Sulfone process for preparation of pyrimidine cyclohexyl glucocorticoid receptor modulators

Abstract

The invention provides a method for preparing a pyrimidine cyclohexyl glucocorticoid receptor modulator, a method for preparing an intermediate of the pyrimidine cyclohexyl glucocorticoid receptor modulator, and a thioether compound.

Description

Cross Reference to Related Applications

[0001] This application claims the priority benefit of U.S. Provisional Patent Application No. 63 / 504,824, filed May 30, 2023, the entire contents of which are incorporated herein by reference. BACKGROUND

[0002] In most species, including humans, the physiological glucocorticoid is cortisol (hydrocortisone). Glucocorticoids are secreted in response to ACTH (adrenocorticotropic hormone), which exhibits circadian variation and elevation in response to stress and food. Cortisol levels are elevated within minutes in response to many physical and physiological stresses, including trauma, surgery, exercise, anxiety, and depression. Cortisol is a steroid and exerts its effects by binding to intracellular glucocorticoid receptors (GR). In humans, the glucocorticoid receptor exists in two forms: a 777 amino acid ligand-binding GR-a; and a GR-ß isoform that lacks 50 carboxy-terminal residues. Since these include the ligand-binding domain, GR-ß cannot bind ligand, is constantly localized in the nucleus, and has no transcriptional activity. GR is also known as GR-II.

[0003] The biological effects of cortisol, including those caused by hypercortisolemia, can be modulated at the level of the GR using receptor modulators, such as agonists, partial agonists, and antagonists. Several different classes of agents are capable of inhibiting the physiological effects of GR-agonist binding. These antagonists include compositions that inhibit the ability of an agonist to effectively bind and / or activate the GR by binding to the 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 the GR with high affinity, with a dissociation constant (Kd) of 10-9 M (Cadepond (1997) Annu. Rev. Med. 48:129).

[0004] In addition to Cortisol, receptor modulators, such as agonists, partial agonists, and antagonists, can be used to modulate the biological effects of other steroids at the GR level. When administered to a subject in need, a steroid can provide the intended therapeutic effects, such as from stimulation of glucocorticoid receptor transcriptional repression, and negative side effects, such as from chronic glucocorticoid receptor transactivation. Miricorilant (CORT118335) is another such glucocorticoid receptor modulator compound, and has been previously described in PCT Publication No. WO 2012 / 129074 and U.S. Patent No. 8,685,973. What is needed in the art is a new process for preparing Miricorilant with lower impurity content. Surprisingly, the present invention meets these and other needs. SUMMARY

[0005] In one embodiment, the present invention provides a process for preparing a compound of Formula I: (I) The process comprises: (a) forming a first reaction mixture comprising a first solvent, a compound of Formula VIII: (VIII), and an oxidizing agent, under conditions suitable for preparing a compound of Formula I, wherein R is C 1-12 alkyl.

[0006] In another embodiment, the present invention provides a process for preparing a compound of Formula VIII: (VIII), The process comprises: (b) forming a second reaction mixture comprising an alkylating agent, a second non-nucleophilic base, a second solvent, and a compound of Formula IX: (IX), wherein R is C 1-12 alkyl; the alkylating agent is C 1-12 alkyl halide or C 1-12 alkyl-OS(O)2R a ; R a is C 1-6 alkyl, C 1-6 haloalkyl, and phenyl substituted with 0, 1, 2, or 3 R a1 ; and each R a1 is independently C1-6 Alkyl, halogen or C 1-6 Halogenated alkyl groups.

[0007] In another embodiment, the present invention provides a method for preparing a compound of formula IX: (IX) The method includes: (c) A third reaction mixture is formed under conditions suitable for the preparation of compound IX, the third reaction mixture comprising thiourea, a third nonnucleophilic base, a third solvent, and a compound of formula III: (III) Where R 1 C 1-6 alkyl.

[0008] In another embodiment, the present invention provides a compound of formula VIII: (VIII) Where R is C 1-12 alkyl. Attached Figure Description

[0009] Figure 1 The proton NMR of compound VIII is shown.

[0010] Figure 2 The XRPD of compound VIII is shown. Detailed Implementation

[0011] I. Overview This disclosure describes the preparation of 6-((1) thioether intermediates via sulfones of formula IX. r 4 r )-4-phenylcyclohexyl)-5-(3-(trifluoromethyl)benzyl)pyrimidine-2,4(1 H ,3 H The method of Example 6 of U.S. Patent No. 8,685,973 is described in α-dione (Formula I). ​​This disclosure also describes novel intermediates.

[0012] II. Definition When referring to values, “about” includes the stated value plus or minus 10% of the stated value. For example, about 50% includes a range of 45% to 55%, while about 10 equivalents includes a range of 9 to 11 equivalents. Therefore, when referring to ranges, “about” means 10% of the stated value for each of the stated values ​​plus or minus each end of the stated range. For example, a ratio of about 1 to about 10 (w / w) includes a range of 0.9 to 11.

[0013] "Forming a reaction mixture" refers to the process of bringing at least two different species into contact, so that they mix together and can react. However, it should be understood that the resulting reaction product can be produced directly from the reaction between the added reagents or from an intermediate from one or more added reagents, which can be generated in the reaction mixture.

[0014] "Solvent" refers to a substance capable of dissolving a solute, such as a liquid. Solvents can be polar or nonpolar, proton or aproton. 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. Proton solvents are characterized by having protons that can be removed, such as having hydroxyl or carboxyl groups. Aproton solvents lack such groups. Representative polar proton solvents include alcohols (methanol, ethanol, propanol, isopropanol, etc.), acids (formic acid, acetic acid, etc.), and water. Representative polar aproton solvents include dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, diethyl ether, acetone, ethyl acetate, N,N-dimethylformamide, dimethylacetamide, acetonitrile, and dimethyl sulfoxide. Representative nonpolar solvents include alkanes (pentane, hexane, etc.), cycloalkanes (cyclopentane, cyclohexane, etc.), benzene, and toluene. Other solvents may be used in this invention.

[0015] An "acid" is a compound that can donate a proton (Brønsted-Lorey acid) or accept an electron pair (Lewis acid). Representative acids include, but are not limited to, hydrochloric acid, sulfuric acid, formic acid, acetic acid, propionic acid, butyric acid, hexanoic acid, octanoic acid, trifluoroacetic acid, and tetrafluoroboric acid (HBF4).

[0016] "Strong acid" refers to an acid that readily dissociates, typically formed by the reaction of pK in water. a It is indicated by a value less than -1. Representative strong acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and perchloric acid.

[0017] "Hydrate" refers to a compound that is complexed with at least one water molecule. The compounds of this invention can be complexed with 1 to 10 water molecules.

[0018] An oxidizing agent is a reagent that can accept an electron pair from another compound, thus oxidizing that compound. Representative oxidizing agents include, but are not limited to, oxygen, hydrogen peroxide, nitrite, nitric acid, and sulfuric acid.

