Method for preparing pyrimidine cyclohexylglucocorticoid receptor modulators

Abstract

The present invention provides a method for preparing pyrimidine cyclohexylglucocorticoid receptor modulators, a method for preparing intermediates of pyrimidine cyclohexylglucocorticoid receptor modulators, and thioether compounds.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 504,824, 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 hypercortisolism, can be regulated at the GR level using receptor modulators such as agonists, partial agonists, and antagonists. Several different classes of agents can inhibit the physiological effects of GR-agonist binding. These antagonists include compositions that, by binding to the GR, inhibit the ability of agonists to bind effectively to and / or activate the GR. Mifepristone, one such known GR antagonist, 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, and the dissociation constant (Kd) is 10~9M (Cadepond (1997) Annu. Rev. Med. 48:129).

[0004] In addition to cortisol, the biological effects of other steroids can be regulated at the GR level using receptor modulators such as agonists, partial agonists, and antagonists. When administered to a subject that requires it, steroids can produce both the intended therapeutic effect, for example, by stimulating transcriptional repression of the glucocorticoid receptor, and negative side effects, for example, by chronic transcriptional activation of the glucocorticoid receptor. Millicorilant (CORT118335) is such another glucocorticoid receptor modulator compound and has been described previously in International Publication No. WO 2012 / 129074, which is a PCT published application, and U.S. Patent No. 8,685,973. What is needed in the art is a novel method for preparing millicorilant with a lower impurity content. Surprisingly, the present invention meets these and other needs. SUMMARY OF THE INVENTION

[0005] In one embodiment, the present invention is a method for preparing a compound of formula I:

[0006]

Chemical formula

[0007] The method is, (a) The first solvent and the compound of formula VIII:

[0008] [ka]

[0009] A first reaction mixture, comprising an oxidizing agent and a compound of formula I, is formed under conditions suitable for preparing the compound of formula I. In the formula, R is C 1~12 This provides a method for alkylating.

[0010] In another embodiment, the present invention relates to a method for preparing a compound of formula VIII:

[0011] [ka]

[0012] The method is, (b) an alkylating agent, a second non-nucleophile, a second solvent, and the compound of formula IX:

[0013] [ka]

[0014] A second reaction mixture, comprising the following, is formed under conditions suitable for preparing the compound of formula VIII: In the formula, R is C 1~12 It is alkyl, Alkylating agents are C 1~12 Alkyl halides, or C 1~12 Alkyl-OS(O)2R a And, R a This is 0, 1, 2, or 3 R a1 Replaced with, C 1~6Alkyl, C 1~6 haloalkyl, and phenyl, and each R a1 is, independently, C 1~6 alkyl, halogen, or C 1~6 haloalkyl, a method is provided.

[0015] In another embodiment, the present invention is a method for preparing a compound of formula IX, comprising:

[0016]

Chemical formula

[0017] The method comprises (c) thiourea, a third non-nucleophilic base, a third solvent, and a compound of formula III:

[0018]

Chemical formula

[0019] forming a third reaction mixture comprising the same under conditions suitable for preparing a compound of formula IX, wherein R 1 is C 1~6 alkyl, a method is provided.

[0020] In another embodiment, the present invention provides a compound of formula VIII, comprising:

[0021]

Chemical formula

[0022] wherein R is C 1~12 alkyl, a compound is provided.

Brief Description of the Drawings

[0023] [Figure 1] Figure 1 shows the proton NMR of the compound of formula VIII. [Figure 2] Figure 2 shows the XRPD of the compound of formula VIII. [Modes for carrying out the invention]

[0024] 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), as Example 6 of U.S. Patent No. 8,685,973, via the formation of a thioether intermediate prepared from a compound of formula IX. This disclosure also describes a novel intermediate.

[0025] II. Definition When referring to a value, "about" includes the stated value ± 10% of the stated value. For example, about 50% includes the range of 45% to 55%, while about 10 equivalents includes the range of 9 to 11 equivalents. Therefore, when referring to a range, "about" refers to the stated value at each endpoint of that range, each ± ​​10% of the aforementioned stated value. For example, the ratio about 1 to about 10 (w / w) includes the range of 0.9 to 11.

[0026] "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 formed from one or more of the added reagents in the reaction mixture.

[0027] 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 having a hydroxyl group or a carboxyl group. 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.

[0028] 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).

[0029] 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.

[0030] 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.

[0031] An "oxidizing agent," or "oxidizing substance," refers to a reagent that can accept an electron pair from another compound and thus oxidize that compound. Typical oxidizing agents include, but are not limited to, oxygen, hydrogen peroxide, nitrites, nitric acid, and sulfuric acid.

[0032] "Alkyl" refers to a linear or branched acyclic hydrocarbon containing normal, secondary, or tertiary carbon atoms. For example, alkyl groups contain 1 to 20 carbon atoms (i.e., C1 to C20). 20 Alkyl), 1 to 12 carbon atoms (i.e., C1 to C 12 It may have an alkyl group, or 1 to 6 carbon atoms (i.e., C1 to C6 alkyl). The alkyl group is, for example, 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 5~6These can contain any number of carbon atoms. Suitable alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-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-pentyl, -C(CH3)2CH2CH3), 3-methyl-2-butyl(neo-Pn, neopentyl, -CH(CH3)CH(CH3)2) , 3-methyl-1-butyl(-CH2CH2CH(CH3)2), 2-methyl-1-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 Examples include, but are not limited to, octyl(-(CH2)7CH3), 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).

