Process for racemizing and isolating the atrop isomer of 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridine-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

Abstract

The present invention provides a highly efficient, scalable, and cost-effective process for isolating (P)-compound A from a mixture and for reusing (P)-compound A to regenerate racemic compound A. In addition, it provides a method for reusing and isolating the free acid or hydrate of tartrat from a composition comprising tartrat, (P)-compound A, and an organic solvent. [Solution] The present invention provides a process comprising heating a composition containing (P)-compound A or a salt thereof and a solvent to a temperature of 250°C to 350°C to form racemized compound A. JPEG2026094261000029.jpg29150

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 088,848, filed on October 7, 2020, and U.S. Provisional Patent Application No. 63 / 162,278, filed on March 17, 2021, the entire contents of each of which are incorporated herein by reference.

Background Art

[0002] The Kirsten rat sarcoma viral oncogene homologue (KRAS) is a cancer - related gene that is most frequently mutated in human cancers. The guanosine triphosphatase (GTPase) encoded thereby shuttles between an active guanosine triphosphate (GTP) - bound state and an inactive guanosine diphosphate (GDP) - bound state to regulate signal transduction. See, for example, Simanshu DK, Nissley DV, McCormick F. “RAS proteins and their regulators in human disease” in Cell 2017;170:17 - 33.

[0003] KRAS mutations are often associated with resistance to targeted therapies and poor outcomes in cancer patients, yet despite more than 30 years of scientific effort until very recently, selective inhibitors of KRAS have yet to be approved. For example, Nadal E, Chen G, Prensner JR, et al. “KRAS-G12C mutation is associated with poor outcome in surgically resected lung adenocarcinoma” in J Thorac Oncol 2014;9:1513-22; Massarelli E, Varella-Garcia M, Tang X, et al. “KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase “G12V and G12A KRAS mutations are associated with poor outcome in patients with metastatic colorectal cancer treated with bevacizumab” in Tumour Biol 2016;37:6823-30;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 JML, Shokat KM. "Direct small molecule inhibitors of KRAS: from structural insights to mechanism-based design" in Nat Rev Drug Discov 2016;15:771-85; Suzawa K, Offin M, Lu D, et al. "Activation of KRAS mediates resistance to targeted therapy in MET exon 14-mutant non-small cell lung cancer" in Clin Cancer Res 2019;25:1248-60; Clarke PA, Roe T, Swabey K, et al. "Dissecting mechanisms of resistance to targeted drug combination therapy in human colorectal cancer" in Oncogene 2019;38:5076-90; and Del Re M, Rofi E, Restante G, et al. "Implications of KRAS mutations in acquired resistance to treatment in NSCLC" in Oncotarget 2017;9:6630-43.

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

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

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

[0007] The AMG 510 has a P2 pocket and KRAS through its unique interaction. G12C It is a small molecule that specifically and irreversibly inhibits other KRAS. G12C KRAS G12CThis keeps it in an inactive GDP-bound state. See, for example, Lito P, Solomon M, Li LS, Hansen R, Rosen N. "Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism" in Science 2016;351:604-8. Preclinical studies have shown that in mice with KRAS p.G12C mutant tumors, AMG 510 almost completely inhibits the detectable phosphorylation of extracellular signal-regulated kinase (ERK), a key downstream effector of KRAS, leading to sustained and complete tumor degeneration. See, for example, Canon J, Rex K, Saiki AY, et al. "The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumor immunity" in Nature 2019;575:217-23.

[0008] AMG 510 has the following chemical structure: [ka] This compound has a chiral center that produces atropisomerism, and the (M) isomer (shown above) has higher activity against the target protein than the (P) isomer.

[0009] One of the synthetic intermediates in the synthesis of AMG 510 is compound A, whose IUPAC name is 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridine-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, and which has the following structure: [ka]

[0010] The atropisomers (P) and (M) of compound A have the following structures: [ka] (M)-Compound A is then sent as a feedstock for the synthesis of AMG 510, while (P)-Compound A is discarded and enters the wastewater stream.

[0011] The separation of (M)- and (P)-compound A can be carried out by various means. For example, compound A can be mixed with dibenzoyl tartaric acid (DBTA) to form DBTA cocrystals of the (P)- and (M)-atropisomers, and the tartrate crystals of (M)-compound A can be separated from the mixture, leaving the tartrate of (P)-compound A in the mother liquor.

[0012] When DBTA salts and (M)-compounds are used for crystallization, waste liquids of (P)-compound A and dibenzoyl tartaric acid are generated. A typical optical resolution of compound A using this (+)-dibenzoyl-d-tartaric acid [(+)-DBTA; CAS 17026-42-5] is shown in Scheme 1. [ka]

[0013] This process yields (M)-compound A with high stereochemical purity, but the maximum theoretical yield is limited to only 50%. This is because half of the substance (i.e., tartrat of (P)-compound A) remains in the mother liquor and is sent to the process's waste flow. Furthermore, X-ray crystallography confirmed that it is possible to isolate two (M)-compound A molecules from one (+)-DBTA molecule by forming a cocrystal. Therefore, only 0.25 equivalents of DBTA are used to recover 0.5 equivalents of (M)-compound A (racemic compound A: 0.5 equivalents of (M)-compound A and 0.5 equivalents of (P)-compound A). Nevertheless, to maximize the enantiomer excess (%ee) and recovery rate of (M)-compound A, 3.0 equivalents of (+)-DBTA are added to the process, resulting in 2.75 equivalents being wasted in the final liquid flow along with (P)-compound A. [Prior art documents] [Non-patent literature]

[0014] [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 Tumor Biol 2016;37:6823-30 [Non-Patent Document 5] Lievre A, Bachet J-B, 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

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[0015] In light of the above, there is a need for an efficient, scalable, and cost-effective process to isolate (P)-compound A from a mixture and reuse (P)-compound A to regenerate racemic compound A. In addition, there is a need to reuse and isolate the free acid of tartrathate or its hydrate from a composition containing tartrathate, (P)-compound A, and an organic solvent. [Means for solving the problem]

[0016] This disclosure describes a method of heating a composition comprising (P)-compound A or a salt thereof and a solvent to a temperature of 250°C to 350°C to racemize compound A: [ka] The process includes forming.

[0017] The disclosure also provides a process for isolating (P)-compound A from a composition comprising (P)-compound A, tartrat, and an organic solvent, comprising the steps of mixing the composition with a base to remove tartrat, and providing a second composition comprising (P)-compound A and an organic solvent.

[0018] Furthermore, this disclosure relates to Tartlat, (P)-Compound A: [ka] A process for isolating the free acid of tartrat or its hydrate from a composition containing an organic solvent: The present invention also provides a process comprising: (a) mixing the composition with an aqueous solution of a base to form a dibasic salt of tartrath in the aqueous phase; (b) separating the aqueous phase from the organic phase containing (P)-compound A and an organic solvent; and (c) adding the aqueous phase to an aqueous solution of an acid to form a composition containing the free acid of tartrath or its hydrate. [Modes for carrying out the invention]

[0019] In this specification, racemized compound A [ka] The present invention provides a process for obtaining (P)-compound A or a salt thereof, and from a mixture of (P)-compound A or a salt thereof, tartrat, and an organic solvent.

[0020] This disclosure provides a method for obtaining (P)-compound A and racemized compound A from feedstock that was previously considered wastewater.

[0021] In some embodiments, the Disclosure provides a process for racemizing (P)-compound A or a salt thereof to form racemized compound A. In some embodiments, the Disclosure also provides a process for isolating (P)-compound A from a composition comprising (P)-compound A, tartrat, and an organic solvent. The racemized compound A and isolated (P)-compound A obtained from the processes disclosed herein can be used, for example, as starting materials, synthetic intermediates, etc., in the synthesis method of AMG 510.

[0022] In some embodiments, the Disclosure provides a process for obtaining a racemized compound A from (P)-compound A, its cocrystal, or a salt or cocrystal of (P)-compound A. Furthermore, in some embodiments, the Disclosure provides a process for obtaining a racemized compound A from a mixture comprising (P)-compound A, its cocrystal, a salt or cocrystal of (P)-compound A, tartrat, and an organic solvent.

[0023] Prior to this disclosure, the time and energy costs associated with the large-scale and efficient reuse / regeneration / racemization / isolation of (P)-compound A were so high that the process was practically unfeasible, especially on an industrial scale. For example, the energy barrier to converting the (M)-atropisomer of compound A to the (P)-atropisomer of compound A by rotating it around a chiral axis was calculated to be approximately 42 kcal / mol. This high energy barrier meant that the reaction time required to completely carry out a typical first-order chemical reaction, racemization as described herein, at 20°C was 1 × 10⁻¹⁶. 9 This is equivalent to becoming longer than a year.

[0024] Furthermore, other conventional methods for isolating (P)-compound A from a mixture containing tartrat and organic solvents, such as washing with an aqueous solution of sodium hydroxide or sodium carbonate or separation by chromatography using silica gel, are unsuitable for efficient large-scale operations due to their low yields.

