Method for preparing pyrimidine cyclohexylglucocorticoid receptor modulators using pyrilium

Abstract

The present invention provides a method for preparing a pyrimidine cyclohexylglucocorticoid receptor modulator, a method for preparing an intermediate of a pyrimidine cyclohexylglucocorticoid receptor modulator, and a pyridinium compound.

Description

[Technical Field] 【0001】 Cross-references to related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 504,823, filed on 30 May 2023, which is incorporated herein by reference in its entirety. 【0002】 In most species, including humans, the physiological glucocorticoid is cortisol (hydrocortisone). Glucocorticoids are secreted in response to ACTH (corticotropin), which exhibits both changes and increases in circadian rhythms in response to stress and food. Cortisol levels respond within minutes to many physical and psychological stresses, including trauma, surgery, exercise, anxiety, and depression. Cortisol is a steroid that acts by binding to intracellular glucocorticoid receptors (GR). In humans, glucocorticoid receptors exist in two forms: the ligand-binding GR-alpha, consisting of 777 amino acids, and the GR-beta isoform, which lacks 50 carboxyl-terminal residues. Because these contain a ligand-binding domain, GR-beta cannot bind ligands, is constitutively localized in the nucleus, and is transcriptionally inactive. GR is also known as GR-II. 【0003】 The biological effects of cortisol, including those caused by hypercortisolemia, can be modulated at the GR level using receptor modulators such as agonists, partial agonists, and antagonists. Several different classes of drugs can inhibit the physiological effects of GR-agonist binding. These antagonists include compositions that inhibit the ability of agonists to effectively bind to and / or activate GR by binding to GR. One such known GR antagonist, mifepristone, has been found to be an effective antiglucocorticoid agent in humans (Bertagna (1984) J. Clin. Endocrinol. Metab. 59:25). Mifepristone binds to GR with high affinity, and its dissociation constant (Kd) is 10⁻⁹ M (Cadepond (1997) Annu. Rev. Med. 48:129). 【0004】 In addition to cortisol, the biological effects of other steroids can be modulated at the GR level using receptor modulators such as agonists, partial agonists, and antagonists. When administered to a target that needs it, steroids can produce both intended therapeutic effects, for example by stimulating transcriptional repression of glucocorticoid receptors, and negative side effects, for example, due to chronic transcriptional activation of glucocorticoid receptors. Myricolinant (CORT118335) is another such glucocorticoid receptor modulator compound and has been described to date in the PCT Publication International Publication No. 2012 / 129074 and U.S. Patent No. 8,685,973. What is needed in the art is a novel method for preparing myricolinant with a lower impurity content. Surprisingly, the present invention satisfies these and other needs. [Overview of the Initiative] 【0005】 In one embodiment, the present invention relates to the following compound of formula I. 【0006】 [ka] A method for preparing is provided. The method is, (a) A first solvent, a strong acid, and a compound of the following formula VII 【0007】 [ka] A first reaction mixture comprising the following is formed under conditions suitable for preparing the compound of formula I: In the formula, the counterion X - These are tetrafluoroborate, chloride, bromide, tetrachloroferrate, pentachlorostanate, hexafluorophosphate, butyltriphenylborate, or tetrakis(4-methoxyphenyl)borate. 【0008】 In another embodiment, the present invention relates to the following compound of formula VII 【0009】 [ka] A method for preparing is provided. The method is, (b) Pyllium salt and 【0010】 [ka] The second solvent and the compound of formula II below, 【0011】 [ka] A second reaction mixture containing either or its hydrate is formed under conditions suitable for preparing the compound of formula VII, In the formula, the counterion X - BF4 - That is the case. 【0012】 In another embodiment, the present invention relates to the following compound of formula VII 【0013】 [Chemical] provides where the counterion X - is tetrafluoroborate, chloride, bromide, tetrachloroperrate, pentachlorostannate, hexafluorophosphate, butyltriphenylborate, or tetrakis(4-methoxyphenyl)borate. [Brief Description of the Drawings] 【0014】 [Figure 1] Figure 1 shows the proton NMR of the compound of formula VII. [Modes for Carrying Out the Invention] 【0015】 I. Overview This disclosure describes a method for preparing 6-((1r,4r)-4-phenylcyclohexyl)-5-(3-(trifluoromethyl)benzyl)pyrimidine-2,4(1H,3H)-dione (Formula I), which is Example 6 of U.S. Patent No. 8,685,973, via the formation of a pyrylium intermediate from a compound of formula II. This disclosure also describes new intermediates. 