Method for preparing pyrimidine cyclohexylglucocorticoid receptor modulators

Abstract

The present invention provides methods for preparing 2-amino-6-((1r,4r)-4-phenylcyclohexyl)-5-(3-(trifluoromethyl)benzyl)pyrimidin-4(3H)-one and 2-amino-6-((1r,4r)-4-phenylcyclohexyl)-5-(3-(trifluoromethyl)benzyl)pyrimidin-4(3H)-one monohydrate, as well as novel intermediate compounds.

Description

[Technical Field]

[0001] Cross-references to related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 128,539, filed on 21 December 2020, which is incorporated herein by reference in its entirety for all purposes.

[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 and acts by binding to intracellular glucocorticoid receptors (GR). In humans, glucocorticoid receptors exist in two forms: the ligand-binding GR-alpha, consisting of 777 amino acids, and the GR-beta isoform, which lacks 50 carboxyl-terminal residues. Because these contain a ligand-binding domain, GR-beta cannot bind ligands, is constitutively localized in the nucleus, and is transcriptionally inactive. GR is also known as GR-II.

[0003] The biological effects of cortisol, including those caused by hypercortisolemia, can be modulated at the GR level using receptor modulators such as agonists, partial agonists, and antagonists. Several different classes of drugs can inhibit the physiological effects of GR-agonist binding. These antagonists include compositions that inhibit the ability of agonists to effectively bind to and / or activate GR by binding to GR. One such known GR antagonist, mifepristone, has been found to be an effective antiglucocorticoid agent in humans (Bertagna (1984) J. Clin. Endocrinol. Metab. 59:25). Mifepristone binds to GR with high affinity, and its dissociation constant (Kd) is 10⁻⁹ M (Cadepond (1997) Annu. Rev. Med. 48:129).

[0004] In addition to cortisol, the biological effects of other steroids can be modulated at the GR level using receptor modulators such as agonists, partial agonists, and antagonists. When administered to a target that needs it, steroids can produce both intended therapeutic effects, for example by stimulating transcriptional repression of glucocorticoid receptors, and negative side effects, for example, due to chronic transcriptional activation of glucocorticoid receptors. Mylacorilant (CORT-118335) is another such glucocorticoid receptor modulator compound and has been described to date in PCT Publication No. 2012 / 129074 and U.S. Patent No. 8,685,973. What is needed in the art is a novel method for preparing Relacorilant with a lower impurity content. Surprisingly, the present invention satisfies these and other needs. There is a demand in the art for a novel method for preparing compounds to modulate GR receptors. Surprisingly, the present invention satisfies these and other needs. [Overview of the Initiative]

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

Chemical formula

Chemical formula

[0006] In another embodiment, the present invention is a method for preparing a compound of formula I, comprising:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0007] In another embodiment, the present invention relates to a method for preparing the following compound of formula II or its hydrate, [ka] The method involves a second reaction mixture comprising (b) guanidine and its salts, and the following compound of formula III, [ka] The process involves forming a compound of formula II or its hydrate under conditions suitable for preparation, wherein R 1 is C 1~6 This provides a method for using alkyl groups.

[0008] In another embodiment, the present invention provides the following compound of formula II or its hydrate. [ka]

[0009] In another embodiment, the present invention provides a compound of the following formula IVa. [ka]

[0010] In another embodiment, the present invention provides compounds of the following formula Va. [ka] [Brief explanation of the drawing]

[0011] [Figure 1] Figure 1 shows the X-ray pattern diffraction (XRPD) of the compound of formula II, 2-amino-6-((1r,4r)-4-phenylcyclohexyl)-5-(3-(trifluoromethyl)benzyl)pyrimidine-4(3H)-one. [Figure 2] Figure 2 shows differential scanning calorimetry of the compound of formula II. [Figure 3] Figure 3 shows the thermogravimetric analysis of the compound of formula II. [Figure 4] Figure 4 shows the X-ray pattern diffraction (XRPD) of the compound of formula IVa, (Z)-2-((1r,4r)-4-(4-chlorophenyl)cyclohexane-1-carbonyl)-3-(3-(trifluoromethyl)phenyl)acrylate ethyl form I. [Figure 5] Figure 5 shows differential scanning calorimetry of compound IVa, form I. [Figure 6] Figure 6 shows the X-ray pattern diffraction (XRPD) of form II of the compound of formula IVa, (Z)-2-((1r,4r)-4-(4-chlorophenyl)cyclohexane-1-carbonyl)-3-(3-(trifluoromethyl)phenyl)acrylate ethyl. [Figure 7] Figure 7 shows differential scanning calorimetry of compound IVa, form II. [Modes for carrying out the invention]

[0012] I. General 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, by oxidation of a compound of Formula II. This disclosure also describes a method for preparing 2-amino-6-((1r,4r)-4-phenylcyclohexyl)-5-(3-(trifluoromethyl)benzyl)pyrimidine-4(3H)-one monohydrate (Formula II) by the reaction of Formula III, such as Compound 11 of U.S. Patent No. 8,685,973, using guanidine or a salt thereof. This disclosure also describes novel intermediates, including 2-amino-6-((1r,4r)-4-phenylcyclohexyl)-5-(3-(trifluoromethyl)benzyl)pyrimidine-4(3H)-one monohydrate (Formula II), (Z)-2-((1r,4r)-4-(4-chlorophenyl)cyclohexane-1-carbonyl)-3-(3-(trifluoromethyl)phenyl)ethyl acrylate (Formula IVa), and 3-((1r,4r)-4-(4-chlorophenyl)cyclohexyl)-3-oxopropanoate ethyl (Formula Va).

[0013] II. Definition

[0014] 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 upper and lower limits of that range, respectively, plus 10% of the stated value. For example, the ratio about 1 to about 10 (w / w) includes the range of 0.9 to 11.

[0015] "Forming a reaction mixture" refers to the process of bringing at least two distinct species into contact so that they can be mixed and react together. However, it will be understood that the resulting reaction product may be produced directly from the reaction between the added reagents, or directly from intermediates from one or more of the added reagents that may be produced in the reaction mixture.

[0016] A "partition mixture" refers to an immiscible mixture of an organic solvent layer and an aqueous solution layer used in solvent-solvent extraction to isolate a desired substance. Suitable organic solvents include, but are not limited to, hexane, diethyl ether, ethyl acetate, and dichloromethane. Suitable aqueous solutions include, but are not limited to, water and various water-soluble salt solutions, such as a 20% sodium chloride solution.

[0017] "Dissolving," "dissolving," or "dissolving" refers to the process of placing a solid material into a solvent system in which the solid material is substantially soluble. For example, a solid material may be soluble in a solvent by more than 90%, or by more than 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.

[0018] "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.

[0019] "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 its reflux temperature or boiling point, or to a temperature between room temperature and its reflux temperature or boiling point.

[0020] "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).

[0021] 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, butanoic acid, hexanoic acid, octanoic acid, trifluoroacetic acid, and tetrafluoroboric acid (HBF4).

[0022] A "base" refers to a compound that can accept a proton (Brønsted-Lowry base) or donate an electron pair (Lewis base). Typical bases include, but are not limited to, inorganic bases, organic bases, acidic salts, non-nucleophilic bases, and amine bases. For example, a base may be sodium hydroxide, sodium acetate, or a mixture thereof.

[0023] "Amine bases" or "non-nucleophilic amine bases" refer to nitrogen-containing bases that are moderately to strongly bases but also have poor nucleophilicity. Representative amine bases include triethylamine, diisopropylethylamine, N,N-diethylaniline, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, and quinuclidine.

[0024] An "oxidizing agent" or "oxidizing substance" refers to a reagent that can accept an electron pair from another compound and thereby oxidize that compound. Typical oxidizing agents include, but are not limited to, oxygen, hydrogen peroxide, nitrites, nitric acid, and sulfuric acid.

[0025] A "reducing agent" refers to a reagent that can reduce another compound by donating electrons to it. Typical reducing agents include, but are not limited to, hydrogenation catalysts, such as hydride reagents like lithium aluminum hydride (LiAlH4) or sodium borohydride (NaBH4), sodium, and formic acid. Hydrogenation catalysts are catalysts that promote the hydrogenation of alkenes or other double bonds. Typical hydrogenation catalysts include, but are not limited to, Pd / C, Pt, Raney nickel, Ru complexes, and Ir complexes.

[0026] A "crystal species" refers to the seed crystal of the target crystal form that you intend to prepare.

[0027] A "carboxyl coupling agent" refers to a reagent that can form an activated ester from a carboxylic acid to promote the formation of a carbon-carbon bond at the carbonyl carbon. Typical carboxyl coupling agents include thionyl chloride, carbodiimide reagents, and others.

[0028] "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 hydroxy group or a carboxy group. Aprotic solvents lack such groups. Representative polar protic solvents include alcohols (such as methanol, ethanol, propanol, isopropanol, etc.), acids (such as formic acid, acetic acid, etc.), and water. Representative polar aprotic solvents include dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, diethyl ether, acetone, ethyl acetate, dimethylformamide, dimethylacetamide, acetonitrile, and dimethyl sulfoxide. Representative nonpolar solvents include alkanes (such as pentane, hexane, etc.), cycloalkanes (such as cyclopentane, cyclohexane, etc.), benzene, and toluene. In the present invention, other solvents are useful.

[0029] "Water scavenger" refers to a compound or substance that captures water in a reaction mixture to reduce the overall water content. Representative water scavengers include alkali aluminosilicates, orthoformates, and the like.

[0030] "Alkyl" refers to a straight-chain or branched acyclic hydrocarbon containing normal, secondary, or tertiary carbon atoms. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C1 - C 20 alkyl), 1 to 10 carbon atoms (i.e., C1 - C 10 alkyl), or 1 to 6 carbon atoms (i.e., C1 - C6 alkyl). Alkyl can be, 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 5~6 It may contain any number of carbon atoms, such as 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)2CH2CH2 Examples include, but are not limited to, CH3, 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).

