Preparation of thiophene derivatives

Abstract

Disclosed is a process for preparing a compound of formula (VII): [Formula 1] TIFF2024545712000084.tif52165Comprises a condensation reaction of a compound of formula (VI) [Case 2] TIFF2024545712000085.tif93165.

Description

Detailed Description of the Invention

[0001] [Field of the Invention] The present disclosure relates generally to the field of medicinal chemistry, and more specifically to the preparation of thiophene derivatives.

[0002] [background] Phosphodiesterase (PDE) refers to enzymes that catalyze the hydrolysis of doubly phosphorylated molecules in oligonucleotides, i.e., polynucleotides. Phosphodiesterases (PDEs) function to hydrolyze intracellular second messengers (cAMP, cyclic adenosine phosphate, or cGMP, guanosine phosphate), degrading intracellular cAMP or cGMP, thereby terminating the biochemical effects transmitted by these second messengers.

[0003] [overview] In one aspect, the disclosure relates to a process for preparing a compound of formula (VII):

[0004] [ka] The compound of formula (VI) or the compound of formula (VIII) is subjected to a condensation reaction.

[0005] [ka] .

[0006] In another aspect, the present disclosure relates to a process for preparing a compound of formula (VI):

[0007] [ka] The compound of formula (V) is hydrolyzed.

[0008] [ka] .

[0009] In a further aspect, the present disclosure relates to a process for preparing a compound of formula (V):

[0010] [ka] The compound of formula (IV) is subjected to a condensation reaction.

[0011] [ka] .

[0012] In yet another aspect, the present disclosure relates to a process for preparing a compound of formula (IV):

[0013] [ka] condensation reaction of a compound of formula (III) with a compound of formula (II) to obtain a compound of formula (IV)

[0014] [ka] .

[0015] In another aspect, the present disclosure relates to a process for preparing a compound of formula (III):

[0016] [ka] comprising reacting a compound of general formula (I)

[0017] [ka] wherein R1 ≠ R2, and R1 and R2 are selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted aryl.

[0018] In a further aspect, the present disclosure relates to a process for preparing a compound of formula (VII), comprising: reacting a compound of general formula (I) to obtain a compound of formula (III); condensation reaction of a compound of formula (III) with a compound of formula (II) to obtain a compound of formula (IV); subjecting a compound of formula (IV) to a condensation reaction to obtain a compound of formula (V); hydrolysis of the compound of formula (V) to obtain a compound of formula (VI); and A condensation reaction of a compound of formula (VI) or a compound of formula (VIII) to obtain a compound of formula (VII).

[0019] In one aspect, the disclosure relates to a process for preparing a compound of formula (VII):

[0020] [ka] The compound of formula (VIII) is reacted with

[0021] [ka] .

[0022] In another aspect, the present disclosure relates to a process for preparing a compound of formula (VIII):

[0023] [ka] The compound of formula (IX) is hydrolyzed.

[0024] [ka] .

[0025] In a further aspect, the present disclosure relates to a process for preparing a compound of formula (IX):

[0026] [ka] The compound of formula (X) is subjected to a condensation reaction.

[0027] [ka] .

[0028] In yet another aspect, the present disclosure relates to a process for preparing a compound of formula (X):

[0029] [ka] condensation reaction of a compound of formula (XI) with a compound of formula (II) to obtain a compound of formula (X).

[0030] [ka] .

[0031] In another aspect, the present disclosure relates to a process for preparing a compound of formula (XI):

[0032] [ka] comprising reacting a compound of general formula (I)

[0033] [ka] wherein R1 ≠ R2, and R1 and R2 are selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted aryl.

[0034] In a further aspect, the present disclosure relates to a process for preparing a compound of formula (VII), comprising: reacting a compound of general formula (I) to obtain a compound of formula (XI); condensation reaction of a compound of formula (II) with a compound of formula (XI) to obtain a compound of formula (X); subjecting a compound of formula (X) to a condensation reaction to obtain a compound of formula (IX); hydrolysis of the compound of formula (IX) to obtain a compound of formula (VIII); and condensation reaction of the compound of formula (VIII) to obtain the compound of formula (VII).

[0035] In one aspect, the disclosure relates to a process for preparing a compound of formula (VII'):

[0036] [ka] The compound of formula (VI') is subjected to a condensation reaction.

[0037] [ka] .

[0038] In another aspect, the present disclosure relates to a process for preparing a compound of formula (VI'):

[0039] [ka] The compound of formula (V') is hydrolyzed.

[0040] [ka] .

[0041] In a further aspect, the disclosure relates to a process for preparing a compound of formula (V'):

[0042] [ka] The compound of formula (IV') is subjected to a condensation reaction.

[0043] [ka] .

[0044] In yet another aspect, the present disclosure relates to a process for preparing a compound of formula (IV'):

[0045] [ka] condensation reaction of a compound of formula (III) with a compound of formula (II') to obtain a compound of formula (IV').

[0046] [ka] .

[0047] In a further aspect, the present disclosure relates to a process for preparing a compound of formula (VII'), comprising: reacting a compound of general formula (I) to obtain a compound of formula (III); condensation reaction of a compound of formula (III) with a compound of formula (II') to obtain a compound of formula (IV'); subjecting the compound of formula (IV') to a condensation reaction to obtain a compound of formula (V'); hydrolysis of the compound of formula (V') to obtain a compound of formula (VI'); and subjecting the compound of formula (VI') to a condensation reaction to obtain a compound of formula (VII').

[0048] In one aspect, the disclosure relates to a process for preparing a compound of formula (VII″):

[0049] [ka] The compound of formula (VI'') is reacted with

[0050] [ka] .

[0051] In another aspect, the present disclosure relates to a process for preparing a compound of formula (VI″):

[0052] [ka] The compound of formula (V'') is hydrolyzed.

[0053] [ka] .

[0054] In yet another aspect, the present disclosure relates to a process for preparing a compound of formula (V″):

[0055] [ka] The compound of formula (IV'') is subjected to a condensation reaction.

[0056] [ka] .

[0057] In yet another aspect, the present disclosure relates to a process for preparing a compound of formula (IV″):

[0058] [ka] by condensation reaction of a compound of formula (III) with a compound of formula (II″) to obtain a compound of formula (IV″).

[0059] [ka] .

[0060] In a further aspect, the present disclosure relates to a process for preparing a compound of formula (VII″), comprising: reacting a compound of general formula (I) to obtain a compound of formula (III); condensation reaction of a compound of formula (III) with a compound of formula (II″) to obtain a compound of formula (IV″); subjecting a compound of formula (IV'') to a condensation reaction to obtain a compound of formula (V''); hydrolysis of the compound of formula (V'') to obtain a compound of formula (VI''); and subjecting the compound of formula (VI'') to a condensation reaction to obtain a compound of formula (VII'').

[0061] [Detailed Description] In the following description, certain specific details are set forth in order to provide a thorough understanding of various disclosed embodiments. However, one skilled in the art will recognize that the embodiments can be practiced without one or more of these specific details, or with other methods, components, materials, etc.

[0062] Unless the context requires otherwise, throughout this specification and the claims which follow, the term "comprise" and variations thereof, such as "comprises" and "comprising," are to be interpreted in their open and inclusive sense of "including, but not limited to."

[0063] As used in this disclosure and the appended claims, singular references without a quantity include plural references unless the context clearly dictates otherwise. References throughout this specification to "one embodiment," or "an embodiment," or "in other embodiments," or "in some embodiments" mean that the particular referent feature or characteristic described in connection with an embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment," "in an embodiment," "in other embodiments," or "in some embodiments" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0064] It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0065] [Definition] Therefore, as used in this specification and the appended claims, unless otherwise specified, the following terms have the meanings indicated: Certain chemical groups designated herein are preceded by a shorthand notation indicating the total number of carbon atoms identified in the designated chemical group. For example, C1-C4 alkyl represents an alkyl group having a total of 1 to 4 carbon atoms, as defined below, C3-C4 alkyl represents an alkyl group having a total of 1 to 4 carbon atoms, as defined below, C4-C6 alkyl represents an alkyl group having a total of 1 to 4 carbon atoms, as defined below, C5-C6 alkyl represents an alkyl group having a total of 1 to 4 carbon atoms, as defined below, C6-C7 alkyl represents an alkyl group having a total of 1 to 4 carbon atoms, as defined below, C7-C8 alkyl represents an alkyl group having a total of 1 to 4 carbon atoms, as defined below, C8-C9 alkyl represents an alkyl group having a total of 1 to 4 carbon atoms, as defined below, C9-C10 alkyl represents an alkyl group having a total of 1 to 4 carbon atoms, as defined below, C1-C11 alkyl represents an alkyl group having a total of 10 Cycloalkyl refers to a cycloalkyl group, as defined below, having a total of 3 to 10 carbon atoms. The total number of carbon atoms in the shorthand notation does not include carbons that may exist in substituents of the group being described.

[0066] The term "hydrocarbyl" as used herein refers to an aliphatic hydrocarbyl group. The hydrocarbyl moiety can be a "saturated hydrocarbyl" group, meaning that it does not contain any alkene or alkyne moieties. The hydrocarbyl moiety can also be an "unsaturated hydrocarbyl" moiety, meaning that it contains at least one alkene or alkyne moiety. An "alkene" moiety refers to a group consisting of 2 to 8 carbon atoms and at least one carbon-carbon double bond, and is attached to the remainder of the molecule by a single bond, e.g., ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. An "alkyne" moiety refers to a straight or branched chain hydrocarbon chain group consisting of 2 to 8 carbon atoms and at least one carbon-carbon triple bond, and is attached to the remainder of the molecule by a single bond. The hydrocarbyl group can be branched or straight, whether saturated or unsaturated.

[0067] The hydrocarbyl groups may have from 1 to 8 carbon atoms (whenever hydrocarbyl groups appear herein, numerical ranges such as "1 to 8" refer to each integer in the given numerical range, e.g., "1 to 8" means that the hydrocarbyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 8 carbon atoms, but this definition also encompasses the occurrence of the term "hydrocarbon" when no numerical range is specified).

[0068] The hydrocarbon group may be optionally substituted, i.e., substituted or unsubstituted. If substituted, the substituents are individually and independently selected from the group consisting of cyclohydrocarbyl, aryl, heteroaryl, heteroalicyclyl, hydroxy, hydrocarbyloxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfinamido, N-sulfinamido, C-carboxyl, O-carboxyl, isocyanate, thiocyano, isothiocyanate, nitro, silyl, trihalomethanesulfonyl, -NR'R'', where R' and R'' are hydrocarbyl groups as defined herein, or amino, including mono- and di-substituted amino groups, and protected derivatives thereof. Exemplary hydrocarbyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, and butynyl. Whenever a substituent is described as "optionally substituted," the substituent may be substituted with one of the above substituents.

[0069] The term "aryl" as used herein refers to a carbocyclic ring (completely carbon), or two or more fused rings (rings sharing two adjacent carbon atoms), with a completely delocalized pi-electron system. Examples of aryl groups include, but are not limited to, fluorenyl, phenyl, and naphthyl. Aryl groups can have, for example, 5 to 12 carbon atoms. The aryl groups of the present disclosure can be substituted or unsubstituted. When substituted, the hydrogen atom is substituted with one or more substituents independently selected from the group consisting of hydrocarbyl, cyclohydrocarbyl, aryl, heteroaryl, heteroalicyclyl, hydroxy, protected hydroxy, hydrocarbyloxy, aryloxy, mercapto, hydrocarbylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfinamido, N-sulfinamido, C-carboxyl, protected C-carboxyl, O-carboxyl, isocyanate, thiocyano, isothiocyanate, nitro, silyl, trihalomethanesulfonyl, -NR'R'', where R' and R'' are hydrocarbyl groups as defined herein, and protected amino. Whenever a substituent is described as "optionally substituted", the substituent may be substituted with one of the above substituents.