[0019] "Alkyl" refers to a straight-chain or branched acyclic hydrocarbon containing normal, secondary, or tertiary carbon atoms. For example, alkyl groups can have 1 to 20 carbon atoms (i.e., C1-C2). 20 Alkyl groups, 1 to 12 carbon atoms (i.e., C1-C1), 12alkyl) or 1 to 6 carbon atoms (i.e., Ci-C6alkyl). Alkyl groups can contain any number of carbons, such as C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 , and C 5-6 Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl ( n -Pr, n - propyl, -CH2CH2CH3), 2-propyl ( i -Pr, i - propyl, -CH(CH3)2), 1-butyl ( n -Bu, n - butyl, -CH2CH2CH2CH3), 2-methyl-l -propyl ( i -Bu, i - butyl, -CH2CH(CH3)2), 2-butyl ( s -Bu, s - butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl ( t -Bu, t - butyl, -C(CH3)3), 1-pentyl ( n - pentyl, -CH2CH2CH2CH2CH3), 2-pentyl ( s -Pn, s - pentyl, -CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl ( t -Pn, t- ethyl (-CH2CH3), n-propyl (-CH2CH2CH3), isopropyl (-CH(CH3)2), n-butyl (-CH2CH2CH2CH3), isobutyl (-CH2CH(CH3)2), sec-butyl (-CH2CH2CH(CH3)2), t-butyl (-C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 3-pentyl (-CH(CH2CH3)(CH2)2), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-methyl-2-butyl (neo-Pn, neopentyl, -CH(CH3)CH(CH3)2), 3-methyl-l-butyl (-CH2CH2CH(CH3)2), 2-methyl-l-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, and octyl (-(CH2)7CH3).

[0020] "Halogen" refers to fluorine, chlorine, bromine, and iodine.

[0021] "Alkylating agent" refers to an agent that has both an alkyl group and a leaving group and is capable of reacting with a second agent to install the alkyl group on the second agent. Representative alkylating agents include, but are not limited to, alkyl halides, alkyl sulfonates, and the like.

[0022] "Alkyl halide" refers to an alkyl group attached to a single halogen. Representative alkyl halides include, but are not limited to, n-octyl iodide.

[0023] "Alkylation additive" refers to an additive that converts an alkyl chloride or alkyl bromide to an alkyl iodide. Representative alkylation additives include, but are not limited to, sodium bromide, sodium iodide, potassium bromide, potassium iodide, or tetraalkylammonium bromide, iodide salts such as those commonly used as phase transfer catalysts, and combinations thereof.

[0024] "Non-nucleophilic base" refers to a compound that is not nucleophilic according to the Bronsted-Lowry definition of being able to accept a proton (H + ) or is an electron pair donor according to the Lewis definition. Non-nucleophilic bases useful in the present application include amines such as trimethylamine, triethylamine, N,N-diisopropylethylamine (DIPEA or Hunig's base), 1,8-diazabicycloundec-7-ene (DBU), 2,6-di-tert-butylpyridine, quinuclidine, and lithium diisopropylamide (LDA). Other bases are known to those skilled in the art.

[0025] "Thiourea" means H2NC(=S)NH2.

[0026] "Cooling" means applying a cooling means to the reaction mixture to reduce the temperature of the reaction mixture by at least 1 degree Celsius. For example, cooling can include, but is not limited to, reducing the temperature of the reaction mixture to room temperature or below room temperature.

[0027] "Heating" means applying heat to the reaction mixture to increase the temperature of the reaction mixture by at least 1 degree Celsius. For example, heating can include, but is not limited to, increasing the temperature of the reaction mixture to room temperature, or to the reflux or boiling temperature of the reaction mixture, or to a temperature between room temperature and the reflux or boiling temperature of the reaction mixture.

[0028] "Room temperature" is the range of air temperatures generally considered suitable for human habitation, or between about 15 degrees Celsius (59 degrees Fahrenheit) and 25 degrees Celsius (77 degrees Fahrenheit).

[0029] "Seed crystal" means a seed crystal of the target crystalline form to be prepared.

[0030] III. Methods of preparing a sulfone of Formula I The present application provides a method for preparing a compound of Formula I 6-((1 r ,4 r )-4-phenylcyclohexyl)-5-(3-(trifluoromethyl)benzyl)pyrimidine-2,4(1 H ,3 H )-dione: (I).

[0031] The compound of Formula I was initially disclosed as Example 6 in U.S. Patent No. 8,685,973.

[0032] A. Preparation of Formula I from Formula VIII In some embodiments, the present application provides a method of preparing a compound of Formula I, or a pharmaceutically acceptable salt thereof: (I) The method comprises: forming a first reaction mixture comprising a first solvent, a compound of Formula VIII: (VIII), and an oxidizing agent, under conditions suitable for preparing a compound of Formula I, wherein R is C 1-12 alkyl.

[0033] Any suitable solvent can be used as the first solvent in the first reaction mixture of the present application. Representative solvents include, but are not limited to, polar protic solvents, polar aprotic solvents, and nonpolar solvents. In some embodiments, the method of making a compound of Formula I includes a method wherein the first solvent includes acetone, methyl acetate, ethyl acetate, isopropyl acetate, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), 2-methyltetrahydrofuran (2-MeTHF), tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), or a combination thereof. In some embodiments, the method of making a compound of Formula I includes a method wherein the first solvent includes N-methyl-2-pyrrolidone (NMP).

[0034] In some embodiments, the method of making a compound of Formula I includes a method wherein R is a C 6-12 alkyl group. In some embodiments, the method of making a compound of Formula I includes a method wherein R is a n-hexyl group, a n-heptyl group, a n-octyl group, a n-nonyl group, or a n-decyl group. In some embodiments, the method of making a compound of Formula I includes a method wherein R is a n-octyl group.

[0035] In some embodiments, the method of making a compound of Formula I includes a method wherein the compound of Formula VIII has the following structure: .

[0036] Any suitable oxidizing agent can be used as the oxidizing agent in the first reaction mixture of the present application. Representative oxidizing agents include, but are not limited to, oxone, hydrogen peroxide, nitric acid, potassium chlorate, sulfuric acid, peroxodisulfuric acid, hypochlorite salts, and potassium permanganate. In some embodiments, the method of making a compound of Formula I includes a method wherein the oxidizing agent includes oxone, hydrogen peroxide, nitric acid, potassium chlorate, sulfuric acid, peroxodisulfuric acid, hypochlorite salts, potassium permanganate, or a combination thereof.

[0037] In some embodiments, the method of making a compound of Formula I includes a method wherein the oxidizing agent includes oxone. In some embodiments, the method of making a compound of Formula I includes a method of: (a) forming a first reaction mixture comprising oxone, N-methyl-2-pyrrolidone, and a compound of Formula VIII under conditions suitable for making a compound of Formula I.

[0038] In some embodiments, the method of making a compound of Formula I includes a method wherein the oxidizing agent includes hydrogen peroxide. In some embodiments, the method of making a compound of Formula I includes a method of: (a) forming a first reaction mixture comprising hydrogen peroxide, N-methyl-2-pyrrolidone, and a compound of Formula VIII under conditions suitable for making a compound of Formula I.

