Synthetic method for preparing pyridine carboxamide compound

Abstract

The present invention describes a synthetic process for the preparation of N-[4-[4-(4-morpholinyl)-7H-pyrrolo [2, 3-d] pyrimidin-6-yl] phenyl]-4-[[3-[(1-oxo-2-propylen-1-yl) amino]-1-piperidinyl] methyl]-2-pyridinecarboxamide, which is an irreversible covalent inhibitor of the menin-MLL interaction.

Description

Invention Field

[0001] This invention describes the preparation of N-[4-[4-(4-morpholino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide, an irreversible inhibitor of menin-MLL. Background of the Invention

[0002] The histone lysine N-methyltransferase 2 (KMT2) protein family, currently composed of at least five members, 4-methylates the lysine residues of histone H3 tails at important regulatory regions in the genome, thereby playing a key role in regulating chromatin structure and DNA accessibility (Morera, Lübbert, and Jung., Clin. Epigenetics 8, 57-(2016)). These enzymes are known to play important roles in the regulation of gene expression during early development and hematopoiesis (Rao & Dou., Nat. Rev. Cancer 15, 334-346(2015)).

[0003] Because of the role of KMT2A, the first member discovered in this disease, the human KMT2 family was initially named the mixed-lineage leukemia (MLL) family, while the member KMT2A is still commonly referred to as MLL1 or MLL in routine clinical practice.

[0004] KMT2A (MLL1) is frequently identified as a cytogenetic target in several types of leukemia (e.g., ALL and AML), and in cases where balanced chromosomal translocations are found, these translocations typically target KMT2A (MLL1) and one of the more than 80 translocation partner genes described to date (Winters and Bernt, Front. Pediatr. 5, 4 (2017)). These chromosomal abnormalities often result in the formation of fusion genes encoding fusion proteins, which are believed to be causally related to the onset and / or progression of the disease. Inhibition of menin may be a promising strategy for treating MLL-related diseases, including leukemia. Invention Abstract

[0005] This invention describes a method for preparing N-[4-[4-(4-morpholino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide, an irreversible inhibitor of the menin-MLL interaction. This invention also describes novel heterocyclic compounds as intermediates.

[0006] In one particular aspect, the present invention describes a method for preparing N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (the compound shown in Formula I): The method comprises the following steps: A5) Make the compound shown in formula V: Reaction with the compound shown in Formula VI: To obtain the compound shown in Formula I; wherein R 2 It is H, Li, Na, K, or Ca.

[0007] In another specific aspect, the present invention describes a method for preparing the compound shown in formula V: The method comprises the following steps: A1) Provides the compound shown in Formula II: Where Prot is an amine protecting group, and R 1 It is an alkyl or benzyl group; A2) Deprotect the compound shown in Formula II to obtain the intermediate compound shown in Formula III: A3) Convert the compound shown in Formula III into the intermediate compound shown in Formula IV: A4) Convert the compound shown in Formula IV into the intermediate compound shown in Formula V: Where R 2 It is H, Li, Na, K, or Ca.

[0008] Other objects, features, and advantages of the methods and compositions described in this invention will become apparent from the detailed description of the invention below. However, it should be understood that while the detailed description and specific embodiments indicate particular implementations, they are given by way of example only, as those skilled in the art will clearly understand various changes and modifications or alterations within the spirit and scope of the invention from the detailed description. The section headings used in this invention are for organizational purposes only and should not be construed as limiting the subject matter. All documents or portions thereof referenced in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are hereby expressly incorporated herein by reference in their entirety for any purpose. Incorporation

[0009] All publications and patent applications mentioned in this specification are incorporated herein by reference to the fullest extent applicable and relevant. Invention Details

[0010] The different roles of menin-MLL interactions in various hematopoietic cell functions suggest that small molecule inhibitors of menin-MLL interactions (e.g., compound A) may be used to reduce the risk of multiple diseases affected by or influencing many cell types of the hematopoietic lineage, including, for example, autoimmune diseases, xenoimmune disorders or diseases, inflammatory diseases, cancers (e.g., B-cell proliferative disorders), and thromboembolic diseases.

[0011] This invention describes a method for preparing N-[4-[4-(4-morpholino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide, an irreversible inhibitor of the menin-MLL interaction. This invention also describes novel heterocyclic compounds as intermediates.

[0012] In one particular aspect, the present invention describes a method for preparing N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (the compound shown in Formula I): The method comprises the following steps: A5) Make the compound shown in formula V: Reaction with the compound shown in Formula VI: To obtain the compound shown in Formula I; wherein R 2 It is H, Li, Na, K, or Ca.

[0013] In some implementation schemes, R 2 It's H.

[0014] In some implementation schemes, R 2 It is Li, Na, K, or Ca.

[0015] In some implementation schemes, R 2 It's Li.

[0016] In some implementations, step A5) is performed in the absence of a solvent.

[0017] In some implementations, step A5) is performed in the presence of a solvent.

[0018] In some embodiments, step A5) is carried out in the presence of a solvent, and the solvent is DMF, DMAc, THF, dioxane, or any other aprotic solvent, or any combination thereof.

[0019] In some implementations, step A5) is performed in DMAc.

[0020] In some implementations, step A5) is carried out in the presence of an alkali.

[0021] In some embodiments, step A5) is carried out in the presence of an alkali; and the alkali is selected from sodium hydride, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, sodium carbonate, potassium acetate, sodium acetate, trialkylamine, dialkylamine, Hunig base, DIPEA, N-methylmorpholine, and any combination thereof.

[0022] In some implementations, step A5) is performed in the presence of DIPEA.

[0023] In some implementations, step A5) is performed in the presence of a coupling agent.

[0024] In some embodiments, step A5) is carried out in the presence of a coupling agent; and the coupling agent is EDCI, CDI, T3P, TBTU, HCTU, HATU, PyBOP, DCC, HOPO, and any combination thereof.

[0025] In some implementations, step A5) is performed in the presence of EDCI.

[0026] In some implementations, step A5) is performed in the presence of HOPO.

[0027] In some implementations, step A5) is performed in the presence of EDCI and HOPO.

