shaped crystal with dimensions 0.33 × 0.27 × 0.19 mm3 was mounted on a nylon loop using paratone oil. Data were collected using an XtaLAB Synergy, Dualflex, HyPix diffractometer equipped with an Oxford Cryosystems cryodevice operating at T = 100.00 (17) K. CRI data were measured using scanning with CuKα radiation (microfocus sealed X-ray tube, 50 kV, 1 mA). The total number of runs and images were based on strategy calculations with the program CrysAlisPro 1.171.41.112a (Rigaku OD, 2021). The resolution achieved was θ = 80.130.

[0189] SCXRD data collection for Form 1: A colorless irregularly shaped crystal with dimensions 0.16 × 0.09 × 0.05 mm3 was mounted on a nylon loop using paratone oil. Data were collected using an XtaLAB Synergy, Dualflex, HyPix diffractometer equipped with an Oxford Cryosystems cryodevice operating at T = 99.98(18) K. CRI data were measured using scanning with CuKα radiation (microfocus sealed X-ray tube, 50 kV, 1 mA). The total number of runs and images were based on strategy calculations with the program CrysAlisPro 1.171.41.112a (Rigaku OD, 2021). The resolution achieved was θ = 80.354.

[0190] Karl Fischer (KF) analysis: Water content (KF) was determined using coulometric KF titration with Hydranal Coulomat AK reagent.

[0191] Comparative Example This comparative example demonstrates a method involving mixing compound B (1 equivalent) and crotonaldehyde (neat), as listed in Table 2, under solvent-free conditions at 110° C. for 2 hours.

[0192] The yield was quantitatively determined using 1,2,4,5-tetrachloro-3-nitrobenzene (TCNB) as an internal standard. 1 The reaction was determined by 1 H NMR and the selectivity was determined by the aromatic proton integral ratio of compounds A and C.

[0193] [Table 6]

[0194] Example 1. This example demonstrates an embodiment of the disclosed method for preparing Compound A using a catalytic reagent comprising a Lewis acid and an organic catalyst. The product Compound A had the following analytical properties: 1H NMR(500MHz,CDCl3)δ 8.57(d,J=5.1Hz,1H),7.11(d,J=5.1Hz,1H),3.55(spt,J=6.8Hz,1H),2.55(s,3H),1.35(d,J =6.8Hz,6H). 13 C NMR(126MHz,CDCl3)δ 169.9,151.6,151.4,122.2,115.8,108.9,34.6,21.7(2C),20.5.IR(neat,cm -1 ):2968,2931,2223,1578,1563,1469,1408,1380,1361,1334,1106,933,833,431.HRMS(DART-TOF)m / z:[M+H] + C 10 H 13 Calculated value for N2: 161.1073; measured value: 161.1074.

[0195] The product, Compound C, had the following analytical properties: 1 H NMR(500MHz,CDCl3)δ 7.77(d,J=7.9Hz,1H),7.08(d,J=7.9Hz,1H),3.52(spt,J=6.9Hz,1H),2.62(s,3H),1.36(d,J=6.9Hz,6H) 13 C NMR(126MHz,CDCl3)δ 169.1,162.3,140.1,120.3,117.2,104.5,34.5,24.9(2C),21.5.

[0196] Compound B (200 mg) and crotonaldehyde (2 equivalents) were mixed in acetonitrile (10 volumes) in the presence of FeCl3 (10 mol%) and (2R)-2-[diphenyl[(trimethylsilyl)oxy]methyl]pyrrolidine (i.e., Hayashi-Jorgensen catalyst) for 4 hours under the conditions described in Table 2a. Item 1 contained no organocatalyst. Item 5 was carried out in a glove box with less than 10 ppm O2. Item 6 was carried out in the presence of 1 equivalent of water. Items 7 and 8 were carried out with 2 g of compound B. The results are shown in Table 3. [ka]

[0197] [Table 7]

[0198] The yield was quantitative. 1 The selectivity was determined by the aromatic proton integral ratio in compounds A and C.

[0199] As demonstrated by the results in Table 3, the presence of an organocatalyst such as the Hayashi-Jorgensen catalyst promotes the 1,4-addition with exclusive regioselectivity, oxygen does not act as an exogenous oxidant, and the presence of water only slightly impairs the yield. Entries 3-5 demonstrate the robustness of the reaction at relatively high temperatures (80 °C versus 50 °C). Entries 7 and 8 demonstrate isolated yields at the multigram scale (2 g) and relatively short time scales (2.5 h; entry 7), as well as relatively long time scales (12 h; entry 8).

