Preparation method of epalgotinib and analogues thereof

Abstract

The invention relates to a preparation method of epalgotinib and analogues thereof. The preparation method provided by the invention is simple to operate, high in yield, low in cost, safe and environment-friendly, further provides two new intermediates A and B. The preparation method provided by the invention is suitable for industrial production of epalgotinib bulk drugs, can meet the requirements of clinical research and drug marketing, and effectively solves the problem of drug accessibility.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a method for preparing epagoglinib and its analogues. Background Technology

[0002] Fibroblast growth factor (FGF) is a family of 22 structure-associated polypeptides with different biological activities. They can regulate cell proliferation, differentiation, migration, and play a major role in limb development, angiogenesis, tissue repair, and tumor formation (Eswarakumar et al., 2005 Cytokine Growth Factor Rev16:139-149; Ornitz and Itoh, 2001 Genome Bio12:Reviews3005).

[0003] The corresponding receptor for FGF (FGFR) belongs to the RPTK family of receptor tyrosine kinases. Currently, four receptors have been identified: FGFR1, FGFR2, FGFR3, and FGFR4 (Ullrich and Schlessinger, 1990 Cell 61:203). Their interaction with their corresponding ligand FGF leads to receptor dimerization and autophosphorylation, thereby initiating multiple downstream signaling cascades, including MAPK and AKT (Powers et al., 2000 Endocr Relat Cancer 7:165-197).

[0004] Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in China and one of the fastest-growing cancers in terms of annual incidence (Shariff et al., 2009 Expert Rev Gastroenterol Hepato 13:353-367). FGF19 is overexpressed in 5-10% of HCC patients, while FGFR4 is the dominant FGFR in human hepatocytes, and its high expression in hepatocytes is considered to be associated with the invasiveness of HCC tumors. Therefore, FGFR4 plays a very important role in liver cancer. Furthermore, the interaction between FGF19 and FGFR4 is also believed to be related to the invasiveness of other cancer types (such as gastric cancer, prostate cancer, lung cancer, colorectal cancer, pancreatic cancer, and ovarian cancer) (Ye et al., 2011 Cancer 5304-5313; Xu et al., 2011 BMC Cancer 11:84; Fawdar et al., 2013 PNAS 110:12426-12431).

[0005] In 2018, Shanghai Heyu Biomedical Technology Co., Ltd. disclosed a highly selective small molecule inhibitor targeting FGFR4 in patent WO2018113584A1. The representative compound is compound 790 in the example, and its chemical structure is as follows:

[0006]

[0007] Meanwhile, the patent also discloses a method for preparing the similar structure embodiment 775, as follows:

[0008]

[0009] In the above preparation method, the azide compounds used in the first three steps are explosive, and each step needs to be carried out at a high temperature close to 100°C, which is highly dangerous and difficult to operate. In the fourth step, an inorganic base reagent is used, and the yield is only 63%. The overall yield of the four steps is only 29.8%. Therefore, this preparation method has the risks of using dangerous reagents, being difficult to operate, having low safety, and having a low overall yield, making it unsuitable for large-scale industrial production.

[0010] Furthermore, the patent also discloses a preparation method for the similar structure embodiment 433, as follows:

[0011]

[0012] In the above preparation method, the first step reaction is carried out under acidic conditions, with a yield of only 79.6%; the second step reaction is carried out at a high temperature of 110°C, with a yield of only 54%; the fourth step reaction uses an inorganic base reagent, with a yield of only 59.5%; and even if the yield of the third step is not calculated and is assumed to be 100%, the total yield of the remaining three steps is only 25.6%. Therefore, this preparation method also requires high-temperature operation, has low safety, and has a low total yield, making it unsuitable for large-scale industrial production and affecting drug accessibility.

[0013] In summary, the intermediates and their preparation methods disclosed in the existing technology are not suitable for industrial application and cannot solve the problem of drug accessibility. Therefore, there is a particular need to develop an industrially scalable preparation method to meet the needs of clinical research and drug market launch of the FGFR4 inhibitor epagoglinib. Summary of the Invention

[0014] This invention relates to a method for preparing epagoglinib and its analogues to address drug accessibility issues and meet the needs of epagoglinib clinical research and market launch.