[0028] In some implementations, step A5) is performed in the presence of DIPEA, EDCI, and HOPO.

[0029] In some embodiments, step A5) is performed at a temperature of about 0°C to about 100°C. In some embodiments, step A5) is performed at a temperature of about 10°C to about 60°C. In some embodiments, step A5) is performed at a temperature of about 15°C to about 40°C. In some embodiments, step A5) is performed at a temperature of about 20-40°C. In some embodiments, step A5) is performed at about 20-30°C, and then at a temperature of 35-40°C. In some embodiments, step A5) is performed at a temperature of about 25°C.

[0030] In some implementations, step A5) lasts for 1 to 100 hours, 15 to 50 hours, or 20 to 50 hours. In some implementations, step A5) lasts for 10 to 15 hours.

[0031] In some implementations, step A5) lasts for approximately 30-35 hours.

[0032] In some embodiments, the intermediate compound shown in Formula V is prepared by a synthetic method, wherein the method comprises the following steps: A1) Provides the compound shown in Formula II: Where Prot is an amine protecting group, and R 1 It is an alkyl or benzyl group; A2) Deprotect the compound shown in Formula II to obtain the intermediate compound shown in Formula III: A3) Convert the compound shown in Formula III into the intermediate compound shown in Formula IV: A4) Convert the compound shown in Formula IV into the intermediate compound shown in Formula V: Where R 2 It is H, Li, Na, K, or Ca.

[0033] In some implementation schemes, R 1 It is a C1-C6 alkyl group. In other embodiments, R 1 It is a C1-C4 alkyl group.

[0034] In some implementations, in step A1), R 1It is Me, Et, i-Pr, or benzyl.

[0035] In some implementations, in step A1), R 1 It's me.

[0036] In some implementations, in step A1), Prot is Boc.

[0037] In some implementations, step A2) is performed in the absence of a solvent.

[0038] In some implementations, step A2) is performed in the presence of a solvent.

[0039] In some embodiments, step A2) is carried out in a solvent, and the solvent is methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, tetrachloroethane, THF, dioxane, or any combination thereof.

[0040] In some implementations, step A2) is carried out in methanol.

[0041] In some implementations, step A2) is performed in the presence of an acid.

[0042] In some embodiments, step A2) is carried out in the presence of an acid; and the acid is selected from methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, TiCl4, SnCl4, chiral camphorsulfonic acid, or any combination thereof, or any combination thereof.

[0043] In some embodiments, step A2) is performed in the presence of HCl / MeOH.

[0044] In some embodiments, step A2) is carried out in the presence of 20% HCl / MeOH.

[0045] In some embodiments, step A2) is performed at a temperature of about 0°C to about 100°C. In some embodiments, step A2) is performed at a temperature of about 10°C to about 50°C. In some embodiments, step A2) is performed at a temperature of about 15°C to about 40°C.

[0046] In some implementations, step A2) is performed at a temperature between 20-25°C.

[0047] In some implementations, step A2) lasts for 1 to 100 hours, 5 to 50 hours, or 6 to 48 hours.

[0048] In some implementations, step A2) lasts approximately 5-15 hours. In some implementations, step A2) lasts approximately 10 hours.

[0049] In some implementations, in step A2), R 2 It's me.

[0050] In some embodiments, the compound shown in Formula III is a monoacid salt, a diacid salt, or a triacid salt.

[0051] In some embodiments, the compound represented by Formula III is a monoacid salt, a diacid salt, or a triacid salt, and the acid salt is a hydrochloride salt, a hydrobromide salt, a methanesulfonate salt, or a trifluoroacetate salt.

[0052] In some implementations, in step A3), R 1 It is Me, Et, i-Pr, or benzyl.

[0053] In some implementations, in step A3), R 1 It's me.

[0054] In some embodiments, in step A3), the conversion is carried out by coupling the compound of formula III with acrylic acid, acrylic anhydride, or acryloyl chloride.

[0055] In some embodiments, in step A3), the conversion is carried out by coupling the compound of formula III with acrylic anhydride.

[0056] In some implementations, step A3) is performed in the absence of a solvent.

[0057] In some implementations, step A3) is performed in the presence of a solvent.

[0058] In some embodiments, step A3) is carried out in a solvent, and the solvent is DCM, toluene, n-heptane, acetonitrile, THF, dioxane, or any other aprotic solvent, or any combination thereof.

[0059] In some implementations, step A3) is performed in the DCM.

[0060] In some implementations, step A3) is carried out in the presence of an alkali.

[0061] In some embodiments, step A3) is carried out in the presence of a base; and the base is selected from trialkylamines, dialkylamines, alkylamines, Hunig bases, pyridine, imidazoles, DIPEA, N-methylmorpholine, and any combination thereof.

[0062] In some implementations, step A3) is carried out in the presence of Hunig base.

[0063] In some implementations, step A3) is performed at a temperature of about 0°C to about 100°C.

[0064] In some embodiments, step A3) is performed at a temperature of approximately 0-20°C. In some embodiments, step A3) is performed at a temperature of approximately 0-5°C.

[0065] In some implementations, step A3) lasts for 1 to 100 hours, 5 to 50 hours, or 6 to 48 hours.

[0066] In some implementations, step A3) lasts approximately 1-5 hours.

[0067] In some implementations, in step A4), R 1 It is Me, Et, i-Pr, or benzyl.

[0068] In some implementations, in step A4), R 1 It's me.

[0069] In some implementations, step A4) is performed in the absence of a solvent.

[0070] In some implementations, step A4) is performed in the presence of a solvent.

[0071] In some embodiments, step A4) is carried out in the presence of a solvent, and the solvent is DMF, DMAc, MeOH, EtOH, isopropanol, acetone, THF, dioxane, water, or any combination thereof.

[0072] In some implementations, step A4) is carried out in a mixture of DMAc and water.

[0073] In some implementations, step A4) is performed in the presence of a reagent.

[0074] In some embodiments, step A4) is performed in the presence of a reagent; and the reagent is selected from LiOH, NaOH, KOH, or Ca(OH)2.

[0075] In some implementations, in step A4), R 2 It is Li; and the reagent is LiOH.