[0200] Example 2. This example demonstrates an embodiment of the disclosed method for preparing compound A using catalytic reagents including Lewis acids and organocatalysts.

[0201] Compound B and crotonaldehyde (2 equivalents) were mixed in acetonitrile (10 volumes) in the presence of 10 mol% FeCl3 and an organic catalyst listed in Table 4 at 80 °C for 4 hours. [ka]

[0202] [Table 8]

[0203] The yields of compounds A, D, and E were determined by the quantitative HPLC method shown in Table 1.

[0204] As demonstrated by the results shown in Table 4, secondary amines and their salts kinetically promote the formation of compound A via compound D, as evidenced by the minimization of the amount of compound D. The data show that achiral pyrrolidine hydrochloride (entries 3-6) provides complete conversion of compound D and higher yields of compound A compared to the free base (entry 2) and the more expensive chiral catalyst (entry 1). Furthermore, the method demonstrates broad functionality with respect to the equivalence of organic catalysts (e.g., pyrrolidine HCl), as evidenced by the small differences in product yields (see entries 3-6).

[0205] Further experiments were carried out under similar conditions using pyrrolidine HCl (1 equivalent) at various reaction times and temperatures as listed in Table 5.

[0206] [Table 9]

[0207] As demonstrated by the results in Table 5, the process for preparing compound A can be carried out in acetonitrile at temperatures between 40 and 80° C., such that comparable reaction yields and selectivities are obtained at lower reaction temperatures.

[0208] Example 3. This example demonstrates an embodiment of the disclosed method for preparing compound A using catalytic reagents including Lewis acids and organocatalysts.

[0209] Compound B and crotonaldehyde (2 equiv.) were mixed in acetonitrile (10 vol.) in the presence of 10 mol % FeCl3 and various organic catalysts listed in Table 6 at 80 °C for 4 h. [ka]

[0210] [Table 10]

[0211] The yields of compounds A, D, and E were determined by the quantitative HPLC method shown in Table 1.

[0212] As demonstrated by the results set forth in Table 6, the disclosed method comprising mixing compound B and crotonaldehyde in acetonitrile in the presence of catalytic reagents, including acid catalysts and organic catalysts, provides compound A substantially free of by-products (e.g., compounds D and E). For example, Entries 5-7 provide compound A substantially free of compound D, indicating complete consumption of intermediate compound D to yield compound A.

[0213] Example 4. This example demonstrates an embodiment of the disclosed method for preparing compound A using catalytic reagents including Lewis acids and organocatalysts on a multigram scale.

[0214] A reaction vessel was charged with FeCl3 (10 mol%) and pyrrolidine HCl (0.5 equiv.) in acetonitrile (10 V). The contents were stirred at room temperature for 5 min. The batch temperature was set to 60° C. Compound B (dosing rate: 6 mL / h) and crotonaldehyde (2 equiv.; dosing rate: 30 mL / h) were added to the reaction mixture in a T r = 60°C. The two dosing lines were rinsed with acetonitrile (0.1 L / kg). The reaction mixture was stirred at 60°C until complete conversion of compound B to compound A, as determined by HPLC described below and shown in Table 1. The reaction mixture was cooled to 20°C and neutralized with 6N NaOH (0.5 L / kg). The resulting solution was filtered, deliquified, and concentrated. The crude product was further purified using fine filtration and vacuum distillation. The reaction conditions are summarized in Table 7 (entry 1). The same reaction was repeated under the conditions shown in Table 7, entries 2 and 3.

[0215] [Table 11]

[0216] The yield of Compound A was determined by the quantitative HPLC method shown in Table 1.

[0217] As demonstrated by the results set forth in Table 7, the disclosed method can provide compound A on a multigram scale in good yield and high purity. The use of acetonitrile results in higher yields when compared to 2-MeTHF (item 1 versus item 3).

[0218] Example 5. This example demonstrates an embodiment of the disclosed method comprising converting compound A, or a salt thereof, to compound F, or a salt thereof, and / or converting compound F, or a salt thereof, to compound G, or a salt thereof.