[0031] "Guanidine" refers to a compound having the following structure: [ka]

[0032] "Isopropylidene malonate" refers to the following structure: [ka]

[0033] A "tautomer" refers to one of two or more structural isomers that exist in equilibrium and can be readily converted from one isomeric form to the other. An example relevant to this application is the two tautomers involved in the 2-amino substituent on the pyrimidine ring of the compound of formula II, which may exist in either the amino or imino form. [ka]

[0034] III. Preparation method for Equation I The present invention provides a method for preparing the compound of formula I, 6-((1r,4r)-4-phenylcyclohexyl)-5-(3-(trifluoromethyl)benzyl)pyrimidine-2,4(1H,3H)-dione. [ka]

[0035] The compound of formula I was originally disclosed as Example 6 in U.S. Patent No. 8,685,973.

[0036] A. Preparation of Equation I from Equation II In some embodiments, the present invention relates to a method for preparing the following compound of formula I: [ka] (a) A first reaction mixture comprising an oxidizing agent and a compound of the following formula II or its hydrate, [ka] The present invention provides a method for forming a compound of formula I under conditions suitable for preparation.

[0037] Any suitable oxidizing agent can be used in the method of the present invention. In some embodiments, the oxidizing agent is sodium nitrite (NaNO2), potassium nitrite (KNO2), or tetrabutylammonium nitrite [(n-C4H9)4N + NO2 -The oxidizing agent comprises at least one of the following: nitrosyl sulfate, [HOSO2-ON=O], methyl nitrite (CH3O-N=O), ethyl nitrite (CH3CH2O-N=O), n-propyl nitrite (CH3CH2CH2O-N=O), isopropyl nitrite [(CH3)2CHO-N=O], n-butyl nitrite [CH3(CH2)3O-N=O], isobutyl nitrite [(CH3)2CH(CH2)2O-N=O], isopentyl nitrite [(CH3)2CH(CH2)2O-N=O], or phenyl nitrite (C6H5O-N=O). In some embodiments, the oxidizing agent comprises sodium nitrite.

[0038] The oxidizing agent may be present in any suitable ratio relative to the compound of formula II or its hydrate. For example, the oxidizing agent may be present in a molar ratio of 0.1 to 10 relative to the compound of formula II, or in 0.1 to 5, 0.5 to 5, 1 to 2, or in a molar ratio of 1 to 1.5 relative to the compound of formula II. The oxidizing agent may be present in a molar ratio of about 0.5 relative to the compound of formula II, or in 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or in a molar ratio of about 2.0 relative to the compound of formula II. In some embodiments, the oxidizing agent is present in a molar ratio of about 1.2 relative to the compound of formula II.

[0039] The first reaction mixture may contain a variety of other components. In some embodiments, the first reaction mixture may contain a first acid. Typical acids include, but are not limited to, organic and inorganic acids. In some embodiments, the first reaction mixture further contains a first acid including hydrochloric acid, sulfuric acid, formic acid, acetic acid, propanoic acid, butanoic acid, hexanoic acid, octanoic acid, trifluoroacetic acid, tetrafluoroboric acid (HBF4), or mixtures thereof. In some embodiments, the first acid contains acetic acid.

[0040] The first acid may be present in any suitable amount.

[0041] The first reaction mixture may also contain a solvent. Typical solvents include nonpolar aprotic solvents, polar aprotic solvents, and polar protic solvents. In some embodiments, the first reaction mixture further contains a first solvent comprising N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), isopropanol, 2-methyltetrahydrofuran (2-MeTHF), tetrahydrofuran, water, or a mixture thereof.

[0042] The compound of formula II may be in the form of a free base or a hydrate. In some embodiments, the compound of formula II may be a free base. In some embodiments, the compound of formula II may be a hydrate. In some embodiments, the compound of formula II may be in the following monohydrate form. [ka]

[0043] In some embodiments, the first reaction mixture comprises acetic acid, sodium nitrite, and a monohydrate form of the compound of formula II.

[0044] Compounds of formula I can be purified by various methods. For example, compounds of formula I can be crystallized. In some embodiments, a method for preparing a compound of formula I also includes (a1) dissolving a compound of formula I in a solvent mixture containing about 15% (v / v) methanol and about 85% (v / v) dichloromethane; (a2) heating the solvent mixture to remove the dichloromethane, adding methanol to the solvent mixture to replace the removed dichloromethane, thereby preparing a methanol solvent mixture; and (a3) ​​cooling the methanol solvent mixture to form crystals of formula I.

[0045] This solvent mixture can be heated to any suitable temperature. For example, the solvent mixture can be heated to remove dichloromethane by distillation at atmospheric pressure.

[0046] B. Preparation of Equation II from Equation III The compound of formula II below or its hydrate can be prepared by various methods. [ka]

[0047] In some embodiments, the compound of formula II or its hydrate is used in a second reaction mixture comprising (b) guanidine and its salt, and the following compound of formula III: [ka] It may be prepared by a method comprising forming the compound of formula II or its hydrate under conditions suitable for preparation, In the formula, R 1 is C 1~6 It is alkyl.

[0048] Further embodiments for the preparation of the compound of formula II are described below in Section IV.

[0049] A method for preparing the compound of formula I may also include the crystallization of the compound of formula II. In some embodiments, the method further includes, after step (b), (b2) adding water to the second reactant to crystallize the compound of formula II or its hydrate.

[0050] In some embodiments, the compound of formula I is (b1) A third reaction mixture containing ethanol, guanidine hydrochloride, and sodium ethoxide is formed to prepare a free guanidine base, (b) A second reaction mixture containing ethyl acetate, guanidine free base, and the compound of formula IIIa is formed under conditions suitable for preparing the monohydrate form of the following compound of formula II, [ka] (a) A first reaction mixture comprising acetic acid, sodium nitrite, and the monohydrate form of the compound of formula II is prepared by forming under conditions suitable for preparing the compound of formula I.

[0051] C. Preparation of Equation III from Equation IV The following compounds of formula III can be prepared by various methods, such as those described in U.S. Patent No. 8,685,973. [ka] In the formula, R 1 is C 1~6 It is alkyl.

[0052] In some embodiments, the compound of formula III is a fourth reaction mixture comprising (c) a reducing agent and the following compound of formula IV, [ka] It is prepared by forming the compound of formula III under conditions suitable for preparation.

[0053] The reducing agent can be any suitable reducing agent. In some embodiments, the reducing agent includes a hydrogenation catalyst, triethylsilane / iron(III) chloride hexahydrate (Et3SiH / FeCl3·6H2O), sodium borohydride in pyridine [(NaBH4) / pyridine], tri-n-butyltin hydride [(nBu3SnH)], tri-(trimethylyl)silane [(Me3Si)3SiH], borane (BH3), and catecholborane [(o-C6H4O2)BH], hydrazine (H2NNH2), formic acid, ammonium formate, cyclohexene, or 1,4-cyclohexadiene. If the reducing agent is a hydrogenation catalyst, the fourth reaction mixture further contains hydrogen. In some embodiments, the reducing agent is a hydrogenation catalyst, and the fourth reaction mixture further contains hydrogen.

[0054] In some embodiments, the reducing agent is a hydrogenation catalyst comprising palladium-carbon (Pd-C), palladium-silicon dioxide, palladium-calcium carbonate, platinum-carbon, palladium hydroxide, platinum hydroxide, palladium(II) chloride, Raney nickel, rhodium-alumina, rhodium(III) chloride trihydrate / Aliquat 336 (N-methyl N-trioctylammonium chloride), Ru(BINAP)]2*NEt3, or nickel boride (Ni2B). In some embodiments, the hydrogenation catalyst comprises palladium-carbon (Pd-C).

[0055] The reducing agent may be present in any suitable amount. For example, the reducing agent may be present in equimolar amounts or catalytic amounts relative to the compound of formula III. The catalytic amount may be a molar ratio of less than 1 relative to the compound of formula III, or a molar ratio of less than 0.1 relative to the compound of formula III. In some embodiments, the reducing agent is present in catalytic amounts.

[0056] The fourth reaction mixture may contain various other components, such as a solvent. In some embodiments, the fourth reaction mixture contains a fourth solvent comprising methanol, ethanol, n-propanol, iso-propanol, n-butanol, ethyl acetate, isopropyl acetate, n-butyl acetate, formic acid, acetic acid, trifluoroacetic acid, water, or mixtures thereof. In some embodiments, the fourth solvent contains ethanol.

[0057] The fourth reaction mixture may also contain a base, such as an organic or inorganic base. The organic base may be an acidic salt, including a carboxylic acid, sulfuric acid, phosphoric acid, or other monosalts, disalts, or trisalts. Representative bases include, but are not limited to, potassium acetate, lithium acetate, sodium propionate, sodium butyrate, sodium hexanoate, sodium 2-ethylhexanoate, sodium octanoate, potassium 2-ethylhexanoate, sodium formate, potassium formate, potassium oxalate, sodium oxalate, sodium citrate tribasic, potassium citrate tribasic, trisodium nitrilotriacetate, disodium ethylenediaminetetraacetic acid (EDTA), or tetrasodium EDTA. In some embodiments, the base contains sodium acetate.

[0058] In some embodiments, R 1 is C 1~6 It is alkyl. In some embodiments, R 1 is C 1~3 It is alkyl. In some embodiments, R 1 is methyl, ethyl, or n-propyl. In some embodiments, R 1 is ethyl. In some embodiments, the compound of formula IV is the compound of formula IVa below. [ka]

[0059] The compound of formula IVa has the IUPAC name (Z)-2-((1r,4r)-4-(4-chlorophenyl)cyclohexane-1-carbonyl)-3-(3-(trifluoromethyl)phenyl)acrylate ethyl.