[0025] In various embodiments, the disclosed process provides a source of (M)-compound A, which can be obtained by racemizing waste (P)-compound A that would normally end up in a waste stream to form (M)-compound A. In this case, the disclosed process for racemizing (P)-compound A or a salt thereof advantageously improves the efficiency of the entire process that uses compound A as a feedstock. For example, it becomes possible to reduce the number of batches by racemizing (P)-compound A or a salt thereof to produce racemized compound A, while reducing waste and costs.

[0026] (P)-Process for racemizing compound A This disclosure provides a process for racemizing (P)-compound A to obtain racemized compound A. As used herein, “racemized compound A” refers to compound A whose stereochemical purity (measured as enantiomeric excess, i.e., as %ee or as enantiomeric ratio P / M) is lower than that of the starting material (P)-compound A. In some cases, (P)-compound A or its salt in the composition before heating has a %ee of 50% or more (e.g., a P / M ratio of 75:25) or a %ee of 75% or more (e.g., a P / M ratio of 87.5:12.5). In some cases, the %ee of (P)-compound A or its salt is 90% or more (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%ee before heating). In various embodiments where the (P)-compound is a starting material derived from the mother liquor recovered from optical resolution, the %ee of (P)-compound A is 70% to 80% (i.e., the P / M ratio is 90:10 to 85:15 or 89:11, 88:12, 87:13 or 86:14). In some embodiments, (P)-compound A or its salt is 76%ee (i.e., P / M is 88:12).

[0027] As described herein, in conjunction with other embodiments described above and below, in various embodiments, the composition containing (P)-compound A and the second composition containing (P)-compound A further contain (M)-compound A. In various cases, the composition containing (P)-compound A or the second composition containing (P)-compound A is an 88:12 P / M mixture (e.g., 24% racemic compound A and 76% (P)-compound A)). Furthermore, in some embodiments, the disclosure process further includes isolating compound A as a racemate from the second composition. While we do not wish to be bound by any particular theory, it has been found that the solubility of racemic compound A differs from the solubility of (P)-compound A in various solvents to a degree sufficient to solidify racemic compound A from the solution while leaving (P)-compound A in the solution. In some embodiments, the solvent of the solution contains anisole. In some embodiments, the solid racemic compound A can be separated or isolated from the (P)-compound A in solution by filtration, in which case the solid racemic compound A is filtered out of the solution and the (P)-compound A remains in the filtrate. Alternatively, or in addition to this, the (P)-compound A can be extracted using a suitable organic solvent (e.g., anisole) to obtain an organic solvent solution of the (P)-compound A, leaving a solid containing the racemic compound A.

[0028] The stereochemical purity (e.g., %ee) of the racemized compound A obtained after heating by the disclosed process is lower than that of the starting (P)-compound A. In various embodiments, the racemized compound A has a %ee of 50% or less after heating. In various embodiments, the %ee of the racemized compound A after heating is 30% or less. In some embodiments, the %ee of the racemized compound A is 0-45%, 0-40%, 0-35%, 0-30%, or 0-25%.

[0029] The process for racemizing compound A disclosed herein is such that the decomposition or degradation of the compound is minimized while racemizing the compound, as expressed by the amount of impurities measured in the resulting racemized compound A. Suitable conditions for evaluating impurities in compound A are described in the examples below. For example, impurities can be evaluated by HPLC using normal-phase or reverse-phase conditions and a chiral or achiral column. In various embodiments, the racemized compound A contains less than 10% by weight of impurities determined by chromatography, for example, 9% or less by weight, 8% or less by weight, 7% or less by weight, 6% or less by weight, 5% or less by weight, 4% or less by weight, 3% or less by weight, 2% or less by weight, 1% or less by weight, or 0.5% or less by weight. In various embodiments, the racemized compound A contains less than 5% by weight of impurities determined by chromatography. In various embodiments, the racemized compound A contains less than 2% by weight of impurities determined by chromatography.

[0030] A process for racemizing (P)-compound A includes heating a composition containing (P)-compound A or a salt thereof and a solvent to a temperature of 250°C to 350°C to form racemized compound A.

[0031] Temperature: The processes disclosed herein are carried out at temperatures unrelated to those conventionally used for the synthesis of pharmaceutically active ingredients. Surprisingly, it has been found that the processes disclosed herein can be carried out at high temperatures necessary to enable the racemization of (P)-compound A or its salt described herein to be carried out in a suitable time (e.g., in hours or minutes, rather than years), and can proceed in a suitable yield, particularly on an industrial scale, while achieving cost savings and waste reduction associated with such processes.

[0032] In various embodiments, a composition comprising (P)-compound A or a salt thereof and a solvent is heated to a temperature of 250°C or higher, for example, 255°C, 260°C, 265°C, 270°C, 275°C, 280°C, 285°C, 290°C, 295°C, or 300°C or higher. Alternatively or in addition thereto, in various embodiments, the disclosed composition is heated to a temperature of 350°C or lower, for example, 345°C, 340°C, 335°C, 330°C, 325°C, 320°C, 315°C, 310°C, or 305°C or lower. Therefore, a composition comprising (P)-compound A or its salt and a solvent can be heated to a temperature within a range (encompassing the boundary values) between any of the boundary values ​​described above (for example, 250-350°C or 255-345°C, 260-340°C, 265-335°C, 270-330°C, 275-325°C, 280-320°C, 285-315°C, 290-310°C, or 295-305°C).

[0033] In some embodiments, the composition containing (P)-compound A or a salt thereof is heated to a temperature of 300-325°C. In some embodiments, the composition containing (P)-compound A or a salt thereof is heated to a temperature of 305-320°C. In some embodiments, the composition containing (P)-compound A or a salt thereof is heated to a temperature of 310°C. In some embodiments, the composition containing (P)-compound A or a salt thereof is heated to a temperature of 315°C.

[0034] Solvent: The solvent may be any suitable solvent as described herein. From the perspective of the temperature of the process disclosed herein, it is desirable that the solvent be stable at the temperature of the process herein. For example, it is well understood that certain solvents may decompose at high temperatures (e.g., DMSO and (1S,5R)-6,8-dioxabicyclo[3.2.1]octan-4-one (dihydrolevoglucocenone, cyrene) TM (The solvent may decompose at 300°C). Solvent decomposition is undesirable because the by-products from the decomposition become by-products of the racemized compound and / or lead to low yields. Therefore, the solvent should be selected to have minimal or no thermal decomposition under the process conditions.

[0035] Furthermore, the solvent should preferably be inert; for example, the solvent should not interact with (P)-compound A or compound A to decompose (P)-compound A or compound A, or reduce the chemical or stereochemical yield of the process.

[0036] In some embodiments, the organic solvent is a nonpolar solvent. As used herein, "nonpolar" refers to a solvent with a dielectric constant (ε) of 10 or less, measured at 20–25°C. The dielectric constants of most solvents are reported in the literature.

[0037] The solvent may have any suitable boiling point, as long as it is stable enough not to undergo large-scale thermal decomposition under the conditions of this process (e.g., reaction temperature and pressure). The boiling point of the solvent may be 80°C or higher, for example, 90°C or higher, 100°C or higher, 110°C or higher, 120°C or higher, 130°C or higher, 140°C or higher, 150°C or higher, 160°C or higher, 170°C or higher, 180°C or higher, 190°C or higher, or 200°C or higher. Alternatively or in addition, the boiling point of the solvent may be 320°C or lower, for example, 310°C or lower, 300°C or lower, 290°C or lower, 280°C or lower, 270°C or lower, 260°C or lower, 250°C or lower, 240°C or lower, 230°C or lower, 220°C or lower, or 210°C or lower. In that case, the solvent may have a boiling point within a range (encompassing this boundary value) that is between any of the boundary values ​​mentioned above (for example, 80-320°C, 90-310°C, 100-300°C, 110-290°C, 120-280°C, 130-270°C, 140-260°C, 150-250°C, 160-240°C, 170-230°C, 180-220°C, or 190-210°C).

[0038] In some cases, the solvent may contain one or more organic solvents. If the solvent contains more than one solvent, the properties of the bulk solvent (e.g., stability, inertness, minimal decomposition, etc.) are the same as those described herein for each individual solvent.

[0039] Intended nonpolar solvents include, but are not limited to, anisole, benzene, bromobenzene, carbon tetrachloride, chlorobenzene, chloroform, cyclohexane, dibutyl ether, dichlorobenzene, dibenzyl ether, dichloromethane, dioxane, diphenyl ether, 1-octadecene, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, trichloroethylene, and xylene, or combinations thereof. In various embodiments, the solvent includes diphenyl ether, 1-octadecene, anisole, or combinations thereof. In some embodiments, the solvent includes diphenyl ether. In some embodiments, the solvent includes 1-octadecene. In some embodiments, the solvent includes anisole.