【0016】 II. Definitions "About" when referring to a value includes the recited value ± 10% of the recited value. For example, about 50% includes the range of 45% - 55%, while about 10 equivalents includes the range of 9 - 11 equivalents. Thus, when referring to a range, "about" refers to ± 10% of the recited value of each of the upper and lower limits of that range. For example, a ratio of about 1 - about 10 (w / w) includes the range of 0.9 - 11. 【0017】 "Forming a reaction mixture" refers to the process of bringing at least two distinct species into contact so that they can be mixed and react together. However, it will be understood that the resulting reaction product may be produced directly from the reaction between the added reagents, or directly from intermediates from one or more of the added reagents that may be produced in the reaction mixture. 【0018】 A "solvent" refers to a substance, such as a liquid, that can dissolve a solute. Solvents can be polar or nonpolar, protic or aprotic. Polar solvents typically have a dielectric constant greater than about 5 or a dipole moment greater than about 1.0, while nonpolar solvents have a dielectric constant less than about 5 or a dipole moment less than about 1.0. Protic solvents are characterized by having protons available for removal, such as those with hydroxyl or carboxyl groups. Aprotic solvents lack such groups. Typical polar protic solvents include alcohols (methanol, ethanol, propanol, isopropanol, etc.), acids (formic acid, acetic acid, etc.), and water. Typical polar aprotic solvents include dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, diethyl ether, acetone, ethyl acetate, N,N-dimethylformamide, dimethylacetamide, acetonitrile, and dimethyl sulfoxide. Typical nonpolar solvents include alkanes (such as pentane and hexane), cycloalkanes (such as cyclopentane and cyclohexane), benzene, and toluene. Other solvents are also useful in this invention. 【0019】 An "acid" refers to a compound that can either donate a proton (Brønsted-Lowry acid) or accept an electron pair (Lewis acid). Typical examples of acids include, but are not limited to, hydrochloric acid, sulfuric acid, formic acid, acetic acid, propanoic acid, butyric acid, hexanoic acid, octanoic acid, trifluoroacetic acid, and tetrafluoroboric acid (HBF4). 【0020】 A "strong acid" refers to an acid that dissociates easily, and this is often an acid with a pK of less than -1 in water. a It is represented by [formula]. Typical strong acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and perchloric acid. 【0021】 A "hydrate" refers to a compound that has formed a complex with at least one water molecule. The compounds of the present invention can form complexes with 1 to 10 water molecules. 【0022】 "Cooling" refers to applying a cooling means to the reaction mixture to reduce its temperature by at least 1 degree Celsius. For example, cooling may include, but is not limited to, lowering the temperature of the reaction mixture to below room temperature. 【0023】 "Heating" means applying heat to a reaction mixture to raise its temperature by at least 1 degree Celsius. For example, heating may include, but is not limited to, raising the temperature of the reaction mixture to room temperature, or to the reflux temperature or boiling point of the reaction mixture, or to a temperature between room temperature and the reflux temperature or boiling point of the reaction mixture. 【0024】 "Room temperature" is the range of temperatures generally considered suitable for human habitation, namely between approximately 15 degrees Celsius (59 degrees Fahrenheit) and 25 degrees Celsius (77 degrees Fahrenheit). 【0025】 A "crystal species" refers to the seed crystal of the target crystal form that you intend to prepare. 【0026】 III. Method for preparing Formula I using pyrilium The present invention provides a method for preparing the compound of the following formula I, 6-((1r,4r)-4-phenylcyclohexyl)-5-(3-(trifluoromethyl)benzyl)pyrimidine-2,4(1H,3H)-dione: 【0027】 [ka] 【0028】 The compound of formula I was originally disclosed as Example 6 in U.S. Patent No. 8,685,973. 【0029】 A. Preparation of Equation I from Equation VII In some embodiments, the present invention relates to the following compound of formula I. 【0030】 [ka] A method for preparing is provided. The method involves (a) a first solvent, a strong acid, and a compound of the following formula VII. 