[0060] In some embodiments, the fourth reaction mixture comprises ethanol, 5% Pd-C, hydrogen, and sodium acetate, and the compound of formula IV is the compound of formula IVa below. [ka] This prepares the compound of formula IIIa shown below. [ka]

[0061] In some embodiments, the compound of formula I is (c) Form a fourth reaction product comprising ethanol, 5% Pd-C, hydrogen, sodium acetate, and the following compound of formula IVa: [ka] This results in the preparation of the compound of formula IIIa below: [ka] (b1) A third reaction mixture containing ethanol, guanidine hydrochloride, and sodium ethoxide is formed to prepare a free guanidine base, (b) A second reaction mixture containing ethyl acetate, guanidine free base, and the compound of formula IIIa is formed under conditions suitable for preparing the monohydrate form of the following compound of formula II, [ka] (a) A first reaction mixture comprising acetic acid, sodium nitrite, and the monohydrate form of the compound of formula II is prepared by forming under conditions suitable for preparing the compound of formula I.

[0062] D. Preparation of Equation IV from Equation V The following compound of formula IV can be prepared by various methods. [ka] In the formula, R 1 is C 1~6 It is alkyl.

[0063] In some embodiments, the compound of formula IV is used in a fifth reaction mixture comprising (d) a first amine base, a second acid, 3-trifluoromethylbenzaldehyde, and the following compound of formula V: [ka] It is prepared by forming the compound of formula IV under conditions suitable for preparation.

[0064] The first amine base can be any suitable amine base. In some embodiments, the first amine base includes triethylamine, N,N-diisopropylethylamine (DIPEA), N,N-dimethylisopropylamine (DIMPA), piperidine, 1-ethylpiperidine, N-methylmorpholine, N-methylpyrrolidine, N,N-dimethylamine, piperazine, N-methylpiperazine, tris(hydroxymethyl)methylamine [(HOCH2)3CNH2], benzylamine, pyridine, N,N-dimethylaniline, N,N-diethylaniline, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine (DMAP), quinuclidine, 4-pyrrolidinopyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO), or mixtures thereof. In some embodiments, the first amine base includes piperidine.

[0065] The first amine base may be present in any suitable amount. For example, the first amine base may be present in equimolar amounts or catalytic amounts relative to the compound of formula IV. A catalytic amount may be a molar ratio of less than 1 relative to the compound of formula IV, or a molar ratio of less than 0.1 relative to the compound of formula IV. In some embodiments, the first amine base is present in a catalytic amount.

[0066] The second acid can be any suitable acid. Typical examples include, but are not limited to, organic and inorganic acids. In some embodiments, the second acid may be hydrochloric acid, sulfuric acid, formic acid, acetic acid, propanoic acid, butanoic acid, hexanoic acid, octanoic acid, trifluoroacetic acid, tetrafluoroboric acid (HBF4), or a mixture thereof. In some embodiments, the second acid includes acetic acid.

[0067] The second acid may be present in any suitable amount. For example, the second acid may be present in equimolar amounts or catalytic amounts relative to the compound of formula IV. The catalytic amount may be a molar ratio of less than 1 relative to the compound of formula IV, or a molar ratio of less than 0.1 relative to the compound of formula IV. In some embodiments, the second acid is present in catalytic amounts.

[0068] Benzaldehyde may be present in any preferred ratio relative to the compound of formula V. For example, benzaldehyde may be present in a molar ratio of 0.1 to 10 relative to the compound of formula V, or in 0.1 to 5, 0.5 to 5, 1 to 3, or in a molar ratio of 1.5 to 3.5 relative to the compound of formula V. Benzaldehyde may be present in a molar ratio of about 1.5 relative to the compound of formula V, or in 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or in a molar ratio of about 2.5 relative to the compound of formula V. In some embodiments, benzaldehyde is present in a molar ratio of about 2.0 relative to the compound of formula V.

[0069] In some embodiments, R 1 is C 1~6 It is alkyl. In some embodiments, R 1 is C 1~3 It is alkyl. In some embodiments, R 1 is methyl, ethyl, or n-propyl. In some embodiments, R 1 is ethyl. In some embodiments, the compound of formula V is the compound of formula Va below. [ka]

[0070] The compound with formula Va has the IUPAC name 3-((1r,4r)-4-(4-chlorophenyl)cyclohexyl)-3-oxopropanoate ethyl.

[0071] The fifth reaction mixture may also contain a solvent. In some embodiments, the fifth reaction mixture further contains a fifth solvent comprising methanol, ethanol, n-propanol, iso-propanol, acetonitrile, dichloromethane, diethyl ether, 2-methyltetrahydrofuran (2-MeTHF), cyclopropyl methyl ether (CPME), tetrahydrofuran, 2,2,2-trifluoroethanol, toluene, xylene, mesitylene, or mixtures thereof. In some embodiments, the fifth solvent contains ethanol.

[0072] In some embodiments, the fifth reaction mixture comprises ethanol, piperidine, acetic acid, and 3-trifluoromethylbenzaldehyde, and the compound of formula V is the compound of formula Va below. [ka] This prepares the compound of formula IVa below. [ka]

[0073] In some embodiments, the compound of formula I is (d) A fifth reaction product is formed comprising ethanol, piperidine, acetic acid, 3-trifluoromethylbenzaldehyde, and a compound of the following formula Va: [ka] This results in the preparation of the compound of formula IVa, [ka] (c) Form a fourth reaction product comprising ethanol, 5% Pd-C, hydrogen, sodium acetate, and the compound of the following formula IVa, thereby preparing the compound of the following formula IIIa, [ka] (b1) A third reaction mixture containing ethanol, guanidine hydrochloride, and sodium ethoxide is formed to prepare a free guanidine base, (b) A second reaction mixture containing ethyl acetate, guanidine free base, and the compound of formula IIIa is formed under conditions suitable for preparing the monohydrate form of the following compound of formula II, [ka] (a) A first reaction mixture comprising acetic acid, sodium nitrite, and the monohydrate form of the compound of formula II is prepared by forming under conditions suitable for preparing the compound of formula I.

[0074] The compound of formula IV can be crystallized by various methods. In some embodiments, the method for preparing the compound of formula IV also includes (d1) adding a crystalline species of the compound of formula IV to the fifth reaction mixture to prepare the compound of formula IV in crystalline form.

[0075] E. Preparation of Equation V from Equation VI The compound of formula V below can be prepared by various methods. [ka] In the formula, R 1 is C 1~6 It is alkyl.

[0076] In some embodiments, the compound of formula V is (e1) A seventh reaction mixture comprising isopropylidene malonate, a carboxyl coupling agent, a second amine base, and a compound of the following formula VI: [ka] To form the intermediate mixture under conditions suitable for preparation, (e2) The compound of formula V is prepared by heating a sixth reaction mixture containing an intermediate mixture, thereby preparing the compound of formula V.

[0077] A carboxyl coupling agent can be any agent capable of forming a carbon-carbon bond at the carbonyl carbon of a carboxylic acid. For example, a carboxyl coupling agent can be an agent that forms an activated ester. In some embodiments, the carboxyl activator is dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (EDAC), bis[[4-(2,2-dimethyl-1,3-dioxolyl (dioxolyl))]methyl]carbodiimide (BDDC), or N-cyclohexyl-N'-(2-morpholinoethyl)carbodiimide Methyl-p-toluenesulfonate, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidemethiozide, thionyl chloride, oxalyl chloride, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), carbonyldiimidazole, bis(1,2,4-triazolyl)methanone, n-propanephosphonic anhydride, ethylmethylphosphonic anhydride (EMPA), cyanuryl chloride, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorphonium chloride (DMTMM), guanidinium salt, uronium salt These include benzotriazole tetramethyluronium hexafluorophosphate (HBTU), azabenzotriazole tetramethyluronium hexafluorophosphate (HATU), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), O-(2-oxo-1(2H)pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TPTU), or N-[[[(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy](dimethylamino)methylene]-N-methylmethaneaminium tetrafluoroborate (TOTU). In some embodiments, the carboxyl activator is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (EDAC).

[0078] The carboxyl activator may be present in any preferred ratio relative to the compound of formula VI. For example, the carboxyl activator may be present in a molar ratio of 0.1 to 10 relative to the compound of formula VI, or in 0.1 to 5, 0.5 to 5, 1 to 2, or in a molar ratio of 1 to 1.5 relative to the compound of formula VI. The carboxyl activator may be present in a molar ratio of about 0.5 relative to the compound of formula VI, or in 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or in a molar ratio of about 2.0 relative to the compound of formula VI. In some embodiments, the carboxyl activator is present in a molar ratio of about 1.2 relative to the compound of formula VI.

[0079] The second amine base may be any suitable amine base. In some embodiments, the second amine base includes triethylamine, N,N-diisopropylethylamine (DIPEA), N,N-dimethylisopropylamine (DIMPA), 1-ethylpiperidine, N-methylmorpholine, N-methylpyrrolidine, pyridine, N,N-dimethylaniline, N,N-diethylaniline, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine (DMAP), quinuclidine, 4-pyrrolidinopyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO), or mixtures thereof. In some embodiments, the second amine base includes 4-dimethylaminopyridine (DMAP).

[0080] The second amine base may be present in any suitable ratio relative to the compound of formula VI. For example, the second amine base may be present in a molar ratio of 0.1 to 10 relative to the compound of formula VI, or in 0.1 to 5, 0.5 to 5, 1 to 2, or in a molar ratio of 1 to 1.5 relative to the compound of formula VI. The second amine base may be present in a molar ratio of about 0.5 relative to the compound of formula VI, or in 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or in a molar ratio of about 2.0 relative to the compound of formula VI. In some embodiments, the second amine base is present in a molar ratio of about 1.1 relative to the compound of formula VI.