[0039] The oxidizing agent can be present in any suitable ratio relative to the compound of Formula VIII. For example, the oxidizing agent can be present in an amount of 0.1 to 10 molar equivalents relative to the compound of Formula VIII, or 1 to 10, 1 to 5, 1 to 7, 4 to 6, or 4.5 to 5.5 molar equivalents relative to the compound of Formula VIII. Representative amounts of the oxidizing agent include, but are not limited to, about 1.0 molar equivalent relative to the compound of Formula VIII, or about 1.5, 2.0, 2.5, 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, 7.5, 8.0, 8.5, 9.0, 9.5, or about 10 molar equivalents relative to the compound of Formula VIII.

[0040] In some embodiments, the method of preparing a compound of Formula I includes a method wherein oxone is present in an amount of 3 to 7 molar equivalents relative to the compound of Formula VIII. In some embodiments, the method of preparing a compound of Formula I includes a method wherein oxone is present in an amount of about 5 molar equivalents relative to the compound of Formula VIII.

[0041] In some embodiments, the method of preparing a compound of Formula I includes a method wherein hydrogen peroxide is present in an amount of 1 to 10 molar equivalents relative to the compound of Formula VIII. In some embodiments, the method of preparing a compound of Formula I includes a method wherein hydrogen peroxide is present in an amount of 3 to 7 molar equivalents relative to the compound of Formula VIII.

[0042] In some embodiments, the method of preparing a compound of Formula I includes a method wherein the first reaction mixture further comprises a strong acid. Any strong acid can be used as the strong acid in the first reaction mixture of the present application. Representative strong acids include, but are not limited to, organic acids and inorganic acids. In some embodiments, the method of preparing a compound of Formula I includes a method wherein 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 of preparing a compound of Formula I includes a method wherein the strong acid comprises sulfuric acid.

[0043] The strong acid can be present in any suitable ratio relative to the compound of Formula VIII. For example, the strong acid can be present in an amount of 0.1 to 10 molar equivalents relative to the compound of Formula VIII, or 1 to 10, 1 to 5, 2 to 4, or 2.5 to 3.5 molar equivalents relative to the compound of Formula VIII. Representative amounts of the strong acid include, but are not limited to, about 1.0 molar equivalent relative to the compound of Formula VIII, or about 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or about 10 molar equivalents relative to the compound of Formula VIII.

[0044] In some embodiments, the method of preparing a compound of Formula I includes a method wherein the sulfuric acid is present in an amount of 1 to 5 molar equivalents relative to the compound of Formula VIII. In some embodiments, the method of preparing a compound of Formula I includes a method wherein the sulfuric acid is present in an amount of about 3 molar equivalents relative to the compound of Formula VIII.

[0045] In some embodiments, the method of preparing a compound of Formula I includes a method wherein: (a) a first reaction mixture comprising oxone, N-methyl-2-pyrrolidone, and a compound of Formula VIII is formed in an amount of about 5 molar equivalents relative to the compound of Formula VIII, under conditions suitable for preparing a compound of Formula I.

[0046] In some embodiments, the method of preparing a compound of Formula I includes a method wherein: (a) a first reaction mixture comprising hydrogen peroxide, sulfuric acid, N-methyl-2-pyrrolidone, and a compound of Formula VIII is formed in an amount of 3 to 7 molar equivalents relative to the compound of Formula VIII, under conditions suitable for preparing a compound of Formula I. In some embodiments, the method of preparing a compound of Formula I includes a method wherein: (a) a first reaction mixture comprising hydrogen peroxide, sulfuric acid in an amount of about 3 molar equivalents relative to the compound of Formula VIII, N-methyl-2-pyrrolidone, and a compound of Formula VIII is formed, under conditions suitable for preparing a compound of Formula I.

[0047] B. Preparation of Formula VIII from Formula IX In some embodiments, the present application provides a method of preparing a compound of Formula VIII: (VIII), The method includes: (b) forming a second reaction mixture comprising an alkylating agent, a second non-nucleophilic base, a second solvent, and a compound of Formula IX: (IX) wherein R is C 1-12alkyl; the alkylating agent is C 1-12 alkyl halide or C 1-12 alkyl-OS(O)2R a ; R a is C 1-6 alkyl, C 1-6 haloalkyl and phenyl substituted with 0, 1, 2, or 3 R a1 ; and each R a1 is independently C 1-6 alkyl, halogen, or C 1-6 haloalkyl.

[0048] Any suitable alkylating agent can be used in the process for preparing Formula VIII. For example, the alkylating agent can be an alkyl halide, an alkyl sulfonate, or other group. In some embodiments, the alkylating agent is a C 1-12 alkyl halide. In some embodiments, the alkylating agent is a C 1-12 alkyl-OS(O)2R a . In some embodiments, the alkylating agent is a C 6-12 alkyl-OS(O)2R a , wherein R a is methyl, trifluoromethyl, or 4-methyl-phenyl. In some embodiments, the alkylating agent is a C 1-12 alkyl ester, a triflate C 1-12 alkyl ester, or a tosylate C 1-12 alkyl ester.

[0049] Any suitable alkyl halide can be used as the C 1-12 alkyl halide in the second reaction mixture. Representative C 1-12 alkyl halides include, but are not limited to, alkyl iodides, alkyl bromides, and alkyl chlorides. In some embodiments, the process for preparing a compound of Formula VIII comprises a process wherein the second reaction mixture comprises a C 6-12 alkyl iodide. In some embodiments, the process for preparing a compound of Formula VIII comprises a process wherein the second reaction mixture comprises n-hexyl iodide, n-heptyl iodide, n-octyl iodide, n-nonyl iodide, or n-decyl iodide. In some embodiments, the process for preparing a compound of Formula VIII comprises a process wherein the second reaction mixture comprises n-octyl iodide.

[0050] alkylating agent or C 1-12 alkyl halide can be present in any suitable amount relative to the compound of Formula IX. For example, the alkylating agent or C 1-12The alkyl halide can be present in an amount of 0.1 to 10 molar equivalents relative to the compound of Formula IX, or 0.2 to 5, 0.5 to 3, 0.8 to 3, 0.9 to 1.5, or 0.9 to 1.1 molar equivalents relative to the compound of Formula IX. The alkylating agent or C 1-12 Representative amounts of alkyl halide include, but are not limited to, about 0.5 molar equivalents relative to the compound of Formula IX, 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 10 molar equivalents relative to the compound of Formula IX. In some embodiments, the method of making the compound of Formula VIII includes a method wherein the alkyl iodide is present in an amount of 0.9 to 2 molar equivalents relative to the compound of Formula IX. In some embodiments, the method of making the compound of Formula VIII includes a method wherein the alkyl iodide is present in an amount of about 1 molar equivalent relative to the compound of Formula IX.

[0051] The alkyl iodide alkylating agent can also be prepared in situ from an alkyl chloride or alkyl bromide with an additive such as, but not limited to, sodium bromide, sodium iodide, potassium bromide, potassium iodide, or a tetraalkylammonium bromide, iodide salt such as those commonly used as phase transfer catalysts, and combinations thereof. In some embodiments, the alkylating agent is an alkyl chloride or alkyl bromide, and the second reaction mixture further comprises an alkylating additive such that the alkyl iodide is formed in situ. In some embodiments, the alkylating additive can be sodium bromide, sodium iodide, potassium bromide, potassium iodide, or a tetraalkylammonium bromide, iodide salt, or combinations thereof.