【0031】 [ka] A first reaction mixture comprising the following is formed under conditions suitable for preparing a compound of formula I, wherein the counterion X - These are tetrafluoroborate, chloride, bromide, tetrachloroferrate, pentachlorostanate, hexafluorophosphate, butyltriphenylborate, or tetrakis(4-methoxyphenyl)borate. 【0032】 Any suitable solvent can be used as the first solvent in the first reaction mixture of the present invention. Typical solvents include, but are not limited to, polar aprotic solvents, polar protic solvents, or nonpolar solvents. In some embodiments, a method for preparing the compound of formula I includes a method in which the first solvent comprises acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, isobutyric acid, isovaleric acid, 4-methylvaleric acid, or 2-ethylcaproic acid. In some embodiments, a method for preparing the compound of formula I includes a method in which the first solvent comprises acetic acid. 【0033】 Any strong acid can be used as the strong acid in the first reaction mixture of the present invention. Typical strong acids include, but are not limited to, organic acids and inorganic acids. In some embodiments, the method for preparing the compound of formula I includes a method in which the strong acid comprises trifluoroacetic acid, trichloroacetic acid, ethane-1,2-disulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hypochlorous acid, chloric acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, or a combination thereof. In some embodiments, the method for preparing the compound of formula I includes a method in which the strong acid comprises hydrochloric acid. In some embodiments, the method for preparing the compound of formula I includes a method in which the strong acid comprises concentrated hydrochloric acid. Concentrated hydrochloric acid may have a normality of about 12 N and a concentration of about 12 M. In some embodiments, the method for preparing the compound of formula I includes a method in which the strong acid is hydrochloric acid at about 37% (w / w). 【0034】 A strong acid may be present in any appropriate amount relative to the compound of formula VII. For example, a strong acid may be present in amounts of 1 to 10 molar equivalents relative to the compound of formula VII, or in amounts of 1 to 8, 2 to 7, 4 to 6, 4.5 to 5.5, 4.6 to 5.4, 4.7 to 5.3, 4.8 to 5.2, or 4.9 to 5.1 molar equivalents relative to the compound of formula VII. Typical amounts of a strong acid include, but are not limited to, about 1.0 molar equivalent relative to the compound of formula VII, or about 2.0, 3.0, 3.5, 4.0, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, or about 10 molar equivalents relative to the compound of formula VII. In some embodiments, the method for preparing the compound of formula I includes a method in which a strong acid is present in an amount of 4 to 6 molar equivalents relative to the compound of formula VII. In some embodiments, the method for preparing the compound of formula I includes a method in which a strong acid is present in an amount of about 5 molar equivalents relative to the compound of formula II. 【0035】 Any suitable counterion can be used as counterion X of the compound of formula VII in the first reaction mixture of the present invention - and. Representative counterion X - includes tetrafluoroborate, chloride, bromide, tetrachlorferrate, pentachlorostannate, hexafluorophosphate, butyltriphenylborate, or tetrakis(4-methoxyphenyl)borate. In some embodiments, the method for preparing the compound of formula I is such that the counterion X - is BF4 - including the method which is. 【0036】 In some embodiments, the method for preparing the compound of formula I includes a method in which the compound of formula VII has the following structure. 【0037】 【Chemical formula】 【0038】 In some embodiments, the method for preparing the compound of formula I includes a method comprising forming a first reaction mixture comprising a compound of formula VII, acetic acid, and concentrated hydrochloric acid under conditions suitable for preparing the compound of formula I. 【0039】 B. Preparation of formula VII from formula II A compound of formula VII which is a salt comprising 1-(6-oxo-4-((1r,4r)-4-phenylcyclohexyl)-5-(3-(trifluoromethyl)benzyl)-1,6-dihydropyrimidin-2-yl)pyridin-1-ium: 【0040】 【Chemical formula】 can be prepared by various methods. 【0041】 In some embodiments, the present invention provides a compound of formula VII as follows 【0042】 [ka] A method for preparing is provided. (b) Pyllium salt and 【0043】 [ka] The second solvent and the compound of formula II below, 【0044】 [ka] or a second reaction mixture comprising the hydrate thereof, This includes forming the compound of formula VII under conditions suitable for preparation, In the formula, the counterion X - BF4 - That is the case. 