[0081] Isopropylidene malonate may be present in any preferred ratio relative to the compound of formula VI. For example, isopropylidene malonate may be present in a molar ratio of 0.1 to 10 relative to the compound of formula VI, or in 0.1 to 5, 0.5 to 5, 1 to 2, or in a molar ratio of 1 to 1.5 relative to the compound of formula VI. Isopropylidene malonate may be present in a molar ratio of about 0.5 relative to the compound of formula VI, or in 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or in a molar ratio of about 2.0 relative to the compound of formula VI. In some embodiments, isopropylidene malonate is present in a molar ratio of about 1.1 relative to the compound of formula VI.

[0082] The seventh reaction mixture may include further components, such as a solvent. In some embodiments, the seventh reaction mixture further includes a seventh solvent, which may include acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, chloroform, toluene, or a mixture thereof. In some embodiments, the seventh solvent includes dichloromethane.

[0083] In some embodiments, the seventh reaction mixture comprises dichloromethane, isopropylidene malonate, EDAC, dimethylaminopyridine (DMAP), and a compound of formula VI.

[0084] The sixth reaction mixture may include further components, such as a solvent. In some embodiments, the sixth reaction mixture further includes a sixth solvent containing methanol, ethanol, n-propanol, iso-propanol, n-butanol, t-butanol, pentanol, hexanol, or mixtures thereof. In some embodiments, the sixth solvent contains ethanol.

[0085] The compound of formula V can be crystallized by various methods. In some embodiments, the method for preparing the compound of formula V also includes the step of (e3) adding heptane to the sixth reaction mixture to crystallize the compound of formula V.

[0086] In some embodiments, the present invention relates to a method for preparing the following compound of formula I: [ka] The said method, (e1) A seventh reaction mixture comprising dichloromethane, isopropylidene malonate, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (EDAC), dimethylaminopyridine (DMAP), and the compound of the following formula VI: [ka] To form the intermediate mixture under conditions suitable for preparation, (e2) The sixth reaction mixture containing the intermediate mixture and ethanol is heated to prepare the compound of the following formula Va, [ka] (e3) Adding heptane to the sixth reaction mixture to crystallize the compound of formula Va, (d) A fifth reaction mixture containing ethanol, piperidine, acetic acid, 3-trifluoromethylbenzaldehyde, and the compound of formula Va is formed under conditions suitable for preparing the following compound of formula IVa: [ka] (d1) Adding a crystalline species of the compound of formula IVa to the fifth reaction mixture to prepare the compound of formula IVa in crystalline form, (c) A fourth reaction mixture containing ethanol, 5% Pd-C, hydrogen, sodium acetate, and the compound of formula IVa is formed under conditions suitable for preparing the following compound of formula IIIa: [ka] (b1) A third reaction mixture containing ethanol, guanidine hydrochloride, and sodium ethoxide is formed to prepare a free guanidine base, (b) A second reaction mixture containing ethyl acetate, guanidine free base, and the compound of formula IIIa is formed under conditions suitable for preparing the monohydrate form of the following compound of formula II, [ka] (a) A method is provided comprising forming a first reaction mixture containing acetic acid, sodium nitrite, and a monohydrate form of the compound of formula II under conditions suitable for preparing the compound of formula I.

[0087] The method for preparing the compound of formula I is: (a1) Dissolving the compound of formula I in a solvent mixture containing approximately 15% (v / v) methanol and approximately 85% (v / v) dichloromethane, (a2) Heat the solvent mixture to remove the dichloromethane, add methanol to the solvent mixture to replace the removed dichloromethane, thereby preparing a methanol solvent mixture. (a3) Cooling the methanol solvent mixture to form crystals of formula I may include

[0088] IV. Preparation method for Formula II The present invention also provides a method for preparing 2-amino-6-((1r,4r)-4-phenylcyclohexyl)-5-(3-(trifluoromethyl)benzyl)pyrimidine-4(3H)-one monohydrate. In some embodiments, the present invention provides a method for preparing the following compound of formula II or its hydrate, [ka] The method involves a second reaction mixture comprising (b) guanidine and its salts, and the following compound of formula III, [ka] The process involves forming a compound of formula II or its hydrate under conditions suitable for preparation, wherein R 1 is C 1~6 It is alkyl.

[0089] Guanidine can be a free base or a salt of it. Typical salt forms of guanidine include, but are not limited to, hydrochloride, sulfonate, phosphate, and acetate. In some embodiments, guanidine is a free guanidine base. In some embodiments, guanidine is a guanidine salt. In some embodiments, guanidine is a guanidine hydrochloride.

[0090] Guanidine may be present in any suitable amount. For example, guanidine may be present in a molar ratio of 1 to 10 relative to the compound of formula III, or in 2 to 8, 3 to 7, 4 to 6, or in a molar ratio of 4 to 5 relative to the compound of formula III. Guanidine may be present in about 4.0 moles relative to the compound of formula III, or in 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or in a molar ratio of about 5.0 relative to the compound of formula III. In some embodiments, guanidine is a free guanidine base present in a molar ratio of about 4.5 relative to the compound of formula III. In some embodiments, guanidine is a guanidine hydrochloride salt present in a molar ratio of about 5.0 relative to the compound of formula III.

[0091] In some embodiments, R 1 is C 1~6 It is alkyl. In some embodiments, R 1 is C 1~3 It is alkyl. In some embodiments, R 1 is methyl, ethyl, or n-propyl. In some embodiments, R 1 is ethyl. In some embodiments, the compound of formula III is the compound of formula IIIa below. [ka]

[0092] The compound of formula IIIa has the IUPAC name 3-oxo-3-((1r,4r)-4-phenylcyclohexyl)-2-(3-(trifluoromethyl)benzyl)propanoate ethyl, which corresponds to compound 11 of U.S. Patent No. 8,685,973.

[0093] The second reaction mixture may contain various further components, such as a solvent. In some embodiments, the second reaction mixture further includes a second solvent comprising ethanol, isopropanol, methyl acetate, ethyl acetate, isopropyl acetate, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), 2-methyltetrahydrofuran (2-MeTHF), tetrahydrofuran (THF), water, or mixtures thereof. In some embodiments, the second solvent comprises ethyl acetate.

[0094] In some embodiments, the second reaction mixture comprises ethyl acetate, guanidine free base, and the compound of formula IIIa under conditions suitable for preparing the monohydrate form of the compound of formula II below. [ka]

[0095] Free guanidine base can be prepared by any preferred method. In some embodiments, the method further includes, prior to step (b), forming a third reaction mixture comprising (b1) a guanidine salt and a base to prepare the free guanidine base.

[0096] In some embodiments, the guanidine salt is guanidine hydrochloride.

[0097] Any suitable base can be used in the third reaction mixture. For example, the base can be an organic base or an inorganic base. In some embodiments, the base includes potassium carbonate, lithium methoxide, potassium methoxide, sodium methoxide, potassium ethoxide, sodium ethoxide, sodium isopropoxide, potassium isopropoxide, potassium tert-butoxide, or sodium tert-butoxide. In some embodiments, the base includes sodium ethoxide.

[0098] The base may be present in any suitable amount. For example, the base may be present in a molar ratio of 1 to 10 relative to the compound of formula III, or in 2 to 8, 3 to 7, 4 to 6, or in a molar ratio of 4 to 5 relative to the compound of formula III. The base may be present in about 4.0 moles relative to the compound of formula III, or in 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or in a molar ratio of about 5.0 relative to the compound of formula III. In some embodiments, the base is present in a molar ratio of about 4.5 relative to the compound of formula III.

[0099] The third reaction mixture may contain various other components, such as a solvent. In some embodiments, the third reaction mixture further includes a third solvent, which may contain methanol, ethanol, n-propanol, isopropanol, water, or a mixture thereof. In some embodiments, the third solvent may contain ethanol.

[0100] In some embodiments, the third reaction mixture further comprises a water scavenger. Typical water scavengers include (a) inorganic solids that absorb water, such as sodium sulfate (Na2SO4), magnesium sulfate (MgSO4), and crystalline metal aluminosilicates (molecular sieves); and (b) organic compounds that chemically react with water, such as methyl orthoformate [(MeO)3CH], ethyl orthoformate [(EtO)3CH], methyl orthoacetate [(MeO)3CMe], ethyl orthoacetate [(EtO)3CMe], methyl acetate (MeO2CMe), and ethyl acetate (tthyl (c)(EtO2CMe)(acetate), isopropyl trifluoroacetate (i-PrO2CCF3), (c) metal alkoxides that react with water: trimethyl borate [(MeO)3B], triethyl borate [(EtO)3B], triisopropyl borate [(i-PrO)3B], tris(2,2,2-trifluoroethyl) borate [(CF3CH2O)3B], tetraethyl orthosilicate [(EtO)4Si], tetrakis(2,2,2-trifluoroethoxy)silane [(CF3CH2 Examples include, but are not limited to, (d) phosphite esters: trimethyl phosphite [(MeO)3P], triethyl phosphite [(EtO)3P], triisopropyl phosphite [(i-PrO)3P], and triisopropyl phosphite [(i-PrO)3P].

[0101] In some embodiments, the method further comprises, prior to step (b), forming a third reaction product comprising (b1) ethanol, guanidine hydrochloride, and sodium ethoxide to prepare a free guanidine base.

[0102] In some embodiments, the compound of formula II is (b1) A third reaction mixture containing ethanol, guanidine hydrochloride, and sodium ethoxide is formed to prepare a free guanidine base, (b) A second reaction mixture containing ethyl acetate, guanidine free base, and the compound of formula IIIa is prepared by forming under conditions suitable for preparing the monohydrate form of the following compound of formula II. [ka]

[0103] A method for preparing the compound of formula II may also include the crystallization of the compound of formula II. In some embodiments, the method further includes, after step (b), (b2) adding water to the second reactant to crystallize the compound of formula II or its hydrate.