[0033] "Halogens" refer to fluorine, chlorine, bromine, and iodine.

[0034] An "alkylating agent" refers to a reagent that has both an alkyl group and a leaving group, and can react with a second reagent to introduce the alkyl group into the second reagent. Typical alkylating agents include, but are not limited to, alkyl halides and alkyl sulfonates.

[0035] "Alkyl halides" refer to alkyl groups linked to a single halogen. Typical alkyl halides include n-octyl iodides, but are not limited to these.

[0036] "Alkylation additives" refer to additives that convert alkyl chlorides or alkyl bromides into alkyl iodides. Typical 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.

[0037] "Non-nucleophilic bases" are defined by the Brønsted-Lowry formula as protons (H + This refers to a compound that can donate an electron pair, or a compound that is an electron pair acceptor in Lewis's definition. Examples of non-nucleophilic bases useful in the present invention include amines such as trimethylamine, triethylamine, N,N-diisopropylethylamine (DIPEA, or Huenig base), 1,8-diazabicycloundeca-7-ene (DBU), 2,6-di-tert-butylpyridine, quinuclidine, and lithium diisopropylamine (LDA). Other bases are known to those skilled in the art.

[0038] "Thiourea" refers to H2NC(=S)NH2.

[0039] "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.

[0040] "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.

[0041] "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).

[0042] A "crystal species" refers to a seed crystal of the target crystal form that you intend to prepare.

[0043] III. Preparation method for Equation I 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:

[0044] [ka]

[0045] The compound of formula I was originally disclosed as Example 6 in U.S. Patent No. 8,685,973.

[0046] A. Preparation of Equation I from Equation VIII In some embodiments, the present invention relates to a method for preparing a compound of formula I:

[0047] [ka]

[0048] The method involves a first solvent and a compound of formula VIII.

[0049] [ka]

[0050] A first reaction mixture comprising a compound of formula I and an oxidizing agent is formed under conditions suitable for preparing a compound of formula I, where R is C 1-12 This provides a method for alkylating.

[0051] Any suitable solvent may be used as the first solvent in the first 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 I includes a method in which the first 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, a method for preparing the compound of formula I includes a method in which the first solvent comprises N-methyl-2-pyrrolidone (NMP).

[0052] In some embodiments, a method for preparing a compound of formula I is such that R is C 6~12 This includes methods in which R is alkyl. In some embodiments, the method for preparing the compound of formula I includes methods in which R is n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl. In some embodiments, the method for preparing the compound of formula I includes methods in which R is n-octyl.

[0053] In some embodiments, a method for preparing the compound of formula I includes a method in which the compound of formula VIII has the following structure:

[0054] [ka]

[0055] Any suitable oxidizing agent may be used as the first oxidizing agent in the first reaction mixture of the present invention. Typical oxidizing agents include, but are not limited to, potassium peroxymonosulfate (OXONE®), hydrogen peroxide, nitric acid, potassium chloride, sulfuric acid, peroxydisulfuric acid, hypochlorous acid, and potassium permanganate. In some embodiments, the method for preparing the compound of formula I includes a method in which the oxidizing agent comprises potassium peroxymonosulfate (OXONE), hydrogen peroxide, nitric acid, potassium chloride, sulfuric acid, peroxydisulfuric acid, potassium hypochlorite, potassium permanganate, or a combination thereof.

[0056] In some embodiments, the method for preparing the compound of formula I includes a method in which the oxidizing agent is potassium peroxymonosulfate (OXONE®). In some embodiments, the method for preparing the compound of formula I includes a method in which a first reaction mixture comprising (a) potassium peroxymonosulfate (OXONE®), N-methyl-2-pyrrolidone, and the compound of formula VIII is formed under conditions suitable for preparing the compound of formula I.

[0057] In some embodiments, the method for preparing the compound of formula I includes a method in which the oxidizing agent comprises hydrogen peroxide. In some embodiments, the method for preparing the compound of formula I includes a method in which a first reaction mixture comprising (a) hydrogen peroxide, N-methyl-2-pyrrolidone, and the compound of formula VIII is formed under conditions suitable for preparing the compound of formula I.

[0058] The oxidizing agent may be present in any preferred ratio relative to the compound of formula VIII. For example, the oxidizing agent may be present in amounts of 0.1 to 10 molar equivalents, or 1 to 10 molar equivalents, or 1 to 5 molar equivalents, or 1 to 7 molar equivalents, 4 to 6 molar equivalents, or 4.5 to 5.5 molar equivalents relative to the compound of formula VIII. Typical amounts of the oxidizing agent include, but are not limited to, about 1.0 molar equivalent, 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.

[0059] In some embodiments, the method for preparing the compound of formula I includes a method in which OXONE is present in an amount of 3 to 7 molar equivalents relative to the compound of formula VIII. In some embodiments, the method for preparing the compound of formula I includes a method in which OXONE is present in an amount of about 5 molar equivalents relative to the compound of formula VIII.