[0040] Pressure: In various embodiments, racemization by heating is carried out under high pressure (greater than 0.1 MPa). In some embodiments, heating is carried out at 1.5 MPa or higher, for example, 1.6 MPa or higher, 1.7 MPa or higher, 1.8 MPa or higher, 1.9 MPa or higher, 2.0 MPa or higher, 2.1 MPa or higher, 2.2 MPa or higher, 2.3 MPa or higher, 2.4 MPa or higher, 2.5 MPa or higher, 2.6 MPa or higher, 2.7 MPa or higher, 2.8 MPa or higher, 2.9 MPa or higher, 3.0 MPa or higher, 3.1 MPa or higher, 3.2 MPa or higher, 3.3 MPa or higher, 3.4 MPa or higher, or 3.5 MPa or higher. Alternatively, or in addition to the above, in some embodiments, heating is performed at 7.0 MPa or less, for example, 6.9 MPa or less, 6.8 MPa or less, 6.7 MPa or less, 6.6 MPa or less, 6.5 MPa or less, 6.4 MPa or less, 6.3 MPa or less, 6.2 MPa or less, 6.1 MPa or less, 6.0 MPa or less, 5.9 MPa or less, 5.8 MPa or less, 5.7 MPa or less, 5.6 MPa or less, 5.5 MPa or less, 5.4 MPa or less, 5.3 MPa or less, 5.2 MPa or less, 5.1 MPa or less, 5.0 MPa or less, 4.9 MPa or less, 4.8 MPa or less, 4.7 MPa or less, 4.6 MPa or less, 4.5 MPa or less, 4.4 MPa or less, 4.3 MPa or less, 4.2 MPa or less, 4.1 MPa or less, 4.0 MPa or less, 3.9 MPa or less, 3.8 MPa or less, 3.7 MPa or less, or 3.6 MPa or less. Therefore, heating can be carried out at any pressure within the range that is sandwiched between (and encompasses) any of the boundary values ​​mentioned above.For example, heating is performed at 1.5~7.0 MPa, 1.6~6.9 MPa, 1.7~6.8 MPa, 1.8~6.7 MPa, 1.9~6.6 MPa, 2.0~6.5 MPa, 2.1~6.4 MPa, 2.2~6.3 MPa, 2.3~6.2 MPa, 2.4~6.1 MPa, 2.5~6.0 MPa, 2.6~5.9 MPa, 2.7~5.8 MPa, 2.8~5.7 MPa, 2.9 It can be carried out at pressures of ~5.6 MPa, 3.0~5.5 MPa, 3.1~5.4 MPa, 3.2~5.3 MPa, 3.3~5.2 MPa, 3.4~5.1 MPa, 3.5~5.0 MPa, 3.6~4.9 MPa, 3.7~4.8 MPa, 3.8~47 MPa, 3.9~4.6 MPa, 4.0~4.5 MPa, 4.1~4.4 MPa, or 4.2~4.3 MPa.

[0041] Reaction time: The disclosed process racemizes compound A for a commercially appropriate reaction time. The process disclosed herein yields racemized compound A in reaction times of hours or minutes, rather than years. In various embodiments, heating is carried out for 5 minutes to 12 hours, for example, 15, 30, or 45 minutes or more. In some cases, heating is carried out for 12 hours or less, for example, 11.5 hours or less, 11 hours or less, 10.5 hours or less, 10 hours or less, 9.5 hours or less, 9 hours or less, 8.5 hours or less, 8 hours or less, 7.5 hours or less, 7 hours or less, 6.5 hours or less, 6 hours or less, 5.5 hours or less, 5 hours or less, 4.5 hours or less, 4 hours or less, 3.5 hours or less, 3 hours or less, 2.5 hours or less, 2 hours or less, 1.5 hours or less, or 1 hour or less. In various embodiments, heating is carried out for 1 to 4 hours.

[0042] Use of racemized compound A: The process of racemizing (P)-compound A as described herein can be incorporated into the synthesis of AMG 510 to obtain (M)-compound (A), which can be incorporated into the synthesis of AMG 510 as disclosed, for example, in U.S. Patent No. 10,519,146 (Example 41-1).

[0043] In various embodiments, the disclosed process further includes subjecting the racemized compound (A) to optical resolution using tartrat (such as dibenzoyl tartaric acid) to crystallize (M)-compound A as tartrat crystals, thereby separating (P)-compound A from (M)-compound A. This (M)-compound A can then be used in the synthesis of AMG 510 (e.g., conversion to AMG 510). The mother liquor containing (P)-compound A obtained from the crystallization step can be incorporated for reuse via the racemization process disclosed herein.

[0044] The isolation of (M)-compound A from racemized compound A can be achieved by many methods other than asymmetric crystallization using Tartrat. In various embodiments, racemized compound A can be subjected to pseudo-mobile bed (SMB) chromatography to separate (P)-compound A from (M)-compound A.

[0045] Other tartarates that can be used in the processes disclosed herein include, for example, (+)-di-O,O'-thuloyl-(D)-tartaric acid, (-)-di-O,O'-thuloyl-(L)-tartaric acid, (+)-di-O,O'-benzoyl-(D)-tartaric acid, and (-)-di-O,O'-benzoyl-(L)-tartaric acid.

[0046] (P)-Process for separating compound A from Tartlat solution Other conventional methods have made it impossible to isolate (P)-compound A from compositions containing high levels of tartrat. For example, the large-scale and efficient removal of large amounts of dibenzoyl tartaric acid, i.e., DBTA (approximately 23% by weight), is extremely difficult and has not been achievable with conventional methods. Removal of DBTA is difficult because of the large amount of DBTA that precipitates, and (P)-compound A is not adequately distributed between the organic and aqueous layers, resulting in a low yield of isolated (P)-compound A.

[0047] It has been found that by using appropriate bases and extraction techniques, the isolation of (P)-compound A from a composition containing tartrat, (P)-compound A, and an organic solvent can be carried out on a commercially viable synthetic scale. Accordingly, this specification provides a process for isolating (P)-compound A from a composition containing (P)-compound A, tartrat, and an organic solvent, comprising: mixing the composition with an aqueous solution of a base to remove the tartrat (into the aqueous solution of the base); and providing a second composition containing (P)-compound A and an organic solvent. In various embodiments, the composition containing (P)-compound A, tartrat, and an organic solvent is added to an aqueous solution of a base. In various embodiments, tartrat is dibenzoyl tartaric acid (e.g., (+)-DBTA). In various embodiments, the composition containing (P)-compound A, tartrat, and an organic solvent contains 10 to 50% by weight of tartrat, for example, 15 to 30% by weight of tartrat or 20 to 25% by weight of tartrat. In some embodiments, the composition contains 23% by weight of tartrat.

[0048] Base: The process of this disclosure involves mixing an aqueous solution of a base with a composition comprising (P)-compound A, tartrat, and an organic solvent. As a result of this mixing, the system becomes two-phase, the aqueous base solution deprotonates the tartrat in the composition and dissolves it in the aqueous phase, while (P)-compound A remains in the organic phase along with the organic solvent. This phase can be separated, and the organic phase of (P)-compound A can be used in further processes disclosed herein, such as the racemization described above.

[0049] A suitable base is one that can deprotonate tartrat to form tartrat soluble in aqueous solution. For example, an aqueous solution of the base can solubilize the deprotonated tartrat. If the base does not exhibit adequate solubility in aqueous solution, or does not impart adequate solubility to the existing (or formed) ionic species, tartrat will form precipitates in the aqueous solution, thereby reducing the efficiency of the process and consequently lowering the yield of isolated (P)-compound A.

[0050] Examples of intended bases include alkali or alkaline earth metal hydroxides, phosphates, carbonates, or bicarbonates, and combinations thereof. In some embodiments, the base is selected from the group consisting of sodium hydroxide, sodium carbonate, potassium carbonate, dipotassium phosphate, and combinations thereof. In various embodiments, the base is a potassium salt. In some embodiments, the base is an alkali metal carbonate. In some embodiments, the base is potassium carbonate (K2CO3). While we do not wish to be bound by any particular theory, potassium carbonate (K2CO3) imparts appropriate solubility to the tartrate and effectively separates the organic and aqueous phases under these process conditions, thereby advantageously minimizing precipitation and allowing (P)-compound A to be isolated in appropriate yield, and in some cases recovered at a rate of over 90% from the composition.

[0051] In various cases, the concentration of the aqueous solution is 10% by weight or more, for example, 11% by weight or more, 12% by weight or more, 13% by weight or more, 14% by weight or more, 15% by weight or more, 16% by weight or more, 17% by weight or more, 18% by weight or more, 19% by weight or more, 20% by weight or more, 21% by weight or more, 22% by weight or more, 23% by weight or more, 24% by weight or more, or 25% by weight or more. In various cases, the concentration of the aqueous base solution is typically 35% by weight or less, for example, 34% by weight or less, 33% by weight or less, 32% by weight or less, 31% by weight or less, 30% by weight or less, 29% by weight or less, 28% by weight or less, 27% by weight or less, or 26% by weight or less. The concentration of a base solution can be within the range (including the boundary values) of any of the boundary values ​​mentioned above (e.g., 10-35 wt%, 11-34 wt%, 12-33 wt%, 13-32 wt%, 14-31 wt%, 15-30 wt%, 16-29 wt%, 17-28 wt%, 18-27 wt%, 19-26 wt%, 20-25 wt%, 21-24 wt%, or 22-23 wt%). In some specific cases, when the base is potassium carbonate, the concentration of potassium carbonate in the water of the base solution can be 10-20 wt%. For example, in various cases, the concentration of the base can be 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, or 20 wt% of potassium carbonate in water.