[0104] V. Compound The present invention also provides compounds of formulas II, IVa, and Va, as well as related crystalline forms.

[0105] A. Formula II In some embodiments, the present invention provides compounds of the following formula II or their hydrates. [ka]

[0106] In some embodiments, the compound of formula II is in monohydrate form. In some embodiments, the compound of formula II is a monohydrate having the following structure. [ka]

[0107] The monohydrate compound of formula II is named 2-amino-6-((1r,4r)-4-phenylcyclohexyl)-5-(3-(trifluoromethyl)benzyl)pyrimidine-4(3H)-one monohydrate using IUPAC nomenclature.

[0108] Compounds of formula II can take on various physical forms, such as amorphous or crystalline. In some embodiments, the monohydrate compound of formula II is in crystalline form. In some embodiments, the crystalline monohydrate compound of formula II is characterized by an X-ray diffraction pattern (XRPD) containing peaks at 2θ ± 0.2° at 20.1, 21.6, 19.7, 11.8, 21.3, 17.9 and 23.1°. In some embodiments, the crystalline monohydrate compound of formula II is further characterized by an X-ray diffraction pattern (XRPD) containing peaks at 2θ ± 0.2° at 10.7, 11.1, 12.6, 13.0, 15.3, 15.9, 18.3, 22.4, 24.4, 25.3, 26.2, 26.3, 28.6, 31.0, 34.5 and 35.0°. In some embodiments, the crystalline compound of the monohydrate of formula II is substantially characterized by a powder X-ray diffraction pattern (XRPD) as shown in Figure 1.

[0109] B. Formula IVa In some embodiments, the present invention provides compounds of the following formula IVa. [ka]

[0110] The compound of formula IVa is named (Z)-2-((1r,4r)-4-(4-chlorophenyl)cyclohexane-1-carbonyl)-3-(3-(trifluoromethyl)phenyl)acrylate ethyl using IUPAC nomenclature.

[0111] Compounds of formula IVa can take on various physical forms, such as amorphous or crystalline. In some embodiments, the compound of formula IVa is in a crystalline form. In some embodiments, the crystalline compound of formula IVa, form I, is characterized by an X-ray diffraction pattern (XRPD) that includes peaks at 2θ ± 0.2° at 5.9, 16.3, 18.0, 18.6, 22.2, and 25.9°. In some embodiments, the crystalline compound of formula IVa, form I, is further characterized by an X-ray diffraction pattern (XRPD) that includes peaks at 2θ ± 0.2° at 12.3, 15.8, 16.1, 18.2, 18.9, 19.2, 19.6, 19.9, 21.5, 22.4, 23.5, 24.4, 25.1, 26.8, and 32.6°. In some embodiments, the crystalline compound of formula IVa, form I, is substantially characterized by a powder X-ray diffraction pattern (XRPD) as shown in Figure 4.

[0112] In some embodiments, the crystalline compound of formula IVa, form II, is characterized by an X-ray diffraction pattern (XRPD) that includes peaks at 2θ ± 0.2° at 16.0, 17.1, 18.3, 20.6, 21.4, and 22.9°. In some embodiments, the crystalline compound of formula IVa, form II, is further characterized by an X-ray diffraction pattern (XRPD) that includes peaks at 2θ ± 0.2° at 8.0, 14.1, 15.0, 16.1, 16.2, 17.6, 19.0, 19.7, 21.2, 23.3, 23.4, 23.7, 24.0, 24.1, 24.7, 25.7, 26.4, 27.5, 27.8, and 35.5°. In some embodiments, the crystalline compound of formula IVa, form II, is substantially characterized by a powder X-ray diffraction pattern (XRPD) as shown in Figure 6.

[0113] C. Equation Va In some embodiments, the present invention provides compounds of the following formula Va. [ka]

[0114] The compound of formula Va is named 3-((1r,4r)-4-(4-chlorophenyl)cyclohexyl)-3-oxopropanoate ethyl using IUPAC nomenclature.

[0115] VI. Examples The following abbreviations will be used in the following methods. [Table 1]

[0116] Powder X-ray diffraction (XRPD). XRPD analysis was performed using a Panalytical Xpert Pro diffractometer equipped with a Cu X-ray tube and a Pixcel detector system. Samples were analyzed by transmission at ambient temperature and held between PVC films. Almac's 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 IVa, run time approximately 11 minutes / count time 22 seconds). Samples were spun at 60 rpm during data acquisition. XRPD patterns were sorted and manipulated using HighScore Plus 2.2c software.

[0117] 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 to a maximum of 200 or 300°C under nitrogen at a rate of 5°C / min.

[0118] Thermogravimetric / Differential Thermal Analysis (TG-DTA).Thermogravimetric (TG) analysis is performed using Mettler Toledo TGA / DSC 1 STAR e The analysis was performed using a simultaneous thermal analyzer. The sample was placed in an aluminum sample tray, inserted into a TG furnace, and accurately weighed. Under a nitrogen flow, the heat flow signal was stabilized at 30°C for one minute at a rate of 10°C / min, and then heated to 300°C.

[0119] Proton nuclear magnetic resonance spectroscopy ( 1 (H-NMR) Proton NMR analysis was performed using a Bruker 500MHz AVANCE NEO instrument equipped with a Prodigy BBO CryoProbe. The sample was dissolved in a suitable deuterated NMR solvent containing tetramethylsilane (TMS) as an internal standard and having an isotopic purity of 99.5 atomic% or more of D, and the sample solution was then analyzed using a 5mm unused NMR tube.

[0120] The reaction process of the present invention can be carried out for any preferred reaction time. For example, the reaction time can be a number of minutes, hours, or days. In some embodiments, the reaction time may be several hours, such as at least 8 hours. In some embodiments, the reaction time may be several hours, such as at least overnight. In some embodiments, the reaction time may be several days. In some embodiments, the reaction time may be at least two hours. In some embodiments, the reaction time may be at least eight hours. In some embodiments, the reaction time may be at least several days. In some embodiments, the reaction time may be about 2 hours, or about 4 hours, or about 6 hours, or about 8 hours, or about 10 hours, or about 12 hours, or about 14 hours, or about 16 hours, or about 18 hours, or about 20 hours, or about 22 hours, or about 24 hours. In some embodiments, the reaction time may be about 1 day, or about 2 days, or about 3 days, or about 4 days, or about 5 days, or about 6 days, or about 1 week, or about 1 week or more.

[0121] The reaction steps of the present invention can be carried out at any suitable reaction temperature. Typical temperatures include, but are not limited to, below room temperature, room temperature, or above room temperature. Other temperatures useful in the method of the present invention include about -40°C to about 65°C, or about room temperature to about 40°C, or about 40°C to about 65°C, or about 40°C to about 60°C. In some embodiments, the reaction mixture can be at a temperature of about room temperature, or about 15°C, or about 20°C, or about 25°C, or about 30°C, or about 35°C, or about 40°C, or about 45°C, or about 50°C, or about 55°C, or about 60°C, or about 65°C.

[0122] Example 1. Preparation of 3-((1r,4r)-4-(4-chlorophenyl)cyclohexyl)-3-oxopropanoate ethyl (formula Va), [ka]

[0123] The compound of formula Va was prepared by the following procedure. 1. Add dichloromethane (160 mL, 4.0 vol) to the reactor at 15-25°C. 2. Add trans-4-(4-chlorophenyl)cyclohexanecarboxylic acid (formula VI; 40.00 g, 1.00 equivalent) at 15-25°C. This will form a fluid slurry. 3. Add DMAP (22.52g, 1.10 equivalents) at 15-25°C. The slurry will effectively thicken. 4. Add isopropylidene malonate (meldrumic acid) (28.98 g, 1.20 equivalents) at 15-25°C. The slurry will mostly dissolve. 5. Add EDC-HCl (38.50g, 1.20 equivalents) in 6 equal portions at intervals of approximately 10-15 minutes at 15-25°C. 6. Adjust the temperature and stir at 20-25°C for 1-1.5 hours. Slowly add 100 mL (2.5 volumes) of 7.2 M HCl to the batch at 15-25°C and stir for at least 15 minutes. After 15 minutes of stirring, sample the batch and test the upper aqueous phase using pH test paper. If the result is > pH 3, adjust further with 2 M HCl. 8. Stir for at least 15 minutes, then let stand for at least 15 minutes to separate the phases. 9. Add dichloromethane (40 mL, 1.0 volume). 10. Stir for at least 15 minutes, then let stand for at least 15 minutes to separate the phases. 11. Combine both organic phases in a container. 12. Add water (100 mL, 2.5 volumes), stir for at least 15 minutes, then let stand for at least 15 minutes to separate the phases. 13. Return the organic phase, add water (100 mL, 2.5 volumes), stir for at least 15 minutes, then let stand for at least 15 minutes to separate the phases. 14. Return the DCM solution to the container. 15. Add ethanol (100 mL, 2.5 volumes) and then heat under atmospheric pressure (atm) until boiling (approximately 40°C). 16. While raising the temperature of this batch to approximately 65°C, collect the distillate (approximately 243 mL, 6 volumes). To achieve this, raise the jacket temperature to 75°C, during which time the batch volume will decrease to approximately 2.5 volumes. 17. Add ethanol (100 mL, 2.5 volumes) and continue distillation until the batch temperature exceeds 75°C. The distillate is expected to be approximately 0.5 to 1 volume. 18. Before sampling, hold the batch at reflux temperature (75-78°C) for 1 to 1.5 hours. 19. Cool the mixture to 40-50°C and take a sample. 20. Distill the ethanol solution under vacuum at approximately 45°C until it is reduced to 100 mL (2.5 volumes). 21. Adjust the temperature to 40-45°C. 22. Add n-heptane (200 mL, 5 volumes) to the ethanol solution and maintain the temperature above 30°C. 23. Cool this batch to 15-20°C. 24. Seed the batch with the title compound [40-50 mg, (wrt) 0.100-0.125% relative to the amount of trans-4-(4-chlorophenyl)cyclohexanecarboxylic acid] as a slurry in heptane (0.0100-0.0125 vol). Maintain at 15-20°C until crystallization is established. If this does not occur within 2 hours, proceed to the next step. 25. Cool the batch to 10-15°C, then seed the title compound again with a seed (40-50 mg, 0.100-0.125 wt%) in heptane (0.0100-0.0125 vol), and then maintain at 10-15°C until crystallization is established. 26. Once crystallization is sufficiently established, the batch is cooled to -10±2°C (-8 to -12°C) over 2.5 to 3.5 hours, and then held for at least 8 hours. 27. Filter the slurry while minimizing any delays that would cause batch heating. 28. Wash the filter cake in two stages using n-heptane (60 mL, 1.5 vol) at -5 to 0°C. 29. Suction dry on filter paper for at least 1 hour. 30. Dry the substance under vacuum at 40-45°C for at least 15 hours.