[0015] The first aspect of this invention provides a method for preparing epagoglinib and its analogues of formula (D) or their acid salts, characterized by comprising the following steps:

[0016] 1) The compound of formula (1) or its acid salt reacts with the compound of formula (2) or its acid salt under alkaline conditions to produce the compound of formula (A) or its acid salt;

[0017] 2) Compound (A) or its acid salt and compound (3) or its acid salt are reacted to prepare compound (B) or its acid salt;

[0018] 3) The compound of formula (B) or its acid salt is prepared by deprotection to obtain the compound of formula (C) or its acid salt;

[0019] 4) Compound (C) or its acid salt and compound (4) are combined by a condensation reaction to prepare compound (D) or its acid salt;

[0020] The reaction route is as follows:

[0021]

[0022] In each formula, Pg is an amino protecting group; X1 and X2 are each an independent halogen.

[0023] R1 and R2 are each independently hydrogen or halogen; R3 and R4 are each independently substituted or unsubstituted C. 1-4 Alkoxy, wherein the substituent is deuterium or halogen;

[0024] R5 represents substituted or unsubstituted C. 1-4 Alkyl group, wherein the substituent is deuterium or halogen; R6 is a substituted or unsubstituted C. 1-4 Alkoxy, wherein the substituent is deuterium or halogen;

[0025] In each of the formulas, the acid salts are each independently an inorganic acid salt or an organic acid salt.

[0026] In a preferred embodiment, in the preparation method, Pg is tert-butyloxycarbonyl; X1 and X2 are each independently chlorine or bromine; R1 and R2 are each independently chlorine or fluorine; R3 and R4 are each independently methoxy, trideuteroxy, or trifluoromethoxy; R5 is methyl, ethyl, trideutermethyl, or trifluoromethyl; and R6 is methoxy, trideuteroxy, or trifluoromethoxy.

[0027] In a preferred embodiment, the inorganic acid salt in the preparation method is selected from hydrochloride, sulfate, hydrobromide, hydrofluoric acid, hydroiodide, and phosphate; the organic acid salt is selected from acetate, dichloroacetate, trichloroacetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, 4-chlorobenzenesulfonate, 1,5-naphthalenedisulfonate, naphthalene-2-sulfonate, ethane-1,2-disulfonate, methanesulfonate, ethanesulfonate, benzoate, decanoate, hexanoate, octanoate, cinnamate, citrate, cyclohexanesulfonate, camphorsulfonate, aspartate, camphorate, gluconate, glucuronate, glutamate, isoascorbate, lactate, malate, mandelate, and pyroglutamate. Tartrate, dodecyl sulfate, benzoyl tartrate, formate, fumarate, galactobionate, gentianate, acetyloxyoxime, malonate, succinate, glutarate, adipate, sebate, 2-ketoglutarate, glycolate, hippurate, hydroxyethyl sulfonate, lactobionate, ascorbate, aspartate, laurate, maleate, nicotinate, oleate, orotate, oxalate, palmitate, dihydroxynaphthyl salt, propionate, 4-acetaminobenzoate, 4-aminobenzoate, salicylate, 4-aminosalicylate, 2,5-dihydroxybenzoate, 1-hydroxy-2-naphthyl carboxate, stearate, thiocyanate, undecenoate, and succinate.

[0028] As a preferred embodiment, in the preparation method, the inorganic acid salt is selected from hydrochloride, sulfate and phosphate; the organic acid salt is selected from acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, benzoate and fumarate.

[0029] As a preferred embodiment, in the preparation method, in step 1), the alkaline condition is an organic base system or an inorganic base system.