[0076] In some implementations, in step A4), R 2 It is Na; and the reagent is NaOH.

[0077] In some implementations, in step A4), R 2 It is K; and the reagent is KOH.

[0078] In some implementations, in step A4), R 2 It is Ca; and the reagent is Ca(OH)2.

[0079] In some implementations, step A4) is performed at a temperature of about 0°C to about 100°C.

[0080] In some implementations, step A4) is performed at a temperature of approximately 20-35°C.

[0081] In some implementations, step A4) lasts for 1 to 100 hours, 5 to 50 hours, or 6 to 48 hours.

[0082] In some implementations, step A4) lasts for approximately 10-20 hours.

[0083] In some embodiments, the compound of product formula V obtained in step A4) is used directly in step A5. In some embodiments, the compound of product formula V obtained in step A4) can be used in step A5 without separation. In some embodiments, the compound of product formula V obtained in step A4) can be used in step A5 without any further purification.

[0084] In some embodiments, the intermediate used to synthesize the compound shown in Formula I is the compound shown in Formula X:

[0085] In some embodiments, the intermediate used to synthesize the compound shown in Formula I is the compound shown in Formula IV: and R 1 It is Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, s-Bu, or t-Bu.

[0086] In some embodiments, the intermediate used to synthesize the compound shown in Formula I is the compound shown in Formula III: and R 1 It is Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, s-Bu, or t-Bu.

[0087] In some implementation schemes, R 1 It is Me or Et.

[0088] In some implementation schemes, R 1 It's me.

[0089] In some embodiments, the intermediate used to synthesize the compound shown in Formula I is the compound shown in Formula XI: Specific terms

[0090] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and do not limit any claimed subject matter. In this application, the use of the singular includes the plural unless expressly stated otherwise. It must be noted that, unless the context clearly indicates otherwise, the singular forms “a” and “described” as used in this specification and the appended claims include the plural referents. In this application, the use of “or” means “and / or” unless otherwise stated. Furthermore, the use of the terms “comprising” and other forms such as “including,” “comprises,” and “covers” is not restrictive.

[0091] The chapter headings used in this invention are for organizational purposes only and should not be construed as limiting the subject matter. All documents or portions thereof cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are hereby expressly incorporated in their entirety by reference for any purpose.

[0092] With respect to the formulations, compositions or ingredients used in this invention, the term "acceptable" or "pharmaceutically acceptable" as used herein means that it does not have a persistent adverse effect on the general health of the treated subject and does not eliminate the biological activity or properties of the compound, and is relatively non-toxic.

[0093] "Alkyl" refers to a straight-chain or branched aliphatic hydrocarbon having 1 to 20 carbon atoms. Specific alkyl groups have 1 to 12 carbon atoms. More specifically, they are lower alkyl groups having 1 to 6 carbon atoms. Another specific group has 1 to 4 carbon atoms. Exemplary straight-chain groups include methyl, ethyl, n-propyl, and n-butyl. Branched means that one or more lower alkyl groups such as methyl, ethyl, propyl, or butyl are attached to a linear alkyl chain; exemplary branched groups include isopropyl, isobutyl, tert-butyl, and isopentyl.

[0094] The term "identity" as used in this invention refers to the similarity of two or more sequences or subsequences. Additionally, as used herein, the term "substantially identical" means that when two or more sequences are compared and aligned in a comparison window or designated region based on maximum identity (e.g., measured using a comparison algorithm or by manual comparison and visual inspection), the percentage of identical sequence units reaches a certain threshold. For example only, if sequence units in a designated region have approximately 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% identity, then two or more sequences can be considered "substantially identical." Such percentages are used to describe the "percentage identity" of two or more sequences. Sequence identity may exist in regions of at least approximately 75-100 consecutive units, regions of approximately 50 consecutive units, or, when not specified, throughout the entire sequence. This definition also refers to complementary sequences of the tested sequence. For example only, when amino acid residues are identical, two or more polypeptide sequences are considered identical; however, if amino acid residues in a specified region have approximately 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% identity, then the two or more polypeptide sequences are considered "substantially identical." Identity can be present in regions of at least approximately 75-100 amino acids, in regions of approximately 50 amino acids, or, when not specified, throughout the entire polypeptide sequence. Similarly, for example only, when nucleic acid residues are identical, two or more polynucleotide sequences are considered identical; however, if nucleic acid residues in a specified region have approximately 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% identity, then the two or more polynucleotide sequences are considered "substantially identical." Identity may exist in regions of at least about 75-100 nucleic acids in length, in regions of about 50 nucleic acids in length, or, if not specified, throughout the entire sequence of the polynucleotide sequence.

[0095] The term "inhibition," "repression," or "inhibitor" used in this invention to refer to the inhibition of menin activity, such as menin-MLL interaction and activity.

[0096] The term "irreversible inhibitor" as used in this invention refers to a compound that, when contacted with a target protein (e.g., menin or menin-MLL), forms a new covalent bond with or within the protein, thereby reducing or eliminating the biological activity (e.g., phosphotransferase activity) of one or more target proteins, regardless of the subsequent presence of an irreversible inhibitor.

[0097] The term "irreversible menin inhibitor" as used in this invention refers to a menin inhibitor that can form a covalent bond with the amino acid residues of menin.

[0098] The term "modulation" as used in this invention refers to interacting directly or indirectly with a target to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or extending the activity of the target.

[0099] As used in this invention, the term "modifier" refers to a compound that alters the activity of a molecule. For example, a modifier can cause an increase or decrease in the magnitude of a molecule's activity compared to the magnitude of activity in the absence of a modifier. In some embodiments, the modifier is an inhibitor that reduces the magnitude of one or more activities of a molecule. In some embodiments, the inhibitor completely inhibits one or more activities of a molecule. In some embodiments, the modifier is an activator that increases the magnitude of at least one activity of a molecule. In some embodiments, the presence of the modifier produces an activity that does not occur in the absence of the modifier.