[0124] The characterization data for the title product was consistent with that of Example 6 of U.S. Patent No. 8,685,973.

[0125] Example 2. Preparation of (Z)-2-((1r,4r)-4-(4-chlorophenyl)cyclohexane-1-carbonyl)-3-(3-(trifluoromethyl)phenyl)ethyl acrylate (formula IVa) [ka]

[0126] The title compound was prepared according to the following procedure: 1. Add the product from Example 1 (240.0 g, 1 equivalent) to the reactor. 2. Separate the anhydrous ethanol (480 mL, 2.0 volume) and add most of it to the reactor. 3. Start stirring at 10-25°C to obtain a slurry. 4. Add 3-(trifluoromethyl)benzaldehyde (271.0 g, 2.0 equivalents) at 10-25°C and rinse with a portion of the remaining ethanol. Most of the slurry will dissolve (endothermic). 5. Add acetic acid (4.67g, 0.1eg) at 10-25°C and rinse with a portion of the remaining ethanol. 6. Add piperidine (6.62g, 0.1eg) at 10-25°C and rinse with the remaining ethanol. 7. Adjust this batch to 20±2℃ (18~22℃), stir for 4~5 hours, and then seed the batch with the title compound (0.24g, (wrt)0.1% relative to the product of Example 1) as a slurry in ethanol (2.4mL, 0.01 vol). 8. At this point, this batch should begin crystallizing within 2 hours of the seeding operation. If not, repeat seeding with the title compound as a slurry in ethanol (2.4 mL, 0.01 vol) (0.24 g, (wrt) 0.1%) relative to the product of Example 1. 9. Once crystallization is established, continue the reaction for another 18-24 hours at 18-22°C, then take a sample to confirm that the reaction is complete. 10. Dilute this batch with anhydrous ethanol (240 mL, 1 volume). 11. Adjust the reaction mixture to 0±2°C (-2 to +2°C) over approximately 1 to 2 hours, and then maintain it at 0±2°C (-2 to +2°C) for at least 2 hours. 12. Filter this batch, and if necessary, return some of the mother liquor to the container to ensure complete transfer. 13. Completely remove the liquid from the filtered cake, while simultaneously cooling the anhydrous ethanol washing solution (240 mL, 1 volume) in the container to below 10°C. 14. Add the washings to the filtered cake and drain completely. 15. Repeat washing with chilled ethanol (240 mL, 1 volume) through the container. Completely remove the filter cake. 16. Dry this batch under vacuum at 40-50°C.

[0127] 1 H-NMR (500MHz; CDCl3): δ7.77(s,1H),7.65(d,2H),7.60(d,2H),7.51(t,1H),7.22(dt,2H),7.06(dt,2H),4.33 (q,2H),2.52-2.38(m,2H),1.94(dd,4H),1.52(qd,2H),1.36(t,3H),1.30(qd,2H).Melting point (DSC): 98.5°C (peak; Form II). [Table 2-1] [Table 2-2] [Table 3-1] [Table 3-2]

[0128] Example 3. Preparation of 3-oxo-3-((1r,4r)-4-phenylcyclohexyl)-2-(3-(trifluoromethyl)benzyl)propanoate ethyl (formula IIIa) [ka]

[0129] Compounds of formula IIIa can be prepared by various methods, such as those described as compound 11 in U.S. Patent No. 8,685,973.

[0130] Alternatively, the compound of formula IIIa can be prepared according to the following method. 1. Charge sodium acetate anhydrous (52.9 g, 1.2 equivalents) into a hydrogenation apparatus. 2. Charge 2.5% Pd-C catalyst, type 394, 50% wet paste (4.375 g, 1.75 wt%) into the vessel. 3. Charge the product of Example 2 (250 g, 0.538 mol, 1.00 equivalent) into the vessel. Then, inertize the vessel with nitrogen. 4. Charge ethanol (1250 mL, 5 volumes) into the vessel, inertize the vessel again, and start stirring at 200 rpm. 5. Pressurize and purge the vessel with hydrogen, then apply a hydrogen pressure of 3 barg (4 barA) to the headspace. Increase the stirring speed to achieve good gas-liquid mixing inside the vessel, and maintain the batch at 20 - 30 °C. 6. Proceed with hydrogenation until no further hydrogen uptake is observed. 7. Continue hydrogenation for at least 1 hour from the point where apparent uptake becomes zero, then sample the batch for analysis. During the holding period of the IPC results, restore the hydrogen atmosphere (3 barg / 4 barA) and raise the batch to approximately 30 °C. 8. Filter the reaction mixture through a Hyflo Supercel pad (37.5 g, 0.15 wt), maintaining a nitrogen atmosphere throughout. 9. Charge ethanol (250 mL, 1 volume) into the reactor, stir at 20 - 25 °C for 5 - 10 minutes, and use it for filter bed washing. 10. Charge ethanol (125 mL, 0.5 volume) into the reactor, stir at 20 - 25 °C for 5 - 10 minutes, and use it for filter bed washing. 11. Finally wash the filter cake with ethanol (125 mL, 0.5 volume). 12. Transfer the filtrate, wash it back into the hydrogenation vessel without intermediate washing, and distill the contents of the reactor under vacuum at ≤ 45 °C to approximately 1.5 volumes. 13. Charge ethyl acetate (750 mL, 3 volumes) into the vessel. 14. Charge deionized water (250 mL, 1 volume) into the vessel. Charge a 15.10% w / w aqueous sodium carbonate solution (0.52 equivalents, 270 mL of solution). 16. Stir and adjust to 15 - 25 °C, then hold for 30 - 45 minutes. 17. Polish - filter this batch into a clean container. 18. Charge ethyl acetate (250 mL, 1 volume) into the first container, and wash by passing through filter paper and the line. 19. Stir this batch at 15 - 25 °C, then sample the batch after about 10 minutes and confirm that the pH is > 7 (test paper). If not, add more sodium carbonate (solid or solution) to achieve this. To ensure that the pH is stable at > 7, perform a second pH check (while stirring) at least 10 minutes after the first check. 20. Let this batch stand for at least 15 minutes, then separate the lower aqueous phase. 21. Charge deionized water (375 mL, 1.5 volumes) into the container and stir at 15 - 25 °C for at least 10 minutes. 22. Let this batch stand for at least 30 minutes, then separate the lower aqueous phase. 23. Charge ethanol (150 mL, 0.6 volume) into this batch. 24. Distill from the container under vacuum targeting a container temperature near 35 - 40 °C (equivalent to approximately 250 mbar of vacuum). Reduce the volume of the batch to about 2 volumes. 25. Charge ethyl acetate (750 mL, 3 volumes) into the container (bringing the total volume of the batch to about 5 volumes), and distill under vacuum to reduce it back to about 2 volumes. 26. Charge ethyl acetate (750 mL, 3 volumes) into the container (here the total volume of the batch is about 5 volumes), and distill under vacuum to reduce it back to about 3 volumes. 27. Charge ethyl acetate (500 mL, 2 volumes) into the container, then distill at atmospheric pressure to reduce the reactor level back to 3 volumes. 28. Charge ethyl acetate (500 mL, 2 volumes) into the container, then distill at atmospheric pressure to reduce the reactor level back to 3 volumes.

[0131] The characterization data for the title compound was identical to that described for compound 11 under U.S. Patent No. 8,685,973.