[0030] As a further preferred embodiment, in the preparation method, in step 1), the organic base is selected from methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, tripropylamine, 1,2-dimethylpropylamine, cyclopropylamine, diisopropylamine, diisopropanolamine, N,N-diisopropylethylamine, triethylamine, n-butylamine, isobutylamine, tert-butylamine, sec-butylamine, diisobutylamine, hexylamine, dicyclohexylamine, decylamine, dodecylamine, triethanolamine, 2-propyleneamine, ethanolamine, 3-propanolamine, isopropanolamine, diisopropanolamine, tri... Isopropanolamine, dimethylethanolamine, diethylethanolamine, ethylenediamine, 1,3-propanediamine, 1,4-butanediamine, 1,5-pentanediamine, 1,6-hexanediamine, 2-methylpiperidine, N-isopropylbenzylamine, N-methylmorpholine, 2,2,6,6-tetramethylpiperidine, 2,2,6-trimethylpiperidine, 2,6-dimethylpiperidine, and 2,5-dimethylpyrrolidine, or mixtures thereof; wherein the inorganic base is selected from K2CO3, KHCO3, Cs2CO3, Na2CO3, and NaHCO3.

[0031] As a further preferred embodiment, in the preparation method, in step 1), the organic base is selected from diisopropanolamine, N,N-diisopropylethylamine, 2-methylpiperidine, N-isopropylbenzylamine, N-methylmorpholine, diisopropylamine, 2,2,6,6-tetramethylpiperidine, 2,2,6-trimethylpiperidine, 2,6-dimethylpiperidine, and 2,5-dimethylpyrrolidine; the inorganic base is selected from K2CO3, KHCO3, Cs2CO3, Na2CO3, and NaHCO3.

[0032] As a preferred embodiment, in the preparation method, in step 1), the reaction solvent used is selected from one or more organic solvents selected from alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides, or sulfoxides.

[0033] As a further preferred embodiment, in the preparation method, in step 1), the solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, tert-butanol, n-butanol, dichloromethane, acetonitrile, N-methylpyrrolidone, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, or 2-methoxyethyl ether.

[0034] As a further preferred embodiment, in the preparation method, in step 1), the solvent is one or a mixture of N-methylpyrrolidone, N,N-dimethylformamide, or methyl tert-butyl ether.

[0035] As a further preferred embodiment, in the preparation method, in step 1), the solvent is N-methylpyrrolidone or a mixed solvent of N,N-dimethylformamide and methyl tert-butyl ether.

[0036] As a preferred embodiment, in the preparation method, in step 1), the molar ratio of the compound of formula (1) or its acid salt to the compound of formula (2) or its acid salt is 1:(0.1~10).

[0037] As a further preferred embodiment, in the preparation method, in step 1), the molar ratio of the feed is 1:(0.5-5).

[0038] As a further preferred embodiment, in the preparation method, in step 1), the molar ratio of the feed is 1:(1.2-3).

[0039] As a preferred embodiment, in the preparation method, in step 1), the reaction is carried out at -15℃ to 30℃.

[0040] As a further preferred embodiment, in the preparation method, in step 1), the reaction is carried out at 0°C to 30°C.

[0041] As a further preferred embodiment, in the preparation method, in step 1), the reaction is carried out at 20°C to 30°C.

[0042] As a preferred embodiment, in step 2) of the preparation method, an alkaline reagent is further added to the reaction system, wherein the alkaline reagent is an organic base or an inorganic base.

[0043] As a further preferred embodiment, in the preparation method, in step 2), the alkaline reagent is an organic base, selected from methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, tripropylamine, 1,2-dimethylpropylamine, cyclopropylamine, diisopropylamine, diisopropanolamine, N,N-diisopropylethylamine, triethylamine, n-butylamine, isobutylamine, tert-butylamine, sec-butylamine, diisobutylamine, hexylamine, dicyclohexylamine, decylamine, dodecylamine, triethanolamine, 2-propyleneamine, ethanolamine, 3-propanolamine, isopropanolamine, diisopropanolamine, tri... Isopropanolamine, dimethylethanolamine, diethylethanolamine, ethylenediamine, 1,3-propanediamine, 1,4-butanediamine, 1,5-pentanediamine, 1,6-hexanediamine, 2-methylpiperidine, N-isopropylbenzylamine, N-methylmorpholine, 2,2,6,6-tetramethylpiperidine, 2,2,6-trimethylpiperidine, 2,6-dimethylpiperidine, and 2,5-dimethylpyrrolidine, or mixtures thereof; the alkaline reagent is an inorganic base selected from K2CO3, KHCO3, Cs2CO3, Na2CO3, and NaHCO3.