[0100] As used in this invention, the terms "treat," "treating," or "treatment" include relieving, alleviating, or improving symptoms of a disease or condition; preventing other symptoms; improving or preventing underlying metabolic causes of symptoms; inhibiting a disease or condition, such as halting its progression; reducing a disease or condition; causing a disease or condition to subside; reducing the symptoms caused by a disease or condition; or stopping the symptoms of a disease or condition. The terms "treat," "treating," or "treatment" include, but are not limited to, preventative and / or therapeutic treatments.

[0101] It should also be understood that compounds with the same molecular formula but different atomic properties, bonding sequences, or spatial arrangements are called "isomers." Isomers with different spatial arrangements of atoms are called "stereoisomers."

[0102] Stereoisomers that are not mirror images of each other are called "diastereomers," while stereoisomers that are not mirror images of each other are called "enantiomers." When a compound has an asymmetry center, for example, if it is attached to four different groups, a pair of enantiomers may exist. Enantiomers are characterized by the absolute configuration of their asymmetry center, which can be described by the Cahn and Prelog R and S ordering rules, or by rotating the molecular polarization plane, and designated as dextrorotatory or levorotatory (i.e., (+) or (-)- isomers, respectively). Chiral compounds can exist as single enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0103] As used in this invention, a pure enantiomeric compound substantially contains no other enantiomers or stereoisomers of the compound (i.e., an enantiomeric excess). In other words, the “S” form of the compound substantially contains no “R” form of the compound, and is therefore an enantiomeric excess of the “R” form. The terms “enantiomerically pure” or “pure enantiomer” mean that the compound contains greater than 75 wt%, greater than 80 wt%, greater than 85 wt%, greater than 90 wt%, greater than 91 wt%, greater than 92 wt%, greater than 93 wt%, greater than 94 wt%, greater than 95 wt%, greater than 96 wt%, greater than 97 wt%, greater than 98 wt%, greater than 98.5 wt%, greater than 99 wt%, greater than 99.2 wt%, greater than 99.5 wt%, greater than 99.6 wt%, greater than 99.7 wt%, greater than 99.8 wt%, or greater than 99.9 wt% of enantiomers. In some embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0104] As used herein, unless otherwise stated, the term "enantiomerically pure R-compound" means at least about 80% by weight of the R-compound and at most about 20% by weight of the S-compound, at least about 90% by weight of the R-compound and at most about 10% by weight of the S-compound, at least about 95% by weight of the R-compound and at most about 5% by weight of the S-compound, at least about 99% by weight of the R-compound and at most about 1% by weight of the S-compound, or at least about 99.9% by weight of the R-compound or at most about 0.1% by weight of the S-compound. In some embodiments, the weight is based on the total weight of the compounds.

[0105] As used herein, unless otherwise stated, the terms "enantiomerically pure S-compound" or "S-compound" refer to at least about 80% by weight of the S-compound and at most about 20% by weight of the R-compound, at least about 90% by weight of the S-compound and at most about 10% by weight of the R-compound, at least about 95% by weight of the S-compound and at most about 5% by weight of the R-compound, at least about 99% by weight of the S-compound and at most about 1% by weight of the R-compound, or at least about 99.9% by weight of the S-compound and at most about 0.1% by weight of the R-compound. In some embodiments, the weight is based on the total weight of the compound.

[0106] In the compositions provided by this invention, enantiomerically pure compounds or their pharmaceutically acceptable salts, solvates, hydrates, or prodrugs may be present together with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R-compound may comprise, for example, about 90% excipients and about 10% enantiomerically pure R-compound. In some embodiments, such compositions may, for example, comprise at least about 95% by weight of the R-compound and at most about 5% by weight of the S-compound (based on the total weight of said compounds). For example, a pharmaceutical composition comprising an enantiomerically pure S-compound may comprise, for example, about 90% excipients and about 10% enantiomerically pure S-compound. In some embodiments, such compositions may, for example, comprise at least about 95% by weight of the S-compound and at most about 5% by weight of the R-compound (based on the total weight of said compounds). In some implementation schemes, the active ingredient may be formulated with a small amount or not with excipients or carriers.

[0107] The compounds of the present invention may have one or more asymmetric centers; therefore, such compounds may be prepared as individual (R)- or (S)- stereoisomers or as mixtures thereof.

[0108] Unless otherwise stated, the description or naming of specific compounds in this specification and claims is intended to include individual enantiomers and mixtures thereof, racemates thereof, or other forms. Methods for determining stereochemistry and isolating stereoisomers are well known in the art. Example

[0109] The following components, formulations, processes, and procedures used to practice the methods disclosed in this invention correspond to those described above.

[0110] The compounds can be prepared from readily available starting materials using the following methods and procedures. It should be understood that other process conditions may be used when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through conventional optimization procedures.

[0111] Furthermore, those skilled in the art will recognize that conventional protecting groups may be necessary to prevent undesirable reactions of certain functional groups. The selection of appropriate protecting groups for specific functional groups, as well as suitable conditions for protection and deprotection, are well known in the art. For example, many protecting groups and their introduction and removal are described in TWGreene and PGMWuts, *Protecting Groups in Organic Synthesis*, Second Edition, Wiley, New York, 1991, and their cited references.

[0112] The compounds can be separated and purified using known standard methods. These methods include (but are not limited to) recrystallization, column chromatography, or HPLC. The following protocols detail the preparation methods for the representative fused heterocyclic compounds listed above. Those skilled in the art of organic synthesis can prepare these compounds using known or commercially available starting materials and reagents.

[0113] The compounds of the present invention can be prepared by the method described in the present invention.