[0070] The term "heteroaryl" as used herein refers to a 5- to 18-membered aromatic ring group containing 1 to 17 carbon atoms and 1 to 10 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may include fused or bridged ring systems. Furthermore, the nitrogen, carbon, or sulfur atom of the heteroaryl group may be optionally oxidized, and the nitrogen atom may be optionally quaternized. Representative examples of heteroaryl are azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolanyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepanyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxolanyl, benzodioxadienyl, benzopyranyl, benzopyronyl, benzofuranyl, benzofuranyl, benzofuranonyl, benzothienyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothienyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, Aryl groups include, but are not limited to, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolyl, quinuclidinyl, isoquinolyl, tetrahydroquinolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl. The aryl groups of the present disclosure may be substituted or unsubstituted.When substituted, the hydrogen atom is substituted with one or more substituents independently selected from the group consisting of hydrocarbyl, cyclohydrocarbyl, aryl, heteroaryl, heteroalicyclyl, hydroxy, protected hydroxy, hydrocarbyloxy, aryloxy, mercapto, hydrocarbylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfinamido, N-sulfinamido, C-carboxyl, protected C-carboxyl, O-carboxyl, isocyanate, thiocyano, isothiocyanate, nitro, silyl, trihalomethanesulfonyl, -NR'R'', where R' and R'' are hydrocarbyl groups as defined herein, and protected amino. Whenever a substituent is described as "optionally substituted", the substituent may be substituted with one of the above substituents.

[0071] The term "cyclohydrocarbyl" as used herein refers to a stable non-aromatic monocyclic or bicyclic hydrocarbyl composed solely of carbon and hydrogen atoms, having from 3 to 15 carbon atoms, and in some embodiments from 3 to 12 carbon atoms, which cyclohydrocarbyl is saturated or unsaturated and attached to the remainder of the molecule via a single bond, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclodecyl, and the like. Unless stated otherwise specifically in this specification, the term "cyclohydrocarbyl" is intended to include cyclohydrocarbyl groups as defined above, which may be optionally substituted with one or more substituents selected from the group consisting of cyclohydrocarbyl, aryl, heteroaryl, heteroalicyclyl, hydroxy, hydrocarbyloxy, aryloxy, mercapto, hydrocarbylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfinamido, N-sulfinamido, C-carboxyl, O-carboxyl, isocyanate, thiocyanate, isothiocyanate, nitro, silyl, trihalomethanesulfonyl, -NR'R'', where R' and R'' are hydrocarbyl groups as defined in this disclosure, or amino, including mono- and di-substituted amino groups, and protected derivatives thereof.

[0072] As used herein, the term "substantially complete" reaction refers to a reaction that contains greater than about 80% (% yield), more preferably greater than about 90% (% yield), even more preferably greater than about 95% (% yield), and most preferably greater than about 97% (% yield) of the desired product.

[0073] The term "about" is used herein to indicate that a given numerical value is approximate. For example, when referring to a reaction temperature, the term "about" means that the temperature referred to includes temperatures with deviations in the range of 30%, 25%, 20%, 15%, 10%, or 5%. Similarly, when referring to a reaction time, the term "about" means that the time referred to includes times with deviations in the range of 30%, 25%, 20%, 15%, 10%, or 5%.

[0074] The term Class 1 solvents as used herein refers to ICHQ3C(R8) Class 1 solvents, which are a class of solvents to be avoided in the manufacture of pharmaceutical products that are known or strongly suspected human carcinogens and are hazardous to the environment, more specifically benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethylene, and 1,1,1-trichloroethane.

[0075] The term Class 2 solvents as used herein refers to ICH Q3C(R8) Class 2 solvents, which are a class of solvents that should be restricted in the manufacture of pharmaceutical products. The solvents in question are those that are non-genotoxic animal carcinogens or that may cause other irreversible toxicity, such as neurotoxicity or teratogenicity, or that have other severe but reversible toxicity, and more specifically refer to acetonitrile, chlorobenzene, chloroform, cumene, cyclohexane, cyclopentyl methyl ether, 1,2-dichloroethylene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, methyl isobutyl ketone, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tert-butanol, tetrahydrofuran, tetrahydronaphthalene, toluene, 1,1,2-trichloroethylene, and xylene.

[0076] The term Class 3 solvents as used herein refers to Class 3 solvents of ICHQ3C(R8), which is a class of solvents with low potential toxicity in the manufacture of pharmaceutical products. The solvents have low potential toxicity to the human body and do not require health-based exposure, more specifically, acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, dimethyl sulfoxide, ethanol, ethyl acetate, diethyl ether, methyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, 2-methyl-1-propanol, 2-methyltetrahydrofuran, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and triethylamine.

[0077] In the event of a discrepancy between a depicted structure and the name of a given structure, the depicted structure should be highlighted. Furthermore, if the stereochemistry of a structure or portion of a structure is not shown, e.g., with bold or dashed lines, the structure or portion of the structure should be interpreted as including all stereoisomers of the structure.

[0078] [Specific embodiment] In one aspect, the disclosure relates to a process for preparing a compound of formula (VII):

[0079] [ka] The compound of formula (VI) or the compound of formula (VIII) is subjected to a condensation reaction.

[0080] [ka] .

[0081] In some embodiments, illustrative examples of reagents that can be used in the condensation reaction to prepare a compound of formula (VII) of the present disclosure include, but are not limited to, N,N'-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), EDCI (EDC·HCl), dichlorosulfoxide (SOCl2), oxalyl chloride ((COCl)2), acetyl chloride (AcCl), acetic anhydride (Ac2O), N,N-dimethylformamide (DMF), and any mixtures thereof.

[0082] In some embodiments, illustrative examples of reagents that can be used in the condensation reaction to prepare a compound of formula (VII) of the present disclosure include, but are not limited to, a combination of dichlorosulfoxide (SOCl) / N,N-dimethylformamide (DMF), oxalyl chloride ((COCl)) / N,N-dimethylformamide (DMF), or acetyl chloride (AcCl) / N,N-dimethylformamide (DMF).

[0083] In some embodiments, illustrative examples of reagents that can be used in the condensation reaction to prepare a compound of formula (VII) of the present disclosure include, but are not limited to, N,N'-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), EDCI (EDC·HCl), dichlorosulfoxide (SOCl2), oxalyl chloride ((COCl)2), acetyl chloride (AcCl), acetic anhydride (Ac2O), N,N-dimethylformamide (DMF), dichlorosulfoxide (SOCl2) / N,N-dimethylformamide (DMF), oxalyl chloride ((COCl)2) / N,N-dimethylformamide (DMF), or acetyl chloride (AcCl) / N,N-dimethylformamide (DMF). The weight ratio of said reagent to the compound of formula (VI) or said reagent to the compound of formula (VIII) is from about 1:1 to about 3:1.

[0084] In some embodiments, illustrative examples of solvents that can be used in the condensation reaction to prepare a compound of formula (VII) in the present disclosure include, but are not limited to, tetrahydrofuran, dichloromethane (DCM), acetic anhydride (AcO), and any mixtures thereof.

[0085] In some embodiments, the condensation reaction to prepare the compound of formula (VII) is carried out at about -5°C to about 150°C. In some embodiments, the condensation reaction to prepare a compound of formula (VII) is carried out at about -10 °C to about 40 °C.

[0086] In some embodiments, the condensation reaction to prepare the compound of formula (VII) is carried out at about 20°C to about 30°C. In some embodiments, the compound of formula (VII) is recrystallized.

[0087] In some embodiments, illustrative examples of solvents that can be used in the recrystallization of the compound of formula (VII) of the present disclosure include, but are not limited to, acetonitrile / isopropanol, ethyl acetate, acetonitrile / water, tetrahydrofuran / water, and any mixture thereof.

[0088] In another aspect, the present disclosure relates to a process for preparing a compound of formula (VI):

[0089] [ka] The compound of formula (V) is hydrolyzed.

[0090] [ka] .

[0091] In some embodiments, the hydrolysis reaction to prepare a compound of formula (VI) is carried out under alkaline conditions. In some embodiments, illustrative examples of salts that can be used in the hydrolysis reaction to prepare a compound of formula (VI) of the present disclosure include, but are not limited to, potassium salts, sodium salts, lithium salts, and any mixtures thereof.

[0092] In some embodiments, illustrative examples of salts that can be used in the hydrolysis reaction to prepare compounds of formula (VI) of the present disclosure include, but are not limited to, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, sodium carbonate, lithium hydroxide, lithium carbonate, and any mixtures thereof.

[0093] In some embodiments, the hydrolysis reaction to prepare a compound of formula (VI) of the present disclosure is carried out at about -5°C to about 35°C. In some embodiments, the hydrolysis reaction to prepare a compound of formula (VI) of the present disclosure is carried out at about 0°C to about 35°C.

[0094] In some embodiments, the hydrolysis reaction to prepare a compound of formula (VI) of the present disclosure is carried out at about 20°C to about 30°C. In some embodiments, illustrative examples of solvents that can be used in the compounds of formula (VI) of the present disclosure include, but are not limited to, ethanol / water, methanol / water, isopropanol / water, acetonitrile / acetone / water, acetonitrile / acetone, ethyl acetate, tetrahydrofuran, tetrahydrofuran / water, acetone / water, and any mixtures thereof.

[0095] In some embodiments, the molar ratio of a compound of formula (V) that can be used to prepare a compound of formula (VI) of the present disclosure to a salt that can be used in a hydrolysis reaction of the present disclosure to prepare a compound of formula (VI) is about 1:1 to about 1:10.

[0096] In some embodiments, the molar ratio of a compound of formula (V) that can be used to prepare a compound of formula (VI) of the present disclosure to a salt that can be used in a hydrolysis reaction of the present disclosure to prepare a compound of formula (VI) is about 1:1 to about 1:6.

[0097] In some embodiments, the molar ratio of the compound of formula (V) that can be used to prepare the compound of formula (VI) of the present disclosure to the salt that can be used to prepare the compound of formula (VI) in the hydrolysis reaction of the present disclosure is about 1:5.

[0098] In a further aspect, the present disclosure relates to a process for preparing a compound of formula (V):

[0099] [ka] The compound of formula (IV) is subjected to a condensation reaction.

[0100] [ka] .

[0101] In some embodiments, illustrative examples of reagents that can be used in the condensation reaction to prepare compounds of formula (V) of the present disclosure include, but are not limited to, acetyl chloride (AcCl), acetic anhydride (AcO), and any mixtures thereof.

[0102] In some embodiments, illustrative examples of reagents that can be used in the condensation reaction to prepare a compound of formula (V) of the present disclosure include, but are not limited to, 4-dimethylaminopyridine (DMAP), N-methylmorpholine (NMM), triethylamine (TEA), pyridine (Py), N,N-diisopropylethylamine (DIEA), pyridine (Py), and any mixtures thereof.