[0052] In various embodiments, the base is present in an amount of 2 molar equivalents or more per mole of (P)-compound A (for example, 2.5 molar equivalents or more, 3 molar equivalents or more, 3.5 molar equivalents or more, 4 molar equivalents or more, or 4.5 molar equivalents or more of (P)-compound A per mole).

[0053] In some embodiments, the composition containing (P)-compound A, tartrat, and an organic solvent, and the aqueous solution of the base are present in a volume ratio of at least 0.5:1. In some embodiments, the composition containing (P)-compound A, tartrat, and an organic solvent, and the aqueous solution of the base are present in a volume ratio of 1:1 to 2:1. In some cases, the volume ratio of composition to aqueous solution is 2:1. In some cases where the volume ratio is 1:1 or greater, the amount of base in the aqueous solution by weight is at least 10% by weight. In various embodiments, the aqueous solution of the base is a 20% by weight aqueous solution of potassium carbonate, and the composition containing (P)-compound A, tartrat, and an organic solvent, and the aqueous solution of the base are present in a volume ratio of 2:1.

[0054] In various embodiments, the process for isolating (P)-compound A further comprises the step of washing the organic phase (second composition) with water to remove any remaining water-soluble chemical species (e.g., tartrates). In some embodiments, the water and second composition used in the washing step are present in a volume ratio of 0.5:1.

[0055] In various embodiments, the resulting composition of (P)-compound A and organic solvent can be further distilled to reduce the volume of the composition containing (P)-compound A. In various embodiments, as a result of the distillation step, the volume is reduced to 30% to 50% of the volume of the starting composition. For example, the volume-reduced composition may have a volume of 30% or more of the volume of the washed composition (e.g., 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50% of the volume of the washed composition). In various embodiments, the distilled composition is initially washed as described above. In some embodiments, the distilled composition is not initially washed.

[0056] The volume-reduced composition can then be subjected to additional processing as needed, such as crystallization and / or racemization. In some examples, (P)-compound A is crystallized from the volume-reduced composition to form crystals of (P)-compound A. In some examples of crystallizing (P)-compound A, a poor solvent can be added to promote the crystallization of (P)-compound A. For example, a poor solvent (e.g., heptane) can be added to the volume-reduced composition obtained from either the volume-reduced second composition and / or the volume-reduced composition after washing. In some examples, the volume-reduced composition is subjected to any of the racemization processes of this disclosure disclosed herein.

[0057] Process for isolating free acid or hydrate of tartrato The present disclosure provides a process for isolating the free acid of tartrath or its hydrate from a composition comprising tartrath, (P)-compound A and an organic solvent, comprising: (a) mixing the composition with an aqueous solution of a base to form a dibasic salt of tartrath in the aqueous phase; (b) separating the aqueous phase from the organic phase comprising (P)-compound A and the organic solvent; and (c) adding the aqueous phase to an aqueous solution of an acid to form a composition comprising the free acid of tartrath or its hydrate.

[0058] In some embodiments, the process further includes washing the aqueous phase with a second organic solvent to form a washed aqueous phase before carrying out step (c), in conjunction with other embodiments described above or below. In these embodiments in which a second organic solvent is present, the second organic solvent can be any suitable organic solvent. Preferably, the second organic solvent has water immiscibility to such an extent that a two-phase system is formed. For example, suitable solvents intended for the second organic solvent include ethyl acetate, isopropyl acetate, methyl ethyl ketone, dichloromethane, methyl tert-butyl ether, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, and combinations thereof. In various embodiments, the second organic solvent is selected from the group consisting of toluene, 2-methyltetrahydrofuran, and combinations thereof. In some embodiments, the second organic solvent is toluene.

[0059] In various embodiments, a composition comprising tartrath, (P)-compound A, and an organic solvent is a composition derived from the synthesis of AMG 510, as described herein. In these embodiments, the properties and characteristics of the composition (e.g., concentration of tartrath, base, base concentration) are the same as those described herein with respect to the process for isolating (P)-compound A. Previously, this composition was considered a waste stream obtained in the synthesis of AMG 510.

[0060] This disclosure provides a process for reusing tartrato. In some embodiments, tartrato is DBTA, for example, formula as used herein: [ka] It is described as having (+)-DBTA (also called d-DBTA). For example, in several embodiments, the organic residue containing (+)-DBTA and (P)-compound A obtained from the synthesis of AMG 510 is extracted into an aqueous phase by adding a suitable amount of base (e.g., a 15 wt% aqueous solution of K2CO3), and optionally washed with a second organic solvent. The aqueous basic phase is then separated, and the tartrate is then crystallized by adding an excess aqueous solution of acid. Exemplary embodiments are summarized in Scheme 2. [ka]

[0061] In some embodiments, the process further includes isolating the free acid of tartrat or its hydrate from the composition. For example, in some embodiments, the process includes crystallizing the free acid of tartrat or its hydrate and filtering the obtained free acid of tartrat or its hydrate. In combination with other embodiments described above or below, in some embodiments, the free acid of tartrat is isolated as a hydrate.

[0062] As used herein, the term "hydrate" refers to a chemical substance formed by combining water with a compound, and includes, for example, hemihydrates, monohydrates, dihydrates, trihydrates, and so on.

[0063] In some embodiments, the isolated tartrat free acid is (+)-DBTA monohydrate. In combination with other embodiments described above or below, in some embodiments, the disclosed process provides cylindrical (+)-DBTA monohydrate crystals having a length of about 70 μm and a width of about 20 μm (e.g., 67 × 17 μm).

[0064] The disclosed process provides isolated tartrat free acid or its hydrate having high chemical and stereochemical purity. As an example, in some embodiments, the process described herein provides (+)-DBTA monohydrate having a chemical purity of 95% or higher (e.g., 95%, 96%, 97%, 98%, 99%, 99.5% or higher) and a high %ee, for example, 90%ee or higher (90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100%ee).

[0065] The isolated tartrat is suitable for use in other processes (e.g., preparation of AMG 510). For example, in some embodiments, the processes disclosed herein further include: mixing the isolated (+)-DBTA monohydrate with racemic compound A to form a cocrystal of (+)-DBTA and (M)-compound A; separating the cocrystal of (+)-DBTA and (M)-compound A from (P)-compound A; and synthesizing AMG 510 using the cocrystal of (+)-DBTA and (M)-compound A.

[0066] Base: The process of this disclosure comprises mixing an aqueous solution of a base with a composition comprising tartrat, (P)-compound A and an organic solvent to form a dibasic salt of tartrat. The base can be any suitable base for forming the dibasic salt of tartrat. In some embodiments, the base comprises an alkali metal carbonate, e.g., potassium carbonate (K2CO3). In other embodiments, in conjunction with other embodiments described above or below, the base is selected from the group consisting of alkali or alkaline earth metal hydroxides, phosphates, carbonates or bicarbonates (e.g., sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, dipotassium phosphate and combinations thereof). In some embodiments, the base is potassium carbonate and exists as a 15% by weight aqueous solution. As described herein, in various embodiments herein, the dibasic salt of tartrat is the dipotassium salt of (+)-DBTA.

[0067] The base is present in any amount suitable for forming a dibasic salt of tartrath. Typically, the base is present in an amount of 2 to 5 molar equivalents per mole of tartrath. In some embodiments, in conjunction with other embodiments described above or below, the aqueous solution of the base is present in a volume ratio of 2:1.

[0068] Acid: The process disclosed herein involves adding a basic aqueous phase containing a dibasic salt of tartrat to an aqueous phase to a solution of acid to form a composition containing free tartrat acid or its hydrate. The acid can be any suitable acid that forms free tartrat acid. Preferably, the pKa of the acid is less than 1.8. Suitable acids include, for example, hydrochloric acid and sulfonic acid, which have a pKa of less than 1.8. In some embodiments, the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, picric acid, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, and combinations thereof. In some embodiments, the acid includes hydrochloric acid.

[0069] Preferably, a basic aqueous phase is added to the acid solution to form the free acid of tartratte. While we do not wish to be bound by any particular theory, it has been found that this addition order optimizes the formation of the free acid of tartratte and minimizes the formation of undesirable monobasic salts of tartratte. For example, in the synthesis of AMG 510, using a monobasic salt of (+)-DBTA (e.g., (+)-DBTA monopotassium) increases the risk of the manufacturing process, especially in large-scale processes. This is because monobasic salts have lower solubility in organic solvents compared to their free form, can precipitate from the solution, resulting in the process not functioning properly and potentially leading to the discarding of the entire batch of API.