[0219] Compound F had the following physical properties: 1 H NMR(500MHz,DMSO-d6)δ(ppm)=8.38(d,J=4.9Hz,1H),7.93(br s,1H),7.65(br s,1H),7.08(d,J=5.1Hz,1H),3.13(spt,J=6.7Hz,1H),2.25(s,3H),1.20(d,J=6.7Hz,6H); 13 C NMR (126 MHz, DMSO-d6) δ (ppm) = 170.3, 161.6, 148.6, 143.0, 133.5, 122.9, 32.8, 23.1, 18.9. IR (neat, cm-1): 3253, 3069, 2962, 1611, 1590, 1464, 1447, 1429, 1380, 812, 732, 696, 689, 616, 438. HRMS (DART-TOF) m / z: [M+H]+ calculated for C10H15N2O+ 179.1179; found 179.1172.

[0220] Compound G had the following physical properties: 1H NMR(500MHz,DMSO-d6)δ(ppm)=8.45(s,1H),7.67(d,J=4.7Hz,1H),6.78(d,J=4.7Hz,1H),4.70(br s,2H),3.25-3.13(m,1H),2.08(s,3H),1.15(d,J=6.7Hz,6H); 13 C NMR (126 MHz, DMSO-d6) δ (ppm) = 149.7, 139.5, 136.8, 128.9, 123.3, 29.0, 21.8, 17.8. IR (neat, cm-1): 3348, 3231, 2962, 2929, 2866, 1620, 1590, 1468, 1453, 1418, 1219, 1053, 818, 535. HRMS (DART-TOF) m / z: calculated for [M+H]+ CHN2+ 151.1230; found 151.1224. [ka]

[0221] A reaction vessel (e.g., a screw cap scintillation vial (Chemglass, 20.0 mL, catalog number CG-4912-05)) was charged with a magnetic stir bar (Biotage, oval, part number 353930), compound A (500 mg, 1.0 equiv.), sulfuric acid (3.5 equiv., 0.47 mL), and water (2.0 L / kg, 1 mL). The contents were stirred and the batch temperature was set to 105° C. The reaction mixture was stirred at 105° C. for 18 hours. The reaction mixture was cooled to 10° C. and neutralized with 6N NaOH. The resulting suspension was filtered and washed with water (3×5 mL). The filtered product was further purified by Biotage chromatography (eluent: 10% MeOH in dichloromethane) to give 268 mg of compound F in 60% isolated yield.

[0222] A reaction vessel (e.g., a screw cap scintillation vial (Chemglass, 20.0 mL, catalog number CG-4912-05)) was charged with a magnetic stir bar (Biotage, oval, part number 353930), compound F (106 mg, 1.0 equiv.), sodium hypochlorite solution (1.15 equiv., 0.39 mL), and sodium hydroxide (1N, 1.19 mL). The contents were stirred and the batch temperature was set to 80° C. The reaction mixture was stirred at 80° C. for 18 hours. The reaction mixture was cooled to 25° C. and 10 wt % sodium bisulfite (0.65 mL) was added. The resulting solution was extracted with ethyl acetate (3×5 mL). The organic layers were combined, dried over anhydrous MgSO4, and concentrated under reduced pressure to determine the conversion of compound F and the yield of compound G. 1 Quantitative analysis was performed by 1 H NMR.

[0223] Example 6. This example demonstrates an embodiment of the disclosed method for preparing Compound A or a salt thereof, which comprises mixing Compound B (10 mg) and crotonaldehyde (2.5 equivalents) in the presence of 10 mol% Lewis acid catalyst and acetonitrile (10 V) under N2 atmosphere at 80° C. overnight. Six processes were carried out using the conditions described below and in Table 8. [ka] The products were analyzed using ultra-performance liquid chromatography (UPLC) using the following conditions: Column—ACQUITY BEH C18 column (2.1×50 mm; 1.7 μm) (Waters Corp.; Milford, MA); Mobile phase A was 0.1% triflic acid in acetonitrile; Mobile phase B was 0.1% triflic acid in water; Flow rate of 0.6 mL / min; and Step gradient (A:B): t0=5:95; t6=95:5; and t 8.1 = 5:95. Liquid chromatographic area percent (LCAP) was determined from integrating the peaks from the UPLC chromatograms. Compound A had a retention time of 2.372 minutes. Compound C had a retention time of 2.735. The results are summarized in Table 8.