[0103] In some embodiments, illustrative examples of reagents that can be used in the condensation reaction to prepare a compound of formula (V) of the present disclosure include, but are not limited to, AcO, AcO / DMAP, AcO / DMAP / NMM, CHCOCl / TEA / DCM / DMAP, and CHCOCl / Py.

[0104] In some embodiments, illustrative examples of solvents that can be used in the condensation reaction to prepare a compound of formula (V) of the present disclosure include, but are not limited to, acetic anhydride, dichloromethane (DCM), pyridine (Py), tetrahydrofuran, acetonitrile, acetone, ethyl acetate, and any mixtures thereof.

[0105] In some embodiments, the condensation reaction to prepare a compound of formula (V) of the present disclosure is carried out at about 0 °C to about 150 °C. In some embodiments, the condensation reaction to prepare a compound of formula (V) of the present disclosure is carried out at about 90°C to about 150°C.

[0106] In some embodiments, the condensation reaction to prepare a compound of formula (V) of the present disclosure is carried out at about 125°C to about 140°C. In some embodiments, illustrative examples of solvents that can be used to purify the compounds of formula (V) of the present disclosure include, but are not limited to, ethanol, methyl tert-butyl ether (MTBE), methanol, ethyl acetate, n-hexane, diethyl ether, tetrahydrofuran (THF), and any mixtures thereof.

[0107] In yet another aspect, the present disclosure relates to a process for preparing a compound of formula (IV):

[0108] [ka] condensation reaction of a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (IV)

[0109] [ka] .

[0110] In some embodiments, illustrative examples of condensing agents that can be used in the preparation of compounds of formula (IV) of the present disclosure include, but are not limited to, carbodiimide-type condensing agents, phosphorus cation condensing agents, urea cation condensing agents, other suitable condensing agents, and any mixtures thereof.

[0111] In some embodiments, illustrative examples of carbodiimide-type condensing agents that can be used in the preparation of compounds of formula (IV) of the present disclosure include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), EDCI (the hydrochloride salt of EDC), and dicyclohexylcarbodiimide (DCC).

[0112] In some embodiments, illustrative examples of phosphorus cation condensing agents that can be used in the preparation of compounds of formula (IV) of the present disclosure include, but are not limited to, 1H-benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP), bromotrispyrrolidinophosphonium hexafluorophosphate (PyBrOP), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP).

[0113] In some embodiments, illustrative examples of urea cation condensing agents that can be used in the preparation of compounds of formula (IV) of the present disclosure include, but are not limited to, N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU).

[0114] In some embodiments, illustrative examples of other suitable condensing agents that can be used in the preparation of compounds of formula (IV) of the present disclosure include, but are not limited to, 1-hydroxybenzotriazole (HOBt), 6-chloro-1-hydroxybenzotriazole (Cl-HOBt), N-hydroxy-7-azabenzotriazole (HOAt), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), 3-diethoxyphosphoryloxy-1,2,3-benzotriazin-4(3H)-one (DEPBT), N-hydroxysuccinimide (HOSu), and pentafluorophenol.

[0115] In some embodiments, illustrative examples of solvents that can be used in the preparation of compounds of formula (IV) of the present disclosure include, but are not limited to, dichloromethane, trichloromethane, acetonitrile, toluene, tetrahydrofuran, dioxane, and any mixtures thereof.

[0116] In some embodiments, the condensation reaction to prepare a compound of formula (IV) of the present disclosure is carried out at about 0°C to about 50°C. In some embodiments, the condensation reaction to prepare a compound of formula (IV) of the present disclosure is carried out at about 25°C to about 35°C.

[0117] In some embodiments, the weight ratio of Formula (III) to Formula (II) in the condensation reaction to prepare a compound of Formula (IV) of the present disclosure is from about 1:1.3 to about 1:1.4.

[0118] In some embodiments, the weight ratio of Formula (III) to Formula (II) in the condensation reaction to prepare a compound of Formula (IV) of the present disclosure is from about 1:1.35 to about 1:1.4.

[0119] In some embodiments, the weight ratio of Formula (III) to Formula (II) in the condensation reaction to prepare a compound of Formula (IV) of the present disclosure is about 1:1.36.

[0120] In another aspect, the present disclosure relates to a process for preparing a compound of formula (III):

[0121] [ka] comprising reacting a compound of general formula (I)

[0122] [ka] wherein R1 ≠ R2, and R1 and R2 are selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted aryl.

[0123] In some embodiments, R and R are each independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, and substituted or unsubstituted C6-C 12 aryl.

[0124] In some embodiments, R1 and R2 are each independently selected from the group consisting of methyl, ethyl, propyl, tert-butyl, benzyl, and allyl.

[0125] In some embodiments, illustrative examples of compounds that can be used in the preparation of formula (III) of the present disclosure include, but are not limited to, trifluoroacetic acid (TFA), hydrochloric acid, hydrobromic acid, sulfonic acid, palladium on carbon, tetrakistriphenylphosphine palladium, or any mixture thereof.

[0126] In some embodiments, the weight ratio of illustrative examples of trifluoroacetic acid (TFA), hydrochloric acid, hydrobromic acid, sulfonic acid, palladium on carbon, tetrakistriphenylphosphine palladium, or any mixture thereof that can be used in the preparation of the compound of formula (III) of the present disclosure to the compound of formula (I) is about 1.5:1 to about 1:1.

[0127] In some embodiments, the weight ratio of illustrative examples of trifluoroacetic acid (TFA), hydrochloric acid, hydrobromic acid, sulfonic acid, palladium on carbon, tetrakistriphenylphosphine palladium, or any mixture thereof that can be used in the preparation of the compound of formula (III) of the present disclosure to the compound of formula (I) is about 1.1:1 to about 1:1.

[0128] In some embodiments, the weight ratio of illustrative examples of trifluoroacetic acid (TFA), hydrochloric acid, hydrobromic acid, sulfonic acid, palladium on carbon, tetrakistriphenylphosphine palladium, or any mixture thereof that can be used in the preparation of the compound of formula (III) of the present disclosure to the compound of formula (I) is about 1.02:1.

[0129] In some embodiments, illustrative examples of solvents that can be used in the preparation of compounds of formula (III) of the present disclosure include, but are not limited to, dichloromethane, toluene, dichloroethane, ethyl acetate, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, and any mixtures thereof.

[0130] In some embodiments, the reactions in the preparation of the compounds of formula (III) of the present disclosure are carried out at -20°C to 0°C. In some embodiments, the reactions in the preparation of the compounds of formula (III) of the present disclosure are carried out at -15°C to -5°C.

[0131] In some embodiments, illustrative examples of compounds that can be used in the preparation of formula (III) of the present disclosure include, but are not limited to, palladium on carbon, tetrakistriphenylphosphine palladium, and any mixtures thereof.

[0132] In a further aspect, the present disclosure relates to a process for preparing a compound of formula (VII), comprising: reacting a compound of general formula (I) to obtain a compound of formula (III); condensation reaction of a compound of formula (III) with a compound of formula (II) to obtain a compound of formula (IV); subjecting a compound of formula (IV) to a condensation reaction to obtain a compound of formula (V); hydrolysis of the compound of formula (V) to obtain a compound of formula (VI); and condensing the compound of formula (VI) to obtain a compound of formula (VII).

[0133] In one aspect, the disclosure relates to a process for preparing a compound of formula (VII):

[0134] [ka] The compound of formula (VIII) is reacted with

[0135] [ka] .

[0136] In some embodiments, illustrative examples of reagents that can be used in the condensation reaction to prepare a compound of formula (VII) of the present disclosure include, but are not limited to, N,N'-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), EDCI (EDC·HCl), dichlorosulfoxide (SOCl2), oxalyl chloride ((COCl)2), acetyl chloride (AcCl), acetic anhydride (Ac2O), N,N-dimethylformamide (DMF), and any mixtures thereof.

[0137] In some embodiments, the condensation reaction to prepare the compound of formula (VII) is carried out using a combination of dichlorosulfoxide (SOCl) / N,N-dimethylformamide (DMF), oxalyl chloride ((COCl)) / N,N-dimethylformamide (DMF), or acetyl chloride (AcCl) / N,N-dimethylformamide (DMF).

[0138] In some embodiments, the condensation reaction to prepare the compound of formula (VII) is carried out using a combination of dichlorosulfoxide (SOCl) / N,N-dimethylformamide (DMF), oxalyl chloride ((COCl)) / N,N-dimethylformamide (DMF), or acetyl chloride (AcCl) / N,N-dimethylformamide (DMF) in a weight ratio of said reagents to the compound of formula (VIII) of about 1:1 to about 3:1.

[0139] In some embodiments, illustrative examples of solvents that can be used in the condensation reaction of the present disclosure to prepare a compound of formula (VII) include, but are not limited to, tetrahydrofuran, dichloromethane (DCM), acetic anhydride (AcO), and any mixtures thereof.

[0140] In some embodiments, the condensation reaction to prepare the compound of formula (VII) is carried out at about -5°C to about 150°C. In some embodiments, the condensation reaction to prepare a compound of formula (VII) is carried out at about -10 °C to about 40 °C.

[0141] In some embodiments, the condensation reaction to prepare the compound of formula (VII) is carried out at about 20°C to about 30°C. In some embodiments, the compound of formula (VII) is recrystallized.

[0142] In some embodiments, illustrative examples of solvents that can be used for recrystallization of the compound of formula (VII) of the present disclosure include, but are not limited to, acetonitrile / isopropanol, ethyl acetate, acetonitrile / water, tetrahydrofuran / water, and any mixture thereof.

[0143] In another aspect, the present disclosure relates to a process for preparing a compound of formula (VIII):

[0144] [ka] The compound of formula (IX) is hydrolyzed.

[0145] [ka] .

[0146] In some embodiments, the hydrolysis reaction to prepare a compound of formula (VIII) is carried out under alkaline conditions. In some embodiments, illustrative examples of salts that can be used in the hydrolysis reaction to prepare a compound of formula (VIII) of the present disclosure include, but are not limited to, potassium salts, sodium salts, lithium salts, and any mixtures thereof.

[0147] In some embodiments, illustrative examples of salts that can be used in the hydrolysis reaction to prepare a compound of formula (VIII) of the present disclosure include, but are not limited to, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, sodium carbonate, lithium hydroxide, lithium carbonate, and any mixtures thereof.

[0148] In some embodiments, the hydrolysis reaction for preparing a compound of formula (VIII) of the present disclosure is carried out at about -5°C to about 35°C. In some embodiments, the hydrolysis reaction for preparing a compound of formula (VIII) of the present disclosure is carried out at about 0°C to about 35°C.

[0149] In some embodiments, the hydrolysis reaction for preparing a compound of formula (VIII) of the present disclosure is carried out at about 20°C to about 30°C. In some embodiments, illustrative examples of solvents that can be used to purify the compound of formula (VIII) of the present disclosure include, but are not limited to, ethanol / water, methanol / water, isopropanol / water, acetonitrile / acetone / water, acetonitrile / acetone, ethyl acetate, tetrahydrofuran, tetrahydrofuran / water, and any mixtures thereof.

[0150] In some embodiments, the molar ratio of the compound of formula (V) that can be used in the preparation of the compound of formula (VIII) of the present disclosure to the salt that can be used in the hydrolysis reaction in the preparation of the compound of formula (VIII) of the present disclosure is from about 1:1 to about 1:10.