[0044] As a further preferred embodiment, in the preparation method, in step 2), the organic base is selected from diisopropanolamine, N,N-diisopropylethylamine, 2-methylpiperidine, N-isopropylbenzylamine, N-methylmorpholine, diisopropylamine, 2,2,6,6-tetramethylpiperidine, 2,2,6-trimethylpiperidine, 2,6-dimethylpiperidine, and 2,5-dimethylpyrrolidine; the inorganic base is selected from K2CO3, KHCO3, Cs2CO3, Na2CO3, and NaHCO3.

[0045] As a preferred embodiment, in the preparation method, in step 2), the reaction solvent used is selected from one or more organic solvents selected from alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides, or sulfoxides.

[0046] As a further preferred embodiment, in the preparation method, in step 2), the reaction solvent used is selected from one or more of methanol, ethanol, n-propanol, isopropanol, tert-butanol, n-butanol, dichloromethane, acetonitrile, N-methylpyrrolidone, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, or 2-methoxyethyl ether.

[0047] As a further preferred embodiment, in the preparation method, in step 2), the reaction solvent used is one or a mixture of tert-butanol, n-butanol, or acetonitrile.

[0048] As a preferred embodiment, in the preparation method, in step 2), the molar ratio of the compound of formula (A) or its acid salt to the compound of formula (3) or its acid salt is 1:(0.1-10).

[0049] As a further preferred embodiment, in the preparation method, in step 2), the molar ratio of the compound of formula (A) or its acid salt to the compound of formula (3) or its acid salt is 1:(1.2-3).

[0050] As a preferred embodiment, in the preparation method, in step 2), the reaction system is carried out at 50℃~110℃.

[0051] As a further preferred embodiment, in the preparation method, in step 2), the reaction system is carried out at 60℃~105℃.

[0052] As a preferred embodiment, in the preparation method, in step 3), the reaction solvent used is selected from one or more of the following: alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides, or sulfoxide organic solvents or water.

[0053] As a further preferred embodiment, in the preparation method, in step 3), the reaction solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, tert-butanol, dichloromethane, acetonitrile, N-methylpyrrolidone, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, 2-methoxyethyl ether, or water.

[0054] As a preferred embodiment, in the preparation method, in step 3), the reaction system reacts under acidic conditions, and the acid is an inorganic acid or an organic acid.

[0055] As a further preferred embodiment, in the preparation method, in step 3), the inorganic acid is selected from hydrochloric acid, sulfuric acid, or phosphoric acid; the organic acid is selected from formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, benzoic acid, fumaric acid, malonic acid, oxalic acid, or salicylic acid.

[0056] As a preferred embodiment, in the preparation method, in step 3), the reaction is carried out at 0℃ to 35℃.

[0057] As a further preferred embodiment, in the preparation method, in step 3), the reaction is carried out at 10℃~30℃.

[0058] As a preferred embodiment, in the preparation method, in step 4), the reaction system reacts under alkaline conditions, and the alkali is an inorganic alkali or an organic alkali.

[0059] As a further preferred embodiment, in the preparation method, in step 4), the base is an organic base, and the organic base is selected from methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, tripropylamine, 1,2-dimethylpropylamine, cyclopropylamine, diisopropylamine, diisopropanolamine, N,N-diisopropylethylamine, triethylamine, n-butylamine, isobutylamine, tert-butylamine, sec-butylamine, diisobutylamine, hexylamine, dicyclohexylamine, decylamine, dodecylamine, triethanolamine, and 2-propene. Amines, ethanolamine, 3-propanolamine, isopropanolamine, diisopropanolamine, triisopropanolamine, dimethylethanolamine, diethylethanolamine, ethylenediamine, 1,3-propanediamine, 1,4-butanediamine, 1,5-pentanediamine, 1,6-hexanediamine, 2-methylpiperidine, N-isopropylbenzylamine, N-methylmorpholine, 2,2,6,6-tetramethylpiperidine, 2,2,6-trimethylpiperidine, 2,6-dimethylpiperidine, and 2,5-dimethylpyrrolidine, or mixtures thereof.