[0224] [Table 12]

[0225] As demonstrated by the results set forth in Table 8, items 4-6 provide compound A in high yields with good regioselectivity. Moreover, item 6 provided one of the highest yields of compound A while using a relatively inexpensive acid catalyst (FeCl3). Moreover, FeCl3 is suitable for carrying out the disclosed method on a large scale.

[0226] Example 7. This example demonstrates an embodiment of the disclosed method for preparing compound A, which includes mixing compound B and crotonaldehyde in the presence of an acid catalyst (10 mol% FeCl3) and a solvent (acetonitrile). Twelve processes were carried out using the conditions described below and in Table 9. [ka]

[0227] [Table 13]

[0228] The yields of compounds A, D and E were quantitative. 1 Determined by 1 H NMR.

[0229] As demonstrated by the results set forth in Table 9, catalytic reagents containing an amine salt (e.g., pyrrolidine HCl) provided faster reaction rates (based on the yield of compound D) and higher yields than catalytic reagents containing a free base (e.g., pyrrolidine) of compound A. Advantageously, pyrrolidine HCl is relatively inexpensive and provides comparable results to catalytic reagents containing a chiral organocatalyst (e.g., Hayashi-Jorgensen catalyst).

[0230] Example 8. This example demonstrates an embodiment of the disclosed method for preparing compound A or a salt thereof, which comprises mixing compound B or a salt thereof and crotonaldehyde (2 equivalents) in the presence of an acid catalyst (10 mol% FeCl3) and an organic catalyst in acetonitrile for 4 hours. Ten processes were carried out using the conditions listed in Table 10. The general reaction conditions were as follows: compound B (1.81 mmol), crotonaldehyde (3.62 mmol), 10 mol% FeCl3, 10 mol% organic catalyst, acetonitrile (0.2 mL) under air unless otherwise stated. [ka]

[0231] [Table 14]

[0232] The yield was quantitatively determined using 1,2,4,5-tetrachloro-3-nitrobenzene (TCNB) as an internal standard. 1 The selectivity was determined by the aromatic proton integral ratio of compounds A and C.

[0233] As demonstrated by the results listed in Table 10, the addition of 10 mol% of the Hayashi-Jorgensen catalyst to the FeCl3-mediated reaction afforded compound A in 66% yield as a single regioisomer (entry 5). To identify a cost-effective alternative to the chiral Hayashi-Jorgensen catalyst, various achiral secondary amines and the corresponding ammonium salts were evaluated as possible organocatalysts for the reaction. Pyrrolidine hydrochloride afforded comparable yields (entry 6). Similar results were obtained when the reaction was carried out under an inert atmosphere, suggesting that oxygen was not the final oxidant for the reaction (entry 8). The absence of FeCl3 resulted in reduced yields of the product (entry 9). Increasing organocatalyst loading from 10 mol% to 50 mol% had minimal impact on the reaction (entries 7 and 10).

[0234] Example 9. This example demonstrates an embodiment of the disclosed method for preparing Compound A or a salt thereof on a multigram scale. Compound B and crotonaldehyde were mixed under the conditions described in Table 11 and below.

[0235] [Table 15]

[0236] To reactor 1 was added pyrrolidine (0.5 equiv.) and anhydrous cyclopentyl methyl ether (CPME, 0.05 L / kg). The reactor contents were cooled to 0° C. Anhydrous hydrogen chloride solution (3.0 M in cyclopentyl methyl ether) (0.5 equiv.) was added at 0° C. and the contents were stirred at 25° C. for 15 min. The white slurry was filtered, deliquored, and washed with CPME (0.05 L / kg). The resulting cake was dissolved in anhydrous acetonitrile (0.1 L / kg) as pyrrolidine catalyst stock solution.

[0237] To reactor 2 was added iron(III) chloride (0.1 equiv.), pyrrolidine catalyst stock solution in MeCN (50 mol%, 0.1 L / kg), and anhydrous acetonitrile (8.0 L / kg). The contents were stirred at room temperature for 5 minutes. The batch temperature was set to 60° C. To the reaction mixture was added compound B (50 g, 1.0 equiv.; dosing rate: 6 mL / h) and crotonaldehyde (2 equiv.; dosing rate: 30 mL / h) in a T r = 60°C. The two dosing lines were rinsed with MeCN (0.1 L / kg). The reaction mixture was stirred at 60°C until complete conversion of compound B to compound A as determined by HPLC. The reaction mixture was cooled to 20°C and neutralized with 6N NaOH (0.5 L / kg). The resulting solution was filtered, dewatered and concentrated. The crude product was further purified using fine filtration and vacuum distillation. Typically, the above procedure resulted in a 60% yield of compound A with a purity of 79% by HPLC using the method described in Table 7.