【0045】 In some embodiments, the method for preparing the compound of formula VII includes a method in which the pyrium salt is a pyrium tetrafluoroborate having the following structure. 【0046】 [ka] 【0047】 Pyryllium salts may be present in any appropriate amount relative to the compound of formula II. For example, pyryllium salts may be present in amounts of 0.1 to 10 molar equivalents, or 0.2 to 5 molar equivalents, or 0.5 to 3 molar equivalents, 1 to 3 molar equivalents, 1 to 1.5 molar equivalents, or 1 to 1.2 molar equivalents relative to the compound of formula II. Typical amounts of pyryllium salts include, but are not limited to, about 0.5 molar equivalents, or about 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, or about 10 molar equivalents relative to the compound of formula II. In some embodiments, the method for preparing the compound of formula VII includes a method in which the pyryllium salt is present in an amount of 1 to 3 molar equivalents relative to the compound of formula II. In some embodiments, the method for preparing the compound of formula VII includes a method in which the pyryllium salt is present in an amount of about 1.1 molar equivalents relative to the compound of formula II. 【0048】 Any suitable solvent can be used as the second solvent in the second reaction mixture of the present invention. Typical second solvents include, but are not limited to, polar protic solvents, polar aprotic solvents, and nonpolar solvents. In some embodiments, a method for preparing the compound of formula VII includes a method in which the second solvent comprises methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-propanol, 1-methoxy-2-propanol, 4-methyl-2-pentanol, 1-hexanol, 2-hexanol, 1-octanol, or 2-octanol, or a combination thereof. In some embodiments, a method for preparing the compound of formula VII includes a method in which the second solvent comprises n-propanol or n-butanol. In some embodiments, a method for preparing the compound of formula VII includes a method in which the second solvent comprises n-butanol. 【0049】 The compound of formula II may be in the form of a free base or a hydrate. In some embodiments, the compound of formula II is a free base. In some embodiments, the compound of formula II is a hydrate. The compound of formula II may be any suitable hydrate. For example, the compound of formula II may be a monohydrate, dihydrate, trihydrate, or tetrahydrate. In some embodiments, the compound of formula II is a monohydrate. 【0050】 In some embodiments, the method for preparing the compound of formula VII includes a method in which the compound of formula II is in monohydrate form. 【0051】 [ka] 【0052】 In some embodiments, a method for preparing the compound of formula VII includes (b) forming a second reaction mixture containing, under conditions suitable for preparing the compound of formula VII, pyrium tetrafluoroborate in an amount of about 1.1 molar equivalents relative to the compound of formula II, n-butanol, and the compound of formula II. 【0053】 In some embodiments, the present invention provides a method for preparing a compound of formula I, and a compound of formula VII is prepared by the method of the present invention. 【0054】 In some embodiments, a method for preparing the compound of formula I includes (b) forming a second reaction mixture containing pyrylium tetrafluoroborate, n-butanol, and the compound of formula II in an amount of about 1.1 molar equivalents relative to the compound of formula II, under conditions suitable for preparing the compound of formula VII, and (a) forming a first reaction mixture containing the compound of formula VII, acetic acid, and concentrated hydrochloric acid under conditions suitable for preparing the compound of formula I. 【0055】 C. Pyrylium intermediate compounds The present invention provides compounds of formula VII. In some embodiments, the present invention provides compounds of formula VII. 【0056】 [ka] Provided, In the formula, the counterion X - These are tetrafluoroborate, chloride, bromide, tetrachloroferrate, pentachlorostanate, hexafluorophosphate, butyltriphenylborate, or tetrakis(4-methoxyphenyl)borate. 【0057】 In some embodiments, the compound of formula VII has the following structure. 【0058】 [ka] 【0059】 The compound of formula VII is named 1-(6-oxo-4-((1r,4r)-4-phenylcyclohexyl)-5-(3-(trifluoromethyl)benzyl)-1,6-dihydropyrimidine-2-yl)pyridine-1-iumtetrafluoroborate using IUPAC nomenclature. [Examples] 【0060】 [Examples] The following acronyms and abbreviations are used in the following methods. 