[0151] In some embodiments, the molar ratio of the compound of formula (V) that can be used in the preparation of the compound of formula (VIII) of the present disclosure to the salt that can be used in the hydrolysis reaction in the preparation of the compound of formula (VIII) of the present disclosure is from about 1:1 to about 1:6.

[0152] In some embodiments, the molar ratio of the compound of formula (V) that can be used to prepare the compound of formula (VIII) of the present disclosure and the salt that can be used to carry out the hydrolysis reaction in the compound of formula (VIII) of the present disclosure is about 1:5.

[0153] In a further aspect, the present disclosure relates to a process for preparing a compound of formula (IX):

[0154] [ka] The compound of formula (X) is subjected to a condensation reaction.

[0155] [ka] .

[0156] In some embodiments, illustrative examples of reagents that can be used in the condensation reaction of the present disclosure to prepare compounds of formula (IX) include, but are not limited to, acetyl chloride (AcCl), acetic anhydride (AcO), and any mixtures thereof.

[0157] In some embodiments, illustrative examples of reagents that can be used in the condensation reaction to prepare a compound of formula (IX) of the present disclosure include, but are not limited to, 4-dimethylaminopyridine (DMAP), N-methylmorpholine (NMM), triethylamine (TEA), pyridine (Py), N,N-diisopropylethylamine (DIEA), pyridine (Py), and any mixtures thereof.

[0158] In some embodiments, illustrative examples of reagents that can be used in the condensation reaction to prepare a compound of formula (IX) of the present disclosure include, but are not limited to, AcO, AcO / DMAP, AcO / DMAP / NMM, CHCOCl / TEA / DCM / DMAP, and CHCOCl / Py.

[0159] In some embodiments, illustrative examples of solvents that can be used in the condensation reaction of the present disclosure to prepare a compound of formula (IX) include, but are not limited to, acetic anhydride, dichloromethane (DCM), pyridine (Py), tetrahydrofuran, acetonitrile, acetone, ethyl acetate, and any mixtures thereof.

[0160] In some embodiments, the condensation reaction to prepare a compound of formula (IX) of the present disclosure is carried out at about 0 °C to about 150 °C. In some embodiments, the condensation reaction to prepare a compound of formula (IX) of the present disclosure is carried out at about 90°C to about 150°C.

[0161] In some embodiments, the condensation reaction to prepare a compound of formula (IX) of the present disclosure is carried out at about 125°C to about 140°C. In some embodiments, illustrative examples of solvents that can be used to purify the compound of formula (IX) of the present disclosure include, but are not limited to, ethanol, methyl tert-butyl ether (MTBE), methanol, ethyl acetate, n-hexane, diethyl ether, tetrahydrofuran (THF), and any mixtures thereof.

[0162] In yet another aspect, the present disclosure relates to a process for preparing a compound of formula (X):

[0163] [ka] condensation reaction of a compound of formula (II) with a compound of formula (XI) to obtain a compound of formula (X).

[0164] [ka] .

[0165] In some embodiments, illustrative examples of condensing agents that can be used in the preparation of compounds of formula (X) of the present disclosure include, but are not limited to, carbodiimide-type condensing agents, phosphorus cation condensing agents, urea cation condensing agents, other suitable condensing agents, and any mixtures thereof.

[0166] In some embodiments, illustrative examples of carbodiimide-type condensing agents that can be used in the preparation of compounds of formula (X) of the present disclosure include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), EDCI (the hydrochloride salt of EDC), and dicyclohexylcarbodiimide (DCC).

[0167] In some embodiments, illustrative examples of phosphorus cation condensing agents that can be used in the preparation of compounds of formula (X) of the present disclosure include, but are not limited to, 1H-benzotriazol-1-yloxytrispyrrolizinophosphonium hexafluorophosphate (PyBOP), bromotrispyrrolizinophosphonium hexafluorophosphate (PyBrOP), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP).

[0168] In some embodiments, illustrative examples of urea cation condensing agents that can be used in the preparation of compounds of formula (X) of the present disclosure include, but are not limited to, N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU).

[0169] In some embodiments, illustrative examples of other suitable condensing agents that can be used in the preparation of compounds of formula (X) of the present disclosure include, but are not limited to, 1-hydroxybenzotriazole (HOBt), 6-chloro-1-hydroxybenzotriazole (Cl-HOBt), N-hydroxy-7-azabenzotriazole (HOAt), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), 3-diethoxyphosphoryloxy-1,2,3-benzotriazin-4(3H)-one (DEPBT), N-hydroxysuccinimide (HOSu), and pentafluorophenol.

[0170] In some embodiments, illustrative examples of solvents that can be used in the preparation of compounds of formula (X) of the present disclosure include, but are not limited to, dichloromethane, trichloromethane, toluene, tetrahydrofuran, dioxane, and any mixtures thereof.

[0171] In some embodiments, the condensation reaction to prepare a compound of formula (X) of the present disclosure is carried out at about 0 °C to about 50 °C. In some embodiments, the condensation reaction to prepare a compound of formula (X) of the present disclosure is carried out at about 25°C to about 35°C.

[0172] In some embodiments, the weight ratio of Formula (XI) to Formula (II) in the condensation reaction to prepare a compound of Formula (X) of the present disclosure is from about 1:1.3 to about 1:1.4.

[0173] In some embodiments, the weight ratio of Formula (XI) to Formula (II) in the condensation reaction to prepare a compound of Formula (X) of the present disclosure is from about 1:1.35 to about 1:1.4.

[0174] In some embodiments, the weight ratio of Formula (XI) to Formula (II) in the condensation reaction to prepare a compound of Formula (X) of the present disclosure is about 1:1.36. In another aspect, the present disclosure relates to a process for preparing a compound of formula (XI):

[0175] [ka] comprising reacting a compound of general formula (I)

[0176] [ka] wherein R1 ≠ R2, and R1 and R2 are selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted aryl.

[0177] In some embodiments, R and R are each independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, and substituted or unsubstituted C6-C 12 aryl.

[0178] In some embodiments, R1 and R2 are each independently selected from the group consisting of methyl, ethyl, propyl, tert-butyl, benzyl, and allyl.

[0179] In some embodiments, illustrative examples of compounds that can be used in the preparation of formula (XI) of the present disclosure include, but are not limited to, trifluoroacetic acid (TFA), hydrochloric acid, hydrobromic acid, sulfonic acid, palladium on carbon, tetrakistriphenylphosphine palladium, and any mixtures thereof.

[0180] In some embodiments, the weight ratio of illustrative examples of trifluoroacetic acid (TFA), hydrochloric acid, hydrobromic acid, sulfonic acid, palladium on carbon, tetrakistriphenylphosphine palladium, or any mixture thereof that can be used in the preparation of the compound of formula (XI) of the present disclosure to the compound of formula (I) is from about 1.5:1 to about 1:1.

[0181] In some embodiments, the weight ratio of illustrative examples of trifluoroacetic acid (TFA), hydrochloric acid, hydrobromic acid, sulfonic acid, palladium on carbon, tetrakistriphenylphosphine palladium, or any mixture thereof that can be used in the preparation of the compound of formula (XI) of the present disclosure to the compound of formula (I) is about 1.1:1 to about 1:1.

[0182] In some embodiments, the weight ratio of illustrative examples of trifluoroacetic acid (TFA), hydrochloric acid, hydrobromic acid, sulfonic acid, palladium on carbon, tetrakistriphenylphosphine palladium, or any mixture thereof that can be used in the preparation of the compound of formula (XI) of the present disclosure to the compound of formula (I) is about 1.02:1.

[0183] In some embodiments, illustrative examples of solvents that can be used in the preparation of compounds of formula (XI) of the present disclosure include, but are not limited to, dichloromethane, benzene, toluene, dichloroethane, ethyl acetate, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, and any mixtures thereof.

[0184] In some embodiments, the reactions in the preparation of the compounds of formula (XI) of the present disclosure are carried out at -20°C to 0°C. In some embodiments, the reactions in the preparation of the compounds of formula (XI) of the present disclosure are carried out at -15°C to -5°C.

[0185] In some embodiments, illustrative examples of compounds that can be used in the preparation of formula (XI) of the present disclosure include, but are not limited to, palladium on carbon, tetrakistriphenylphosphine palladium, and any mixtures thereof.

[0186] In a further aspect, the present disclosure relates to a process for preparing a compound of formula (VII), comprising: reacting a compound of general formula (I) to obtain a compound of formula (XI); condensation reaction of a compound of formula (XI) with a compound of formula (II) to obtain a compound of formula (X); subjecting a compound of formula (X) to a condensation reaction to obtain a compound of formula (IX); hydrolysis of the compound of formula (IX) to obtain a compound of formula (VIII); and condensation reaction of the compound of formula (VIII) to obtain the compound of formula (VII).

[0187] In one aspect, the disclosure relates to a process for preparing a compound of formula (VII'):

[0188] [ka] The compound of formula (VI') is subjected to a condensation reaction.

[0189] [ka] .

[0190] In some embodiments, illustrative examples of reagents that can be used in the condensation reaction to prepare a compound of formula (VII') of the present disclosure include, but are not limited to, N,N'-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), EDCI (EDC·HCl), dichlorosulfoxide (SOCl2), oxalyl chloride ((COCl)2), acetyl chloride (AcCl), acetic anhydride (Ac2O), N,N-dimethylformamide (DMF), and any mixtures thereof.

[0191] In some embodiments, illustrative examples of reagents that can be used in the condensation reaction to prepare a compound of formula (VII') of the present disclosure include, but are not limited to, a combination of dichlorosulfoxide (SOCl2) / N,N-dimethylformamide (DMF), oxalyl chloride ((COCl)2) / N,N-dimethylformamide (DMF), or acetyl chloride (AcCl) / N,N-dimethylformamide (DMF).

[0192] In some embodiments, illustrative examples of reagents that can be used in the condensation reaction to prepare the compound of formula (VII') of the present disclosure include, but are not limited to, N,N'-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), EDCI (EDC·HCl), dichlorosulfoxide (SOCl2), oxalyl chloride ((COCl)2), acetyl chloride (AcCl), acetic anhydride (Ac2O), N,N-dimethylformamide (DMF), dichlorosulfoxide (SOCl2) / N,N-dimethylformamide (DMF), oxalyl chloride ((COCl)2) / N,N-dimethylformamide (DMF), or acetyl chloride (AcCl) / N,N-dimethylformamide (DMF). The weight ratio of the above reagent to the compound of formula (VI') is about 1:1 to about 3:1.

[0193] In some embodiments, illustrative examples of solvents that can be used in the condensation reaction to prepare a compound of formula (VII') of the present disclosure include, but are not limited to, tetrahydrofuran, dichloromethane (DCM), acetic anhydride (AcO), and any mixtures thereof.

[0194] In some embodiments, the condensation reaction to prepare the compound of formula (VII') is carried out at about -5°C to about 150°C. In some embodiments, the condensation reaction to prepare a compound of formula (VII') is carried out at about -10 °C to about 40 °C.

[0195] In some embodiments, the condensation reaction to prepare the compound of formula (VII') is carried out at about 20°C to about 30°C. In some embodiments, the compound of formula (VII') is recrystallized.