[0070] When a basic aqueous stream of (+)-DBTA dipotassium salt is added to an excess aqueous solution of a strong acid, it is believed that the pH during DBTA crystallization should be kept lower than the pKa of fully protonated DBTA (pKa 1.85, 2×CO2H) to prevent the formation of a monobasic salt. In contrast, if the order of addition is reversed and the acid solution is added to the basic stream, the internal pH will start at pH 9 during DBTA crystallization and stabilize at approximately pH 4.9 when the first carboxylic acid portion is protonated. The monobasic DBTA salt precipitated from the resulting solution forms a slurry, and even if excess acid (HCl) is added to the reaction at this point to lower the pH to below 1, it will have no effect on the stable monobasic salt of (+)-DBTA precipitated from the solution.

[0071] In light of the above, the acid is present in an amount suitable for ensuring the formation of free tartrat free acid. In some embodiments, the acid is present in an amount of at least 30 ± 5 mol equivalents based on the number of moles of tartrat present. For example, in some embodiments, the acid is present in an amount of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 mol equivalents based on the number of moles of tartrat present. In some embodiments, the pH of the aqueous solution of the acid is always maintained at a pH of less than 2, less than 1.9, less than 1.85, less than 1.7, less than 1.5, less than 1.3, or less than 1. In some embodiments, the pH of the aqueous solution of the acid is maintained at a pH of less than 1.85. In some embodiments, the pH of the aqueous solution of the acid is maintained within a range (encompassing the above values) between any of the above values ​​(e.g., 2 to 1, 1.85 to 1, 2 to 1.5, etc.).

[0072] Temperature: With respect to the processes disclosed herein, the aqueous phase is added to the aqueous solution of the acid at a temperature of 35–55°C. In some embodiments, in conjunction with other embodiments described above or below, the temperature is 35–55°C (e.g., 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55°C). In some embodiments, in conjunction with other embodiments described above or below, the temperature is 40–50°C. In some embodiments, the temperature is 45°C.

[0073] In some embodiments, in conjunction with other embodiments described above or below, the composition containing free tartratte acid or its hydrate is cooled to a temperature of 5 to 20°C (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20°C). In some embodiments, the composition containing free tartratte acid or its hydrate is cooled to a temperature of 10°C. In various embodiments, the composition containing free tartratte acid or its hydrate is cooled for 1 hour or more (e.g., 1 to 12 hours), for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours. In some embodiments, the composition containing free tartratte acid or its hydrate is cooled for 5 hours.

[0074] Embodiment 1. A composition containing (P)-compound A or a salt thereof and a solvent is heated to a temperature of 250°C to 350°C to obtain racemized compound A: [ka] A process that includes forming [something].

[0075] 2. The process according to Embodiment 1, wherein the solvent is a nonpolar solvent.

[0076] 3. The process according to Embodiment 1 or 2, wherein the solvent is selected from the group consisting of diphenyl ether, 1-octadecene, anisole, and combinations thereof.

[0077] 4. The process according to any one of Embodiments 1 to 3, wherein the solvent is anisole.

[0078] 5. The process according to any one of Embodiments 1 to 4, wherein the composition is heated to a temperature of 300°C to 325°C.

[0079] 6. The process according to Embodiment 5, wherein the temperature is 305°C to 320°C.

[0080] 7. The process according to Embodiment 5, wherein the temperature is 310°C.

[0081] 8. The process according to Embodiment 5, wherein the temperature is 315°C.

[0082] 9. Heating is carried out at a pressure of 1.7 to 7.0 MPa, as described in any one of Embodiments 1 to 8.

[0083] 10. The process according to any one of Embodiments 1 to 9, wherein the %ee of (P)-compound A in the composition before heating is 50% or more.

[0084] 11. The process according to Embodiment 10, wherein the %ee of (P)-compound A in the composition before heating is 75% or more.

[0085] 12. The process according to Embodiment 10, wherein the %ee of (P)-compound A in the composition before heating is 90% or more.

[0086] 13. The process according to any one of Embodiments 1 to 11, wherein the %ee of the racemized compound A is 50% or less.

[0087] 14. The process according to Embodiment 13, wherein the %ee of racemized compound A is 30% or less.

[0088] 15. The process according to any one of Embodiments 1 to 14, wherein the racemized compound A after heating contains less than 10% by weight of impurities determined by chromatography.

[0089] 16. The process according to Embodiment 15, wherein the racemized compound A after heating contains less than 5% by weight of impurities determined by chromatography.

[0090] 17. The process according to Embodiment 16, wherein the racemized compound A after heating contains less than 2% by weight of impurities determined by chromatography.

[0091] 18. The process according to any one of Embodiments 1 to 17, wherein heating is performed for 5 minutes to 12 hours.

[0092] 19. The process according to Embodiment 18, wherein heating is performed for 1 to 4 hours.

[0093] 20. The process according to any one of Embodiments 1 to 19, further comprising subjecting the racemized compound A to pseudo-mobile bed chromatography in order to separate (P)-compound A from (M)-compound A.

[0094] 21. The process according to any one of Embodiments 1 to 19, further comprising subjecting the racemized compound A to optical resolution using Tartrat in order to separate (P)-compound A and (M)-compound A.

[0095] 22. The process according to Embodiment 20 or 21, further comprising converting (M)-compound A to AMG 510.

[0096] 23.(P)-Compound A [ka] A process for isolating (P)-compound A from a composition comprising tartrat and an organic solvent: A process comprising: mixing this composition with an aqueous solution of a base to remove tartrat; and providing a second composition comprising (P)-compound A and an organic solvent.

[0097] 24. The process according to Embodiment 23, comprising tartrat, dibenzoyl tartaric acid ("DBTA").

[0098] 25. Tartrato is (+)-DBTA: [ka] The process described in Embodiment 24.

[0099] 26. The process according to any one of Embodiments 23 to 25, wherein the composition comprises 10 to 50% by weight of tartrato.

[0100] 27. The process according to Embodiment 26, wherein the composition contains 15-30% by weight of tartrato.

[0101] 28. The process according to Embodiment 26, wherein the composition contains 20-25% by weight of tartrato.

[0102] 29. The process according to any one of Embodiments 23 to 28, wherein the base is selected from the group consisting of alkali or alkaline earth metal hydroxides, phosphates, carbonates or bicarbonates and combinations thereof.

[0103] 30. The process according to Embodiment 29, wherein the base is selected from the group consisting of sodium hydroxide, sodium carbonate, potassium carbonate, dipotassium phosphate, and combinations thereof.

[0104] 31. The process according to any one of Embodiments 23 to 30, wherein the base comprises an alkali metal carbonate.

[0105] 32. The process according to Embodiment 31, wherein the alkali metal carbonate is potassium carbonate (K2CO3).

[0106] 33. The process according to any one of Embodiments 23 to 32, wherein the base is present in an amount of 2 to 5 molar equivalents per mole of (P)-compound A.

[0107] 34. The process according to any one of Embodiments 23 to 32, wherein the composition and the aqueous solution of the base are present in a volume ratio of 2:1.

[0108] 35. The process according to embodiments 23 to 34, further comprising distilling the second composition to form a second composition with reduced volume.

[0109] 36. The process according to Embodiment 35, further comprising crystallizing (P)-compound A from a second composition with reduced volume to form crystals of (P)-compound A.

[0110] 37. The crystallization process according to Embodiment 36, comprising the use of a poor solvent.

[0111] 38. The process according to Embodiment 37, wherein the poor solvent is heptane.

[0112] 39. The process according to any one of Embodiments 35 to 38, further comprising subjecting a volume-reduced second composition or crystal of (P)-compound A to the process according to any one of Embodiments 1 to 21 to form racemized compound A.

[0113] 40. The process according to any one of Embodiments 23 to 39, further comprising washing the second composition with water to form a washed composition comprising (P)-compound A and an organic solvent.

[0114] 41. The process according to Embodiment 40, wherein water and the second composition are present in a volume ratio of 0.5:1.

[0115] 42. The process according to Embodiment 40 or 41, further comprising distilling the washed composition to form a volume-reduced washed composition having a volume of 30% to 50% of the volume of the washed composition, comprising (P)-compound A.

[0116] 43. The process according to Embodiment 42, further comprising crystallizing (P)-compound A from a volume-reduced washed composition to form crystals of (P)-compound A.

[0117] 44. The crystallization process according to Embodiment 43, comprising the use of a poor solvent.

[0118] 45. The process according to Embodiment 44, wherein the poor solvent is heptane.

[0119] 46. ​​The process according to any one of Embodiments 36 to 38 and 40 to 44, further comprising subjecting a volume-reduced washed composition containing (P)-compound A or crystals of (P)-compound A to the process according to any one of Embodiments 1 to 21 to form racemized compound A.

[0120] 47. The process according to any one of Embodiments 23 to 46, wherein a composition containing (P)-compound A further contains (M)-compound A, and a second composition containing (P)-compound A further contains (M)-compound A.

[0121] 48. The process according to Embodiment 47, wherein the composition, the second composition, or both comprises (P)-compound A and (M)-compound A in a P / M ratio of 88:12.

[0122] 49. The process according to Embodiment 47 or 48, further comprising isolating compound A from the second composition as a racemate by forming a solid racemic compound A in the second composition, filtering the resulting mixture to isolate the racemate, and leaving (P)-compound A in the filtrate.

[0123] 50. The process according to Embodiment 49, wherein the formation of solid racemic compound A comprises adding anisole to the second composition to precipitate racemic compound A.