[0052] In some embodiments, the method of making the compound of Formula VIII includes a method comprising: (b) forming a second reaction mixture comprising an alkyl bromide, an alkylating additive, potassium carbonate, N-methyl-2-pyrrolidone, and the compound of Formula IX under conditions suitable for forming the compound of Formula VIII. In some embodiments, the method of making the compound of Formula VIII includes a method comprising: (b) forming a second reaction mixture comprising an alkyl chloride, an alkylating additive, potassium carbonate, N-methyl-2-pyrrolidone, and the compound of Formula IX under conditions suitable for forming the compound of Formula VIII.

[0053] The alkylating additive can be present in the second reaction mixture in any suitable amount relative to the compound of Formula IX. For example, the alkylating additive can be present in catalytic amounts, or in an amount of 0.01 to 10 molar equivalents relative to the compound of Formula IX, or 0.05 to 5, or 0.1 to 1 molar equivalents relative to the compound of Formula IX.

[0054] Any non-nucleophilic base can be used as the second non-nucleophilic base in the second reaction mixture of the present application. Representative second non-nucleophilic bases include, but are not limited to, potassium carbonate, sodium carbonate, alkoxides such as potassium tert-butoxide and sodium tert-butoxide, hexamethylsilazane (HMDS), lithium hexamethyldisilazane, sodium hexamethyldisilazane, potassium hexamethyldisilazane, lithium diisopropylamide (LDA), lithium hydride, sodium hydride, potassium hydride, n-butyllithium, and amine bases such as triethylamine (Et3N), N,N-diisopropylethylamine (iPr2NEt; DIPEA), 1,8-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), N,N-diethylaniline, pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine, and quinuclidine. Non-nucleophilic bases include non-nucleophilic amine bases.

[0055] In some embodiments, the method of making a compound of Formula VIII includes where the second non-nucleophilic base includes sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, N,N-diisopropylethylamine (DIPEA), N,N-dimethylisopropylamine (DIMPA), piperidine, 1-ethylpiperidine, N-methylmorpholine, N-methylpyrrolidine, N,N-dimethylamine, piperazine, N-methylpiperazine, pyridine, N,N-dimethylaniline, N,N-diethylaniline, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine (DMAP), quinuclidine, 4-pyrrolidinopyridine, 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), or a combination thereof. In some embodiments, the method of making a compound of Formula VIII includes where the second non-nucleophilic base includes sodium carbonate, potassium carbonate, or cesium carbonate. In some embodiments, the method of making a compound of Formula VIII includes where the second non-nucleophilic base includes potassium carbonate.

[0056] The second non-nucleophilic base can be present in any suitable amount relative to the compound of Formula IX. For example, the second non-nucleophilic base can be present in an amount of 0.1 to 10 molar equivalents relative to the compound of Formula IX, or 0.2 to 5, 0.5 to 3, 0.8 to 2, 0.9 to 1.5, or 0.9 to 1.1 molar equivalents relative to the compound of Formula IX. Representative amounts of the second non-nucleophilic base include, but are not limited to, about 0.5 molar equivalents relative to the compound of Formula IX, 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 10 molar equivalents relative to the compound of Formula IX. In some embodiments, the method of making the compound of Formula VIII includes a method wherein the second non-nucleophilic base is present in an amount of 0.9 to 2 molar equivalents relative to the compound of Formula IX. In some embodiments, the method of making the compound of Formula VIII includes a method wherein the second non-nucleophilic base is present in an amount of about 1 molar equivalent relative to the compound of Formula IX.

[0057] Any suitable solvent can be used as the second solvent in the second reaction mixture of the present application. Representative second solvents include, but are not limited to, polar protic solvents, polar aprotic solvents, and non-polar solvents. In some embodiments, the method of making the compound of Formula VIII includes a method wherein the second solvent includes acetone, methyl acetate, ethyl acetate, isopropyl acetate, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), 2-methyltetrahydrofuran (2-MeTHF), tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), or a combination thereof. In some embodiments, the method of making the compound of Formula VIII includes a method wherein the second solvent includes N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP), or a combination thereof. In some embodiments, the method of making the compound of Formula VIII includes a method wherein the second solvent includes N-methyl-2-pyrrolidone (NMP).

[0058] In some embodiments, the method of making the compound of Formula VIII includes a method comprising: (b) forming a second reaction mixture comprising n-octyl iodide in an amount of about 1 molar equivalent relative to the compound of Formula IX, potassium carbonate in an amount of about 1 molar equivalent relative to the compound of Formula IX, N-methyl-2-pyrrolidone, and the compound of Formula IX, under conditions suitable for forming the compound of Formula VIII.

[0059] In some embodiments, the method of making the compound of Formula VIII includes a method wherein the compound of Formula VIII is made by the method of the present application.

[0060] In some embodiments, the method of preparing a compound of Formula VIII comprises a method comprising: (b) forming a second reaction mixture comprising n-octyl iodide in an amount of about 1 molar equivalent relative to the compound of Formula IX, potassium carbonate in an amount of about 1 molar equivalent relative to the compound of Formula IX, N-methyl-2-pyrrolidone, and the compound of Formula IX under conditions suitable to form a compound of Formula VIII; and (a) forming a first reaction mixture comprising hydrogen peroxide in an amount of 3 to 7 molar equivalents relative to the compound of Formula VIII, sulfuric acid, N-methyl-2-pyrrolidone, and the compound of Formula VIII under conditions suitable to prepare a compound of Formula I.

[0061] C. preparing Formula IX from Formula III The present application provides a method of preparing a compound of Formula IX: (IX) The method comprises: (c) forming a third reaction mixture comprising thiourea, a third non-nucleophilic base, a third solvent, and a compound of Formula III under conditions suitable to prepare a compound of Formula IX: (III), wherein R 1 is C 1-6 alkyl.

[0062] In some embodiments, the method of preparing a compound of Formula IX is a method wherein R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, isobutyl, pentyl, or hexyl. In some embodiments, the method of preparing a compound of Formula IX is a method wherein R 1 is methyl, ethyl, or n-propyl. In some embodiments, the method of preparing a compound of Formula IX is a method wherein R 1 is ethyl.

[0063] In some embodiments, the method of preparing a compound of Formula IX is a method wherein the compound of Formula III has the structure: .

[0064] Any suitable solvent can be the third solvent in the third reaction mixture of the present application. Representative third solvents include, but are not limited to, polar protic solvents, polar aprotic solvents, and nonpolar solvents. In some embodiments, the method of making a compound of Formula IX is a method wherein the third solvent comprises acetone, methyl acetate, ethyl acetate, isopropyl acetate, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), 2-methyltetrahydrofuran (2-MeTHF), tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), or a combination thereof. In some embodiments, the method of making a compound of Formula IX is a method wherein the third solvent comprises N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP), or a combination thereof. In some embodiments, the method of making a compound of Formula IX is a method wherein the third solvent comprises N,N-dimethylformamide (DMF).