[0114] The following abbreviations may be used in this specification: Example 1 Option I:

[0115] Synthesis of (R)-4-((3-aminopiperidin-1-yl)methyl)pyridinecarboxylate·HCl(2):

[0116] Compound 1 (5.0 g, 2.86 mmol) was dissolved in methanol (40 mL), and the mixture was cooled to 0–5 °C. A methanol-HCl solution (3.0 M, 15 mL, 9.0 mmol) was slowly added over 15 minutes while maintaining the temperature between 0 and 5 °C. The mixture was heated to room temperature and stirred for approximately 10 hours. The methanol was concentrated under vacuum to obtain a residue. Ethyl acetate (25 mL) was added to the residue, and the mixture was concentrated to 10 mL. The mixture was cooled to 0–5 °C, filtered, and dried in a vacuum oven at 40–50 °C. Weight: 3.2 g; Yield: 90%. 1H-NMR(CDCl3): δppm 12.27(br s,1H),8.79(d,J=4.82Hz,1H),8.67(br s,3H),8.33(s,1H),8.01(br d,J=4.39Hz,1H),4.46-4.59(m,2H),3.87(s,3H),3.60(br s,1H),3.41(br d,J=9.87Hz,1H),3.30(br d,J=10.30Hz,1H),3.12(d,J=0.66Hz,1H),2.97(br t,J=11.18Hz,1H),2.86(br s,1H),2.06(br d,J=10.52Hz,1H),1.79-1.98(m,2H),1.45-1.63(m,1H).M +1 :250.47.

[0117] Synthesis of (R)-4-((3-acrylamidopiperidin-1-yl)methyl)pyridinecarboxylate (3):

[0118] Crude (R)-4-((3-aminopiperidin-1-yl)methyl)pyridinecarboxylate·HCl (2, 3.0 g, 10.5 mmol) was suspended in dichloromethane (15 mL), and the mixture was cooled to 0–5 °C. Hunig base (4.2 mL, 24.0 mmol) was slowly added, and the mixture was stirred for 15 minutes. Acrylic anhydride (1.46 g, 11.57 mmol) was slowly added via syringe while maintaining the temperature below 0 °C. The mixture was stirred for 3.0 hours, and the pH was adjusted to 7.0 with citric acid solution (5%). The mixture was slowly heated to room temperature and stirred for 1.0 hour, then transferred to a separatory funnel. The DCM layer was separated, and the aqueous layer was extracted with DCM (20 mL). The combined DCM layers were separated and washed with 10% Na₂SO₄ solution. The DCM layer was concentrated under vacuum and ground with toluene to give compound 3. Weight: 2.0 g; Yield: 82%. 1H-NMR(CDCl3): δppm 8.57(d,J=5.04Hz,1H),8.13(s,1H),7.62(dd,J=4.93,1.21Hz,1H),6.11-6.30 (m,2H),5.61(dd,J=9.76,2.30Hz,1H),3.89-4.03(m,4H),3.62(s,2H),2.81(br d,J=8.99Hz,1H),2.56-2.69(m,1H),2.17(br t,J=9.54Hz,1H),2.05(br t,J=9.54Hz,1H),1.70-1.88(m,2H),1.55-1.69(m,1H),1.27-1.40(m,2H).M +1 :304.18.

[0119] Synthesis of (R)-4-((3-acrylamidopiperidin-1-yl)methyl)pyridinecarboxylic acid (4):

[0120] Compound 3 (5.0 g, 16.48 mmol) was dissolved in a mixture of N,N'-dimethylacetamide (DMAc, 25 mL) and deionized water (0.5 mL). Lithium hydroxide (0.83 g, 34.6 mmol) was added in small batches to the resulting clear solution at room temperature, and the mixture was stirred at 25–35 °C for 20 hours. After hydrolysis, the mixture was cooled to 5–10 °C, and the pH was adjusted to approximately 7.0 with 10% H₂SO₄-DMAc solution while maintaining the temperature below 10 °C. The mixture was concentrated under vacuum and then azeotropically distilled with toluene to obtain a DMAc solution of compound 4, which could be used for the next coupling reaction without any purification.

[0121] Synthesis of 4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)aniline (7) (US11,084,825) (incorporated by reference in its entirety):

[0122] Potassium carbonate (6.2 g, 45 mmol), deionized water (15 mL), and THF (65 mL) were placed in a round-bottom flask, and N2 was bubbled through the mixture for 10 minutes. Pd(OAc)2 (0.117 g, 0.52 mmol) and Ad2(n-Bu)P (0.322 g, 0.90 mmol) were placed in a round-bottom flask, and N2 was bubbled through the mixture for 10 minutes. Compound 5 (5.0 g, 15.15 mmol) and compound 6 (3.8 g, 17.35 mmol) were added under N2 atmosphere, and N2 was bubbled through the mixture for 10 minutes. The reaction mixture was slowly heated to 60–70 °C and stirred for 40 hours. After the reaction was complete, the THF was concentrated under vacuum, and the mixture was quenched with deionized water (100 mL). The mixture was stirred for another 10 hours at room temperature, and the precipitated solid was filtered to give compound 7. Weight: 3.20 g; Yield: 72%. 1 H-NMR(CDCl3): δ12.27(br s,1H),8.08(s,1H),6.88(s,1H),3.80 -3.77(m,4H),3.70-3.68(m,4H).M +1 296.58.

[0123] Synthesis of (R)-4-((3-acrylamidopiperidin-1-yl)methyl)-N-(4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)pyridineamide (8):

[0124] Compound 4 (12 g, 41.4 mmol, assay corrected) and N,N'-dimethylacetamide (10 mL) were placed in a round-bottom flask and stirred at room temperature. EDAC·HCl (13.03 g, 68 mmol), 2-hydroxypyridine-1-oxide (7.5 g, 67.5 mmol), and N,N'-diisopropylethylamine (17.57 g, 136 mmol) were added sequentially, while maintaining the temperature below 25 °C. After stirring the mixture for 0.5 h, compound 7 (10.0 g, 34 mmol, dissolved in 40 mL N,N'-DMAc) was slowly added over 1.0 h, while maintaining the temperature below 25 °C. The reaction mixture was stirred overnight at 35–40 °C, and then quenched with water (100 mL) at room temperature. The precipitated solid was filtered, washed with water (50 mL), and dried under vacuum to give the pure compound. Weight: 13.40 g, Yield: 70%. 1H-NMR(DMSO): δppm 12.21(s,1H),10.74(s,1H),8.69(d,J=5.01Hz,1H),8.19(s,1H),8.12 (s,1H),7.96-8.04(m,3H),7.81-7.94(m,2H),7.63(d,J=4.53Hz,1H), 7.17(d,J=1.43Hz,1H),6.17-6.29(m,1H),6.00-6.11(m,1H),5.47-5. 63(m,1H),3.80-3.98(m,5H),3.70-3.80(m,4H),3.66(s,2H),2.79(br d,J=7.99Hz,1H),2.66(br d,J=11.68Hz,1H),1.97-2.14(m,1H),2.12(s,1H),1.82-1.97(m,1H),1.64-1.83(m,2H),1.46 -1.60(m,1H),1.10-1.31(m,1H).M +1 :567.44.