[0238] Example 10. This example demonstrates an embodiment of the disclosed method in which compound A, or a salt thereof, is converted to compound F, or a salt thereof. [ka]

[0239] [Table 16]

[0240] A reactor was charged with compound A (1.0 equiv.) and 1N NaOH (5.0 L / kg, 161 mL). The contents were stirred and the batch temperature was set to 100° C. The reaction mixture was stirred at 100° C. for 18 hours. The resulting solution was filtered and deliquored. The filter cake was slurry washed with 20 wt % sodium chloride (5.0 L / kg, 161 mL) and then with toluene (5.0 L / kg, 161 mL). The product compound F was dried to constant weight under a stream of nitrogen at ambient temperature and used in the next step without further purification.

[0241] Example 11. This example demonstrates an embodiment of the disclosed method for preparing compound G, or a salt thereof, which comprises combining compound F with an oxidizing agent and a base. [ka]

[0242] [Table 17]

[0243] To the reactor was added compound F (1.0 equiv), 1N NaOH (11.2 L / kg, 296 mL) and sodium hypochlorite (1.5 equiv, ca. 11 wt %, 167 mL). The batch temperature was set to below 30° C. and the contents were stirred for 45 minutes. The reaction mixture was cooled to 20° C. 6N HCl (3.1 L / kg, 81.3 mL) was added to the solution to ensure an end point pH of less than 2. Sodium hydroxide (10N) (1.7 L / kg, 44.4 mL) was added to the solution to ensure an end point pH of greater than 13. Isopropyl acetate (10.0 L / kg, 264 mL) was added to the solution and stirred for 5 minutes. The resulting solution was allowed to phase separate and the aqueous layer was deliquified. The organic phase was concentrated to ca. (2.0 L / kg). Distillation of the concentrated oil afforded crude compound G. The crude material can be redistilled or recrystallized to further purify compound G.

[0244] An exemplary method for recrystallizing Compound G is as follows: A reactor was charged with crude Compound G (1.0 equiv.) and anhydrous acetonitrile (0.67 L / kg). The batch temperature was set at 20° C. The solution was added to water (1.23 L / kg) at a rate of 0.2 mL / min. The contents were stirred at 25° C. for 12 hours. The resulting slurry solution was filtered, deliquified, and washed with acetonitrile / water=1 / 6 (1.85 L / kg) and water (1.85 L / kg). A reslurry wash was performed on the wet cake with acetonitrile / water=1 / 6 (3.3 L / kg) at 15° C. for 4 hours. The resulting slurry solution was filtered and deliquified. The product Form 2 was dried under a nitrogen stream at ambient temperature to a constant weight. XRPD analysis confirmed that the isolated material was Form 2.

[0245] The isolated solid Compound G was characterized by DSC / TGA and XRPD (see Figures 1A, 1B, 2A, 2B, 3A, and 3B). Temperature data for the isolated material indicated that Form 2 was likely a hemihydrate of Compound G.

[0246] Approximately 10.95 g of Compound G (Form 2) was placed in a vacuum oven at 35° C. and then at 40° C. Samples were analyzed by DSC / TGA, KF and XRPD to assess the form conversion from Form 2 to Form 1. Data from the drying study are summarized in Table 14. From day 17 to day 22, XRPD and DSC showed the presence of only Form 1, indicating complete conversion of Form 2 to Form 1.

[0247] [Table 18]

[0248] Single crystal X-ray diffraction (SCXRD) studies were performed on Compound G at 99.98 degrees Kelvin. Compound G crystalline Form 1 was found to be an anhydrous form having the crystalline properties shown in Tables 15a and 15b.