[0060] In some embodiments, the method for preparing the compound of formula I includes a method in which 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 for preparing the compound of formula I includes a method in which hydrogen peroxide is present in an amount of 3 to 7 molar equivalents relative to the compound of formula VIII.

[0061] In some embodiments, a method for preparing a compound of formula I includes a method in which 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 invention. Typical strong acids include, but are not limited to, organic acids and inorganic acids. In some embodiments, a method for preparing a 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, a method for preparing a compound of formula I includes a method in which the strong acid comprises sulfuric acid.

[0062] A strong acid may be present in any suitable amount relative to the compound of formula VIII. For example, a strong acid may be present in amounts of 0.1 to 10 molar equivalents, or 1 to 10 molar equivalents, 1 to 5 molar equivalents, 2 to 4 molar equivalents, or 2.5 to 3.5 molar equivalents relative to the compound of formula VIII. Typical amounts of a 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 VII.

[0063] In some embodiments, the method for preparing the compound of formula I includes a method in which 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 for preparing the compound of formula I includes a method in which sulfuric acid is present in an amount of about 3 molar equivalents relative to the compound of formula VIII.

[0064] In some embodiments, a method for preparing the compound of formula I includes a method comprising (b) forming a first reaction mixture containing about 5 molar equivalents of oxone, N-methyl-2-pyrrolidone, and the compound of formula VIII, under conditions suitable for preparing the compound of formula I.

[0065] In some embodiments, a method for preparing the compound of formula I includes a method in which a first reaction mixture comprising (a) 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 is formed under conditions suitable for preparing the compound of formula I.

[0066] B. Preparation of Equation VIII from Equation IX In some embodiments, the present invention is a method for preparing a compound of formula VIII:

[0067] [ka]

[0068] The method involves (b) an alkylating agent, a second non-nucleophilic base, a second solvent, and a compound of formula IX:

[0069] [ka]

[0070] A second reaction mixture comprising and formed under conditions suitable for forming a compound of formula VIII, wherein R is C 1~12 It is alkyl, and the alkylating agent is C 1~12 Alkyl halides, or C1~12 Alkyl-OS(O)2R a And R a C 1~6 Alkyl, C 1~6 Haloalkyl and 0, 1, 2, or 3 R a1 Phenyl substituted with each R a1 Independently, C 1~6 Alkyl, halogen, or C 1~6 This provides a method for using haloalkyl.

[0071] Any suitable alkylating agent can be used in the method for preparing formula VIII. For example, the alkylating agent may be an alkyl halide, an alkyl sulfonate, or another group. In some embodiments, the alkylating agent is C 1~12 It is an alkyl-halide. In some embodiments, the alkylating agent is C 1~12 Alkyl-OS(O)2R a In some embodiments, the alkylating agent is C 6~12 Alkyl-OS(O)2R a And in the formula, R a is methyl, trifluoromethyl, or 4-methylphenyl. In some embodiments, the alkylating agent is C 1~12 Alkyl mesylate, C 1~12 Alkyl triflate, or C 1~12 It is an alkyl tosylate.

[0072] Any suitable alkyl halide is added to the second reaction mixture, C 1~12 It can be used as an alkyl halide. Typical C 1~12 Examples of alkyl halides include, but are not limited to, alkyl iodides, alkyl bromides, and alkyl chlorides. In some embodiments, a method for preparing the compound of formula VIII is to use a second reaction mixture, C 6~12The method includes a method comprising alkyl-iodide. In some embodiments, the method for preparing the compound of formula VIII includes a method in which 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 method for preparing the compound of formula VIII includes a method in which the second reaction mixture comprises n-octyl-iodide.

[0073] Alkylating agent, or C 1~12 Alkyl halides may be present in any suitable amount relative to the compound of formula IX. For example, alkylating agents, or C 1~12 Alkyl halides may be present in amounts of 0.1 to 10 molar equivalents relative to the compound of formula IX, or in amounts of 0.2 to 5 molar equivalents, or 0.5 to 3 molar equivalents, 0.8 to 3 molar equivalents, 0.9 to 1.5 molar equivalents, or 0.9 to 1.1 molar equivalents relative to the compound of formula XI. Alkylating agent, or C 1~12 Typical amounts of alkylhalides 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 about 10 molar equivalents relative to the compound of formula IX. In some embodiments, the method for preparing the compound of formula VIII includes a method in which 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 for preparing the compound of formula VIII includes a method in which the alkyl-iodide is present in an amount of about 1 molar equivalent relative to the compound of formula IX.

[0074] Alkyl iodide alkylating agents can also be prepared in situ from alkyl chlorides or alkyl bromides using additives such as sodium bromide, sodium iodide, potassium bromide, potassium iodide, or tetraalkylammonium bromide, iodide salts 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 so that the alkyl iodide is formed in situ. In some embodiments, the alkylating additive may be sodium bromide, sodium iodide, potassium bromide, potassium iodide, or tetraalkylammonium bromide, iodide salts, or combinations thereof.

[0075] In some embodiments, a method for preparing the compound of formula VIII includes a method comprising forming a second reaction mixture containing (b) 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.