[0125] Synthesis of Compound 4 (US11,084,825) (in which all are incorporated herein by reference): Option II

[0126] Synthesis of 2-bromopyridin-4-yl-methanol(1):

[0127] Under a nitrogen atmosphere, Pd(dppf)Cl2.CH2Cl2 (0.10 g, 0.12 mmol, 0.005 mmol) was added to a methanol (20 mL) solution of compound 1 (5.0 g, 26.60 mmol) and triethylamine (9.42 g, 93 mmol, 3.50 mmol). The suspension was degassed and purged three times with CO. The mixture was stirred at 80 °C for 12 hours under CO (2 MPa). After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to give a crude solid. The crude product was ground together with DME (15 mL) and then filtered to give compound 2, a pink solid. Weight: 3.0 g, yield: 69%. 1 H-NMR(CDCl3):8.54(d,J=4.88Hz,1H),8.03(s,1H),7.44(br d,J=4.88Hz,1H),4.75(s,2H),3.80-4.03(m,4H).M +1 :168.47.

[0128] Synthesis of methyl 4-(methylsulfonyl)oxy)methyl)pyridinecarboxylate (2):

[0129] Compound 2 (10 g, 59.82 mmol) and N,N'-diisopropylaminoethylamine (15.46 g, 120 mmol) were added to a solution of dichloromethane (50 mL) with methanesulfonyl chloride (10.27 g, 89.73 mmol). The mixture was stirred at 0–5 °C for 2.0 h. After the reaction was complete, the mixture was quenched with water (20 mL) and then extracted with DCM (2 × 25 mL). The combined DCM layers were washed with water and brine and dried over sodium sulfate. The DCM layers were filtered, concentrated under vacuum, and the residue was ground with n-heptane (25 mL). The precipitated solid was filtered and dried. Weight: 9.8 g, yield: 67%. 1 H-NMR(CDCl3): δppm 8.74(d,J=4.85Hz,1H),8.10(s,1H),7.49(d,J=4.19Hz,1H),5.27(s,2H),3.91-4.04(m,3H),3.00-3.11(m,3H).M +1 :246.37.

[0130] Synthesis of (R)-4-(3-tert-butoxycarbonyl)amino)piperidin-1-yl)methyl)pyridinecarboxylate (4):

[0131] Anhydrous potassium carbonate (17 g, 123 mmol) was added to a solution of compound 3 (10 g, 40.7 mmol) and (R)-piperidin-3-yl-carboxylic acid tert-butyl ester (8.57 g, 42.8 mmol) at 20 °C. The mixture was slowly heated to 100 °C and maintained for 12 h. The mixture was cooled to room temperature and quenched with water (60 mL). The mixture was extracted with ethyl acetate (2 × 30 mL), concentrated under vacuum, and the residue was ground with n-heptane (25 mL) to give a pale yellow solid. Weight: 10.5 g, yield: 74%. 1 H-NMR(CDCl3): δppm8.61(d,J=4.88Hz,1H),8.00(s,1H),7.41(br d,J=4.38Hz,1H),4.84(br s,1H),3.87-4.06(m,3H),3.57-3.80(m,1H),3.47(s,2H),2.54(br d,J=8.88Hz,1H),2.26(br d,J=15.13Hz,3H),1.62(br s,2H),1.46-1.55(m,1H),1.37(s,10H).M +1 350.24.

[0132] Synthesis of compound 7: Option III

[0133] Synthesis of 4-chloro-7-(benzenesulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (2):

[0134] t-BuONa (7.67 g, 68.37 mmol) was added to a THF (100 mL) solution of compound 1 (10 g, 65.1 mmol), followed by dropwise addition of PhSO₂Cl (11.50 g, 65.1 mol) at 10 °C. The resulting mixture was stirred at 20 °C for 5 hours. TLC (petroleum ether / ethyl acetate = 3 / 1, R) f =0.51) indicates the reaction is complete. The reaction mixture was quenched with deionized water (50 mL), the precipitated solid was filtered off, washed with MeOH (20 × 2), and dried in a vacuum oven. Weight: 17.4 g, yield: 91%. 1 H-NMR(DMSO): δ8.81(s,1H),8.17-8.12(m,3H),7.77-7.75(m,1H),7.68-7.64(m,2H),6.95(d,J=4.0Hz,1H).M +1 :294.79.

[0135] Synthesis of 4-chloro-7-(benzenesulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (3):

[0136] At -60°C, LDA (2M, 25.5mL) was added dropwise to a THF (75mL) solution of compound 2 (10g, 34mmol). After the addition, the mixture was stirred at this temperature for 1h, and then a THF (25mL) solution of I2 (11.23g, 44.25mol) was added dropwise at -60°C. The resulting mixture was stirred at -65°C for 12h. After the reaction was complete, the mixture was quenched with 1M HCl (50mL) at 0°C. The organic layer was concentrated under reduced pressure to obtain a residue, which was then ground together with MTBE. The precipitated solid was filtered, washed with MTBE, and dried in a vacuum oven. Weight: 6.3g, Yield: 44%. 1 H-NMR(DMSO): δ8.76(s,1H),8.11-8.09(m,2H),7.82-7.76(m,1H),7.77-7.69(m,2H),7.37(s,1H).M +1 :420.17.

[0137] Synthesis of 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (4):

[0138] To a THF (80 mL) solution of compound 3 (8.0 g, 19.06 mmol), 20 mL of 2 M NaOH was added. The mixture was stirred at 25 °C for 12 hours. After the reaction was complete, the THF was concentrated under reduced pressure, and the pH of the resulting mixture was adjusted to pH 7.0 with 2 M HCl. The precipitated solid was filtered, washed with water, and dried under vacuum to give a grayish-white solid. Weight: 4.68 g. Yield: 88%. 1 H-NMR(DMSO): δ13.13(br s,1H),8.51(s,1H),6.87(d,J=2.0Hz,1H).M +1 :280.32.