[0249] [Table 19]

[0250] [Table 20]

[0251] Crystalline Form 1 Compound G (anhydrous) was characterized by an X-ray powder diffraction (XRPD, CuKα radiation (1.54 Å)) pattern that included peaks at 7.17, 8.59, 11.44, 12.76, 13.62, 14.17, 15.34, 17.69, 20.25, 24.05, 24.34, 25.56, 29.85, 30.12, 31.38, and 34.37 (±0.2° 2θ). XRPD peaks unique to crystalline Form 1 Compound G (anhydrous) included peaks at 7.17, 8.57, 12.74, 13.61, 21.53, 24.35, 29.85, and 34.99 (±0.2° 2θ).

[0252] Crystalline Compound G crystalline Form 2 was found to be a hemihydrate having the crystalline properties shown in Tables 16a and 16b.

[0253] [Table 21]

[0254] [Table 22]

[0255] SCXRD data confirmed the presence of 0.5 water molecules for every molecule of Compound G. Additionally, TGA for Form 2 showed a weight loss of approximately 5.8% from 25 to 60 °C, which is consistent with a hemihydrate.

[0256] Crystalline Form 2 Compound G (hemihydrate) was characterized by an X-ray powder diffraction (XRPD, CuKα radiation (1.54 Å)) pattern that included peaks at 10.82, 11.76, 14.07, 15.26, 16.02, 17.78, 20.79, 21.73, 22.27, 23.62, 24.78, 26.03, 29.2 30.04, 31.09, 32.22, 36.76, 40.39 and 41.44 (±0.2° 2θ). XRPD peaks unique to crystalline Form 2 Compound G (hemihydrate) included peaks at 10.82, 21.73, 30.04, 32.22 and 40.39 (±0.2° 2θ).

[0257] Alternatively, Form 1 was obtained as follows: single crystals of Form 1 were obtained by drying approximately 100 mg of Compound G (Form 2, obtained by crystallization of supplier material with acetonitrile and water) in a vacuum oven at 40° C. to yield Form 1 single crystals after 4 days. Compound G (Form 2) was suspended in 1:9 MeCN:H2O and this sample was used as is for SCXRD analysis.

[0258] All references cited in this specification, including publications, patent applications, and patents, are incorporated by reference herein to the same extent as if each reference was individually and specifically indicated to be incorporated by reference herein and was set forth in its entirety herein.

[0259] The use of the terms "a" and "an" as well as "the" and similar referents in relation to the description of the present invention (especially in relation to the embodiments below) should be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the term "at least one" followed by a list of one or more items (e.g., "at least one of A and B") should be construed to mean one item (A or B) selected from the listed items or any combination of two or more of the listed items (A and B), 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 intended to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated herein as if it were individually recited herein. All of the methods described herein may 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., "etc.") provided herein is intended merely to further clarify the invention and does not impose limitations on the scope of the invention unless otherwise asserted. Nothing in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

Claims

1. Compound A or a salt thereof 【Chemistry 1】 1. A method for preparing combining Compound B or a salt thereof and crotonaldehyde in a solvent and in the presence of a catalytic reagent to form Compound A or a salt thereof; The method, wherein the catalytic reagent comprises an acid catalyst, an organic catalyst, or a combination thereof. 【Chemistry 2】

2. 10. The method of claim 1, wherein the acid catalyst comprises Bronsted-Lowry acid.

3. 3. The method of claim 2, wherein the Bronsted-Lowry acid is triflic acid (TfOH).

4. The method of claim 1 , wherein the acid catalyst comprises a Lewis acid.

5. 5. The method of claim 4, wherein the Lewis acid comprises a metal halide, a triflate, a boron etherate, or a combination thereof.

6. The metal halide is AlCl ３ , CuCl ２ , FeCl ３ , ZnBr ２ 6. The method of claim 5, wherein the compound is selected from the group consisting of:

7. The metal halide is FeCl ３ The method of claim 6, wherein

8. 8. The method of any one of claims 5 to 7, wherein the triflate is selected from the group consisting of metal triflates, silyl triflates, and combinations thereof.

9. The metal triflate is Al(OTf) ３ , Bi(OTf) ３ , Cu(OTf) ２ , Sc(OTf) ３ , In(OTf) ３ , La(OTf) ３ , Yb(OTf) ３ , Zn(OTf) ２ 9. The method of claim 8, wherein the hydroxyl group is selected from the group consisting of:

10. 9. The method of claim 8, wherein the triflate is a silyl triflate.

11. 11. The method of claim 10, wherein the silyl triflate is TMSOTf.