[0132] Example 4. Preparation of 2-amino-6-((1r,4r)-4-phenylcyclohexyl)-5-(3-(trifluoromethyl)benzyl)pyrimidine-4(3H)-one monohydrate (Formula II) [ka]

[0133] The compound of formula II was prepared as follows. 1. Place 39.1g (5 equivalents) of guanidine hydrochloride into a container at room temperature. 2. Add ethanol (0.36 vol, 12.9 mL) directly to the container, but do not start stirring. Add 119.4 g (4.5 equivalents) of 3.21% w / w sodium ethoxide solution. Start stirring at 15-25°C. 4. Add ethanol (0.56 vol, 20 mL) as a washing solution. 5. Repeat rinsing with ethanol (0.56 volume, 20 mL). 6. Stir at 20-25°C for approximately 30 minutes, ensuring that the mixture is a free-flowing, lumpy slurry. If not, stir for another 30 minutes. 7. Add the ethyl acetate solution from Example 3 (88.5 g of solution, 40% w / w = 35.4 g of the product from Example 3, 1.00 equivalent) through a dry line at 20-30°C. 8. Wash the added material with ethyl acetate (19.0 g, approximately 21.2 mL, 2.64 equivalents). 9. Heat the reaction mixture to reflux temperature and maintain it at reflux temperature (expected to be around 75-78°C) for 4-5 hours. 10. Adjust the batch temperature to 47-53°C, while simultaneously preparing a 50% w / w aqueous acetic acid solution (39.3 g, 4 equivalents), and then adding it to the batch over at least 5-10 minutes. This addition will generate a very slight exothermic reaction. Maintain this batch at 47-53°C during steps 11-17 of the following procedure. 11. Slowly add water (40 mL, 1.13 vol) over at least 15-20 minutes. 12. Seed this batch with a seed of the title compound (18 mg, 0.05% w / w) that had been pre-slurred in a mixture of ethanol (0.09 mL, 0.0025 vol) and purified water (0.09 mL, 0.0025 vol). 13. Slowly add water (40 mL, 1.13 vol) over at least 15-20 minutes. 14. Seed this batch with a seed of the title compound (18 mg, 0.05% w / w) that had been pre-slurred in a mixture of ethanol (0.09 mL, 0.0025 vol) and purified water (0.09 mL, 0.0025 vol). 15. Slowly add water (40 mL, 1.13 vol) over at least 15-20 minutes. 16. Slowly add water (40 mL, 1.13 vol) over at least 15-20 minutes. 17. Cool this batch to 10-20°C (target 15°C) over approximately 1-2 hours and hold for at least 2 hours. 18. On the other hand, prepare a mixture of EtOH, ¼, and water (about 5 volumes) in a specific ratio. Measure each component separately, then mix them. 19. Filter the batch at 15°C and collect the product. 20. A portion of the mixture prepared in step 19 (70 mL, 2 volumes) was placed in a container for rinsing, cooled to 10-20°C (target: 15°C), transferred to filter paper for washing, immersed in the filter cake, and then vacuumed. 21. Pour the second portion of the mixture prepared in step 19 (70 mL, 2 volumes) into a container for rinsing, cool to 10-20°C (target: 15°C), transfer to filter paper for washing, and immerse in the filter cake before vacuuming. 22. Completely drain this batch. 23. Dry the unpurified title compound under vacuum at approximately 45±3°C (42-48°C) with nitrogen efflux for at least 6 hours. 24. Once the solid is deemed sufficiently dry to physically disintegrate, the drying temperature is increased to 60±3°C (57-63°C). The resulting solid is maintained at that temperature until the set limit for drying loss is satisfied.

[0134] 1 H-NMR(500 MHz; DMSO-d6): δ 10.79 (s, 1H), 7.58 (s, 1H), 7.53 - 7.47 (m, 3H), 7.27 (t, 2H), 7.22 (d, 2H), 7.16 (t, 1H), 6.33 (s, 1H), 3.83 (s, 2H), 2.78 - 2.73 (m, 1H), 2.46 - 2.41 (m, 1H), 1.78 - 1.65 (m, 4H), 1.51 - 1.39 (m, 4H). Melting point (DSC): An initial broad melting with a maximum peak endotherm at 196.3 °C with an accompanying loss of water based on thermogravimetric analysis (TGA), followed by a sharp melting at 275.1 °C.

Table 4-1

Table 4-2

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

Chemical Structure

[0136] The method for preparing the compound of Formula I proceeded as follows: 1. In a clean and dry container, add water (80.0 mL, 1.0 volume) to acetic acid (720.0 mL, 9.0 volumes) to prepare an aqueous acetic acid solution. 2. Adjust the temperature to 15 - 25 °C. 3. Charge the product of Example 4 (80.0 g, 1.0 equivalent). 4. Adjust the temperature of this batch to 70 ± 3 °C (67 - 73 °C). 5. On the other hand, in a separate container, charge sodium nitrite (24.8 g, 2.0 equivalents) and water (46.8 g, 0.585 wt), and stir at 18 - 25 °C until dissolved (to a volume of 0.75). 6. The sodium nitrite solution from Step 5 (total approximately 71.6 g, 0.898 wt) is added in portions at a constant rate, while maintaining the reaction temperature at 67-73°C, so that the active addition period is at least 3 hours (see steps below). Stop the addition if necessary to maintain temperature control, and then resume at the same rate. Stop the addition to perform seeding operations during the addition, as specified below. 7. Add 40% of the total sodium nitrite amount (28.6 g, 23 mL) over a minimum of 70 minutes. 8. Seed this batch with a slurry of the title compound (40 mg, 0.0005 wt) in an 85% v / v acetic acid aqueous solution (0.025 vol, 2 mL), hold for 8-10 minutes, confirm crystallization, and then proceed to the next step. 9. Add 5% sodium nitrite solution (3.6 g, approximately 2.9 mL) over at least 10 minutes. Repeat the seeding procedure using a slurry of the title compound (40 mg, 0.0005 wt) in a 10.85% v / v aqueous acetic acid solution (0.025 vol, 2 mL). Hold for 8-10 minutes, confirm crystallization, and then proceed to the next step. 11. Add 5% sodium nitrite solution (3.6 g, approximately 2.9 mL) over at least 10 minutes. Repeat the seeding procedure using a slurry of the title compound (40 mg, 0.0005 wt) in a 12.85% v / v aqueous acetic acid solution (0.025 vol, 2 mL). Hold for 8-10 minutes, confirm crystallization, and then proceed to the next step. 13. Add the remaining 50% of the sodium nitrite solution over at least 90 minutes. 14. Rinse with the remaining sodium nitrite solution and water (4.0 mL, 0.05 vol). 15. The reaction mixture is maintained at 67-73°C for 45-75 minutes, then sampled to confirm the completion of the reaction. 16. After the reaction was complete, the reaction mixture was cooled to 10-15°C over a minimum of 2 hours, and then held at that temperature for at least 1 hour. 17. Filter this batch, smooth the filter cake if necessary, and compress it to achieve effective deliquidation. 18. Cool and wash (10-15°C) with 85% v / v acetic acid aqueous solution (160 mL, 2 volumes) through the container. Immerse in the filter cake and then vacuum. 19. Perform a second cooling wash (10-15°C) with 85% v / v acetic acid aqueous solution (160 mL, 2 volumes) through the container. Immerse the filter cake in the solution and then evacuate. Completely remove the liquid from the filter cake. 20. Perform a final wash with chilled methanol (10-15°C, 160 mL, 2 volumes). Immerse in the filter cake and then vacuum. Completely remove the liquid from the filter cake. 21. Dry the unpurified title compound under vacuum and nitrogen evaporate at approximately 45±3°C (42-48°C) for at least 6 hours. 22. Once the solid is deemed sufficiently dry to physically disintegrate, the drying temperature is increased to 60±3°C (57-63°C). The resulting solid is maintained at that temperature until the set limit for drying loss is satisfied.

[0137] The crystallization of the compound of formula I was carried out as follows: 1. Add dichloromethane (420 mL, 8.4 volumes (wrt) relative to the unpurified title compound). 2. Add the dried, unpurified title compound (50.0 g, 1 equivalent) (measured content, not total weight). 3. Add methanol (85 mL, 1.7 vol) and heat the batch to approximately 30-35°C to obtain the solution. 4. Filter this batch into a clean container using a polishing filter. 5. The raw material containers, filters, and lines are washed with a mixture of dichloromethane (130 mL, 2.6 vol) and methanol (25 mL, 0.50 vol) before reaching the crystallization apparatus. 6. Heat this batch to a boil at atmospheric pressure (estimated 38-40°C) to initiate solvent distillation, removing a total of 20 volumes. Initially, this is mostly dichloromethane. During distillation, add 1 volume of MeOH for every 1 volume of recovered distillate to maintain the batch volume at approximately 13-14 volumes. As the batch temperature will rise to approximately 65°C during the solvent exchange process, the jacket temperature can be increased as needed to maintain a reasonable distillation rate. During distillation, perform the following seeding steps: 7. Seed the batch by pumping a slurry of the title compound (25 mg, 0.05 wt%) in methanol (1.25 mL, 0.025 vol) into the reactor in a solvent exchange of approximately 3 volumes. This seeding operation should be performed regardless of whether the batch already appears to be beginning to crystallize, and it should be held for approximately 10 minutes, paying attention to any changes in the appearance of the batch. 8. Seed the batch by pumping a slurry of the title compound (25 mg, 0.05 wt%) in methanol (1.25 mL, 0.025 vol) into the reactor in a solvent exchange of approximately 4 volumes. This seeding operation should be performed regardless of whether the batch appears to have already begun to crystallize, and it should be held for approximately 10 minutes, paying attention to any changes in the appearance of the batch. 9. Seed the batch by pumping a slurry of the title compound (25 mg, 0.05 wt%) in methanol (1.25 mL, 0.025 vol) into the reactor with a solvent exchange of approximately 5 volumes. Hold for approximately 10 minutes and observe whether crystallization has begun. This step may be omitted if the batch has already substantially crystallized. 10. Once the batch temperature has stabilized, distill an additional 4 volumes (approximate) of solvent to reduce the batch volume to approximately 10 volumes. 11. For each batch, initiate steady-state cooling over at least two hours, bringing the batch from approximately 65°C to 10±3°C (7-13°C, target: 10°C), and then maintain the batch within this range for at least two hours. 12. Filter this batch. If necessary, smooth and compress the filter cake to ensure effective deliquidation, but do not allow the filter cake to dry on the filter paper. 13. Add methanol (100 mL, 2 volumes) to the container, stir, and cool to 10-15°C. 14. Discharge this washing solution onto filter paper, immerse it in the filter cake, and then remove the liquid. 15. Add methanol (100 mL, 2 volumes) to the container, stir, and then cool to 10-15°C. 16. Discharge this washing solution onto filter paper, immerse the cake in it, and then completely drain the liquid. 17. Using a nitrogen evaporator, dry the pure solid corresponding to Formula I under vacuum at a maximum of approximately 60°C (batch temperature) for at least 8 hours.