[0139] Synthesis of 4-(6-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine(5):

[0140] Morpholine (9.33 g, 107 mmol) was added to a solution of compound 4 (15 g, 53.67 mmol) in n-butanol (80 mL). The mixture was stirred at 100 °C for 12 hours. After the reaction was complete, the mixture was cooled to 10–15 °C. The resulting solid was filtered and washed with cold n-butanol to give compound 5 as a white solid. Weight: 13.8 g, yield: 78%. 1 H-NMR(DMSO): δ12.27(br s,1H),8.08(s,1H),6.88(s,1H),3.80-3.77(m,4H),3.70-3.68(m,4H).M +1 :331.18.

[0141] Synthesis of 4-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine(6):

[0142] Under N2 atmosphere, Pd(dppf)Cl2 (0.52 g, 0.72 mmol) and K2CO3 (10 kg, 72 mmol) were added to a solution of compound 5 (12 g, 36.3 mmol) and pinacol 4-aminophenylboronic acid (9.46 g, 43.2 mmol) in dioxane (90 mL) and H2O (20 mL). The mixture was stirred at 100 °C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, and an additional 200 mL of water was slowly added over 30 minutes. The precipitated solid was filtered, washed with excess water, and dried in a vacuum oven at 55 °C for 24 hours. Weight: 7.3 g. Yield: 68%. 1H-NMR(DMSO): δ11.92(s,1H),8.12(s,1H),7.58-7.55(m,2H),6.82(s,1H) ),6.60-6.58(m,2H),5.29(s,2H),3.84-3.82(m,4H),3.74-3.72(m,4H).M +1 :296.12.

[0143] The embodiments and implementation schemes described in this invention are illustrative, and various modifications or changes suggested to those skilled in the art are included within the scope of this invention. Those skilled in the art should understand that the specific components or ingredients listed in the above embodiments can be replaced by other functionally equivalent components or ingredients, such as diluents, adhesives, lubricants, fillers, etc.

Claims

1. Method for preparing the compound shown in Formula I: The method comprises the following steps: A5) Make the compound shown in formula V: Reaction with the compound shown in Formula VI: To obtain the compound shown in Formula I; wherein R 2 It is H, Li, Na, K, or Ca.

2. The method according to claim 1, wherein, R 2 It is H.

3. The method according to claim 1, wherein, R 2 It is Li, Na, K, or Ca.

4. The method according to claim 1, wherein, R 2 It is He.

5. The method according to any one of claims 1-4, wherein, Step A5) is performed in the absence of solvent.

6. The method according to any one of claims 1-4, wherein, Step A5) is performed in the presence of a solvent.

7. The method according to any one of claims 1-4, wherein, Step A5) is carried out in the presence of a solvent, and the solvent is DMF, DMAc, THF, dioxane, or any other aprotic solvent, or any combination thereof.

8. The method according to any one of claims 1-4, wherein, Step A5) is performed in DMAc.

9. The method according to any one of claims 1-8, wherein, Step A5) is carried out in the presence of an alkali.

10. The method according to any one of claims 1-8, wherein, Step A5) is carried out in the presence of a base; and the base is selected from sodium hydride, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, sodium carbonate, potassium acetate, sodium acetate, trialkylamine, dialkylamine, Hunig base, DIPEA, N-methylmorpholine, and any combination thereof.

11. The method according to any one of claims 1-8, wherein, Step A5) is performed in the presence of DIPEA.

12. The method according to any one of claims 1-11, wherein, Step A5) is performed in the presence of a coupling agent.

13. The method according to any one of claims 1-11, wherein, Step A5) is carried out in the presence of a coupling agent; and the coupling agent is EDCI, CDI, T3P, TBTU, HCTU, HATU, PyBOP, DCC, HOPO, and any combination thereof.

14. The method according to any one of claims 1-11, wherein, Step A5) is performed in the presence of EDCI.

15. The method according to any one of claims 1-11, wherein, Step A5) is performed in the presence of HOPO.

16. The method according to any one of claims 1-11, wherein, Step A5) is performed in the presence of EDCI and HOPO.

17. The method according to any one of claims 1-11, wherein, Step A5) is performed in the presence of DIPEA, EDCI, and HOPO.

18. The method according to any one of claims 1-17, wherein, Step A5) is performed at a temperature of about 0°C to about 100°C.

19. The method according to any one of claims 1-17, wherein, Step A5) is performed at around 20-30°C, and then at 35-40°C.

20. The method according to any one of claims 1-20, wherein, Step A5) lasts for 1 to 100 hours, 20 to 50 hours, or 6 to 48 hours.

21. The method according to any one of claims 1-20, wherein, Step A5) lasts approximately 10-15 hours.

22. The method according to any one of claims 1-21, wherein, The intermediate compound shown in Formula V is prepared by a synthetic method comprising the following steps: A1) Provides the compound shown in Formula II: Where Prot is an amine protecting group, and R 1 It is an alkyl or benzyl group; A2) Deprotect the compound shown in Formula II to obtain the intermediate compound shown in Formula III: A3) Convert the compound shown in Formula III into the intermediate compound shown in Formula IV: A4) Convert the compound shown in Formula IV into the intermediate compound shown in Formula V: and R 2 It is H, Li, Na, K, or Ca.

23. The method according to claim 22, wherein, In step A1), R 1 It is Me, Et, i-Pr, or benzyl.

24. The method according to claim 22, wherein, In step A1), R 1 It's me.

25. The method according to any one of claims 22-24, wherein, In step A1), Prot is Boc.

26. The method according to any one of claims 22-25, wherein, Step A2) is performed in the absence of a solvent.

27. The method according to any one of claims 22-25, wherein, Step A2) is performed in the presence of a solvent.

28. The method according to any one of claims 22-25, wherein, Step A2) is carried out in a solvent, and the solvent is methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, tetrachloroethane, THF, dioxane, or any combination thereof.