12. The boron etherate is BF ３ Et ２ The method of claim 5, wherein

13. 2. The method of claim 1, wherein the acid catalyst is present in an amount of 5 to 75 mol % based on compound B.

14. 2. The method of claim 1, wherein the acid catalyst is present in an amount of 5 to 50 mol % based on compound B.

15. 2. The method of claim 1, wherein the acid catalyst is present in an amount of 5 to 20 mol % based on compound B.

16. 2. The method of claim 1, wherein the acid catalyst is present in an amount of 50 mol % based on compound B.

17. 10. The method of claim 1, wherein the organic catalyst comprises an amine or a salt thereof.

18. 18. The method of claim 17, wherein the amine comprises an amino acid or a salt thereof.

19. 18. The method of claim 17, wherein the amine comprises a secondary amine or a salt thereof.

20. 20. The method of claim 19, wherein the secondary amine or salt thereof is a dialkylamine, a heterocyclic amine, or a combination thereof.

21. 20. The method of claim 19, wherein the secondary amine or salt thereof is selected from the group consisting of benzylmethylamine, diisopropylamine, β-alanine, D,L-proline, L-proline, prolinol, morpholine, piperidine, pyrrolidine, and combinations thereof.

22. 10. The method of claim 1, wherein the organic catalyst comprises pyrrolidine or a salt thereof.

23. 23. The method of claim 22, wherein the pyrrolidine salt is selected from the group consisting of pyrrolidine hexafluorophosphate, pyrrolidine benzoate, pyrrolidine mesylate, pyrrolidine fluoroborate, pyrrolidine hydrochloride, pyrrolidine trifluoroacetate, pyrrolidine acetate, and combinations thereof.

24. 10. The method of claim 1, wherein the organic catalyst comprises pyrrolidine hydrochloride.

25. The organic catalyst is 【Transformation 3】 and combinations thereof.

26. 2. The method of claim 1, wherein the organic catalyst is present in an amount of 5 to 200 mol % based on compound B.

27. 2. The method of claim 1, wherein the organic catalyst is present in an amount of 5 to 150 mol % based on compound B.

28. 2. The method of claim 1, wherein the organic catalyst is present in an amount of 5 to 100 mol % based on compound B.

29. 2. The method of claim 1, wherein the organic catalyst is present in an amount of 5 to 75 mol % based on compound B.

30. 2. The method of claim 1, wherein the organic catalyst is present in an amount of 5 to 50 mol % based on compound B.

31. 10. The method of claim 1, wherein the organic catalyst is present in an amount of 10 mol % based on compound B.

32. The method of claim 1 , wherein the solvent comprises a polar aprotic solvent.

33. 2. The method of claim 1, wherein the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, acetic acid, acetonitrile, acetone, cyclopentyl methyl ether, ethyl acetate, methyl isobutyl ketone, isopropyl acetate, tetrahydrofuran, methyl tert-butyl ether, N-methylpyrrolidone, dimethyl sulfoxide, dimethylformamide, toluene, n-heptane, and combinations thereof.

34. 2. The method of claim 1, wherein the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, acetic acid, acetonitrile, dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, and combinations thereof.

35. 10. The method of claim 1, wherein the solvent is selected from the group consisting of cyclopentyl methyl ether, ethyl acetate, acetonitrile, tetrahydrofuran, and combinations thereof.

36. The method of claim 1 , wherein the solvent comprises acetonitrile.

37. 10. The method of claim 1, wherein the solvent is present in an amount of 5 to 40 volumes based on Compound B (L / kg).

38. 2. The method of claim 1, wherein the solvent is present in an amount of 10 volumes (L / kg) based on compound B.

39. 10. The method of claim 1, wherein the mixing is carried out at a temperature of from 0°C to 150°C.

40. 40. The method of claim 39, wherein the temperature is from 20°C to 110°C.

41. 40. The method of claim 39, wherein the temperature is between 40°C and 80°C.

42. 40. The method of claim 39, wherein the temperature is from 50°C to 70°C.

43. 40. The method of claim 39, wherein the temperature is 60°C.

44. 10. The method of claim 1, wherein crotonaldehyde is present in a molar excess relative to compound B.

45. 2. The method of claim 1, wherein crotonaldehyde is present in an amount of 1.1 to 5 molar equivalents relative to compound B.

46. 10. The method of claim 1, wherein crotonaldehyde is present in 2 molar equivalents relative to compound B.