[0196] In some embodiments, illustrative examples of solvents that can be used in the recrystallization of the compound of formula (VII') of the present disclosure include, but are not limited to, acetonitrile / isopropanol, ethyl acetate, acetonitrile / water, tetrahydrofuran / water, and any mixtures thereof.

[0197] In another aspect, the present disclosure relates to a process for preparing a compound of formula (VI'):

[0198] [ka] The compound of formula (V') is hydrolyzed.

[0199] [ka] .

[0200] In some embodiments, the hydrolysis reaction to prepare a compound of formula (VI') is carried out under alkaline conditions. In some embodiments, illustrative examples of salts that can be used in the hydrolysis reaction to prepare a compound of formula (VI') of the present disclosure include, but are not limited to, potassium salts, sodium salts, lithium salts, and any mixtures thereof.

[0201] In some embodiments, illustrative examples of salts that can be used in the hydrolysis reaction to prepare a compound of formula (VI') of the present disclosure include, but are not limited to, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, sodium carbonate, lithium hydroxide, lithium carbonate, and any mixtures thereof.

[0202] In some embodiments, the hydrolysis reaction to prepare a compound of formula (VI') of the present disclosure is carried out at about -5°C to about 35°C. In some embodiments, the hydrolysis reaction to prepare a compound of formula (VI') of the present disclosure is carried out at about 0°C to about 35°C.

[0203] In some embodiments, the hydrolysis reaction to prepare a compound of formula (VI') of the present disclosure is carried out at about 20°C to about 30°C. In some embodiments, illustrative examples of solvents that can be used in the compound of formula (VI') of the present disclosure include, but are not limited to, ethanol / water, methanol / water, isopropanol / water, acetonitrile / acetone / water, acetonitrile / acetone, ethyl acetate, tetrahydrofuran, tetrahydrofuran / water, and any mixtures thereof.

[0204] In some embodiments, the molar ratio of the compound of formula (V') that can be used to prepare the compound of formula (VI') of the present disclosure and the salt that can be used to carry out the hydrolysis reaction of the compound of formula (VI') of the present disclosure is about 1:1 to about 1:10.

[0205] In some embodiments, the molar ratio of the compound of formula (V') that can be used to prepare the compound of formula (VI') of the present disclosure and the salt that can be used to carry out the hydrolysis reaction of the compound of formula (VI') of the present disclosure is about 1:1 to about 1:6.

[0206] In some embodiments, the molar ratio of the compound of formula (V') that can be used to prepare the compound of formula (VI') of the present disclosure and the salt that can be used to carry out the hydrolysis reaction of the compound of formula (VI') of the present disclosure is about 1:5.

[0207] In a further aspect, the disclosure relates to a process for preparing a compound of formula (V'):

[0208] [ka] The compound of formula (IV') is subjected to a condensation reaction.

[0209] [ka] .

[0210] In some embodiments, illustrative examples of reagents that can be used in the condensation reaction to prepare a compound of formula (V') of the present disclosure include, but are not limited to, acetyl chloride (AcCl), acetic anhydride (AcO), and any mixtures thereof.

[0211] In some embodiments, illustrative examples of reagents that can be used in the condensation reaction to prepare a compound of formula (V') of the present disclosure include, but are not limited to, 4-dimethylaminopyridine (DMAP), N-methylmorpholine (NMM), triethylamine (TEA), dichloromethane (DCM), pyridine (Py), N,N-diisopropylethylamine (DIEA), and any mixtures thereof.

[0212] In some embodiments, illustrative examples of reagents that can be used in the condensation reaction to prepare a compound of formula (V') of the present disclosure include, but are not limited to, Ac2O, Ac2O / DMAP, Ac2O / DMAP / NMM, CH3COCl / TEA / DCM / DMAP, and CH3COCl / Py.

[0213] In some embodiments, illustrative examples of solvents that can be used in the condensation reaction to prepare a compound of formula (V') of the present disclosure include, but are not limited to, acetic anhydride, dichloromethane (DCM), pyridine (Py), tetrahydrofuran, acetonitrile, acetone, ethyl acetate, and any mixtures thereof.

[0214] In some embodiments, the condensation reaction to prepare a compound of formula (V') of the present disclosure is carried out at about 0°C to about 150°C. In some embodiments, the condensation reaction to prepare a compound of formula (V') of the present disclosure is carried out at about 90°C to about 150°C.

[0215] In some embodiments, the condensation reaction to prepare a compound of formula (V') of the present disclosure is carried out at about 125°C to about 140°C. In some embodiments, illustrative examples of solvents that can be used to purify the compound of formula (V') of the present disclosure include, but are not limited to, ethanol, methyl tert-butyl ether (MTBE), methanol, ethyl acetate, n-hexane, diethyl ether, tetrahydrofuran (THF), and any mixtures thereof.

[0216] In yet another aspect, the present disclosure relates to a process for preparing a compound of formula (IV'):

[0217] [ka] condensation reaction of a compound of formula (III) with a compound of formula (II') to obtain a compound of formula (IV').

[0218] [ka] .

[0219] In some embodiments, illustrative examples of condensing agents that can be used in the preparation of compounds of formula (IV') of the present disclosure include, but are not limited to, carbodiimide-type condensing agents, phosphorus cation condensing agents, urea cation condensing agents, other suitable condensing agents, and any mixtures thereof.

[0220] In some embodiments, illustrative examples of carbodiimide-type condensing agents that can be used in the preparation of compounds of formula (IV') of the present disclosure include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), EDCI (the hydrochloride salt of EDC), and dicyclohexylcarbodiimide (DCC).

[0221] In some embodiments, illustrative examples of phosphorus cation condensing agents that can be used in the preparation of compounds of formula (IV') of the present disclosure include, but are not limited to, 1H-benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP), bromotrispyrrolidinophosphonium hexafluorophosphate (PyBrOP), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP).

[0222] In some embodiments, illustrative examples of urea cation condensing agents that can be used in the preparation of compounds of formula (IV') of the present disclosure include, but are not limited to, N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU).

[0223] In some embodiments, illustrative examples of other suitable condensing agents that can be used in the preparation of compounds of formula (IV') of the present disclosure include, but are not limited to, 1-hydroxybenzotriazole (HOBt), 6-chloro-1-hydroxybenzotriazole (Cl-HOBt), N-hydroxy-7-azabenzotriazole (HOAt), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), 3-diethoxyphosphoryloxy-1,2,3-benzotriazin-4(3H)-one (DEPBT), N-hydroxysuccinimide (HOSu), and pentafluorophenol.

[0224] In some embodiments, illustrative examples of solvents that can be used in the preparation of the compound of formula (IV') of the present disclosure include, but are not limited to, dichloromethane, trichloromethane, acetonitrile, toluene, tetrahydrofuran, dioxane, and any mixtures thereof.

[0225] In some embodiments, the condensation reaction to prepare a compound of formula (IV') of the present disclosure is carried out at about 0°C to about 50°C. In some embodiments, the condensation reaction to prepare a compound of formula (IV') of the present disclosure is carried out at about 25°C to about 35°C.

[0226] In some embodiments, the weight ratio of Formula (III) to Formula (II') in the condensation reaction to prepare a compound of Formula (IV') of the present disclosure is from about 1:1.3 to about 1:1.4.

[0227] In some embodiments, the weight ratio of Formula (III) to Formula (II') in the condensation reaction to prepare a compound of Formula (IV') of the present disclosure is from about 1:1.35 to about 1:1.4.

[0228] In some embodiments, the weight ratio of Formula (III) to Formula (II') in the condensation reaction to prepare a compound of Formula (IV') of the present disclosure is about 1:1.36. In a further aspect, the present disclosure relates to a process for preparing a compound of formula (VII'), comprising: reacting a compound of general formula (I) to obtain a compound of formula (III); condensation reaction of a compound of formula (III) with a compound of formula (II') to obtain a compound of formula (IV'); subjecting the compound of formula (IV') to a condensation reaction to obtain a compound of formula (V'); hydrolysis of the compound of formula (V') to obtain a compound of formula (VI'); and subjecting the compound of formula (VI') to a condensation reaction to obtain a compound of formula (VII').

[0229] In one aspect, the disclosure relates to a process for preparing a compound of formula (VII″):

[0230] [ka] The compound of formula (VI'') is reacted with

[0231] [ka] .

[0232] In some embodiments, illustrative examples of reagents that can be used in the condensation reaction to prepare a compound of formula (VII″) of the present disclosure include, but are not limited to, N,N′-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), EDCI (EDC·HCl), dichlorosulfoxide (SOCl2), oxalyl chloride ((COCl)2), acetyl chloride (AcCl), acetic anhydride (Ac2O), N,N-dimethylformamide (DMF), and any mixtures thereof.

[0233] In some embodiments, illustrative examples of reagents that can be used in the condensation reaction to prepare a compound of formula (VII″) of the present disclosure include, but are not limited to, a combination of dichlorosulfoxide (SOCl2) / N,N-dimethylformamide (DMF), oxalyl chloride ((COCl)2) / N,N-dimethylformamide (DMF), or acetyl chloride (AcCl) / N,N-dimethylformamide (DMF).

[0234] In some embodiments, illustrative examples of reagents that can be used in the condensation reaction to prepare a compound of formula (VII'') of the present disclosure include, but are not limited to, N,N'-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), EDCI (EDC·HCl), dichlorosulfoxide (SOCl2), oxalyl chloride ((COCl)2), acetyl chloride (AcCl), acetic anhydride (Ac2O), N,N-dimethylformamide (DMF), dichlorosulfoxide (SOCl2) / N,N-dimethylformamide (DMF), oxalyl chloride ((COCl)2) / N,N-dimethylformamide (DMF), or acetyl chloride (AcCl) / N,N-dimethylformamide (DMF). The weight ratio of the above reagents to the compound of formula (VI'') is about 1:1 to about 3:1.

[0235] In some embodiments, illustrative examples of solvents that can be used in the condensation reaction to prepare a compound of formula (VII″) of the present disclosure include, but are not limited to, tetrahydrofuran, dichloromethane (DCM), acetic anhydride (AcO), and any mixtures thereof.

[0236] In some embodiments, the condensation reaction to prepare a compound of formula (VII'') is carried out at about -5°C to about 150°C. In some embodiments, the condensation reaction to prepare a compound of formula (VII'') is carried out at about -10°C to about 40°C.

[0237] In some embodiments, the condensation reaction to prepare a compound of formula (VII'') is carried out at about 20°C to about 30°C. In some embodiments, the compound of formula (VII'') is recrystallized.

[0238] In some embodiments, illustrative examples of solvents that can be used in the recrystallization of the compound of formula (VII″) of the present disclosure include, but are not limited to, acetonitrile / isopropanol, ethyl acetate, acetonitrile / water, tetrahydrofuran / water, and any mixtures thereof.

[0239] In another aspect, the present disclosure relates to a process for preparing a compound of formula (VI″):

[0240] [ka] The compound of formula (V'') is hydrolyzed.

[0241] [ka] .

[0242] In some embodiments, the hydrolysis reaction to prepare a compound of formula (VI'') is carried out under alkaline conditions. In some embodiments, illustrative examples of salts that can be used in the hydrolysis reaction to prepare a compound of formula (VI'') of the present disclosure include, but are not limited to, potassium salts, sodium salts, lithium salts, and any mixtures thereof.