[0060] As a preferred embodiment, in the preparation method, in step 4), the reaction solvent used is selected from one or more of the following: alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides, or sulfoxide organic solvents or water.

[0061] As a further preferred embodiment, in the preparation method, in step 4), the reaction solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, tert-butanol, n-butanol, dichloromethane, acetonitrile, N-methylpyrrolidone, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, 2-methoxyethyl ether, or water.

[0062] As a preferred embodiment, in the preparation method, in step 4), the reaction is carried out at -90℃ to 10℃.

[0063] As a further preferred embodiment, in the preparation method, in step 4), the reaction is carried out at -70℃ to 5℃.

[0064] A second aspect of the present invention provides a method for preparing epagoglinib or its acid salt, characterized by comprising the following steps:

[0065] 1) A compound of formula (A'-1) or its acid salt reacts with a compound of formula (G-2) or its acid salt under alkaline conditions to produce a compound of formula (A') or its acid salt;

[0066] 2) Compound of formula (A') or its acid salt and compound of formula (3') or its acid salt are reacted to prepare compound of formula (B') or its acid salt;

[0067] 3) The compound of formula (B') or its acid salt is prepared by deprotection to obtain the compound of formula (C') or its acid salt;

[0068] 4) Ipatagotinib or its acid salt is prepared by condensation reaction of compound (C') or its acid salt and compound (4');

[0069] The reaction route is as follows:

[0070]

[0071] In each of the formulas, the acid salts are each independently an inorganic acid salt or an organic acid salt, wherein the inorganic acid salts are selected from hydrochloride, sulfate, or phosphate; and the organic acid salts are selected from acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, benzoate, or fumarate.

[0072] In step 1), the alkaline condition is an organic base system or an inorganic base system, wherein the organic base is selected from methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, tripropylamine, 1,2-dimethylpropylamine, cyclopropylamine, diisopropylamine, diisopropanolamine, N,N-diisopropylethylamine, triethylamine, n-butylamine, isobutylamine, tert-butylamine, sec-butylamine, diisobutylamine, hexylamine, dicyclohexylamine, decylamine, dodecylamine, triethanolamine, 2-propyleneamine, ethanolamine, 3-propanolamine, isopropanolamine, diisopropanolamine, tri... Isopropanolamine, dimethylethanolamine, diethylethanolamine, ethylenediamine, 1,3-propanediamine, 1,4-butanediamine, 1,5-pentanediamine, 1,6-hexanediamine, 2-methylpiperidine, N-isopropylbenzylamine, N-methylmorpholine, 2,2,6,6-tetramethylpiperidine, 2,2,6-trimethylpiperidine, 2,6-dimethylpiperidine, and 2,5-dimethylpyrrolidine, or mixtures thereof; wherein the inorganic base is selected from K2CO3, KHCO3, Cs2CO3, Na2CO3, and NaHCO3.

[0073] As a preferred embodiment, in the preparation method, in step 1), the alkaline condition is an organic base system or an inorganic base system. The organic base is selected from diisopropanolamine, N,N-diisopropylethylamine, 2-methylpiperidine, N-isopropylbenzylamine, N-methylmorpholine, diisopropylamine, 2,2,6,6-tetramethylpiperidine, 2,2,6-trimethylpiperidine, 2,6-dimethylpiperidine, and 2,5-dimethylpyrrolidine; the inorganic base is selected from K2CO3, KHCO3, Cs2CO3, Na2CO3, and NaHCO3.

[0074] As a preferred embodiment, in the preparation method, in step 1), the reaction solvent used is selected from one or more of methanol, ethanol, n-propanol, isopropanol, tert-butanol, n-butanol, dichloromethane, acetonitrile, N-methylpyrrolidone, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, or 2-methoxyethyl ether.

[0075] As a further preferred embodiment, in the preparation method, in step 1), the solvent is one or a mixture of N-methylpyrrolidone, N,N-dimethylformamide, or methyl tert-butyl ether.