[0138] The characterization data for the title product was consistent with that of Example 6 of U.S. Patent No. 8,685,973.

[0139] 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 the following formula I, 【Chemistry 1】 (a) A first reaction mixture comprising an oxidizing agent, a first acid, and a compound of the following formula II or its hydrate, 【Chemistry 2】 The method comprises forming and preparing a compound of formula I, wherein the oxidizing agent comprises sodium nitrite and the first acid comprises acetic acid.

2. The method according to claim 1, wherein the first reaction mixture further comprises a first solvent comprising N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), isopropanol, 2-methyltetrahydrofuran (2-MeTHF), tetrahydrofuran, water, or a mixture thereof.

3. The method according to claim 1 or 2, wherein the compound of formula II is in the following monohydrate form. 【Transformation 3】

4. (a1) Dissolve the compound of formula I in a solvent mixture containing approximately 15% (v / v) methanol and approximately 85% (v / v) dichloromethane. (a2) Heat the solvent mixture to remove the dichloromethane, add methanol to the solvent mixture to replace the removed dichloromethane, thereby preparing a methanol solvent mixture, and (a3) Cool the methanol solvent mixture to form crystals of formula I. The method according to any one of claims 1 to 3, further comprising:

5. The compound of formula II or its hydrate is (b) A second reaction mixture comprising guanidine or a salt thereof and the compound of formula III below: 【Chemistry 4】 Prepared by a method comprising forming and preparing the compound of formula II or its hydrate, In the formula, R １ is C １～６ The method according to any one of claims 1 to 4, wherein the alkyl group is alkyl.

6. The method according to claim 5, wherein the compound of formula III is the compound of formula IIIa below. 【Transformation 5】

7. The method according to claim 5 or 6, wherein the second reaction mixture further comprises a second solvent comprising ethanol, isopropanol, methyl acetate, ethyl acetate, isopropyl acetate, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), 2-methyltetrahydrofuran (2-MeTHF), tetrahydrofuran (THF), water, or a mixture thereof.

8. The guanidine is a free guanidine base, and, The above method, before step (b), The method according to any one of claims 5 to 7, further comprising (b1) forming a third reaction mixture comprising a guanidine salt and a base to prepare a guanidine free base to be used in step (b).

9. The method according to claim 8, wherein the third reaction mixture further comprises a third solvent comprising methanol, ethanol, n-propanol, isopropanol, water, or a mixture thereof.

10. The method according to claim 9, wherein the third reaction mixture further comprises a water scavenger.

11. The above method, after step (b), (b) The method according to any one of claims 8 to 10, further comprising adding water to the second reactant to crystallize the compound of formula II or its hydrate.

12. The compound of formula III is (c) A fourth reaction mixture comprising a reducing agent and a compound of the following formula IV: 【Transformation 6】 (In the formula, R １ C １－６ (It is alkyl.) Form and prepare the compound of formula III. The method according to any one of claims 5 to 11, prepared by...

13. The reducing agent is palladium-carbon (Pd-C), palladium-silicon dioxide, palladium-calcium carbonate, platinum-carbon, palladium hydroxide, platinum hydroxide, palladium(II) chloride, Raney nickel, rhodium-alumina, rhodium(III) chloride trihydrate / Aliquat 336 (N-methyl N-trioctylammonium chloride), Ru (BINAP). ２ *NET ３ , or nickel boride (Ni ２ The method according to claim 12, wherein the hydrogenation catalyst contains B).

14. The method according to claim 12 or 13, wherein the fourth reaction mixture comprises a fourth solvent including methanol, ethanol, n-propanol, isopropanol, n-butanol, ethyl acetate, isopropyl acetate, n-butyl acetate, formic acid, acetic acid, trifluoroacetic acid, water, or a mixture thereof.

15. The method according to any one of claims 12 to 14, wherein the compound of formula IV is a compound of the following formula IVa. 【Transformation 7】

16. The compound of formula IV is (d) A fifth reaction mixture comprising a first amine base, a second acid, 3-trifluoromethylbenzaldehyde, and a compound of the following formula V: 【Transformation 8】 (wherein, R １ is C １－６ alkyl) Form and prepare the compound of formula IV. The method according to any one of claims 12 to 15, prepared by...

17. The first amine base is triethylamine, N,N-diisopropylethylamine (DIPEA), N,N-dimethylisopropylamine (DIMPA), piperidine, 1-ethylpiperidine, N-methylmorpholine, N-methylpyrrolidine, N,N-dimethylamine, piperazine, N-methylpiperazine, tris(hydroxymethyl)methylamine [(HOCH] ２ ) ３ CNH ２ The method according to claim 16, comprising benzylamine, pyridine, N,N-dimethylaniline, N,N-diethylaniline, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine (DMAP), quinuclidine, 4-pyrrolidinopyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO), or a mixture thereof.

18. The method according to claim 16 or 17, wherein the compound of formula V is a compound of the following formula Va. 【Chemistry 9】

19. The method according to any one of claims 16 to 18, wherein the fifth reaction mixture further comprises a fifth solvent comprising methanol, ethanol, n-propanol, iso-propanol, acetonitrile, dichloromethane, diethyl ether, 2-methyltetrahydrofuran (2-MeTHF), cyclopropyl methyl ether (CPME), tetrahydrofuran, 2,2,2-trifluoroethanol, toluene, xylene, mesitylene, or a mixture thereof.

20. The compound of formula V is (e1) A seventh reaction mixture comprising isopropylidene malonate, a carboxyl coupling agent, a second amine base, and a compound of the following formula VI: 【Chemistry 10】 To form and prepare an intermediate mixture, and (e2) Heat the sixth reaction mixture containing the intermediate mixture to prepare the compound of formula V. The method according to any one of claims 16 to 19, prepared by...

21. The carboxyl coupling agents are dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (EDAC), bis[[4-(2,2-dimethyl-1,3-dioxolyl(dioxolyl))]methyl]carbodiimide (BDDC), and N-cyclohexyl-N'-(2-morpholinoethyl)carbodiimide. Methyl-p-toluenesulfonate, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidemethiozide, thionyl chloride, oxalyl chloride, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), carbonyldiimidazole, bis(1,2,4-triazolyl)methanone, n-propanephosphonic anhydride, ethylmethylphosphonic anhydride (EMPA), cyanuryl chloride, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorphonium chloride (DMTMM), guanidinium salt, uronium salt, benzotri The method according to claim 20, wherein the salt is azoletetramethyluronium hexafluorophosphate (HBTU), azabenzotriazoletetramethyluronium hexafluorophosphate (HATU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), O-(2-oxo-1(2H)pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TPTU), or N-[[[(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy](dimethylamino)methylene]-N-methylmethaneaminium tetrafluoroborate (TOTU).

22. The method according to claim 20 or 21, wherein the second amine base includes triethylamine, N,N-diisopropylethylamine (DIPEA), N,N-dimethylisopropylamine (DIMPA), 1-ethylpiperidine, N-methylmorpholine, N-methylpyrrolidine, pyridine, N,N-dimethylaniline, N,N-diethylaniline, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine (DMAP), quinuclidine, 4-pyrrolidinopyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO), or a mixture thereof.

23. The method according to any one of claims 20 to 22, wherein the seventh reaction mixture further comprises a seventh solvent comprising acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, chloroform, toluene, or a mixture thereof.

24. The method according to any one of claims 20 to 23, wherein the sixth reaction mixture further comprises a sixth solvent comprising methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, pentanol, hexanol, or a mixture thereof.

25. (e3) The method according to any one of claims 20 to 24, further comprising the step of adding heptane to the sixth reaction mixture to crystallize the compound of formula V.

26. A method for preparing the compound of the following formula I, 【Chemistry 11】 The method described above is (e1) A seventh reaction mixture comprising dichloromethane, isopropylidene malonate, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (EDAC), dimethylaminopyridine (DMAP), and a compound of the following formula VI: 【Chemistry 12】 Forming and preparing an intermediate mixture, (e2) The sixth reaction mixture containing the intermediate mixture and ethanol is heated to prepare the compound of the following formula Va, 【Chemistry 13】 (e3) Adding heptane to the sixth reaction mixture to crystallize the compound of formula Va, (d) A fifth reaction mixture comprising ethanol, piperidine, acetic acid, 3-trifluoromethylbenzaldehyde, and the compound of formula Va is formed to prepare the following compound of formula IVa: 【Chemistry 14】 (c) A fourth reaction mixture comprising ethanol, 5% Pd-C, hydrogen, sodium acetate, and the compound of formula IVa is formed to prepare the following compound of formula IIIa: 【Chemistry 15】 (b1) A third reaction mixture containing ethanol, guanidine hydrochloride, and sodium ethoxide is formed to prepare a free guanidine base, (b) A second reaction mixture comprising ethyl acetate, guanidine free base, and the compound of formula IIIa is formed to prepare the monohydrate form of the following compound of formula II: 【Chemistry 16】 (a) A method comprising preparing a compound of formula I by forming a first reaction mixture containing acetic acid, sodium nitrite, and a monohydrate form of the compound of formula II.

27. A method for preparing the compound of formula II or its hydrate, 【Chemistry 17】 The method described above is (b) A second reaction mixture comprising guanidine and its salts, and the compound of formula III shown below: [Chemistry 18] This includes forming and preparing the compound of formula II or its hydrate, In the formula, R １ is C １～６ A method that is alkyl.

28. The compound of formula II below, or its hydrate. 【Chemistry 19】

29. The compound of the following formula IVa. 【Chemistry 20】

30. The compound of the following formula Va. 【Chemistry 21】

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