47. 2. The method of claim 1, wherein compound A is substantially free of compound D. 【Chemistry 4】

48. 2. The method of claim 1, wherein compound A is substantially free of compound E. 【Transformation 5】

49. 10. The method of claim 1, wherein compound A is substantially free of compound C. 【Transformation 6】

50. The method comprises: 【Transformation 7】 10. The method of claim 1, wherein compound A is provided in a molar ratio of from 1.5:1 to 99:1 or greater.

51. 51. The method of claim 50, wherein the molar ratio of compound A to compound C is greater than 99:

1.

52. 2. The method of claim 1, wherein the yield of compound A is 10% to 90% based on compound B.

53. 2. The method of claim 1, wherein the yield of compound A is 50% to 75% based on compound B.

54. 10. The method of claim 1, further comprising combining pyrrolidine and hydrochloric acid in a second solvent to form pyrrolidine hydrochloride.

55. 10. The method of claim 1, further comprising heating compound A or a salt thereof to a temperature of at least 30°C in the presence of an acid or a base to form compound F or a salt thereof. 【Transformation 8】

56. 56. The method of claim 55, wherein compound A or a salt thereof is heated to a temperature of 65°C to 110°C.

57. 57. The method of claim 56, wherein the temperature is 100°C.

58. 56. The method of claim 55, wherein the acid is selected from the group consisting of sulfuric acid, hydrochloric acid, phosphoric acid, and combinations thereof.

59. 56. The method of claim 55, wherein the acid comprises sulfuric acid.

60. 56. The method of claim 55, wherein the base comprises a metal hydroxide.

61. 56. The method of claim 55, wherein the base is a metal hydroxide.

62. 61. The method of claim 60, wherein the metal hydroxide is sodium hydroxide.

63. 56. The method of claim 55, further comprising combining compound F with an oxidizing agent and a base to form compound G. 【Chemistry 9】

64. 64. The method of claim 63, wherein the oxidizing agent is selected from the group consisting of sodium hypochlorite, sodium hypobromite, N-bromosuccinimide, lead tetraacetate, and combinations thereof.

65. 64. The method of claim 63, wherein the oxidizing agent comprises sodium hypochlorite.

66. 64. The method of claim 63, wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, 1,8-diazabicyclo[5.4.0]undec-7-ene, and combinations thereof.

67. 64. The method of claim 63, wherein the base comprises sodium hydroxide.

68. 68. The method of any one of claims 55 to 67, wherein the heating of any one of claims 55 to 67 and the mixing of any one of claims 63 to 67 are carried out in a single reaction vessel.

69. 2. The method of claim 1, further comprising forming sotorasib using any one of compound A or a salt thereof, compound B or a salt thereof, compound F or a salt thereof, and compound G or a salt thereof.

70. 10. The method of claim 1, further comprising using compound A or a salt thereof to form compound F or a salt thereof.

71. 56. The method of claim 55, further comprising using compound F or a salt thereof to form compound G or a salt thereof.

72. 72. The method of claim 71, wherein Compound G is crystalline and characterized by an X-ray powder diffraction (XRPD, CuKα radiation (1.54 Å)) pattern comprising peaks (±0.2 degrees 2θ) at 7.17, 8.59, 11.44, 12.76, 13.62, 14.17, 15.34, 17.69, 20.25, 24.05, 24.34, 25.56, 29.85, 30.12, 31.38, and 34.

37.

73. 72. The method of claim 71, wherein compound G is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.17, 8.57, 12.74, 13.61, 21.53, 24.35, 29.85, and 34.99 (±0.2 degrees 2θ).

74. 74. The method of claim 72 or 73, wherein compound G is anhydrous.

75. 72. The method of claim 71, wherein Compound G is crystalline and characterized by an X-ray powder diffraction (XRPD, CuKα radiation (1.54 Å)) pattern comprising peaks (±0.2 degrees 2θ) at 10.82, 11.76, 14.07, 15.26, 16.02, 17.78, 20.79, 21.73, 22.27, 23.62, 24.78, 26.03, 29.2, 30.04, 31.09, 32.22, 36.76, 40.39, and 41.

44.

76. 72. The method of claim 71, wherein compound G is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 10.82, 21.73, 30.04, 32.22, and 40.39 (±0.2° 2θ).

77. 77. The method of claim 75 or 76, wherein compound G is a hemihydrate.

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