[0076] As a further preferred embodiment, in the preparation method, in step 1), the solvent is N-methylpyrrolidone or a mixed solvent of N,N-dimethylformamide and methyl tert-butyl ether.

[0077] As a preferred embodiment, in step 2) of the preparation method, a basic reagent is further added to the reaction system. The basic reagent is an organic or inorganic base. If the basic reagent is an organic base, the organic base is selected from methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, tripropylamine, 1,2-dimethylpropylamine, cyclopropylamine, diisopropylamine, diisopropanolamine, N,N-diisopropylethylamine, triethylamine, n-butylamine, isobutylamine, tert-butylamine, sec-butylamine, diisobutylamine, hexylamine, dicyclohexylamine, decylamine, dodecylamine, triethanolamine, 2-propenylamine, ethanolamine, and 3-propanolamine. The reagent may contain isopropanolamine, diisopropanolamine, triisopropanolamine, dimethylethanolamine, diethylethanolamine, ethylenediamine, 1,3-propanediamine, 1,4-butanediamine, 1,5-pentanediamine, 1,6-hexanediamine, 2-methylpiperidine, N-isopropylbenzylamine, N-methylmorpholine, 2,2,6,6-tetramethylpiperidine, 2,2,6-trimethylpiperidine, 2,6-dimethylpiperidine, and 2,5-dimethylpyrrolidine, or mixtures thereof; the alkaline reagent is an inorganic base selected from K2CO3, KHCO3, Cs2CO3, Na2CO3, or NaHCO3.

[0078] As a further preferred embodiment, in the preparation method, in step 2), an alkaline reagent is further added to the reaction system. The organic base is selected from diisopropanolamine, N,N-diisopropylethylamine, 2-methylpiperidine, N-isopropylbenzylamine, N-methylmorpholine, diisopropylamine, 2,2,6,6-tetramethylpiperidine, 2,2,6-trimethylpiperidine, 2,6-dimethylpiperidine, and 2,5-dimethylpyrrolidine; the inorganic base is selected from K2CO3, KHCO3, Cs2CO3, Na2CO3, and NaHCO3.

[0079] As a preferred embodiment, in the preparation method, in step 2), the reaction solvent used is selected from one or more of methanol, ethanol, n-propanol, isopropanol, tert-butanol, n-butanol, dichloromethane, acetonitrile, N-methylpyrrolidone, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, or 2-methoxyethyl ether.

[0080] As a further preferred embodiment, in the preparation method, in step 2), the reaction solvent used is one or a mixture of tert-butanol, n-butanol, or acetonitrile.

[0081] As a preferred embodiment, in the preparation method, in step 3), the reaction system reacts under acidic conditions, wherein the acid is an inorganic acid or an organic acid, the inorganic acid being selected from hydrochloric acid, sulfuric acid, or phosphoric acid; and the organic acid being selected from formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, benzoic acid, fumaric acid, malonic acid, oxalic acid, or salicylic acid.

[0082] As a preferred embodiment, in the preparation method, in step 3), the reaction solvent used is selected from one or more of methanol, ethanol, n-propanol, isopropanol, tert-butanol, dichloromethane, acetonitrile, N-methylpyrrolidone, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, 2-methoxyethyl ether, or water.

[0083] As a preferred embodiment, in the preparation method, in step 4), the reaction system reacts under alkaline conditions, wherein the base is an inorganic base or an organic base, and the organic base is selected from methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, tripropylamine, 1,2-dimethylpropylamine, cyclopropylamine, diisopropylamine, diisopropanolamine, N,N-diisopropylethylamine, triethylamine, n-butylamine, isobutylamine, tert-butylamine, sec-butylamine, diisobutylamine, hexylamine, dicyclohexylamine, decylamine, and dodecylamine. Amines, triethanolamine, 2-propenylamine, ethanolamine, 3-propanolamine, isopropanolamine, diisopropanolamine, triisopropanolamine, dimethylethanolamine, diethylethanolamine, ethylenediamine, 1,3-propanediamine, 1,4-butanediamine, 1,5-pentanediamine, 1,6-hexanediamine, 2-methylpiperidine, N-isopropylbenzylamine, N-methylmorpholine, 2,2,6,6-tetramethylpiperidine, 2,2,6-trimethylpiperidine, 2,6-dimethylpiperidine and 2,5-dimethylpyrrolidine, or mixtures thereof.