[0243] In some embodiments, illustrative examples of salts that can be used in the hydrolysis reaction to prepare compounds of formula (VI″) of the present disclosure include, but are not limited to, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, sodium carbonate, lithium hydroxide, lithium carbonate, and any mixtures thereof.

[0244] In some embodiments, the hydrolysis reaction for preparing a compound of formula (VI'') of the present disclosure is carried out at about -5°C to about 35°C. In some embodiments, the hydrolysis reaction for preparing a compound of formula (VI'') of the present disclosure is carried out at about 0°C to about 35°C.

[0245] In some embodiments, the hydrolysis reaction for preparing a compound of formula (VI'') of the present disclosure is carried out at about 20°C to about 30°C. In some embodiments, illustrative examples of solvents that can be used to purify the compound of formula (VI'') of the present disclosure include, but are not limited to, ethanol / water, methanol / water, isopropanol / water, acetonitrile / acetone / water, acetonitrile / acetone, ethyl acetate, tetrahydrofuran, tetrahydrofuran / water, and any mixtures thereof.

[0246] In some embodiments, the molar ratio of a compound of formula (V'') that can be used to prepare a compound of formula (VI'') of the present disclosure to a salt that can be used to carry out a hydrolysis reaction of a compound of formula (VI'') of the present disclosure is from about 1:1 to about 1:10.

[0247] In some embodiments, the molar ratio of a compound of formula (V'') that can be used to prepare a compound of formula (VI'') of the present disclosure to a salt that can be used to carry out a hydrolysis reaction of a compound of formula (VI'') of the present disclosure is about 1:1 to 1:6.

[0248] In some embodiments, the molar ratio of a compound of formula (V'') that can be used to prepare a compound of formula (VI'') of the present disclosure and a salt that can be used to carry out a hydrolysis reaction of a compound of formula (VI'') of the present disclosure is about 1:5.

[0249] In yet another aspect, the present disclosure relates to a process for preparing a compound of formula (V″):

[0250] [ka] The compound of formula (IV'') is subjected to a condensation reaction.

[0251] [ka] .

[0252] In some embodiments, illustrative examples of reagents that can be used in the condensation reaction to prepare a compound of formula (V'') of the present disclosure include, but are not limited to, acetyl chloride (AcCl), acetic anhydride (AcO), and any mixtures thereof.

[0253] In some embodiments, illustrative examples of solvents that can be used in the condensation reaction of a compound of formula (V'') of the present disclosure include, but are not limited to, 4-dimethylaminopyridine (DMAP), N-methylmorpholine (NMM), triethylamine (TEA), dichloromethane (DCM), pyridine (Py), N,N-diisopropylethylamine (DIEA), and any mixtures thereof.

[0254] In some embodiments, illustrative examples of reagents that can be used in the condensation reaction to prepare a compound of formula (V'') of the present disclosure include, but are not limited to, Ac2O, Ac2O / DMAP, Ac2O / DMAP / NMM, CH3COCl / TEA / DCM / DMAP, and CH3COCl / Py.

[0255] In some embodiments, illustrative examples of solvents that can be used in the condensation reaction to prepare a compound of formula (V'') of the present disclosure include, but are not limited to, acetic anhydride, dichloromethane (DCM), pyridine (Py), tetrahydrofuran, acetonitrile, acetone, ethyl acetate, and any mixtures thereof.

[0256] In some embodiments, the condensation reaction to prepare a compound of formula (V'') of the present disclosure is carried out at about 0°C to about 150°C. In some embodiments, the condensation reaction to prepare a compound of formula (V'') of the present disclosure is carried out at about 90°C to about 150°C.

[0257] In some embodiments, the condensation reaction to prepare a compound of formula (V'') of the present disclosure is carried out at about 125°C to about 140°C. In some embodiments, illustrative examples of solvents that can be used to purify the compounds of formula (V'') of the present disclosure include, but are not limited to, ethanol, methyl tert-butyl ether (MTBE), methanol, ethyl acetate, n-hexane, diethyl ether, tetrahydrofuran (THF), and any mixtures thereof.

[0258] In yet another aspect, the present disclosure relates to a process for preparing a compound of formula (IV″):

[0259] [ka] by condensation reaction of a compound of formula (III) with a compound of formula (II″) to obtain a compound of formula (IV″).

[0260] [ka] .

[0261] In some embodiments, illustrative examples of condensing agents that can be used in the preparation of compounds of formula (IV'') of the present disclosure include, but are not limited to, carbodiimide-type condensing agents, phosphorus cation condensing agents, urea cation condensing agents, other suitable condensing agents, and any mixtures thereof.

[0262] In some embodiments, illustrative examples of carbodiimide-type condensing agents that can be used in the present disclosure include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), EDCI (the hydrochloride salt of EDC), and dicyclohexylcarbodiimide (DCC).

[0263] In some embodiments, illustrative examples of phosphorus cation condensing agents that can be used in the present disclosure include, but are not limited to, 1H-benzotriazol-1-yloxytrispyrrolizinophosphonium hexafluorophosphate (PyBOP), bromotrispyrrolizinophosphonium hexafluorophosphate (PyBrOP), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP).

[0264] In some embodiments, illustrative examples of urea cation condensing agents that can be used in the present disclosure include, but are not limited to, N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU).

[0265] In some embodiments, illustrative examples of other suitable condensing agents that can be used in the present disclosure include, but are not limited to, 1-hydroxybenzotriazole (HOBt), 6-chloro-1-hydroxybenzotriazole (Cl-HOBt), N-hydroxy-7-azabenzotriazole (HOAt), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), 3-diethoxyphosphoryloxy-1,2,3-benzotriazin-4(3H)-one (DEPBT), N-hydroxysuccinimide (HOSu), and pentafluorophenol.

[0266] In some embodiments, illustrative examples of solvents that can be used in the present disclosure include, but are not limited to, dichloromethane, trichloromethane, toluene, tetrahydrofuran, dioxane, and any mixtures thereof.

[0267] In some embodiments, the condensation reaction to prepare a compound of formula (IV'') of the present disclosure is carried out at about 0°C to about 50°C. In some embodiments, the condensation reaction to prepare a compound of formula (IV'') of the present disclosure is carried out at about 25°C to about 35°C.

[0268] In some embodiments, the weight ratio of Formula (III) to Formula (II'') in the condensation reaction to prepare a compound of Formula (IV'') of the present disclosure is from about 1:1.3 to about 1:1.4.

[0269] In some embodiments, the weight ratio of Formula (III) to Formula (II'') in the condensation reaction to prepare a compound of Formula (IV'') of the present disclosure is from about 1:1.35 to about 1:1.4.

[0270] In some embodiments, the weight ratio of Formula (III) to Formula (II'') in the condensation reaction to prepare a compound of Formula (IV'') of the present disclosure is about 1:1.36. In a further aspect, the present disclosure relates to a process for preparing a compound of formula (VII″), comprising: reacting a compound of general formula (I) to obtain a compound of formula (III); condensation reaction of a compound of formula (III) with a compound of formula (II″) to obtain a compound of formula (IV″); subjecting a compound of formula (IV'') to a condensation reaction to obtain a compound of formula (V''); hydrolysis of the compound of formula (V'') to obtain a compound of formula (VI''); and subjecting the compound of formula (VI'') to a condensation reaction to obtain a compound of formula (VII'').

[0271] 1The H nuclear magnetic resonance (NMR) spectrum is consistent with the proposed structure. Characteristic chemical shifts (δ) are parts per million downfield from trimethylsilane, and characteristic peaks are designated with conventional abbreviations: e.g., s indicates singlet, dd indicates double doublet, d indicates doublet, t indicates triplet, q indicates quartet, h indicates hexplet, m indicates multiplet, and br indicates broad peak.

[0272] The preparation method of the present disclosure does not require chromatographic purification and is easy to scale up production. The reaction conditions of the present disclosure are easy to control, easy to scale up production, and easy to obtain stability and reproducibility. The preparation method of the present disclosure is more effective than the previously disclosed methods. It is unexpected that the compound obtained directly by the preparation method and route of the present disclosure without complicated purification steps meets clinical quality standards. Clinical specifications refer to substances of sufficient purity suitable for administration to humans. The preparation method of the present disclosure does not use Class 1 solvents and has excellent safety to the human body in terms of residual solvents. The preparation method of the present disclosure is economical and uses readily available raw materials. The preparation method of the present disclosure has better one-step yield and also better overall yield.

[0273] In order to better understand various aspects and advantages of the present disclosure, the present disclosure will be described in detail below through the following examples. However, it should be understood that the following examples are not limiting and are only used to illustrate some embodiments of the present disclosure. Those skilled in the art can make appropriate adjustments according to the reaction device, the scale of the reaction device, the principle of the reaction device, etc. to implement the solutions disclosed herein.

[0274] [Example] Abbreviation: CDI N,N'-Carbonyldiimidazole HPLC High Performance Liquid Chromatography DMF N,N-Dimethylformamide Cl-HOBt 6-Chloro-1-hydroxybenzotriazole EDC HCl 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride TLC Thin Layer Chromatography

[0275] Example 1 Preparation of (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide In a 100 mL single neck flask, (S)-5-acetamido-4-[[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]aminocarbonyl]thiophene-3-carboxylic acid (5 g, 10.3 mmol) and tetrahydrofuran (25 mL) were added. The mixture was dissolved with stirring at room temperature (25° C.). CDI (5 g, 31.0 mol) was added in portions to the single neck flask. The mixture was stirred at room temperature for 2 to 5 hours and monitored by HPLC. The reaction was stopped and quenched with water. The mixture was concentrated in vacuum to obtain a concentrate. The concentrate was dissolved in dichloromethane, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed to obtain a residue. The residue was added to acetonitrile (5 mL) and heated to reflux until clear. Isopropanol (30 mL) was added and refluxed for 2 hours. Heating was stopped. The resulting product was cooled to room temperature with stirring. The resulting product was filtered through a pump to obtain a filter cake, which was then dried in vacuum to obtain 3.7 g of the title compound (purity 99.32%, yield 77.1%). 1 HNMR(500MHz,DMSO-d6)δ11.71(s,1H),7.73(s,1H),7.04(s,1H),6.91-6.94(m,2H),5.71(dd,1H ),4.33(dd,1H),4.09(dd,1H),3.99(q,2H),3.72(s,3H),3.00(s,3H),2.23(s,3H),1.31(t,3H). 13CNMR(100MHz,DMSO-d6)δ170.03,162.69,162.30,149.53,148.54,141.70,131.45,130.60,120.42,1 20.23,115.00,15.39,112.47,23.07,56.20,53.74,47.99,41.74,23.07,15.39.LCMS:489.1([M+Na] + ), 465.0([MH] - ). Elemental analysis results: [C 20 H 22 N2O7S2]: C, 50.78; H, 4.80; N, 5.93; Measured: C, 50.33; H, 4.70; N, 5.69.

[0276] Example 2 Preparation of (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide To the reaction kettle was added (S)-5-acetamido-4-[[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]aminocarbonyl]thiophene-3-carboxylic acid (4.47 g) and tetrahydrofuran (23.5 mL). The mixture was dissolved with stirring at room temperature. CDI (7.83 g) was added in portions to the reaction vessel. The reaction was run at 25° C. for 6 hours, stopped by HPLC monitoring, and quenched with water. The mixture was concentrated in vacuo to give an oil. The oil was dissolved in dichloromethane, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed to give a residue. The residue was added to acetonitrile (15 mL) and heated to reflux until clear. Isopropanol (90 mL) was added and refluxed for 2 hours. Heating was stopped. The resulting product was stirred at room temperature overnight and filtered by pump to give a filter cake. The filter cake was dried in vacuum to give 2.58 g of the title compound (yield: 60%, purity: 98.3%).