[0124] 51. Tartrato, (P)-Compound A: [ka] A process for isolating the free acid of tartrat or its hydrate from a composition containing an organic solvent: (a) Mixing the composition and an aqueous solution of the base to form a dibasic salt of tartrath in the aqueous phase; (b) Separating the aqueous phase from the organic phase containing (P)-compound A and the organic solvent; (c) A process comprising adding an aqueous phase to an aqueous solution of an acid to form a composition containing free tartrat acid or its hydrate.

[0125] 52. The process according to Embodiment 51, comprising tartratoate dibenzoyl tartaric acid ("DBTA").

[0126] 53. Tartrato is (+)-DBTA: [ka] The process described in Embodiment 52.

[0127] 54. The process according to any one of Embodiments 51 to 53, wherein the composition comprises 10 to 50% by weight of tartrato.

[0128] 55. The process according to Embodiment 54, wherein the composition contains 15-30% by weight of tartrato.

[0129] 56. The process according to Embodiment 54, wherein the composition contains 20-25% by weight of tartrato.

[0130] 57. The process according to any one of embodiments 51 to 56, wherein the base is selected from the group consisting of alkali or alkaline earth metal hydroxides, phosphates, carbonates or bicarbonates and combinations thereof.

[0131] 58. The process according to Embodiment 57, wherein the base is selected from sodium hydroxide, sodium carbonate, potassium carbonate, dipotassium phosphate, and combinations thereof.

[0132] 59. The process according to any one of embodiments 51 to 58, wherein the base comprises an alkali metal carbonate.

[0133] 60. The process according to Embodiment 58 or 59, wherein the alkali metal carbonate is potassium carbonate (K2CO3).

[0134] 61. The process according to any one of embodiments 51 to 60, wherein the base is present in an amount of 2 to 5 molar equivalents per mole of tartrath.

[0135] 62. The process according to any one of Embodiments 51 to 61, wherein the composition and the aqueous solution of the base are present in a volume ratio of 2:1.

[0136] 63. The process according to any one of embodiments 60 to 62, wherein potassium carbonate is present as a 15% by weight aqueous solution.

[0137] 64. A process according to any one of embodiments 51 to 63: The process further comprises washing the aqueous phase with a second organic solvent to form a washed aqueous phase before performing step (c).

[0138] 65. The process according to Embodiment 64, wherein the second organic solvent is selected from the group consisting of toluene, 2-methyltetrahydrofuran, and combinations thereof.

[0139] 66. The process according to embodiment 65, wherein the second organic solvent is toluene.

[0140] 67. The process according to any one of Embodiments 51 to 66, wherein the acid is present in an amount of at least 25 mol equivalents, based on the number of moles of tartrat.

[0141] 68. The process according to any one of Embodiments 51 to 67, wherein the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, picric acid, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, and combinations thereof.

[0142] 69. The process according to Embodiment 68, wherein the acid includes hydrochloric acid.

[0143] 70. The process according to any one of embodiments 51 to 69, wherein the aqueous phase is added to an aqueous solution of acid at a temperature of 35 to 55°C.

[0144] 71. The process according to embodiment 70, wherein the temperature is 40-50°C.

[0145] 72. The process according to embodiment 70, wherein the temperature is 45°C.

[0146] 73. The process according to any one of embodiments 51 to 72, further comprising cooling the composition formed in step (c).

[0147] 74. The process according to Embodiment 73, wherein the composition formed in step (c) is cooled to a temperature of 5 to 20°C.

[0148] 75. The process according to Embodiment 74, wherein the composition formed in step (c) is cooled to a temperature of 10°C.

[0149] 76. The process according to embodiment 74 or 75, wherein the composition formed in step (c) is cooled for a period of time of one hour or more.

[0150] 77. The process according to any one of embodiments 51 to 76, further comprising isolating the free acid of tartrat or its hydrate from the composition of step (c).

[0151] 78. The process according to Embodiment 77, wherein isolation comprises crystallizing the free acid of tartrath or its hydrate and filtering the resulting crystals of the free acid of tartrath or its hydrate.

[0152] 79. The process according to any one of embodiments 51 to 78, wherein the free acid of tartrato is a hydrate.

[0153] 80. The process according to any one of Embodiments 51 to 79, wherein the free acid of tartrato is (+)-DBTA monohydrate.

[0154] 81. The process according to Embodiment 80, wherein the isolated (+)-DBTA monohydrate has a purity of 95% or higher.

[0155] 82. The process according to Embodiment 81, wherein the isolated (+)-DBTA monohydrate contains less than 0.5% by weight of monopotassium salt of (+)-DBTA.

[0156] 83. The process according to any one of embodiments 80 to 82, further comprising: mixing isolated (+)-DBTA monohydrate with racemic compound A to form a cocrystal of (+)-DBTA and (M)-compound A; separating the cocrystal of (+)-DBTA and (M)-compound A from (P)-compound A; and synthesizing AMG 510 using the cocrystal of (+)-DBTA and (M)-compound A. [Examples]

[0157] The following embodiments further illustrate the disclosure process, but needless to say, these should not be interpreted as limiting its scope in any way.

[0158] In this specification, the following abbreviations are used: NMR stands for nuclear magnetic resonance (spectroscopy); NMPr stands for N-methyl-2-pyrrolidone; DMI stands for 1,3-dimethyl-2-imidazolidinone; TFA stands for trifluoroacetic acid; DBU stands for 1,8-diazabicyclo[5.4.0]undeca-7-ene; MSA stands for methanesulfonic acid; DIPEA stands for N,N-diisopropylethylamine, TEA stands for triethylamine; Yb(OTf)3 stands for trifluoromethanesulfone 1 is ytterbium(III) acid; 2 is iron(III) chloride; 3 is ML represents the mother liquor; 4 is sodium hydroxide; 5 is cesium carbonate; 6 is sodium carbonate; 7 is sodium carbonate; 8 is potassium carbonate; 9 is dipotassium phosphate; 10 is copper sulfate hexahydrate; 11 is potassium bicarbonate; 12 is potassium acetate; and 13 represents quantitative nuclear magnetic resonance.

[0159] HPLC method In batch and flow studies, achiral high-performance liquid chromatography (HPLC) was used to determine the purity profile of the samples throughout the reaction and after isolation. This method was also used to measure the concentration of the samples to obtain additional solubility tests and mass balance data.

[0160] Chiral stationary phase (e.g., normal phase) HPLC was used for batch and flow tests to determine the efficiency of the racemization process. This method was also used to determine the %ee of the solid-versus-supernatant ratio. This data was useful for determining the eutectic point of the mixture and the crystallization efficiency of compound A in solution (e.g., anisole).

[0161] The following is an example of the achiral reversed-phase method used: Column: ACE Excel Super® C18, 3 μm, 3 × 50 mm (Advanced Chromatography Technologies, Ltd., Aberdeen, Scotland); Mobile phase A: 0.05% trifluoroacetic acid in water; Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile; Sample concentration: approx. 0.25 mg / mL; Temperature: -35°C; Flow rate: approx. 1.5 mL / min; UV detection: 215 nm (bandwidth: 4 nm) and / or 254 nm (bandwidth: 8 nm); Injection volume: 1 μL; Operating time: 7.5 min; Post-time: 1.5 min; Gradient elution was performed as follows: Time 0 to 95: 5 (A / B); Time 4.5 min to 0: 100 (A / B); Time 7.5 min to 0: 100 (A / B).

[0162] The following is an example of the achiral reversed-phase method used: Column - Poroshell® 120 (4.6 × 150 mm, 2.7 μm) (Agilent, SantaClara, California); Column temperature: 21°C; Mobile phase A: 20 mM ammonium formate aqueous solution; Mobile phase B: Acetonitrile; Injection volume: 5 μL; Flow rate: 0.9 mL / min; UV detection: 256 nm (bandwidth 4 nm); The following gradient elution was performed: Time 0 min ~ 80:20 (A / B); Time 10 min ~ 25:75 (A / B); Time 10.1 min ~ 10:90 (A / B); Time 13 min ~ 10:90 (A / B); Time 13.1 min ~ 80:20 (A / B); Time 17 min ~ 80:20 (A / B); Sample tray temperature: 5°C.

[0163] The following is an example of the chiral normal-phase method used: Column: Chiralpak® IC-3 (4.6 × 100 mm, 3 μm) (Daicel Corp.); Column temperature: 40°C; Mobile phase A: n-heptane; Mobile phase B: methanol / ethanol (1:1); Injection volume: 5 μL; Flow rate: 1 mL / min; UV detection: 256 nm (bandwidth 4 nm); Isocratic elution was performed as shown below: Time 0 min ~ 75:25 (A / B); Time 10 min ~ 75:25 (A / B); Sample tray temperature: 2 ~ 8°C.

[0164] Example 1 - Solvent Screening Test The suitability of several solvents in the process of racemizing (P)-compound A or its salt was evaluated. Compositions containing (P)-compound A or (M)-compound A and a solvent were prepared or obtained and heated as specified. The results are summarized in Tables 1-3. In the tables, LCAP is the area percentage measured by liquid chromatography, i.e., the amount of substance (e.g., compound A) in the reaction mixture.