[0084] As a preferred embodiment, in the preparation method, the reaction solvent used in step 4) is selected from one or more of methanol, ethanol, n-propanol, isopropanol, tert-butanol, n-butanol, dichloromethane, acetonitrile, N-methylpyrrolidone, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, 2-methoxyethyl ether, or water.

[0085] A third aspect of the present invention provides a compound of formula (A) or an acidic salt thereof:

[0086]

[0087] Wherein, Pg is an amino protecting group selected from tert-butoxycarbonyl; X1 is a halogen;

[0088] R1 and R2 are each independently hydrogen or halogen; R3 and R4 are each independently substituted or unsubstituted C. 1-4 Alkoxy, wherein the substituents are deuterium and halogen;

[0089] The acid salt is an inorganic acid salt or an organic acid salt. The inorganic acid salt is selected from hydrochloride, sulfate or phosphate; the organic acid salt is selected from acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, benzoate or fumarate.

[0090] As a preferred embodiment, in the compound of formula (A) or its acid salt, X1 is chlorine; R1 and R2 are each independently chlorine or fluorine; and R3 and R4 are each independently methoxy, trideuteroxy, or trifluoromethoxy.

[0091] The fourth aspect of the present invention provides a method for preparing a compound of formula (A) or an acidic salt thereof, characterized in that it includes the following steps: reacting a compound of formula (1) or an acidic salt thereof with a compound of formula (2) or an acidic salt thereof under alkaline conditions to generate a compound of formula (A) or an acidic salt thereof;

[0092]

[0093] In each formula, Pg is an amino protecting group selected from tert-butoxycarbonyl; X1 is a halogen;

[0094] R1 and R2 are each independently hydrogen or halogen; R3 and R4 are each independently substituted or unsubstituted C. 1-4 Alkoxy, wherein the substituent is deuterium or halogen;

[0095] R5 represents substituted or unsubstituted C. 1-4 Alkyl group, wherein the substituent is deuterium or halogen; R6 is a substituted or unsubstituted C. 1-4 Alkoxy, wherein the substituent is deuterium or halogen;

[0096] Each of the acid salts is independently an inorganic acid salt or an organic acid salt, wherein the inorganic acid salt is selected from hydrochloride, sulfate or phosphate; and the organic acid salt is selected from acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, benzoate or fumarate.

[0097] The alkaline conditions are either an organic base system or an inorganic base system, wherein the organic base is selected from methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, tripropylamine, 1,2-dimethylpropylamine, cyclopropylamine, diisopropylamine, diisopropanolamine, N,N-diisopropylethylamine, triethylamine, n-butylamine, isobutylamine, tert-butylamine, sec-butylamine, diisobutylamine, hexylamine, dicyclohexylamine, decylamine, dodecylamine, triethanolamine, 2-propyleneamine, ethanolamine, 3-propanolamine, isopropanolamine, diisopropanolamine, triisopropylamine, etc. The inorganic base is selected from K2CO3, KHCO3, Cs2CO3, Na2CO3, or NaHCO3. The inorganic base is also selected from: propanolamine, dimethylethanolamine, diethylethanolamine, ethylenediamine, 1,3-propanediamine, 1,4-butanediamine, 1,5-pentanediamine, 1,6-hexanediamine, 2-methylpiperidine, N-isopropylbenzylamine, N-methylmorpholine, 2,2,6,6-tetramethylpiperidine, 2,2,6-trimethylpiperidine, 2,6-dimethylpiperidine, and 2,5-dimethylpyrrolidine.

[0098] The fifth aspect of the present invention provides a compound of formula (A-1) or an acid salt thereof:

[0099]

[0100] The acid salt is an inorganic acid salt or an organic acid salt. The inorganic acid salt is selected from hydrochloride, sulfate or phosphate; the organic acid salt is selected from acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, benzoate or fumarate.