【0061】 [Table 1] 【0062】 Powder X-ray diffraction (XRPD). XRPD analysis was performed using a Panalytical Xpert Pro diffractometer equipped with a Cu X-ray tube and a Pixcel detector system. Samples were analyzed by transmission at ambient temperature and held between PVC films. A default XRPD program was used (for the compound of formula II, 2θ in the range of 3–40°, step size 0.013°, count time 99 seconds, run time approximately 22 minutes / count time 49 seconds; and for both forms of the compound of formula VII, run time approximately 11 minutes / count time 22 seconds; during data acquisition, the sample was centrifuged at 60 rpm). XRPD patterns were sorted and manipulated using HighScore Plus 2.2c software. 【0063】 Differential scanning calorimetry (DSC). DSC analysis was performed using a Perkin Elmer Jade differential scanning calorimeter. Accurately weighed samples were placed in a gold tray and secured with a lid. Each sample was heated to a maximum of 200 or 300°C under nitrogen at a rate of 5°C / min. 【0064】 Thermogravimetric / differential thermal analysis (TG-DTA). Thermogravimetric (TG) analysis with Mettler Toledo TGA / DSC 1 STAR e The analysis was performed using a simultaneous thermal analyzer. The sample was placed in an aluminum sample tray, inserted into a TG furnace, and accurately weighed. Under a nitrogen flow, the heat flow signal was stabilized at 30°C for one minute at a rate of 10°C / min, and then heated to 300°C. 【0065】 Proton nuclear magnetic resonance spectroscopy ( 1 (H-NMR). Proton NMR analysis was performed using a Bruker 500MHz AVANCE NEO instrument equipped with a Prodigy BBO CryoProbe. The sample was dissolved in a suitable deuterated NMR solvent containing tetramethylsilane (TMS) as an internal standard and having an isotopic purity of 99.5 atomic% or more of D, and the sample solution was then analyzed using a 5mm unused NMR tube. 【0066】 The “preferred conditions” for carrying out the method of the present invention include the time and temperature for carrying out the method as defined below. 【0067】 The reaction process of the present invention can be carried out for any preferred reaction time. For example, the reaction time may be any number of minutes, any number of hours, or any number of days. In some embodiments, the reaction time may be several hours, such as at least 8 hours. In some embodiments, the reaction time may be several hours, such as at least overnight. In some embodiments, the reaction time may be several days. In some embodiments, the reaction time may be at least 2 hours. In some embodiments, the reaction time may be at least 8 hours. In some embodiments, the reaction time may be at least several days. In some embodiments, the reaction time may be about 2 hours, or about 4 hours, or about 6 hours, or about 8 hours, or about 10 hours, or about 12 hours, or about 14 hours, or about 16 hours, or about 18 hours, or about 20 hours, or about 22 hours, or about 24 hours. In some embodiments, the reaction time may be about 1 day, or about 2 days, or about 3 days, or about 4 days, or about 5 days, or about 6 days, or about 1 week, or more than about 1 week. 【0068】 The reaction steps of the present invention can be carried out at any suitable reaction temperature. Typical temperatures include, but are not limited to, below room temperature, room temperature, or above room temperature. Other temperatures useful in the method of the present invention include about -40°C to about 65°C, or about room temperature to about 40°C, or about 40°C to about 65°C, or about 40°C to about 60°C. In some embodiments, the reaction mixture can be at a temperature of about room temperature, or about 15°C, or about 20°C, or about 25°C, or about 30°C, or about 35°C, or about 40°C, or about 45°C, or about 50°C, or about 55°C, or about 60°C, or about 65°C. 【0069】 Example 1. Preparation of 6-((1r,4r)-4-phenylcyclohexyl)-2-(1λ4-pyrillium-1-yl)-5-(3-(trifluoromethyl)benzyl)pyrimidine-4(3H)-onetetrafluoroborate (formula VII). 【0070】 [ka] 【0071】 Formula II was prepared according to the method described in WO2022 / 140293. 【0072】 Formula II (33 g, 94 wt%, 72.6 mmol, 1 equivalent) was slurryed in nBuOH (42 times the volume, 1386 mL). The slurry was concentrated to 35 times the volume (1155 mL) under vacuum. The slurry was transferred to an inactivating jacketed container equipped with an overhead stirrer and treated with pyririum ●BF4 (11 g, 97.7 wt%, 65.3 mmol, 0.9 equivalents). The contents were heated to 100°C and aged for 2 hours. The reaction product was analyzed by HPLC and it was shown that 16.0 L CAP of Formula II was still present. 【0073】 The reaction mixture was distilled under vacuum to a 30-fold volume, and then nBuOH (5-fold volume, 165 mL) was added, followed by pyririum●BF4 (1.21 g, 7.25 mmol, 0.1 equivalent). After aging at 100°C for 1 hour, HPLC showed that 7.7 L CAP of SM remained. The reaction mixture was distilled to a 30-fold volume, and then nBuOH (5 volumes, 165 mL) was added, followed by pyririum●BF4 (0.61 g, 0.05 equivalent, 3.62 mmol). After aging at 100°C for 1 hour, HPLC showed that 5.6 L CAP of formula II remained. 