29. The method according to any one of claims 22-25, wherein, Step A2) is carried out in methanol.

30. The method according to any one of claims 22-29, wherein, Step A2) is carried out in the presence of acid.

31. The method according to any one of claims 22-29, wherein, Step A2) is carried out in the presence of an acid; and the acid is selected from methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, TiCl4, SnCl4, chiral camphorsulfonic acid, or any combination thereof, or any combination thereof.

32. The method according to any one of claims 22-29, wherein, Step A2) is carried out in the presence of HCl / MeOH.

33. The method according to any one of claims 22-29, wherein, Step A2) is carried out in the presence of 20% HCl / MeOH.

34. The method according to any one of claims 22-33, wherein, Step A2) is performed at a temperature of about 0°C to about 100°C.

35. The method according to any one of claims 22-33, wherein, Step A2) is performed at a temperature between 20-25°C.

36. The method according to any one of claims 22-35, wherein, Step A2) lasts for 1 to 100 hours, 5 to 50 hours, or 6 to 48 hours.

37. The method according to any one of claims 22-35, wherein, Step A2) lasts approximately 5-15 hours.

38. The method according to claim 22, wherein, In step A2), R 2 It's me.

39. The method according to claim 22, wherein, The compound shown in Formula III is a monoacid salt, a diacid salt, or a triacid salt.

40. The method according to claim 22, wherein, The compound represented by Formula III is a monoacid salt, diacid salt, or triacid salt, and the acid salt is a hydrochloride salt, hydrobromide salt, methanesulfonate salt, or trifluoroacetate salt.

41. The method according to claim 22, wherein, In step A3), R 1 It is Me, Et, i-Pr, or benzyl.

42. The method according to claim 22, wherein, In step A3), R 1 It's me.

43. The method according to any one of claims 22-42, wherein, In step A3), the conversion is carried out by coupling the compound of formula III with acrylic acid, acrylic anhydride, or acryloyl chloride.

44. The method according to any one of claims 22-42, wherein, In step A3), the conversion is carried out by coupling the compound of formula III with acrylic anhydride.

45. The method according to any one of claims 22-44, wherein, Step A3) is performed in the absence of solvent.

46. ​​The method according to any one of claims 22-44, wherein, Step A3) is performed in the presence of a solvent.

47. The method according to any one of claims 22-44, wherein, Step A3) is carried out in a solvent, and the solvent is DCM, toluene, n-heptane, acetonitrile, THF, dioxane, or any other aprotic solvent, or any combination thereof.

48. The method according to any one of claims 22-44, wherein, Step A3) is performed in the DCM.

49. The method according to any one of claims 22-48, wherein, Step A3) is carried out in the presence of an alkali.

50. The method according to any one of claims 22-48, wherein, Step A3) is carried out in the presence of a base; and the base is selected from trialkylamines, dialkylamines, alkylamines, Hunig bases, pyridine, imidazoles, DIPEA, N-methylmorpholine, and any combination thereof.

51. The method according to any one of claims 22-48, wherein, Step A3) is carried out in the presence of Hunig base.

52. The method according to any one of claims 22-51, wherein, Step A3) is performed at a temperature of about 0°C to about 100°C.

53. The method according to any one of claims 22-51, wherein, Step A3) is performed at a temperature of approximately 0-5°C.

54. The method according to any one of claims 22-53, wherein, Step A3) lasts for 1 to 100 hours, 5 to 50 hours, or 6 to 48 hours.

55. The method according to any one of claims 22-53, wherein, Step A3) lasts approximately 1-5 hours.

56. The method according to any one of claims 22-55, wherein, In step A4), R 1 It is Me, Et, i-Pr, or benzyl.

57. The method according to any one of claims 22-55, wherein, In step A4), R 1 It's me.

58. The method according to any one of claims 22-57, wherein, Step A4) is performed in the absence of solvent.

59. The method according to any one of claims 22-57, wherein, Step A4) is performed in the presence of a solvent.

60. The method according to any one of claims 22-57, wherein, Step A4) is carried out in the presence of a solvent, and the solvent is DMF, DMAc, MeOH, EtOH, isopropanol, acetone, THF, dioxane, water, or any combination thereof.

61. The method according to any one of claims 22-57, wherein, Step A4) is carried out in a mixture of DMAc and water.

62. The method according to any one of claims 22-61, wherein, Step A4) is performed in the presence of the reagent.

63. The method according to any one of claims 22-61, wherein, Step A4) is performed in the presence of a reagent; and the reagent is selected from LiOH, NaOH, KOH, or Ca(OH)2.

64. The method according to any one of claims 22-61, wherein, Step A4) is performed in the presence of a reagent; and the reagent is selected from LiOH or NaOH.

65. The method according to any one of claims 22-61, wherein, In step A4), R 2 It is Li; and the reagent is LiOH.

66. The method according to any one of claims 22-61, wherein, In step A4), R 2 It is Na; and the reagent is NaOH.

67. The method according to any one of claims 22-61, wherein, In step A4), R 2 It is K; and the reagent is KOH.

68. The method according to any one of claims 22-61, wherein, In step A4), R 2 It is Ca; and the reagent is Ca(OH)2.

69. The method according to any one of claims 22-68, wherein, Step A4) is performed at a temperature of about 0°C to about 100°C.

70. The method according to any one of claims 22-68, wherein, Step A4) is performed at a temperature of approximately 20-35°C.

71. The method according to any one of claims 22-70, wherein, Step A4) lasts for 1 to 100 hours, 5 to 50 hours, or 6 to 48 hours.

72. The method according to any one of claims 22-70, wherein, Step A4) lasts approximately 10-20 hours.

73. The method according to any one of claims 1-70, wherein, The compound of product V obtained in step A4) is used in step A5 without any further purification.

74. The compound shown in formula X:

75. The compound shown in Formula IV: Wakanaka R 1 It is Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, s-Bu, or t-Bu.

76. The compound shown in Formula III: Wakanaka R 1 It is Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, s-Bu, or t-Bu.

77. The method according to any one of claims 1-70, wherein, R 1 It is Me or Et.

78. The method according to any one of claims 1-70, wherein, R 1 It's me.

79. The compound shown in formula XI:

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