[0076] The alkylating additive may be present in the second reaction mixture in any suitable amount relative to the compound of formula IX. For example, the alkylating additive may be present in a catalytic amount of 0.01 to 10 molar equivalents, or 0.05 to 5 molar equivalents, or 0.1 to 1 molar equivalent relative to the compound of formula IX.

[0077] Any non-nucleophilic base can be used as the second non-nucleophilic base in the second reaction mixture of the present invention. Typical second non-nucleophilic bases include potassium carbonate, sodium carbonate, alkoxides such as potassium tert-butoxide and sodium tert-butoxide, hexamethylsilazane (HMDS), lithium hexamethyldisilazane, sodium hexamethyldisilazane, potassium hexamethyldisilazane, lithium diisopropylamine (LDA), lithium hydride, sodium hydride, potassium hydride, n-butyllithium, and amine bases such as tri Examples of non-nucleophilic bases include, but are not limited to, ethylamine (Et3N), N,N-diisopropylethylamine (iPr2NEt, DIPEA), 1,8-diazabicycloundeca-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-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, and quinuclidines. Examples of non-nucleophilic bases include non-nucleophilic amine bases.

[0078] In some embodiments, the method for preparing the compound of formula VIII is such that the second nonnucleophilic base is 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, The method includes methods comprising N-dimethylaniline, N,N-diethylaniline, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine (DMAP), quinuclidine, 4-pyrrolidinopyridine, 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), or combinations thereof. In some embodiments, the method for preparing the compound of formula VIII includes a method in which the second non-nucleophile is sodium carbonate, potassium carbonate, or cesium carbonate. In some embodiments, the method for preparing the compound of formula VIII includes a method in which the second non-nucleophile is potassium carbonate.

[0079] The second nonnucleophile can be present in any suitable amount relative to the compound of formula IX. For example, the second nonnucleophile can 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, 0.8 to 2 molar equivalents, 0.9 to 1.5 molar equivalents, or 0.9 to 1.1 molar equivalents relative to the compound of formula IX. Typical amounts of the second nonnucleophile 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 IX. In some embodiments, the method for preparing the compound of formula VIII includes a method in which the second non-nucleophile is present in an amount of 0.9 to 2 molar equivalents relative to the compound of formula IX. In some embodiments, the method for preparing the compound of formula VIII includes a method in which the second non-nucleophile is present in an amount of about 1 molar equivalent relative to the compound of formula IX.

[0080] Any suitable solvent may 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 VIII includes a method in which the second 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 for preparing the compound of formula VII includes a method in which the second solvent comprises N-methyl-2-pyrrolidone (NMP).

[0081] In some embodiments, a method for preparing the compound of formula VIII includes (b) a second reaction mixture comprising about 1 molar equivalent of n-octyl iodide relative to the compound of formula IX, about 1 molar equivalent of potassium carbonate relative to the compound of formula IX, N-methyl-2-pyrrolidone, and the compound of formula IX, which is formed under conditions suitable for forming the compound of formula VIII.

[0082] In some embodiments, a method for preparing a compound of formula VIII includes a method by which a compound of formula VIII is prepared by the method of the present invention.

[0083] In some embodiments, a method for preparing the compound of formula VIII includes: (b) forming a second reaction mixture containing about 1 molar equivalent of n-octyl iodide relative to the compound of formula IX, about 1 molar equivalent of potassium carbonate 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 a first reaction mixture containing 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 for preparing the compound of formula I.

[0084] C. Preparation of Equation IX from Equation III In one embodiment, the present invention is a method for preparing a compound of formula IX,

[0085] [ka]

[0086] The method is, (c) Thiourea, a third non-nucleophilic base, a third solvent, and the compound of formula III:

[0087] [ka]

[0088] A third reaction mixture, comprising the following, is formed under conditions suitable for preparing the compound of formula IX: In the formula, R 1 C 1~6 This provides a method for alkylating.

[0089] In some embodiments, the method for preparing the compound of formula IX is R 1 The method involves methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl, or hexyl. In some embodiments, the method for preparing the compound of formula IX is R 1 The method involves methyl, ethyl, or n-propyl. In some embodiments, the method for preparing the compound of formula IX is R 1 However, this is the method using ethyl.

[0090] In some embodiments, a method for preparing the compound of formula IX is a method in which the compound of formula III has the following structure:

[0091] [ka]

[0092] Any suitable solvent may be used as the third solvent in the third reaction mixture of the present invention. Typical third 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 IX is a method in which 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, a method for preparing the compound of formula IX is a method in which the third solvent comprises N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP), or a combination thereof. In some embodiments, a method for preparing the compound of formula IX is a method in which the third solvent comprises n-butanol.

[0093] In the third reaction mixture of the present invention, any non-nucleophilic base can be used as the third non-nucleophilic base. Typical third non-nucleophilic bases include potassium carbonate, sodium carbonate, alkoxides, such as potassium tert-butoxide and sodium tert-butoxide, hexamethylsilazane (HMDS), lithium hexamethyldisilazane, sodium hexamethyldisilazane, potassium hexamethyldisilazane, lithium diisopropylamine (LDA), lithium hydride, sodium hydride, potassium hydride, n-butyllithium, and amine bases, such as tri Examples of non-nucleophilic bases include, but are not limited to, ethylamine (Et3N), N,N-diisopropylethylamine (iPr2NEt, DIPEA), 1,8-diazabicycloundeca-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-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, and quinuclidines. Examples of non-nucleophilic bases include non-nucleophilic amine bases.