[0277] Example 3 Preparation of (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide To a 50 mL single neck flask was added (S)-5-acetamido-4-[[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]aminocarbonyl]thiophene-3-carboxylic acid (5 g) and acetic anhydride (15 mL). The mixture was heated to reflux for 2 to 3 hours and monitored by HPLC until the reaction was substantially complete. After cooling to room temperature, the reaction was diluted with dichloromethane, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed to give a residue. The residue was added to acetonitrile (5 ml) and heated to reflux until clear. Isopropanol (30 mL) was added and refluxed for 2 hours. Heating was stopped. The resulting product was stirred at room temperature and filtered by pump to give a filter cake. The filter cake was dried under vacuum to give 3.4 g of the title compound (89% purity, 71% yield). 1 HNMR(600MHz,CDCl3-d1)δ9.39(s,1H),7.33(s,1H),7.07-7.09(m,2H),6.84(d,1H),5.83(dd,1H),4.57(d d,1H),4.11(q,2H),3.86(s,3H),3.76(dd,1H),2.89(s,3H),2.30(s,3H),1.47(t,3H).LCMS:489.3([M+Na] + ), 465.4([MH] - ).

[0278] Example 4 Preparation of (S)-5-acetamido-4-[[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]aminocarbonyl]thiophene-3-carboxylic acid To a 500 mL 3-neck flask was added (S)-methyl-5-acetamido-4-[[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]aminocarbonyl]thiophene-3-carboxylate (16 g, 0.0321 mol) and ethanol (160 mL). The mixture was stirred to dissolve and cooled to below 0° C. 160 mL of 4.2% aqueous lithium hydroxide was added dropwise. During the addition, the temperature inside the 3-neck bottle was controlled to be below 0° C. After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 3 to 6 hours and monitored by HPLC until the reaction was essentially complete. After the reaction was complete, 4 mol / L hydrochloric acid was added dropwise to adjust the pH to 5 to 6. The mixture was concentrated in vacuum to give an oil. The oil was dissolved in water. 4 mol / L hydrochloric acid was added dropwise to adjust the pH to 1 to 2. Acetonitrile (120mL) and acetone (40mL) were added to the mixture. The resulting product was stirred for 3 hours and filtered by pump to obtain a filter cake. The filter cake was dried in vacuum to obtain 11.3g of the title compound (purity 98%, yield: 73%). 1 HNMR(600MHz,DMSO-d6)δ11.41(s,1H),10.09(d,1H),7.85(s,1H),7.09(d,1H),6.98(dd,1H),6.93(d,1H), 5.55(dd,1H),4.05(q,2H),3.80(dd,1H),3.75(s,3H),3.65(dd,1H),2.90(s,3H),2.19(s,3H),1.34(t,3H). LCMS:507.4([M+Na] + ), 483.4([MH] - ).

[0279] Example 5 Preparation of (S)-2-Methyl-5-acetamido-4-[[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]aminocarbonyl]thiophene-3-carboxylate In a 250 mL three-neck flask, (S)-methyl-5-amino-4-[[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]aminocarbonyl]thiophene-3-carboxylate (20 g) and acetic anhydride (70 mL) were added. The mixture was heated to reflux and stirred for 0.5 h until clear. After cooling to 80-90° C., the reaction mixture was stirred with ethanol (210 mL) to precipitate a solid. The solid was further stirred at room temperature and filtered by pump to obtain a filter cake. The filter cake was dried in vacuum to obtain 17.8 g of the title compound (yield: 82%, purity: 99%). 1 HNMR(600MHz,CDCl3-d1)δ12.97(s,1H),11.04(d,1H),7.85(s,1H),7.03-7.04(m,2H),6.91(d,1H),5.67(dd,1 H),4.18(q,2H),3.93(S,3H),3.89(s,3H),3.74(dd,1H),3.49(dd,1H),2.70(s,3H),2.29(s,3H),1.50(t,3H). LCMS:521.3([M+Na] + ), 497.5([MH] - ).

[0280] Example 6 Preparation of (S)-2-Methyl-5-acetamido-4-[[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]aminocarbonyl]thiophene-3-carboxylate To the reaction kettle was added (S)-methyl-5-amino-4-[[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]aminocarbonyl]thiophene-3-carboxylate (3.63 g) and acetic anhydride (12.7 mL). The mixture was heated to 125° C. to 140° C. and stirred for 0.5 h. After cooling to 80° C. to 90° C., the reaction mixture was stirred with ethanol (38 mL) to precipitate a solid. The solid was further stirred at room temperature for 5 h and filtered by pump to obtain a filter cake. The filter cake was dried in vacuum to obtain 3.52 g of the title compound (yield: 89%, purity 99.50%).

[0281] Example 7 Preparation of (S)-2-Methyl-5-acetamido-4-[[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]aminocarbonyl]thiophene-3-carboxylate A 100 mL single-neck flask was charged with (S)-methyl-5-amino-4-[[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]aminocarbonyl]thiophene-3-carboxylate (12 g, 0.0263 mol), acetyl chloride (2.5 g, 0.0318 mol), and pyridine (30 mL). The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuum to give a concentrate. The concentrate was dissolved in dichloromethane, washed with 2 mol / L hydrochloric acid, water, and brine, and dried over anhydrous sodium sulfate. The solvent was removed to give a residue. The residue was purified to give 10.1 g of the title compound (77.1% yield, 96% purity). 1 HNMR(600MHz,CDCl3-d1)δ12.98(s,1H),11.05(d,1H),7.86(s,1H),7.03-7.05(m,2H),6.91(d,1H),5.67(dd,1 H),4.17(t,2H),3.93(S,3H),3.89(s,3H),3.74(dd,1H),3.49(dd,1H),2.70(s,3H),2.29(s,3H),1.51(t,3H). LCMS:521.3([M+Na] + ), 497.5([MH] - ).

[0282] Example 8 Preparation of (S)-methyl-5-amino-4-[[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]aminocarbonyl]thiophene-3-carboxylate In a 500mL three-necked bottle, 2-amino-4-(methoxycarbonyl)thiophene-3-carboxylic acid (25g, 0.124mol), (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (34g, 0.125mol) (prepared according to patent CN104245668B), Cl-HOBt (25.3g, 0.150mol), and dichloromethane (300mL) were added. The mixture was stirred for 10 to 20 minutes. EDC·HCl (28.5g, 0.149mol) was added to the three-necked bottle. After the addition was complete, the reaction was stopped after heating at an internal temperature of 25°C to 35°C for 3 to 6 hours. After the reaction was completed, 1mol / L hydrochloric acid was added to the three-necked flask. The solid was precipitated and filtered by pump. The filtrate was separated from the organic layer. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was added to ethyl acetate (250 mL). The mixture was heated to reflux for 2 hours. The heating was stopped. The resulting product was cooled to room temperature and filtered by pump to obtain a filter cake. The filter cake was dried in vacuum to obtain 36.2 g of the title compound (yield: 64%, purity: 99%). 1 HNMR(500MHz,DMSO-d6)δ9.31(d,1H),7.31(s,1H),7.26(s,2H),36.2 / 7.06(s,1H),6.92(s,2H),5 .45(dd,1H),4.05(q,2H),3.73(s,3H),3.69(s,3H),3.57-3.66(m,2H),2.79(s,3H),1.33(t,3H). 13 CNMR(100MHz,DMSO-d6)δ165.12,164.63,162.16,149.03,15.42,133.52,128.90,119. 81,119.79,112.45,112.29,106.52,64.34,59.53,56.15,52.94,48.47,41.94,15.42. LCMS:457.1([M+H] + ), 455.0([MH] - ).

[0283] Example 9 Preparation of (S)-methyl-5-amino-4-[[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]aminocarbonyl]thiophene-3-carboxylate 2-Amino-4-(methoxycarbonyl)thiophene-3-carboxylic acid (7.5 g), (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (9.3 g), Cl-HOBt (7.6 g) and dichloromethane (102 mL) were stirred for 10 to 20 minutes. EDC·HCl (8.6 g) was added to the reaction solution. After the addition was complete, the reaction was heated to an internal temperature of 25 to 35 °C. The reaction was monitored by HPLC for 3 to 6 hours. After the reaction was complete, 1 mol / L hydrochloric acid (1.6 g) was added to the reaction vessel. The solid was allowed to precipitate. The organic layer was filtered by pump. The filtrate was separated, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed and the residue was added to ethyl acetate (6.7 g) and heated to reflux for 2 hours. Heating was stopped. The resulting product was cooled to room temperature and filtered by pump to obtain a filter cake. The filter cake was dried in vacuum to give 14.6 g of the title compound (yield: 60%, purity: 97%).

[0284] Alternatively, (S)-methyl-5-amino-4-[[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]aminocarbonyl]thiophene-3-carboxylate was prepared in the same manner as in Example 12 or Example 13 above, except that N-hydroxysuccinimide (HOSu), N-hydroxy-7-azobenzotriazole (HOAt) or HOBt was used instead of Cl-HOBt, and similar reaction results were obtained.

[0285] As an alternative, (S)-Methyl-5-amino-4-[[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]aminocarbonyl]thiophene-3-carboxylate was prepared in the same manner as in Example 12 or Example 13 above, except that tetrahydrofuran, N,N-dimethylformamide, or trichloromethane was used instead of dichloromethane, and the same reaction effect was obtained.

[0286] As an alternative, (S)-Methyl-5-amino-4-[[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]aminocarbonyl]thiophene-3-carboxylate was similarly prepared according to the method of Example 12 or Example 13 above, except that the reaction temperature was changed from about 15° C. to about 35° C., and similar reaction results were obtained.

[0287] Example 10 Preparation of 2-amino-4-(methoxycarbonyl)thiophene-3-carboxylic acid In a 250 mL three-necked bottle, 3-tert-butyl-4-methyl-2-aminothiophene-3,4-dicarboxylate (47 g, 0.183 mol, prepared by the method disclosed in Organic Letters, 13(1), 38-41; 2011) and dichloromethane (60 mL) were added. The mixture was dissolved under stirring and cooled to -10°C. Trifluoroacetic acid (48 g, 0.421 mol) was added to dichloromethane (30 mL) to prepare solution A. Solution A was added dropwise to the three-necked bottle. During the addition, the temperature inside the three-necked bottle was controlled to be less than -5°C. After the addition was completed, the internal temperature was controlled to be less than 0°C for 10 to 30 minutes. The reaction mixture was stirred with methyl tert-butyl ether (300 ml) for 2 hours and filtered by pump to obtain a filter cake. The filter cake was dried in vacuum to give 28.2 g of the title compound (yield: 77%, purity: 97.4%). 1 HNMR (600MHz, acetone-d6) δ 7.75(s,1H), 7.52(s,H), 3.96(s,3H). LCMS: 202.1([M+H] + ).