[0065] Any non-nucleophilic base can be used as the third non-nucleophilic base in the third reaction mixture of the present application. Representative third non-nucleophilic bases include, but are not limited to, potassium carbonate, sodium carbonate, alkoxides such as potassium tert-butoxide and sodium tert-butoxide, hexamethylsilazane (HMDS), lithium hexamethyldisilazane, sodium hexamethyldisilazane, potassium hexamethyldisilazane, lithium diisopropylamide (LDA), lithium hydride, sodium hydride, potassium hydride, n-butyllithium, and amine bases such as triethylamine (Et3N), N,N-diisopropylethylamine (iPr2NEt; DIPEA), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), N,N-diethylaniline, pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine, and quinuclidine. The non-nucleophilic base includes a non-nucleophilic amine base.

[0066] In some embodiments, the method of preparing a compound of Formula IX is a method wherein the third non-nucleophilic base comprises triethylamine, N,N-diisopropylethylamine (DIPEA), N,N-dimethylisopropylamine (DIMPA), piperidine, 1- ethylpiperidine, N-methylmorpholine, N-methylpyrrolidine, N,N-dimethylamine, piperazine, N-methylpiperazine, pyridine, N,N-dimethylaniline, N,N-diethylaniline, 2,6- dimethylpyridine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine (DMAP), quinuclidine, 4-pyrrolidinopyridine, 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), or a combination thereof. In some embodiments, the method of preparing a compound of Formula IX is a method wherein the third non-nucleophilic base comprises 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU).

[0067] The third non-nucleophilic base can be present in any suitable amount relative to the compound of Formula III. For example, the third non-nucleophilic base can be present in an amount of 1 to 10 molar equivalents relative to the compound of Formula III, or 1 to 8, 1.5 to 7, 2 to 6, 2 to 3, 2.1 to 2.9, 2.2 to 2.8, 2.3 to 2.7, or 2.4 to 2.6 molar equivalents relative to the compound of Formula III. Representative amounts of the third non-nucleophilic base include, but are not limited to, about 0.5 molar equivalents relative to the compound of Formula III, or about 1.0, 1.5, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, or about 10 molar equivalents relative to the compound of Formula III. In some embodiments, the method of preparing a compound of Formula IX is a method wherein the third non-nucleophilic base is present in an amount of 1 to 5 molar equivalents relative to the compound of Formula III. In some embodiments, the method of preparing a compound of Formula IX is a method wherein the third non-nucleophilic base is present in an amount of about 2.5 molar equivalents relative to the compound of Formula III.

[0068] The thiourea can be present in any suitable amount relative to the compound of Formula III. For example, the thiourea can be present in an amount of 1 to 10 molar equivalents relative to the compound of Formula III, or 1 to 8, 2 to 7, 5 to 7, 5.5 to 6.5, 5.6 to 6.4, 5.7 to 6.3, 5.8 to 6.2, or 5.9 to 6.1 molar equivalents relative to the compound of Formula III. Representative amounts of thiourea include, but are not limited to, about 1.0 molar equivalent relative to the compound of Formula III, or about 2.0, 3.0, 4.0, 4.5, 5.0, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 7.0, 8.0, 9.0, or about 10 molar equivalents relative to the compound of Formula III.

[0069] In some embodiments, the method of preparing the compound of Formula IX includes a method wherein the thiourea is present in an amount of 5 to 7 molar equivalents relative to the compound of Formula III. In some embodiments, the method of preparing the compound of Formula IX includes a method wherein the thiourea is present in an amount of about 6 molar equivalents relative to the compound of Formula III.

[0070] In some embodiments, the method of preparing the compound of Formula IX is a method comprising: (c) forming a third reaction mixture comprising thiourea, DBU in an amount of about 2.5 molar equivalents relative to the compound of Formula III, N,N-dimethylformamide, and the compound of Formula III, under conditions suitable for preparing the compound of Formula IX.

[0071] In some embodiments, the method of preparing the compound of Formula IX is a method comprising: (c) forming a third reaction mixture comprising thiourea in an amount of about 6 molar equivalents relative to the compound of Formula III, DBU in an amount of about 2.5 molar equivalents relative to the compound of Formula III, N,N-dimethylformamide, and the compound of Formula III, under conditions suitable for preparing the compound of Formula IX.

[0072] In some embodiments, the method of preparing the compound of Formula VIII is a method wherein the compound of Formula IX is prepared by a method of the present application. In some embodiments, the method of preparing the compound of Formula I is a method wherein the compound of Formula IX is prepared by a method of the present application.

[0073] In some embodiments, the method of making a compound of Formula VIII or the method of making a compound of Formula I is a method comprising: (c) forming a third reaction mixture comprising thiourea, DBU in an amount of about 2.5 molar equivalents relative to the compound of Formula III, N,N-dimethylformamide, and the compound of Formula III under conditions suitable to make a compound of Formula IX; (b) forming a second reaction mixture comprising n-octyl iodide in an amount of about 1 molar equivalent relative to the compound of Formula IX, potassium carbonate in an amount of about 1 molar equivalent relative to the compound of Formula IX, N-methyl-2-pyrrolidone, and the compound of Formula IX under conditions suitable to form a compound of Formula VIII; and (a) forming a first reaction mixture comprising oxone, N-methyl-2-pyrrolidone, and the compound of Formula VIII under conditions suitable to make a compound of Formula I.

[0074] In some embodiments, the method of making a compound of Formula VIII or the method of making a compound of Formula I is a method comprising: (c) forming a third reaction mixture comprising thiourea, DBU in an amount of about 2.5 molar equivalents relative to the compound of Formula III, N,N-dimethylformamide, and the compound of Formula III under conditions suitable to make a compound of Formula IX; (b) forming a second reaction mixture comprising n-octyl iodide in an amount of about 1 molar equivalent relative to the compound of Formula IX, potassium carbonate in an amount of about 1 molar equivalent relative to the compound of Formula IX, N-methyl-2-pyrrolidone, and the compound of Formula IX under conditions suitable to form a compound of Formula VIII; and (a) forming a first reaction mixture comprising hydrogen peroxide in an amount of 3 to 7 molar equivalents relative to the compound of Formula VIII, sulfuric acid, N-methyl-2-pyrrolidone, and the compound of Formula VIII under conditions suitable to make a compound of Formula I.

[0075] D. Sulfone intermediate compounds The present application provides a compound of Formula VIII. In some embodiments, the present application provides a compound of Formula VIII: (VIII) wherein R is C 1-12 alkyl.

[0076] In some embodiments, the compound of Formula VIII is a compound wherein R is C 6-12 alkyl. In some embodiments, the compound of Formula VIII is a compound wherein R is n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl. In some embodiments, the compound of Formula VIII is a compound wherein R is n-octyl.

[0077] In some embodiments, the compound of Formula VIII has the following structure: .

[0078] The compound of formula VIII is named 2-(octylthio)-6-((1r,4r)-4-phenylcyclohexyl)-5-(3-(trifluoromethyl)benzyl)pyrimidin-4(3H)-one using the IUPAC nomenclature.

[0079] IV. Examples The following acronyms and abbreviations are used in the methods described below:

[0080] X-ray powder diffraction (XRPD) was performed using a Panalytical Xpert Pro diffractometer equipped with a Cu X-ray tube and Pixcel detector system. Samples were analyzed in transmission mode at ambient temperature and held between PVC films. The default XRPD program was used (range 3–40°2θ, step size 0.013°, count time 99 sec; approximately 22 min run time / 49 sec count time for Formula II compounds; approximately 11 min run time / 22 sec count time for both forms of Formula VII compounds). Samples were rotated at 60 rpm during data collection. XRPD patterns were classified and manipulated using HighScore Plus 2.2c software.