[0094] In some embodiments, a method for preparing the compound of formula IX is a method in which the third nonnucleophilic 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-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine (DMAP), quinuclidine, 4-pyrrolidinopyridine, 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]unde-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), or a combination thereof. In some embodiments, the method for preparing the compound of formula IX is a method in which the third nonnucleophilic base is 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU).

[0095] The third nonnucleophile can be present in any suitable amount relative to the compound of formula III. For example, the third nonnucleophile can be present in amounts of 1 to 10 molar equivalents relative to the compound of formula III, or in amounts of 1 to 8 molar equivalents, 1.5 to 7 molar equivalents, 2 to 6 molar equivalents, 2 to 3 molar equivalents, 2.1 to 2.9 molar equivalents, 2.2 to 2.8 molar equivalents, 2.3 to 2.7 molar equivalents, or 2.4 to 2.6 molar equivalents relative to the compound of formula III. Typical amounts of the third nonnucleophile 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 equivalents relative to the compound of formula III. In some embodiments, the method for preparing the compound of formula IX is such that the third nonnucleophile is present in an amount of 1 to 5 molar equivalents relative to the compound of formula III. In some embodiments, the method for preparing the compound of formula IX is such that the third nonnucleophile is present in an amount of about 2.5 molar equivalents relative to the compound of formula III.

[0096] Thiourea may be present in any suitable amount relative to the compound of formula III. For example, thiourea may be present in amounts of 1 to 10 molar equivalents relative to the compound of formula III, or in amounts of 1 to 8 molar equivalents, 2 to 7 molar equivalents, 5 to 7 molar equivalents, 5 to 6.5 molar equivalents, 5.6 to 6.4 molar equivalents, 5.7 to 6.3 molar equivalents, 5.8 to 6.2 molar equivalents, or 5.9 to 6.1 molar equivalents relative to the compound of formula III. Typical amounts of thiourea include, but are not limited to, approximately 1.0 molar equivalent, or approximately 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 approximately 10 molar equivalents relative to the compound of formula III.

[0097] In some embodiments, the method for preparing the compound of formula IX is such that thiourea is present in an amount of 5 to 7 molar equivalents relative to the compound of formula III. In some embodiments, the method for preparing the compound of formula IX is such that thiourea is present in an amount of about 6 molar equivalents relative to the compound of formula III.

[0098] In some embodiments, a method for preparing the compound of formula IX is a method in which a third reaction mixture comprising (c) thiourea, about 2.5 molar equivalents of DBU relative to the compound of formula III, N,N-dimethylformamide, and the compound of formula III is formed under conditions suitable for preparing the compound of formula IX.

[0099] In some embodiments, a method for preparing the compound of formula VX is a method in which a third reaction mixture comprising (c) about 6 molar equivalents of thiourea relative to the compound of formula III, about 2.5 molar equivalents of DBU relative to the compound of formula III, N,N-dimethylformamide, and the compound of formula III is formed under conditions suitable for preparing the compound of formula IX.

[0100] In some embodiments, a method for preparing the compound of formula VIII is a method by which the compound of formula IX is prepared by the method of the present invention. In some embodiments, a method for preparing the compound of formula I is a method by which the compound of formula IX is prepared by the method of the present invention.

[0101] In some embodiments, a method for preparing a compound of formula VIII or a compound of formula I comprises: (c) a third reaction mixture comprising thiourea, about 2.5 molar equivalents of DBU relative to the compound of formula III, N,N-dimethylformamide, and the compound of formula III, forming conditions suitable for preparing a compound of formula IX; (b) a second reaction mixture comprising about 1 molar equivalent of n-octyl iodide relative to the compound of formula IX, about 1 molar equivalent of potassium carbonate relative to the compound of formula IX, N-methyl-2-pyrrolidone, and the compound of formula IX, forming conditions suitable for forming a compound of formula VIII; and (a) a first reaction mixture comprising potassium peroxomonosulfate (OXONE), N-methyl-2-pyrrolidone, and the compound of formula VIII, forming conditions suitable for preparing a compound of formula I.

[0102] In some embodiments, a method for preparing a compound of formula VIII or a compound of formula I comprises: (c) a third reaction mixture comprising thiourea, about 2.5 molar equivalents of DBU relative to the compound of formula III, N,N-dimethylformamide, and the compound of formula III, forming conditions suitable for preparing a compound of formula IX; (b) a second reaction mixture comprising about 1 molar equivalent of n-octyl iodide relative to the compound of formula IX, about 1 molar equivalent of potassium carbonate relative to the compound of formula IX, N-methyl-2-pyrrolidone, and the compound of formula IX, forming conditions suitable for forming a compound of formula VIII; and (a) 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, forming conditions suitable for preparing a compound of formula I.

[0103] D. Sulfone intermediate compounds The present invention provides compounds of formula VIII. In some embodiments, the present invention provides compounds of formula VIII,

[0104] [ka]

[0105] In the formula, R is C 1~12 We provide a compound that is alkyl.