【0074】 The reaction mixture was distilled to a final volume of 165 mL (5 times the original volume), and the resulting slurry was aged overnight. The concentration of Equation VII in the liquid phase was determined to be 8.2 mg / mL. The product was isolated by filtration, and the cake was washed with nBuOH (2 × 2 times the volume, 66 mL). The product was transferred to a vacuum oven and dried overnight at 50°C. A total of 39.1 g of Equation VII was isolated as a light brown crystalline solid. m / z[M+H]: 490.30. 19 F NMR(DMSO-d6): -61.1, -148.3. 1 The 1H NMR (DMSO-d6) is shown in Figure 1. 【0075】 Example 2. Preparation of 6-((1r,4r)-4-phenylcyclohexyl)-5-(3-(trifluoromethyl)benzyl)pyrimidine-2,4(1H,3H)-dione (Formula I) 【0076】 [ka] 【0077】 Formula VII (72.2 g, 93.6 wt%, 117.1 mmol, 1.0 equivalent) was placed in an inactivated 1 L round-bottom flask equipped with an overhead stirrer. AcOH (8 times the volume, 578 mL) was added, and the contents were stirred. Concentrated HCl (approximately 37%, 48.8 mL, 58.1 g, 585.5 mmol, 5 equivalents) was added to the slurry. The contents were heated to 70°C and allowed to mature. The degree of conversion was monitored by HPLC. 【0078】 After 3 hours, the reaction was deemed complete, and the contents were cooled to 20°C over approximately 1 hour, during which time a slurry was formed. Water (1 volume, 72 mL) was added dropwise to the slurry over approximately 1 hour. The slurry was allowed to mature for 30 minutes, and the concentration of Formula I in the liquid phase was determined to be 2.8 mg / mL. The slurry was allowed to mature for a further 1 hour, and the solution concentration decreased to 2.5 mg / mL. The product was isolated by filtration, and the filtration cake was sequentially washed with AcOH:water (8:1, 2x2 volumes, 144 mL) and water (2x2 volumes, 144 mL). The product was transferred to a vacuum oven and dried overnight at 50°C. CORT118335 (myricolinant) (52.8 g) was isolated as a pale yellow crystalline solid. 1H-NMR was consistent with the Formula I standard, and the product was thought to be an AcOH solvate. 【0079】 Formula I (50 g, 89.7 wt%, 104.7 mmol, 1 equivalent) was slurryed in DCM (11 times the volume, 550 mL) in an inert 1 L round-bottom flask equipped with an overhead stirrer. The slurry was heated to 30°C to form a solution. The solution was filtered through GF / A grade filter paper (to remove colored impurities), and the DCM (1 time the volume, 50 mL) line was washed. The DCM solutions were combined, and MeOH (3 times the volume, 150 mL) was added. The solution was distilled at atmospheric pressure (T = approximately 50°C) to a final volume of 5 times the volume (250 mL). MeOH (500 mL, 10 times the volume) was added to the solution, and when genuine Formula I (0.1 wt%, 50 mg, 0.105 mmol) was seeded into the solution, a mobile white slurry was formed, and its viscosity increased over time. The slurry was distilled under atmospheric pressure (T approx. 60°C) to a final volume of 5 times its original volume (250 mL), and the solution was treated with MeOH (500 mL, 10 times its original volume). The solution was then distilled under atmospheric pressure (T approx. 65°C) to a final volume of 5 times its original volume (250 mL). The slurry was treated with MeOH (250 mL, 5 times its original volume), and the batch was cooled to 20-25°C over 2 hours. A sample of the slurry was taken and analyzed by XRPD, confirming the formation of the correct polymorph. The concentration of myricolinant in the liquid phase was determined to be 4.1 mg / ml. The product was isolated by filtration, and the cake was washed with MeOH (2 × 1 times, 50 mL). The product was transferred to a vacuum oven and dried overnight at 50°C. Pure formula I was obtained as a white crystalline solid (42.4 g). 【0080】 The characterization data for the title product were consistent with those for Example 6 of U.S. Patent No. 8,685,973 and Example 2 of U.S. Patent No. 11,548,856. 【0081】 The invention described above has been explained in some detail by examples and illustrations for the purpose of clarity of understanding, but those skilled in the art will understand that certain changes and modifications may be implemented within the scope of the appended claims. Furthermore, each reference provided herein is incorporated by reference to the same extent as each individual reference is incorporated by reference. In the event of any conflict between this application and the references provided herein, the application shall prevail.