[0081] Differential scanning calorimetry (DSC). DSC analysis was performed on a Perkin Elmer Jade differential scanning calorimeter. Precisely weighed samples were placed in a gold dish and secured with a lid. Each sample was heated to a maximum of 200 or 300 °C at a rate of 5 °C / min under nitrogen atmosphere.

[0082] Thermogravimetric differential thermal analysis (TG-DTA). At Mettler Toledo TGA / DSC 1 STAR e Thermogravimetric (TG) analysis was performed on a simultaneous thermal analysis instrument. The sample was placed in an aluminum sample pan, inserted into the TG furnace, and accurately weighed. Under a nitrogen flow, the heat flux signal was stabilized at 30°C for one minute before heating to 300°C at a rate of 10°C / min.

[0083] Proton nuclear magnetic resonance spectroscopy ( 1 (H-NMR). Proton NMR analysis was performed on a 500 MHz BrukerAVANCE 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 with isotopic purity ≥99.5 atomic% D, and the solution of the sample was then analyzed using a 5 mm Virgin NMR tube.

[0084] “Suitable conditions” for carrying out the methods of the application include time and temperature for carrying out the methods, as defined below.

[0085] The reaction steps of the application can be carried out for any suitable reaction time. For example, the reaction time can last for minutes, hours, or days. In some embodiments, the reaction time can last for several hours, such as at least eight hours. In some embodiments, the reaction time can last for several hours, such as at least overnight. In some embodiments, the reaction time can last for several days. In some embodiments, the reaction time can last for at least two hours. In some embodiments, the reaction time can last for at least eight hours. In some embodiments, the reaction time can last for at least several days. In some embodiments, the reaction time can last for about two 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 can last for about 1 day, or about two days, or about three days, or about four days, or about five days, or about six days, or about one week, or about more than one week.

[0086] The reaction steps of the application can be carried out at any suitable reaction temperature. Representative temperatures include, but are not limited to, below room temperature, at room temperature, or above room temperature. Other temperatures that can be used in the methods of the application 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 at about 15 °C, or at about 20 °C, or at about 25 °C, or at about 30 °C, or at about 35 °C, or at about 40 °C, or at about 45 °C, or at about 50 °C, or at about 55 °C, or at about 60 °C, or at about 65 °C.

[0087] Example 1. Preparation of 2-(octylthio)-6-((1 r,4r)-4-phenylcyclohexyl)-5-(3- (trifluoromethyl)benzyl)pyrimidin-4(3H)-one (Formula VIII) Figure 1 Preparation of 6-((1r,4r)-4-phenylcyclohexyl)-2-thioxo-5-(3- (trifluoromethyl)benzyl)-2,3-dihydropyrimidin-4(1H)-one (Formula IX) Formula III is prepared according to the method described in WO 2022 / 140293.

[0088] Formula III (58.0 g, 134.1 mmol, 1 eq.) and thiourea (61.2 g, 804.7 mmol, 6 eq.) were slurried in DMF (5 vol., 290 ml). The contents were stirred under N2until a solution was formed. DBU (51.0 g, 50.1 ml, 335.3 mmol, 2.5 eq.) was added and the contents were warmed to 80 °C. The stream was aged at 80 °C overnight, then analyzed for consumption of Formula III by HPLC (remaining <2 LCAP Formula III). MeCN (3 vol., 174 ml) was added (to dissolve solids and avoid gelling upon addition of acid), followed by 1 M HC1 (3.5 vol., 203 ml) over ~1 h, resulting in an initially fine slurry that slowly converted to a more thick, mobile white slurry. The slurry was determined to have a liquid loss of 0.5 mg / ml by HPLC, and the product was isolated via filtration. The wet cake was washed sequentially with MeCN (3 vol., 174 ml), 1 : 1 MeCN:water (3 vol., 174 ml), and water (3 vol., 174 ml). The product was dried under vacuum at 50 °C overnight. Thiouracil Formula IX (42.5 g) was isolated as a white crystalline solid.

[0089] The characterization data for the title product were consistent with that previously described.

[0090] Preparation of 2-(octylthio)-6-((1 r,4r)-4-phenylcyclohexyl)-5-(3- (trifluoromethyl)benzyl)pyrimidin-4(3H)-one (Formula VIII) Thiourea pyrimidine of Formula IX (41 g, 92.2 mmol, 1 eq.) and K2CO3(12.7 g, 92.2 mmol, 1 eq.) were slurry in NMP (410 ml, 10 vol.) under N2. After aging for 30 minutes, 1-iodooctane (22.1 g, 16.6 ml, 92.2 mmol, 1 eq.) was added dropwise over ~ 15 minutes. The mixture was aged at 25 °C for 4 hours. HPLC indicated complete consumption of thiourea pyrimidine of Formula IX. The mixture was treated with MeCN (3 vol., 123 ml) and water (13 vol., 533 ml) was added over ~ 1 hour to generate a flowable white slurry. The slurry was assayed for liquid loss by HPLC as 0.98 mg / ml and the product was isolated via filtration. The product was washed sequentially with MeCN (3 vol., 123 ml), 1:1 MeCN:water (3 vol., 123 ml), and water (3 vol., 123 ml). After drying under suction for 1 hour, the wet cake was reslurried in MeCN:water (4:1, 3 vol., 123 ml) and aged overnight. The next morning, the slurry was filtered and washed with water (3 vol., 123 ml). The product was dried under vacuum at 50 °C overnight. Sulfide of Formula VIII (47.3 g) was isolated as a crystalline white solid. m / z [M+H]: 557.4.1H NMR (DMSO-d6) is provided in Figure 2 XRPD is provided in Example 2. Oxone preparation of 6-((1 r,4r)-4-phenylcyclohexyl)-5-(3- (trifluoromethyl)benzyl)pyrimidine-2,4(1 H,3H)-dione (Formula I)

[0091] Example 3. Hydrogen peroxide preparation of 6-((1 r,4r)-4-phenylcyclohexyl)-5-(3- (trifluoromethyl)benzyl)pyrimidine-2,4(1 H,3H)-dione (Formula I) ​ A 2 L vessel was rinsed with NMP prior to use. Formula VIII (39.0 g, 69.9 mmol, 1.0 eq.) and OXONE® (107.4 g, 349.6 mmol, 5.0 eq.) were charged to the vessel and the vessel was purged with a positive pressure of nitrogen for 15 min. NMP (390 mL, 10 vol.) was charged and the vessel jacket was heated to 80 °C. The reaction mixture was aged for 4 h.