[0106] In some embodiments, the compound of formula VIII is such that R is C 6~12 It is an alkyl compound. In some embodiments, the compound of formula VIII is a compound in which R is n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl. In some embodiments, the compound of formula VIII is a compound in which R is n-octyl.

[0107] In some embodiments, the compound of formula VIII has the following structure:

[0108] [ka]

[0109] The compound of formula VIII is named 2-(octylthio)-6-((1r,4r)-4-phenylcyclohexyl)-5-(3-(trifluoromethyl)benzyl)pyrimidine-4(3H)-one using IUPAC nomenclature.

[0110] IV. Examples The following acronyms and abbreviations are used in the following methods.

[0111] [Table 1-1] [Table 1-2]

[0112] Powder X-ray diffraction (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; samples were centrifuged at 60 rpm during data acquisition). XRPD patterns were sorted and manipulated using HighScore Plus 2.2c software.

[0113] Differential scanning calorimetry (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 at a rate of 5°C / min under nitrogen to a maximum of 200 or 300°C.

[0114] Thermogravimetric Differential Thermal Analysis (TG-DTA) Thermogravimetric (TG) analysis is carried out by 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 1 minute at a rate of 10°C / min, and then heated to 300°C.

[0115] Proton nuclear magnetic resonance spectroscopy ( 1 Proton NMR (H-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. The sample solution was then analyzed using a 5mm unused NMR tube.

[0116] 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.

[0117] The reaction process of the present invention can be carried out for any preferred reaction time. For example, the reaction time can be any number of minutes, any number of hours, or any number of days. In some embodiments, the reaction time can be several hours, such as at least 8 hours. In some embodiments, the reaction time can be several hours, such as at least overnight. In some embodiments, the reaction time can be several days. In some embodiments, the reaction time can be at least 2 hours. In some embodiments, the reaction time can be at least 8 hours. In some embodiments, the reaction time can be at least several days. In some embodiments, the reaction time can 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 can 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.

[0118] 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 may 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. [Examples]

[0119] Example 1: Preparation of 2-(octylthio)-6-((1r,4r)-4-phenylcyclohexyl)-5-(3-(trifluoromethyl)benzyl)pyrimidine-4(3H)-one (formula VIII) Preparation of 6-((1r,4r)-4-phenylcyclohexyl)-2-thioxo-5-(3-(trifluoromethyl)benzyl)pyrimidine-2,3-dihydropyrimidine-4(1H)-one (formula IX)

[0120] [ka]

[0121] Formula III was prepared according to the method described in International Publication No. 2022 / 140293.

[0122] Formula III (58.0 g, 134.1 mmol, 1 equivalent) and thiourea (61.2 g, 804.7 mmol, 6 equivalents) were slurryed in DMF (5 vols, 290 ml). The contents were stirred under N2 until a solution was formed. DBU (51.0 g, 50.1 ml, 335.3 mmol, 2.5 equivalents) was added, and the contents were heated to 80°C. The flow was aged overnight at 80°C, and then the consumption of Formula III (<2 LCAP Formula III residue) was analyzed by HPLC. MeCN (3 vols, 174 ml) was added (to solubilize the solid and avoid gumming after acid addition), and then 1 M HCl (3.5 vols, 203 ml) was added over 1 hour to generate a fine slurry in the initial stage, which was gradually converted into a thicker, mobile white slurry. The slurry loss was determined to be 0.5 mg / ml by HPLC, and the product was isolated by filtration. The wet cake was sequentially washed with MeCN (3 vol, 174 ml), 1:1 MeCN:water (3 vol, 174 ml), and water (3 vol, 174 ml). The product was dried overnight under vacuum at 50°C. Thiouracil formula IX (42.5 g) was isolated as a white crystalline solid.

[0123] The characteristic evaluation data for the product in the title was consistent with that described above.

[0124] Preparation of 2-(octylthio)-6-((1r,4r)-4-phenylcyclohexyl)-5-(3-(trifluoromethyl)benzyl)pyrimidine-4(3H)-one (formula VIII)

[0125] [ka]

[0126] Thiouracil formula IX (41 g, 92.2 mmol, 1 equivalent) and K2CO3 (12.7 g, 92.2 mmol, 1 equivalent) were slurryed in NMP (410 ml, 10 vols) under N2. After aging for 30 minutes, 1-iodooctane (22.1 g, 16.6 ml, 92.2 mmol, 1 equivalent) was added dropwise over approximately 15 minutes. This mixture was aged at 25°C for 4 hours. HPLC showed complete consumption of thiouracil formula IX. The mixture was treated with MeCN (3 vols, 123 ml) and water (13 vols, 533 ml), added over approximately 1 hour to produce a mobile white slurry. The liquid loss of the slurry was determined by HPLC as 0.98 mg / ml, and the product was isolated by filtration. The product was sequentially washed with MeCN (3 vol, 123 ml), 1:1 MeCN:water (3 vol, 123 ml), and water (3 vol, 123 ml). After drying under vacuum for 1 hour, the wet cake was re-slurried 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 overnight at 50°C under vacuum. Sulfide 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 1. XRPD is provided in Figure 2.