[0288] Example 11 Preparation of 2-amino-4-(methoxycarbonyl)thiophene-3-carboxylic acid 3-tert-Butyl-4-methyl-2-aminothiophene-3,4-dicarboxylate (5.5g) and dichloromethane (9.6g) were dissolved under stirring and cooled to -10°C. The resulting solution was designated as A. Trifluoroacetic acid (5.6g) was added to dichloromethane (4.8g) to prepare solution B. Solution B was cooled to below 0°C. Solution B was added dropwise to solution A. During the dropwise addition, the temperature was controlled below -10±5°C. After the dropwise addition was completed, the reaction was carried out for 10 to 30 minutes. After the reaction was completed, the reaction solution was added to methyl tert-butyl ether (78.3g), stirred for 2 hours, and filtered by pump to obtain a filter cake. The filter cake was dried in vacuum to obtain 3.7g of the title compound (yield: 86%, sample purity: 97.4%).

[0289] Example 12 Preparation of 2-amino-4-(methoxycarbonyl)thiophene-3-carboxylic acid 3-Benzyl-4-methyl-2-aminothiophene-3,4-dicarboxylate (50 g, 0.172 mol, prepared by the method disclosed in Organic Letters, 13(1), 38-41; 2011) was added to ethyl acetate (900 ml). The mixture was stirred to dissolve, which was designated as solution A. A 2 L hydrogenation flask was inerted with nitrogen, after which 10% wet Pd / C (12.5 g) was added. Ethyl acetate (100 mL) was added to the hydrogenation flask to soak the catalyst. Solution A and glacial acetic acid (150 mL) were added successively to the hydrogenation bottle, and the cap was tightened. The hydrogenation bottle was purged twice with nitrogen and then twice with hydrogen. The reaction was run by introducing hydrogen (15 psi pressure) until the reaction was substantially complete. After completion of the reaction, the feed solution was exposed to diatomaceous earth to remove Pd / C. The filtrate was concentrated under reduced pressure to remove the solvent and obtain a residue. The residue was stirred with methyl tert-butyl ether (300 mL) for 2 hours and filtered by pump to obtain a filter cake, which was dried in vacuum to obtain 20.3 g of the title compound (yield: 59%, purity: 95.4%). 1 HNMR (600MHz, acetone-d6) δ 7.75(s,1H), 7.53(s,H), 3.96(s,3H). LCMS: 202.1([M+H] + ).

[0290] In this disclosure, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another, and do not necessarily require or imply any actual relationship or order.

[0291] It will be appreciated from the foregoing description that, although specific embodiments of the present disclosure have been described for purposes of illustration, various modifications or improvements can be made by those skilled in the art without departing from the spirit and scope of the present disclosure, which changes or modifications are intended to be included within the scope of the claims appended hereto.

Claims

1. Preparing a compound of formula (VII) comprising: 【Chemistry 1】 Condensation reaction of a compound of formula (VI) or a compound of formula (VIII) 【Chemistry 2】 。

2. 2. The process according to claim 1, wherein the condensation reaction is carried out using N,N'-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), EDCI (EDC.HCl), dichlorosulfoxide (SOCl ２ ), oxalyl chloride ((COCl) ２ ), acetyl chloride (AcCl), acetic anhydride (Ac ２ The reaction is carried out using a reagent selected from the group consisting of N,N'-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) or a salt thereof (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), oxalyl chloride (COCl), ２ ), acetyl chloride (AcCl), acetic anhydride (Ac ２ O), N,N-dimethylformamide (DMF), and mixtures thereof.

3. 3. The process according to claim 1 or claim 2, wherein the weight ratio of reagent to compound of formula (VI) or reagent to compound of formula (VIII) is from about 1:1 to about 3:

1.

4. 4. The process according to claim 1, wherein the condensation reaction is carried out in a solvent selected from the group consisting of tetrahydrofuran, dichloromethane (DCM), acetic anhydride (Ac), ２ O), and any mixtures thereof.

5. 5. The process according to any one of claims 1 to 4, wherein the condensation reaction is carried out at about -5°C to about 150°C.

6. 6. The process according to any one of claims 1 to 5, wherein the condensation reaction is carried out at about 20°C to about 30°C.

7. 7. The process according to any one of claims 1 to 6, further comprising recrystallizing the obtained compound of formula (VII).

8. 8. The method of claim 7, wherein the solvent for recrystallization is selected from the group consisting of acetonitrile / isopropanol, ethyl acetate, acetonitrile / water, tetrahydrofuran / water, and any mixture thereof.

9. A process for preparing a compound of formula (VI) comprising: 【Chemistry 3】 subjecting the compound of formula (V) to a hydrolysis reaction. 【Chemistry 4】 。

10. 10. The process according to claim 9, wherein the hydrolysis reaction is carried out under alkaline conditions, preferably using potassium salts, sodium salts, lithium salts, or any mixture thereof, more preferably potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, sodium carbonate, lithium hydroxide, lithium carbonate, or any mixture thereof.

11. 11. The process according to claim 9 or claim 10, wherein the hydrolysis reaction is carried out at about -5°C to about 35°C, preferably about 0°C to about 35°C, more preferably about 20°C to about 30°C.

12. 12. The process according to any one of claims 9 to 11, wherein the hydrolysis reaction is carried out in a solvent selected from the group consisting of ethanol / water, methanol / water, isopropanol / water, acetonitrile / acetone / water, acetonitrile / acetone, ethyl acetate, tetrahydrofuran, tetrahydrofuran / water, acetone / water, and any mixture thereof.

13. 13. The process according to any one of claims 9 to 12, wherein the molar ratio of the compound of formula (V) to the reaction reagent according to claim 10 is from about 1:1 to about 1:10, preferably from about 1:1 to about 1:6, more preferably about 1:

5.

14. Preparing a compound of formula (V) comprising: 【Chemistry 5】 subjecting a compound of formula (IV) to a condensation reaction. 【Chemistry 6】 。

15. 15. The process according to claim 14, wherein the condensation reaction is carried out using acetyl chloride (AcCl), acetic anhydride (AcCl), ２ O), and any mixture thereof.

16. 16. The process according to claim 14 or claim 15, wherein the condensation reaction is carried out in a reagent selected from the group consisting of 4-dimethylaminopyridine (DMAP), N-methylmorpholine (NMM), triethylamine (TEA), N,N-diisopropylethylamine (DIEA), pyridine (Py), and any mixture thereof.

17. 17. The process according to any one of claims 14 to 16, wherein the condensation reaction is carried out by reacting Ac ２ O, A ２ O / DMAP, Ac ２ O / DMAP / NMM, CH ３ COCl / TEA / DCM / DMAP, and CH ３ COCl / Py.

18. 18. The process according to any one of claims 14 to 17, wherein the condensation reaction is carried out in a solvent selected from the group consisting of acetic anhydride, dichloromethane (DCM), pyridine (Py), tetrahydrofuran, acetonitrile, acetone, ethyl acetate, and any mixture thereof.

19. 19. The process according to any one of claims 14 to 18, wherein the condensation reaction is carried out at about 0°C to about 150°C, preferably about 90°C to about 150°C, more preferably about 125°C to about 140°C.

20. 20. The process according to any one of claims 14 to 19, wherein the solvent used to purify the compound of formula (V) is selected from the group consisting of ethanol, methyl tert-butyl ether (MTBE), methanol, ethyl acetate, n-hexane, diethyl ether, tetrahydrofuran (THF), and any mixture thereof.

21. Preparing a compound of formula (IV) comprising: 【Chemistry 7】 Condensation reaction of a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (IV). 【Chemistry 8】 。

22. 22. The process according to claim 21, wherein the condensation reaction is carried out using a condensing agent selected from the group consisting of a carbodiimide type condensing agent, a phosphorus cationic condensing agent, a urea cationic condensing agent, other suitable condensing agents, and any mixture thereof, wherein the carbodiimide type condensing agent is preferably selected from the group consisting of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), EDCI (EDC.HCl) and dicyclohexylcarbodiimide (DCC), the phosphorus cationic condensing agent is preferably selected from the group consisting of 1H-benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP), bromotrispyrrolidinophosphonium hexafluorophosphate (PyBrOP), and / or benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), and the urea The cationic condensing agent is preferably selected from the group consisting of N,N,N,N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), and the other suitable condensing agents are preferably 1-hydroxybenzotriazole (HOBt), 6- chloro-1-hydroxybenzotriazole (Cl-HOBt), N-hydroxy-7-azabenzotriazole (HOAt), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), 3-diethoxyphosphoryloxy-1,2,3-benzotriazin-4(3H)-one (DEPBT), N-hydroxysuccinimide (HOSu), and / or pentafluorophenol.

23. 23. The process of claim 21 or claim 22, wherein the solvent for carrying out the condensation reaction is selected from the group consisting of dichloromethane, trichloromethane, acetonitrile, toluene, tetrahydrofuran, dioxane, and any mixture thereof.

24. 24. The process according to any one of claims 21 to 23, wherein the condensation reaction is carried out at about 0°C to about 50°C, preferably about 25°C to about 35°C.

25. 25. The process according to any one of claims 21 to 24, wherein the weight ratio of the amount of the compound of formula (III) to the amount of the compound of formula (II) is from about 1:1.3 to about 1:1.

4.

26. Preparing a compound of formula (III) comprising: 【Chemistry 9】 reacting a compound of general formula (I), 【Chemistry 10】 In the formula, R １ ≠R ２ and R １ and R ２ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted aryl, preferably R １ ≠R ２ and R １ and R ２ each independently represents a substituted or unsubstituted C １ ~C ６ Alkyl, substituted or unsubstituted C ２ ~C ６ Alkenyl, and substituted or unsubstituted C ６ ~C １２ aryl, more preferably R １ ≠R ２ and R １ and R ２ are each independently selected from the group consisting of methyl, ethyl, propyl, tert-butyl, benzyl, and allyl.

27. 27. The process of claim 26, wherein the reaction is carried out in the presence of trifluoroacetic acid (TFA), hydrochloric acid, hydrobromic acid, sulfonic acid, palladium on carbon, tetrakistriphenylphosphine palladium, or any mixture thereof.

28. 28. The process according to claim 26 or 27, wherein the reaction is carried out in a weight ratio of trifluoroacetic acid (TFA), hydrochloric acid, hydrobromic acid, sulfonic acid, palladium on carbon, tetrakistriphenylphosphine palladium, or any mixture thereof to the compound of formula (I) of about 1.5:1 to about 1:1, preferably in a weight ratio of trifluoroacetic acid (TFA), hydrochloric acid, hydrobromic acid, sulfonic acid, palladium on carbon, tetrakistriphenylphosphine palladium, or any mixture thereof to the compound of formula (I) of about 1.1:1 to about 1:

1.

29. 29. The process of claim 26 or claim 28, wherein the solvent is selected from the group consisting of dichloromethane, toluene, dichloroethane, ethyl acetate, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, and any mixture thereof.

30. 30. The process according to any one of claims 26 to 29, wherein the hydrolysis reaction is carried out at about -20°C to about 0°C, preferably about -15°C to about -5°C.

31. Preparing a compound of formula (VII) comprising: reacting a compound of general formula (I) to obtain a compound of formula (III); condensation reaction of the compound of formula (III) with a compound of formula (II) to obtain a compound of formula (IV); subjecting the compound of formula (IV) to a condensation reaction to obtain a compound of formula (V); hydrolyzing the compound of formula (V) to obtain a compound of formula (VI); and The compound of formula (VI) or the compound of formula (VIII) is subjected to a condensation reaction to obtain a compound of formula (VII).

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