[0092] ​Charge H2O (19.5 mL, 0.5 vol.) and allow the reaction mixture to age for 17 h. Charge MeCN (117 mL, 3 vol.). Slowly charge H2O (273 mL, 7.5 vol.) over 0.5 h. Allow the resulting slurry to age for 0.5 h before sampling for liquid concentration by HPLC. Filter the slurry, then wash the filter cake with MeCN (117 mL, 3 vol.), 1 : 1 MeCN / H2O (117 mL, 3 vol.), and H2O (117 mL, 3 vol.) and dry under vacuum for 15 min. Charge the wet filter cake and H2O (390 mL, 10 vol.) into a vessel and allow the contents to age at 80 °C for 1 h. Filter the slurry, wash the filter cake with H2O (3 x 150 mL, 3 x 3 vol.) and dry under vacuum for 15 min. Dry the filter cake under vacuum at 50 °C for 72 h and analyze for Wt%. Obtain 24.0 g of isolated Formula I, corresponding to 80% yield.

[0093] Charge Formula I (23.9 g, 55.8 mmol) into a 500 mL 3 -necked round bottom flask equipped with an overhead stirrer. Charge THF (155 mL, 6.5 vol.) into the vessel and heat the vessel to 60 °C at which point Formula I is in solution. Cool the vessel to RT. At ~40 °C, charge the seed (50 mg). Once the target temperature (20 °C) is reached, charge 1-2 volumes of heptane and allow the mixture to age for 0.5 h, then sample the slurry and filter. Analyze the resulting filtrate by HPLC to determine the product content in the filtrate. Repeat the process until the HPLC analysis of the resulting mother liquor is ~1.33 mg / mL. After a total of 8 volumes of heptane are added, filter the slurry, then wash with 3:4 THF / heptane (72 mL, 3 vol.), heptane (2 x 72 mL, 2 x 3 vol.). Filter the slurry, then wash with 3:4 THF / heptane (72 mL, 3 vol.), heptane (2 x 72 mL, 2 x 3 vol.).

[0094] Dry the filter cake under vacuum at 50 °C for 72 h and analyze for Wt%. Obtain 22.9 g of Formula I as a white crystalline solid, corresponding to a 96% yield of recrystallization (total yield of isolated Formula I is 77%).

[0095] Karl-Fischer titration detected 3.21 ppm of H2O present in Formula I.

[0096] The characterization data for the title product is consistent with the characterization data of Example 6 of U.S. Patent No. 8,685,973 and Example 2 of U.S. Patent No. 11,548,856.

[0097] ​ ​ Dissolve the octyl sulfide intermediate (Formula VIII, 8 g, 14.36 mmol, 1 eq) in NMP (5 vol, 40 mL). Treat the solution with H2SO4 (3 eq, 2.3 ml, 4.2 g, 43.1 mmol). Heat the contents to 80 °C. To the solution, add H2O2 (50% in water, 3 eq, 2.44 ml, 2.93 g, 43.1 mmol) via syringe pump over 3 hours. Age the contents at 80 °C overnight. After aging, cool the contents to 20 °C and assay the stream for measured yield (89% product observed).

[0098] Treat the solution with MeCN (3 vol, 24 ml) then add water (7.5 vol, 60 ml) over 1 hour. Age the subsequent slurry overnight. Isolate the product via filtration and wash with MeCN (3 vol, 24 mL), 1:1 MeCN:water (3 vol, 24L), and water (3 vol, 24 L) sequentially. Re-slurry the crude product in water (10 vol, 80 mL) and warm to 80 °C for 1 hour. Cool the slurry to 20 °C and age for 1 hour. Isolate the product via filtration and wash with water (3 x 3 vol, 24 mL each). Transfer the product to a vacuum oven and dry at 50 °C overnight. Yield = 4.85 g (79%); LCWP = 98.2%.

[0099] The characterization data for the title product is consistent with that of Example 6 of U.S. Patent No. 8,685,973 and Example 2 of U.S. Patent No. 11,548,856.

[0100] While the foregoing application has been described in some detail for the purposes of clarity and understanding, it will be appreciated that certain changes and modifications can be practiced within the scope of the appended claims. In addition, each of the references provided herein are incorporated by reference in their entireties to the same extent as if each reference was individually incorporated by reference. In the event of a conflict between the text of the specification and the attached claims, the attached claims shall control.

Claims

1. A method of preparing a compound of Formula I: （I） the method comprising: (a) forming a first reaction mixture under conditions suitable to prepare said compound of formula I, said first reaction mixture comprising a first solvent, a compound of formula VIII: (VIII), and an oxidizing agent, wherein R is C 1-12 alkyl.

2. The method of claim 1, wherein the first solvent comprises acetone, methyl acetate, ethyl acetate, isopropyl acetate, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethylsulfoxide (DMSO), 2-methyltetrahydrofuran (2-MeTHF), tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), or a combination thereof.

3. The method of claim 1 or 2, wherein the first solvent comprises N-methyl-2- pyrrolidone (NMP).

4. The method of any one of claims 1 to 3, wherein R is C 6-12 alkyl.

5. The method of any one of claims 1 to 4, wherein R is n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl.

6. The method of any one of claims 1 to 5, wherein R is n-octyl.

7. The method of any one of claims 1 to 6, wherein the compound of Formula VIII has the structure: 。 8. The method of any one of claims 1 to 7, wherein the oxidizing agent comprises oxone, hydrogen peroxide, nitric acid, potassium chlorate, sulfuric acid, peroxodisulfuric acid, hypochlorite, potassium permanganate, or a combination thereof.

9. The method of any one of claims 1 to 8, wherein the oxidizing agent comprises oxone.

10. The method of any one of claims 1 to 9, the method comprising: (a) forming the first reaction mixture comprising oxone, N-methyl-2-pyrrolidone, and the compound of Formula VIII under conditions suitable for preparing the compound of Formula I.

11. The method of any one of claims 1 to 8, wherein the oxidizing agent comprises hydrogen peroxide.

12. The method of claim 11, wherein the hydrogen peroxide is present in an amount of 1 to 10 molar equivalents relative to the compound of Formula VIII.

13. The method of claim 11 or 12, wherein the hydrogen peroxide is present in an amount of 3 to 7 molar equivalents relative to the compound of Formula VIII.

14. The method of any one of claims 11 to 13, wherein the first reaction mixture further comprises a strong acid.

15. The method of claim 14, wherein 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.

16. The method of claim 14 or 15, wherein the strong acid comprises sulfuric acid.

17. The method of any one of claims 14 to 16, the method comprising: (a) forming the first reaction mixture comprising hydrogen peroxide, sulfuric acid, N-methyl-2-pyrrolidone, and the compound of Formula VIII in an amount of 3 to 7 molar equivalents relative to the compound of Formula VIII under conditions suitable for preparing the compound of Formula I.

18. A method of making a compound of Formula VIII: (VIII), comprising: (b) forming a second reaction mixture comprising an alkylating agent, a second non-nucleophilic base, a second solvent, and a compound of Formula IX: (IX) wherein R is C 1-12 alkyl; The alkylating agent is C 1-12 alkyl halide or C 1-12 alkyl-OS(O)2R a ; R a is C 1-6 alkyl, C 1-6 haloalkyl and phenyl substituted with 0, 1, 2 or 3 R a1 substituted phenyl; and each R is independently C a1 independently C 1-6 alkyl, halo, or C 1-6 haloalkyl.

19. The method of claim 18, wherein the alkylating agent is C 1-12 alkyl halide.

20. The method of claim 18 or 19, wherein the second reaction mixture comprises C 6-12 alkyl iodide.

21. The method of claim 20, wherein the second reaction mixture comprises n-hexyl iodide, n-heptyl iodide, n-octyl iodide, n-nonyl iodide, or n-decyl iodide.