Claims

[Claim 1] A method for preparing the compound of the following formula I, 【Chemistry 1】 The method described above is (a) The first solvent, a strong acid, and the compound of the following formula VII 【Chemistry 2】 A first reaction mixture comprising the following is formed under conditions suitable for preparing the compound of formula I: In the formula, the counterion X － A method wherein the substance is tetrafluoroborate, chloride, bromide, tetrachloroferrate, pentachlorostanate, hexafluorophosphate, butyltriphenylborate, or tetrakis(4-methoxyphenyl)borate. [Claim 2] The method according to claim 1, wherein the first solvent comprises acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, isobutyric acid, isovaleric acid, 4-methylvaleric acid, or 2-ethylcaproic acid. [Claim 3] The method according to claim 1 or claim 2, wherein the strong acid includes trifluoroacetic acid, trichloroacetic acid, ethane-1,2-disulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hypochlorous acid, chloric acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, or a combination thereof. [Claim 4] The method according to any one of claims 1 to 3, wherein the strong acid includes hydrochloric acid. [Claim 5] Counterion X － BF ４ － The method according to any one of claims 1 to 4. [Claim 6] The method according to any one of claims 1 to 5, wherein the compound of formula VII has the following structure. 【Transformation 3】 [Claim 7] (a) The method according to any one of claims 1 to 6, comprising forming the first reaction mixture comprising the compound of formula VII, acetic acid, and concentrated hydrochloric acid under conditions suitable for preparing the compound of formula I. [Claim 8] A method for preparing the compound of the following formula VII, 【Chemistry 4】 (b) Pyrylene salt and 【Transformation 5】 The second solvent and the compound of formula II below, 【Transformation 6】 A second reaction mixture containing either or its hydrate is formed under conditions suitable for preparing the compound of formula VII, In the formula, the counterion X － BF ４ － The method. [Claim 9] The method according to claim 8, wherein the pyririum salt is a pyririum tetrafluoroborate having the following structure. 【Transformation 7】 [Claim 10] The method according to any one of claims 8 or 9, wherein the pyrylium salt is present in an amount of 1 to 3 molar equivalents relative to the compound of formula II. [Claim 11] The method according to any one of claims 8 to 10, wherein the pyrylium salt is present in an amount of about 1.1 molar equivalents relative to the compound of formula II. [Claim 12] The method according to any one of claims 8 to 11, wherein the second solvent comprises methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-propanol, 1-methoxy-2-propanol, 4-methyl-2-pentanol, 1-hexanol, 2-hexanol, 1-octanol, or 2-octanol, or a combination thereof. [Claim 13] The method according to any one of claims 8 to 12, wherein the second solvent comprises n-propanol or n-butanol. [Claim 14] The method according to any one of claims 8 to 13, wherein the compound of formula II is in the following monohydrate form. 【Transformation 8】 [Claim 15] (b) The method according to any one of claims 8 to 14, comprising forming the second reaction mixture comprising, under conditions suitable for preparing the compound of formula VII, pyrium tetrafluoroborate in an amount of about 1.1 molar equivalents relative to the compound of formula II, n-butanol, and the compound of formula II. [Claim 16] The method according to any one of claims 1 to 7, wherein the compound of formula VII is prepared by the method according to any one of claims 8 to 15. [Claim 17] (b) Forming the second reaction mixture containing about 1.1 molar equivalents of pyrium tetrafluoroborate, n-butanol, and the compound of formula II, under conditions suitable for preparing the compound of formula VII, (a) The method according to any one of claims 1 to 15, comprising forming the first reaction mixture comprising the compound of formula VII, acetic acid, and concentrated hydrochloric acid under conditions suitable for preparing the compound of formula I. [Claim 18] The following compound of formula VII, 【Chemistry 9】 In the formula, the counterion X － Compounds that are tetrafluoroborate, chloride, bromide, tetrachloroferrate, pentachlorostanate, hexafluorophosphate, butyltriphenylborate, or tetrakis(4-methoxyphenyl)borate. [Claim 19] The compound according to claim 18, wherein the compound of formula VII has the following structure. 【Chemistry 10】

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