[0127] Example 2 Preparation of 6-((1r,4r)-4-phenylcyclohexyl)-5-(3-(trifluoromethyl)benzyl)pyrimidine-2,4(1H,3H)-dione (Formula I)

[0128] [ka]

[0129] Before use, the 2L container was rinsed with NMP. Formula VIII (39.0g, 69.9mmol, 1.0 equivalent) and OXONE® (107.4g, 349.6mmol, 5.0 equivalents) were filled into the container, and the container was purged with positive nitrogen pressure for 15 minutes. NMP (390mL, 10 volumes) was added, and the container jacket was heated to 80°C. The reaction mixture was aged for 4 hours.

[0130] The reaction mixture was packed with H2O (19.5 mL, 0.5 vol) and aged for 17 hours. MeCN (117 mL, 3 vol) was then packed in. H2O (273 mL, 7.5 vol) was slowly packed in over 0.5 hours. The resulting slurry was aged for 0.5 hours, after which a sample was taken and the liquid concentration was measured by HPLC. The slurry was filtered, and the filtered cake was washed with MeCN (117 mL, 3 vol), 1:1 MeCN / H2O (117 mL, 3 vol), and H2O (117 mL, 3 vol), and dried under vacuum for 15 minutes. The wet cake and H2O (390 mL, 10 vol) were packed into a container, and the contents were aged at 80°C for 1 hour. The slurry was filtered, and the cake was washed with H2O (3 × 150 mL, 3 × 3 vol) and dried under vacuum for 15 minutes. The cake was dried at 50°C under vacuum for 72 hours and analyzed for weight (Wt%). The resulting isolated 24.0 g of Formula I corresponds to an 80% yield.

[0131] Formula I (23.9 g, 55.8 mmol) was packed into a 500 mL three-necked round-bottom flask equipped with overhead stirring. THF (155 mL, 6.5 vol) was packed into the container, and the container was heated to 60°C, at which point Formula I was in solution. The container was cooled to room temperature. Seed (50 mg) was packed in at approximately 40°C. Once the target temperature (20°C) was reached, 1-2 vol of heptane was packed in, and the mixture was allowed to mature for 0.5 hours. Then the slurry was sampled and filtered. The resulting filtrate was analyzed by HPLC to determine the product content in the filtrate. This process was repeated until the HPLC analysis of the resulting mother liquor yielded approximately 1.33 mg / mL. After adding a total of 8 volumes of heptane, the slurry was filtered and then washed with 3:4 THF / heptane (72 mL, 3 volumes) and heptane (2 × 72 mL, 2 × 3 volumes). The slurry was filtered and then washed with 3:4 THF / heptane (72 mL, 3 volumes) and heptane (2 × 72 mL, 2 × 3 volumes).

[0132] The cake was dried at 50°C under vacuum for 72 hours and analyzed for Wt%. 22.9 g of Formula I was obtained as a white crystalline solid, which corresponds to a recrystallization yield of 96% (77% overall yield for the isolation of Formula I).

[0133] Karl-Fischer titration detected the presence of 3.21 ppm of H2O in formula I.

[0134] 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.

[0135] Example 3 Preparation of hydrogen peroxide and 6-((1r,4r)-4-phenylcyclohexyl)-5-(3-(trifluoromethyl)benzyl)pyrimidine-2,4(1H,3H)-dione (Formula I)

[0136] [ka]

[0137] Octyl sulfide intermediate (formula VIII, 8 g, 14.36 mmol, 1 equivalent) was dissolved in NMP (5 vols, 40 mL). The solution was treated with H2SO4 (3 equivalents, 2.3 ml, 4.2 g, 43.1 mmol). The contents were heated to 80°C. H2O2 (50% in water, 3 equivalents, 2.44 ml, 2.93 g, 43.1 mmol) was added to the solution via a syringe pump over 3 hours. The contents were aged overnight at 80°C. After aging, the contents were cooled to 20°C, and the flow was analyzed for assay yield (89% of the product was observed).

[0138] The solution was treated with MeCN (3 vol, 24 ml), and then water (7.5 vol, 60 ml) was added over 1 hour. The slurry was then aged overnight. The product was isolated by filtration and washed sequentially with MeCN (3 vol, 24 mL), 1:1 MeCN:water (3 vol, 24 L), and water (3 vol, 24 L). The crude product was re-slurried in water (10 vol, 80 mL) and heated to 80°C for 1 hour. This slurry was cooled to 20°C and aged for 1 hour. The product was isolated by filtration, and the cake was washed with water (3 × 3 vol, 24 mL each). The product was transferred to a vacuum oven and dried overnight at 50°C. Yield = 4.85 g (79%), LCWP = 98.2%.

[0139] 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.

[0140] 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

1. A method for preparing the compound of formula I, 【Chemistry 1】 The method described above is (a) The first solvent and the compound of formula VIII, 【Chemistry 2】 A first reaction mixture comprising an oxidizing agent and C is formed under conditions suitable for preparing the compound of formula I, where R is C １～１２ A method that is alkyl.

2. The method according to claim 1, wherein the first 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.

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

4. R is C ６～１２ The method according to any one of claims 1 to 3, wherein the alkyl group is alkyl.

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

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

7. The method according to any one of claims 1 to 6, wherein the compound of formula VIII has the following structure: 【Transformation 3】

8. The method according to any one of claims 1 to 7, wherein the oxidizing agent comprises potassium peroxymonosulfate (OXONE®), hydrogen peroxide, nitric acid, potassium chlorate, sulfuric acid, peroxydisulfate, hypochlorite, potassium permanganate, or a combination thereof.