22. The method of claim 20 or 21, wherein the second reaction mixture comprises n-octyl iodide.

23. The method of any one of claims 20 to 22, wherein the alkyl iodide is present in an amount of 0.9 to 2 molar equivalents relative to the compound of Formula IX.

24. The method of any one of claims 20 to 23, wherein the alkyl iodide is present in an amount of about 1 molar equivalent relative to the compound of Formula IX.

25. The method of any one of claims 18 to 24, wherein the second non-nucleophilic base comprises sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, N,N- diisopropylethylamine (DIPEA), N,N-dimethylisopropylamine (DIMPA), piperidine, 1- ethylpiperidine, N-methylmorpholine, N-methylpyrrolidine, N,N-dimethylamine, piperazine, N-methylpiperazine, pyridine, N,N-dimethylaniline, N,N-diethylaniline, 2,6- dimethylpyridine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine (DMAP), quinuclidine, 4-pyrrolidinopyridine, 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), or a combination thereof.

26. The method of any one of claims 18 to 25, wherein the second non-nucleophilic base comprises potassium carbonate.

27. The method of any one of claims 18 to 26, wherein the second non-nucleophilic base is present in an amount of 0.9 to 2 molar equivalents relative to the compound of Formula IX.

28. The method of any one of claims 18 to 27, wherein the second non-nucleophilic base is present in an amount of about 1 molar equivalent relative to the compound of Formula IX.

29. The method of any one of claims 18 to 28, wherein the second solvent comprises N- methyl-2-pyrrolidinone (NMP).

30. The method of any one of claims 18 to 29, comprising: (b) forming a second reaction mixture comprising n-octyl iodide in an amount of about 1 molar equivalent relative to the compound of Formula IX, potassium carbonate in an amount of about 1 molar equivalent relative to the compound of Formula IX, N-methyl-2- pyrrolidinone, and the compound of Formula IX, under conditions suitable for forming the compound of Formula VIII.

31. The method of any one of claims 1 to 17, wherein the compound of Formula VIII is made by the method of any one of claims 18 to 30.

32. The method of any one of claims 1 to 31, comprising (b) forming a second reaction mixture comprising about 1 molar equivalent amount of n-octyl iodide relative to the compound of Formula IX, about 1 molar equivalent amount of potassium carbonate relative to the compound of Formula IX, N-methyl-2-pyrrolidone, and the compound of Formula IX, under conditions suitable to form the compound of Formula VIII; and (a) forming a first reaction mixture comprising 3 to 7 molar equivalents of hydrogen peroxide relative to the compound of Formula VIII, sulfuric acid, N-methyl-2-pyrrolidone, and the compound of Formula VIII, under conditions suitable to make the compound of Formula I.

33. A method of making a compound of Formula IX: (XI) the method comprising: (c) forming a third reaction mixture comprising thiourea, a third non-nucleophilic base, a third solvent, and a compound of Formula III: (III) wherein R 1 is C 1-6 alkyl.

34. The method of claim 33, wherein R 1 is methyl, ethyl or n-propyl.

35. The method of claim 33 or 34, wherein the compound of Formula III has the structure: 。 36. The method of any one of claims 33 to 35, wherein the third solvent comprises acetone, methyl acetate, ethyl acetate, isopropyl acetate, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethylsulfoxide (DMSO), 2-methyltetrahydrofuran (2-MeTHF), tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), or a combination thereof.

37. The method of any one of claims 33 to 36, wherein the third solvent comprises N,N-dimethylformamide (DMF).

38. The method of any one of claims 33 to 37, wherein the third non-nucleophilic base comprises triethylamine, N,N-diisopropylethylamine (DIPEA), N,N-dimethylisopropylamine (DIMPA), piperidine, 1-ethylpiperidine, N-methylmorpholine, N-methylpyrrolidine, N,N-dimethylamine, piperazine, N-methylpiperazine, pyridine, N,N-dimethylaniline, N,N-diethylaniline, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine (DMAP), quinuclidine, 4-pyrrolidinopyridine, 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), or a combination thereof.

39. The method of any one of claims 33 to 38, wherein the third non-nucleophilic base comprises 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

40. The method of any one of claims 33 to 39, wherein the third non-nucleophilic base is present in an amount of 1 to 5 molar equivalents relative to the compound of Formula III.

41. The method of any one of claims 33 to 40, wherein the third non-nucleophilic base is present in an amount of about 2.5 molar equivalents relative to the compound of Formula III.

42. The method of any one of claims 33 to 41, comprising (c) forming the third reaction mixture comprising thiourea, DBU in an amount of about 2.5 molar equivalents relative to the compound of Formula III, N,N- dimethylformamide, and the compound of Formula III, under conditions suitable for preparing the compound of Formula IX.

43. The method of any one of claims 18 to 32, wherein the compound of Formula IX is prepared by the method of any one of claims 33 to 42.

44. The method of any one of claims 1 to 43, comprising (c) forming the third reaction mixture comprising thiourea, DBU in an amount of about 2.5 molar equivalents relative to the compound of Formula III, N,N- dimethylformamide, and the compound of Formula III, under conditions suitable for preparing the compound of Formula IX; (b) forming the second reaction mixture comprising n-octyl iodide in an amount of about 1 molar equivalent relative to the compound of Formula IX, potassium carbonate in an amount of about 1 molar equivalent relative to the compound of Formula IX, N- methyl-2-pyrrolidone, and the compound of Formula IX, under conditions suitable for forming the compound of Formula VIII; and (a) forming the first reaction mixture comprising oxone, N-methyl-2- pyrrolidone, and the compound of Formula VIII, under conditions suitable for preparing the compound of Formula I.

45. The method of any one of claims 1 to 43, comprising (c) forming the third reaction mixture comprising thiourea, DBU in an amount of about 2.5 molar equivalents relative to the compound of Formula III, N,N- dimethylformamide, and the compound of Formula III, under conditions suitable for preparing the compound of Formula IX; (b) forming the second reaction mixture comprising n-octyl iodide in an amount of about 1 molar equivalent relative to the compound of Formula IX, potassium carbonate in an amount of about 1 molar equivalent relative to the compound of Formula IX, N- methyl-2-pyrrolidone, and the compound of Formula IX, under conditions suitable for forming the compound of Formula VIII; and (a) forming the first reaction mixture comprising hydrogen peroxide in an amount of 3 to 7 molar equivalents relative to the compound of Formula VIII, sulfuric acid, N- methyl-2-pyrrolidone, and the compound of Formula VIII, under conditions suitable for preparing the compound of Formula I.

46. A compound of Formula VIII: (VIII) wherein R is C 1-12 alkyl.

47. The compound of claim 46, wherein R is C 6-12 alkyl.

48. The compound of claim 46 or 47, wherein R is n-hexyl, n-heptyl, n-octyl, n- nonyl, or n-decyl.

49. The compound of any one of claims 46 to 48, wherein R is n-octyl.

50. The compound of any one of claims 46 to 49, wherein the compound of Formula VIII has the structure: 。

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