[0165] [Table 1]

[0166] [Table 2]

[0167] [Table 3]

[0168] These results indicate that diphenyl ether, 1-octadecene, and anisole are suitable solvents for racemizing (P)-compounds while minimizing thermal decomposition. Furthermore, when toluene, NMP, or sulfolane were used as solvents, compound A underwent the least thermal decomposition and / or racemization at 250°C.

[0169] Furthermore, these results demonstrate that using anisole not only minimizes thermal decomposition even after 36 hours of stirring, but also achieves high stereochemical and chemical purity.

[0170] Further solvent screening confirmed that anisole is a suitable solvent because it has high solubility for (P)-compound A, lower solubility for compound A, and a low vapor pressure. These physical properties combined made it possible to carry out the process at a mild pressure. These results are shown in Table 4.

[0171] [Table 4]

[0172] The suitability of heptane as a poor solvent for crystallization was evaluated using compound A (99.1% by weight). The results are shown in Table 5.

[0173] [Table 5]

[0174] When heptane was used, the solubility of compound A decreased as the amount of heptane increased. Subsequently, the solubility of compound A in pure anisole at ambient temperature was observed to be lower than 69 mg / mL (approximately 18 mg / mL), suggesting the existence of a crystalline form with lower solubility and higher thermodynamic stability. These results suggest that cold crystallization can also be used for the isolation of compound A.

[0175] Example 2 (P)-compound A was extracted from an 88:12 (P / M) solid mixture at room temperature using anisole to prepare a solution of (P)-compound A, yielding a 10 wt% (P)-compound A solution and a solid phase containing compound A as a racemate. The solid and liquid phases were separated by filtration, and the resulting liquid was racemized at 315°C and 2.5 MPa for approximately 10 minutes. After racemization, the product was recovered by cooling and crystallization in anisole. Solid compound A was used as the seed crystal for crystallization. The overall process yield was 77%, and a crystallized product containing less than 10 wt% impurities was obtained.

[0176] Example 3 In a semi-continuous process, a feedstock (14.72 kg) containing (P)-compound A was diluted with 1.4 L of anisole to prepare a composition containing (P)-compound A (1.48 kg of (P)-compound A). To remove solids, the feedstock was passed through a 100 micron filter, and then discharged using a gear pump and check valve. After passing through the check valve, the mixture was preheated in a tube-in-tube heat exchanger to a set temperature of 315°C, and then pumped to a tube-in-tube flow-through reactor (1 L capacity) heated to a set temperature of 315-320°C at an average flow rate of 80 g / min for 3.25 hours. After cooling the converted crude product in a tube-in-tube heat exchanger, the pressure was reduced, and the crude product flow was transferred to a jacketed reactor (120°C) to crystallize. The cooler was set to 120°C, and the downstream equipment was heat-trace to maintain the product temperature above 120°C, thereby preventing crystallization of the product within the equipment. The cooled product flow was passed through a 100-micron filter to remove solids and through a back pressure regulator (2.55 MPa) to maintain pressure within the system. A series of pressure and temperature sensors were used to monitor the system status, and a mass flow meter was placed after the gear pump to monitor the flow rate, which could be controlled via a flow transmitter and control device connected to the gear pump. In case the system unexpectedly experienced excessive pressure, a high-pressure rupture disc designed to divert the flow was installed to safely capture the flow and allow for remedial action.

[0177] This process yielded a bulk racemized product containing 53.3% (P)-compound A and 46.7% (M)-compound A before crystallization. The recovered crude product was cooled to 90°C, and compound A (380g) was added as a seed crystal. After seed crystal inoculation, the temperature was lowered to 10°C (0.1°C / min) and held for 16 hours. The temperature was then lowered to 0°C and held for 30 hours. The material was then vacuum filtered from the reaction vessel, and the recovered solid cake was washed with anisole (1.5L) and dried at 60-70°C for 72 hours to obtain 1.43 kg of compound A with a P / M ratio of 50.5 / 49.5 and an achiral purity of 99.2%. The isolation yield was 76.9%.

[0178] In another example, solid (P)-compound A (1.93 kg, 88:12 (P / M)) was suspended in anisole (5 L / kg). This slurry was filtered to separate the (P)-compound in anisole solution and a solid phase (0.38 kg) containing compound A. Additional anisole was added to the (P)-compound A solution to bring the potency to 10% by weight. To remove the solid, the feed material was passed through a 100 micron filter, and then the feed material was discharged using a gear pump and check valve. After passing through the check valve, the mixture was preheated in a tube-in-tube heat exchanger at a set temperature of 315°C, and then pumped at an average flow rate of 80 g / min for 3.25 hours into a tube-in-tube flow-through reactor (capacity 1 L) heated to a set temperature of 315-320°C. After the converted crude product was cooled in a tube-in-tube heat exchanger, the pressure was reduced and the crude product flow was transferred to a jacketed reactor (120°C) for crystallization. The cooler was set to 120°C, and the downstream equipment was heat-trace to maintain the product temperature above 120°C, thereby preventing the product from crystallizing within the equipment. The cooled product flow was passed through a 100-micron filter to remove solids and through a back pressure regulator (2.55 MPa) to maintain the pressure in the system. A series of pressure and temperature sensors were used to monitor the system status, and a mass flow meter was placed after the gear pump to monitor the flow rate, which could be controlled via a flow transmitter and control device connected to the gear pump. In case the system unexpectedly experienced excessive pressure, a high-pressure rupture disc designed to divert the flow was installed to safely capture the flow and allow for remedial action.

[0179] Example 4 A batch reaction was carried out in a 25 mL Parr 5500 reactor system. (P)-Compound A (520 mg) (>99% ee) was dissolved in 15 mL of anisole (approximately 30 times its volume) and heated to 300 °C. The reactor was heated to 300 °C over approximately 55 minutes, and this temperature was maintained for approximately 10 minutes before the reactor was cooled to ambient temperature. Samples of the reaction product were taken periodically and analyzed by chiral HPLC. The mixture was cooled to ambient temperature and stirred for 36 hours, resulting in a product with 4% ee.

[0180] Further batch reactions were carried out using five times the volume of anisole. The reaction mixture of (P)-compound A (>99%ee) was heated at 300°C for approximately 15 minutes and then cooled to ambient temperature. After stirring overnight at ambient temperature, the mixture was found to have a 2%ee content. However, compared to the more diluted reactants, the higher concentration reaction mixture contained more impurities; while the initial reaction contained 99% compound A, this time it was approximately 91%.

[0181] Example 5 - Screening test of bases for Tartlat extraction The ability of several inorganic bases to solubilize / remove tartrat in aqueous solution was qualitatively evaluated.

[0182] In short, 2 mL of a basic aqueous solution was added to each of the seven containers, and DBTA was added in increments of 25-50 mg until the solid precipitate no longer disappeared. The results are summarized in Tables 6 and 7.

[0183] [Table 6]

[0184] Furthermore, using the mother liquor (ML) containing (P)-compound A and an organic solvent, obtained by subjecting compound A to conventional optical resolution, as the raw material, the ability of several potassium bases to solubilize / remove DBTA in aqueous solution was qualitatively evaluated.

[0185] In short, solutions of potassium bicarbonate, potassium carbonate, dipotassium phosphate, and potassium acetate were prepared and mixed with the mother liquor in various amounts as shown in Table 7. After mixing, the composition was visually inspected for the presence of insoluble matter.

[0186] [Table 7]

[0187] Visual inspection revealed that potassium bicarbonate and potassium carbonate solutions, particularly compositions containing 20% ​​by weight of potassium base, exhibited the lowest amount of insoluble matter. More specifically, compositions containing 20% ​​by weight of potassium bicarbonate with a 1:1 ml / aqueous solution ratio and compositions containing 20% ​​by weight of potassium carbonate with a 2:1 ml / aqueous solution ratio showed good solubility.

[0188] Furthermore, the effect of potassium carbonate aqueous solution on solubilizing and extracting DBTA from the mother liquor (ML) containing the organic phase (P)-compound A was evaluated. As shown in Table 8, in addition to four concentrations of potassium carbonate aqueous solution (compositions 1-4), different volume ratios of the organic phase relative to water (ratios A-C) were also evaluated.

[0189] A 5-20% by weight K2CO3 solution was prepared and mixed with the mother liquor containing (P)-compound A, tartrat, and an organic solvent in the volume ratios shown in Table 8. After mixing, each composition was analyzed by HPLC to determine the concentration of (P)-compound A in the aqueous and organic phases. The results are summarized in Table 8.

[0190] [Table 8]

[0191] DBTA was not detected in any of the organic phases analyzed by HPLC. Furthermore, most of the mixed compositions were advantageously substantially free of solids, and the organic and aqueous phases separated cleanly. However, as shown in Table 8, compositions 1B, 1C, and 2C, which contained 5-10% by weight of potassium carbonate and had a relatively high / maximum organic phase content, produced an undesirable mixture of solids. In contrast, no solids were observed in the other compositions, and a clear boundary was seen between the organic and aqueous phases after mixing. Furthermore, compositions 1A, 2B, 3B, 3C, and 4C preferably showed relatively low amounts of (P)- compounds in the aqueous phase. Moreover, compositions 2B, 3B, 3C, and 4C are desirable when a relatively small amount of aqueous phase is required, and processing will be easier as it will be possible to use smaller capacity reactors.