9. The method according to any one of claims 1 to 8, wherein the oxidizing agent comprises potassium peroxymonosulfate (OXONE®).

10. (a) The method according to any one of claims 1 to 9, wherein the first reaction mixture, comprising potassium peroxomonosulfate (OXONE), N-methyl-2-pyrrolidone, and compound VIII, is formed under conditions suitable for preparing the compound of formula I.

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

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

15. The method according to claim 14, 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.

16. The method according to claim 14 or 15, wherein the strong acid includes sulfuric acid.

17. (a) The method according to any one of claims 14 to 16, wherein the first reaction mixture, comprising 3 to 7 molar equivalents of hydrogen peroxide, sulfuric acid, N-methyl-2-pyrrolidone, and the compound of formula VIII, is formed under conditions suitable for preparing the compound of formula I.

18. A method for preparing a compound of formula VIII, 【Chemistry 4】 The method described above is (b) an alkylating agent, a second non-nucleophilic base, a second solvent, and a compound of formula IX: 【Transformation 5】 A second reaction mixture, comprising the following, is formed under conditions suitable for preparing the compound of formula VIII: In the formula, R is C １～１２ It is alkyl, The alkylating agent is C １～１２ Alkyl halides, or C １～１２ Alkyl-OS(O)2R ａ And, R ａ is 0, 1, 2, or 3 R ａ１ substituted, C １～６ alkyl, C １～６ haloalkyl, and phenyl, and Each R ａ１ However, independently, C １～６ Alkyl, halogen, or C １～６ A method involving haloalkyl groups.

19. The alkylating agent is C １～１２ The method according to claim 18, wherein the compound is an alkyl-halide.

20. The second reaction mixture is C ６～１２ The method according to claim 18 or 19, comprising an alkyl-iodide.

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

23. The method according to 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 according to 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 aforementioned second non-nucleophilic base is 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 The method according to any one of claims 18 to 24, comprising n, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine (DMAP), quinuclidine, 4-pyrrolidinopyridine, 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), or a combination thereof.

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

27. The method according to any one of claims 18 to 26, wherein the second nonnucleophilic base is present in an amount of 0.9 to 2 molar equivalents with respect to the compound of formula IX.

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

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

30. (b) The method according to any one of claims 18 to 29, wherein the second reaction mixture comprises about 1 molar equivalent of n-octyl-iodide relative to the compound of formula IX, about 1 molar equivalent of potassium carbonate relative to the compound of formula IX, N-methyl-2-pyrrolidone, and the compound of formula IX, and the mixture is formed under conditions suitable for forming the compound of formula VIII.

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

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

33. A method for preparing a compound of formula IX, 【Transformation 6】 The method described above is (c) Thiourea, a third non-nucleophilic base, a third solvent, and the compound of formula III: 【Transformation 7】 A third reaction mixture, comprising the following, is formed under conditions suitable for preparing the compound of formula IX: In the formula, R １ However, C １～６ A method that is alkyl.

34. R １ The method according to claim 33, wherein the compound is methyl, ethyl, or n-propyl.

35. The method according to claim 33 or 34, wherein the compound of formula III has the following structure: 【Transformation 8】

36. The method according to any one of claims 33 to 35, wherein the third 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.

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

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

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

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

41. The method according to 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. (c) The method according to any one of claims 33 to 41, wherein 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, is formed under conditions suitable for preparing the compound of formula IX.

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

44. (c) 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, is formed under conditions suitable for preparing the compound of formula IX. (b) The second reaction mixture, comprising about 1 molar equivalent of n-octyl-iodide relative to the compound of formula IX, about 1 molar equivalent of potassium carbonate relative to the compound of formula IX, N-methyl-2-pyrrolidone, and the compound of formula IX, is formed under conditions suitable for forming the compound of formula VIII. (a) The method according to any one of claims 1 to 43, wherein the first reaction mixture, comprising potassium peroxomonosulfate (OXONE), N-methyl-2-pyrrolidone, and compound VIII, is formed under conditions suitable for preparing the compound of formula I.

45. (c) 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, is formed under conditions suitable for preparing the compound of formula IX. (b) The second reaction mixture, comprising about 1 molar equivalent of n-octyl-iodide relative to the compound of formula IX, about 1 molar equivalent of potassium carbonate relative to the compound of formula IX, N-methyl-2-pyrrolidone, and the compound of formula IX, is formed under conditions suitable for forming the compound of formula VIII. (a) The method according to any one of claims 1 to 43, wherein the first reaction mixture, comprising 3 to 7 molar equivalents of hydrogen peroxide, sulfuric acid, N-methyl-2-pyrrolidone, and the compound of formula VIII, is formed under conditions suitable for preparing the compound of formula I.

46. A compound of formula VIII, 【Chemistry 9】 In the formula, R is C １～１２ A compound that is alkyl.

47. R is C ６～１２ The compound according to claim 46, wherein it is alkyl.

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

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

50. The compound according to any one of claims 46 to 49, wherein the compound of formula VIII has the following structure: 【Chemistry 10】

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