[0192] Furthermore, when these screening tests were performed using K2CO3, a clear phase boundary was observed between the aqueous phase containing (+)-DBTA and the organic phase containing (P)-compound A when the residual MeTHF / heptane solution from the AMG 510 synthesis was extracted. Methyl tetrahydrofuran (MeTHF), a typical solvent used in large quantities in the AMG 510 synthesis, is partially miscible with water, and therefore distributes (P)-compound A to the aqueous stream initially extracted from the K2CO3 treatment. It is known that the quality grade of (+)-DBTA is impaired in the presence of (P)-compound A.

[0193] Example 6 By reusing DBTA from aqueous solutions, a reliable and continuous supply of (+)-DBTA with the required chiral purity is ensured. In the crystallization of (M)-compound A by classical resolution, 3.0 equivalents of (+)-DBTA are added, but only 0.5 equivalents of (M)-compound A are used for cocrystallization.

[0194] Using the product stream obtained from the isolation of (P)-compound A, the remaining aqueous liquid (pH=9~10) containing (+)-DBTA) (1.6 equivalents in 4.2 volumes of water) in 15 wt% K2CO3 was treated with hydrochloric acid (HCl) to recover the desired (+)-DBTA). An HCl solution was prepared in a jacketed container using 30.0 equivalents of acid and water (4.2 volumes). The jacket was heated to 45°C, and the (+)-DBTA / K2CO3 aqueous solution was carefully added to the HCl solution over 2 hours while observing foaming, resulting in the appearance of a white solid slurry. After the addition was complete, the slurry was cooled to 10°C over 5 hours. This was filtered to obtain crystals of (d)-DBTA monohydrate, which were washed with water (8.8 volumes). After vacuum drying at 40°C, 93% of the isolated (+)-DBTA) monohydrate was recovered. The purity was 99.5% by weight, and the optical purity was 100% ee, making it ready for use in the subsequent classical resolution crystallization of (M)-compound A.

[0195] Stereochemical purity was analyzed by chiral HPLC under the following conditions: HPLC column: Chiralpak IC-3, 3 μm, 4.6 × 100 mm (Chiral Technologies, Inc., catalog no. 83523); gradient pump, temperature-controlled autosampler, temperature-controlled column compartment, UV detector with 10 mm flow cell (other flow cell sizes may be used if sensitivity requirements are met), and chromatography data system (e.g., Agilent 1200 or equivalent).

[0196] The following reference materials and solvents were obtained: (+)-dibenzoyl-d-tartaric acid (DBTA), CAS RN: 17026-42-5, TCI, product number: D3826; (-)-dibenzoyl-l-tartaric acid (DBTA), CAS RN: 2743-38-6, TCI, product number: D3492; methanol (MeOH), HPLC grade (Sigma-Aldrich, catalog number 34860); ethanol (EtOH), 200 proof (Decon Labs, catalog number 2701); n-heptane 99%, HPLC grade (Sigma-Aldrich, catalog number 650536).

[0197] Stock solutions of (+)-DBTA) and (-)-DBTA) (approximately 0.5 mg / mL) were prepared in MeOH / EtOH 1:1 (v / v) as a diluent. Sample solutions containing approximately 5 mg / mL and 0.05 mg / mL of (+)-DBTA) were prepared, respectively. The samples were analyzed under the following conditions: column temperature: 30°C; isocratic mobile phase: 0.05% TFA / 20% MeOH / EtOH (1:1) / 80% heptane (v / v); flow rate: 0.8 mL / min; injection volume: 2 μL; UV detection at 230 nm; acquisition time: 6 minutes; autosampler temperature: 10°C. Under these conditions, the retention time of (+)-DBTA) was approximately 2.52 minutes, and the retention time of l-DBTA was approximately 4.01 minutes.

[0198] Example 7 This example demonstrates that the free acid of (+)-DBTA monohydrate is isolated by the process of the present disclosure.

[0199] (+)-DBTA monohydrate (purity 99.4% by weight) was obtained by following the procedure described in Example 6. The loss into the residual liquid was less than 1%. Analysis of the crystals by mass spectrometry (e.g., inductively coupled plasma mass spectrometry (ICP-MS)) revealed that only trace amounts of potassium were present (e.g., 0.4% by weight). The low potassium content confirmed that the isolated (+)-DBTA was completely protonated, as shown in Table 9. The neutralization reaction that occurs in the disclosed reaction is as follows: K2CO3 + HCl = H2O + CO2 + KCl, which washes away the potassium chloride (KCl) covering the (+)-DBTA crystals with water, resulting in a wet cake which is then dried.

[0200] [Table 9]

[0201] When the prepared (+)-DBTA monohydrate was used in the synthesis of AMG 510, no adverse effects were observed on the formation of (M)-compound A in terms of classical resolution performance (yield, achiral / chiral purity). The presence of water-saturated Me-THF did not affect the classical resolution process and posed no risk.

[0202] All references cited herein, including publications, patent applications, and patents, are incorporated herein by reference to the same extent as each reference is incorporated individually and specifically by reference, and to the same extent as they are incorporated in whole herein.

[0203] The descriptions of value ranges in this specification are intended solely as a simplified way of referring to each distinct value and each boundary value within that range, unless otherwise specified herein, and each distinct value and boundary value are incorporated herein as if they were individually described herein.

[0204] The terms “one (a),” “one (an),” and “it,” as well as similar references, used in the description of the present invention (particularly in the following claims), should be construed as encompassing both singular and plural unless otherwise indicated herein or unless explicitly contradicted by the context.

[0205] When a list of one or more items is followed by the term “at least one” (e.g., “at least one of A and B”), unless otherwise specified herein or unless the context clearly contradicts it, it should be interpreted as meaning one item (A or B) selected from the items listed, or any combination of two or more items (A and B) listed. The terms “include,” “have,” “contain,” and “contain” are interpreted as open-ended terms unless otherwise specified (i.e., “include, but not limited to”). The descriptions of value ranges herein are intended merely as a concise way of referring individually to each distinct value that falls within that range, unless otherwise indicated herein, and each distinct value is invoked herein as if it were individually enumerated herein. All methods described herein may be carried out in any appropriate order unless otherwise specified or unless the context clearly contradicts it. The use of any examples or illustrative terms provided herein (e.g., "etc.") is merely to further illustrate the invention and, unless otherwise claimed, does not impose any limitation on the scope of the invention. No expression herein should be construed as indicating that any non-claimed component is essential to the practice of the invention.

Claims

1. (P)-Compound A: 【Chemistry 1】 A composition comprising or a salt thereof; and a solvent, wherein the solvent is suitable for heating to a temperature of 250°C to 350°C.

2. The composition according to claim 1, wherein the solvent is suitable for heating to a temperature of 305°C to 320°C.

3. The composition according to claim 1 or 2, wherein the solvent undergoes minimal or no thermal decomposition when heated to a temperature of 250°C to 350°C.

4. The composition according to any one of claims 1 to 3, wherein the solvent comprises diphenyl ether, 1-octadecene, anisole, or a combination thereof.

5. The composition according to any one of claims 1 to 3, wherein the solvent is diphenyl ether, 1-octadecene, anisole, or a combination thereof.

6. The composition according to any one of claims 1 to 3, wherein the solvent comprises anisole.

7. The composition according to any one of claims 1 to 3, wherein the solvent is anisole.

8. (M)-Compound A: 【Chemistry 2】 The composition according to any one of claims 1 to 7, further comprising:

9. The composition according to any one of claims 1 to 7, wherein the %ee of (P)-compound A is 50% or more.

10. The composition according to any one of claims 1 to 7, wherein the %ee of (P)-compound A is 75% or more.

11. The composition according to any one of claims 1 to 7, wherein the %ee of (P)-compound A is 90% or more.

12. The composition according to any one of claims 1 to 7, wherein the %ee of (P)-compound A is 99% or more.

13. The composition according to any one of claims 1 to 12, wherein the (P)-compound A is crystalline.

14. The composition according to any one of claims 1 to 13, wherein the composition is suitable for heating to a temperature of 250°C to 350°C for 5 minutes to 12 hours.

15. The composition according to any one of claims 1 to 14, wherein the composition is suitable for heating to a temperature of 250°C to 350°C for 1 to 4 hours.

16. AMG 510: 【Transformation 3】 A process for preparing, The process involves heating the composition according to any one of claims 1 to 15 to a temperature of 250°C to 350°C to obtain racemic compound A: 【Chemistry 4】 To form, and To synthesize AMG 510 using racemic compound A, A process that includes this.

17. The process according to claim 16, wherein the %ee of racemic compound A is 50% or less.

18. The process according to claim 16, wherein the %ee of racemic compound A is 30% or less.

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