[0101] The sixth aspect of the present invention provides a compound of formula (B) or an acidic salt thereof:

[0102]

[0103] Wherein, Pg is an amino protecting group, selected from tert-butoxycarbonyl;

[0104] R1 and R2 are each independently selected from hydrogen, deuterium, or halogen; R3 and R4 are each independently selected from substituted or unsubstituted C. 1-4 Alkoxy, wherein the substituent is selected from deuterium and halogen;

[0105] R5 is selected from substituted or unsubstituted C. 1-4 Alkyl group, wherein the substituent is selected from deuterium and halogen; R6 is selected from substituted or unsubstituted C6. 1-4 Alkoxy, wherein the substituent is selected from deuterium and halogen;

[0106] The acid salt is an inorganic acid salt or an organic acid salt. The inorganic acid salt is selected from hydrochloride, sulfate or phosphate; the organic acid salt is selected from acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, benzoate or fumarate.

[0107] As a preferred embodiment, in the compound of formula (B) or its acid salt, R1 and R2 are each independently chlorine or fluorine; R3 and R4 are each independently methoxy, trideuteroxy, or trifluoromethoxy; R5 is methyl, ethyl, trideuteroxy, or trifluoromethyl; and R6 is methoxy, trideuteroxy, or trifluoromethoxy.

[0108] The seventh aspect of the present invention provides a method for preparing a compound of formula (B) or an acidic salt thereof, characterized in that, in the presence of K2CO3, KHCO3, Cs2CO3, Na2CO3, NaHCO3, diisopropanolamine, N,N-diisopropylethylamine, 2-methylpiperidine, N-isopropylbenzylamine, N-methylmorpholine, diisopropylamine, 2,2,6,6-tetramethylpiperidine, 2,2,6-trimethylpiperidine, 2,6-dimethylpiperidine or 2,5-dimethylpyrrolidine, the compound of formula (A) or an acidic salt thereof reacts with the compound of formula (3) or an acidic salt thereof to prepare the compound of formula (B) or an acidic salt thereof;

[0109]

[0110] Wherein, Pg is an amino protecting group, selected from tert-butoxycarbonyl;

[0111] R1 and R2 are each independently hydrogen, deuterium, or halogen; R3 and R4 are each independently substituted or unsubstituted C. 1-4 Alkoxy, wherein the substituent is deuterium or halogen;

[0112] R5 represents substituted or unsubstituted C. 1-4 Alkyl group, wherein the substituent is deuterium or halogen; R6 is a substituted or unsubstituted C. 1-4 Alkoxy, wherein the substituent is deuterium or halogen;

[0113] The acid salt is an inorganic acid salt or an organic acid salt. The inorganic acid salt is selected from hydrochloride, sulfate or phosphate; the organic acid salt is selected from acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, benzoate or fumarate.

[0114] As a preferred embodiment, in the preparation method, R1 and R2 are each independently chlorine or fluorine; R3 and R4 are each independently methoxy, trideuteroxy, or trifluoromethoxy; R5 is methyl, ethyl, trideutermethyl, or trifluoromethyl; and R6 is methoxy, trideuteroxy, or trifluoromethoxy.

[0115] This invention provides a novel method for preparing epagoglinib and its analogues, and provides two new intermediates A and B, which have the following advantages compared with the prior art:

[0116] (1) This invention uses non-azide compounds as intermediates, and the reaction is carried out at room temperature, which is safe and simple to operate.

[0117] (2) The present invention uses alkaline reagents to prepare intermediate A, which greatly improves the reaction yield and product purity;

[0118] (3) The new synthetic route achieves a total yield of 67% in four steps, which is much higher than the total yield of 29.8% in the existing technology;

[0119] (4) The new synthetic route is simple to operate, reduces production costs, and is suitable for large-scale production. Attached Figure Description

[0120] 1. Appendix Figure 1 The HPLC chromatogram of the product from Example 1 is shown below.

[0121] 2. Appendix Figure 2 Impurity A-1 in Example 1 1 HNMR;

[0122] 3. Appendix Figure 3 LC-MS of impurity A-1 in Example 1;

[0123] 4. Appendix Figure 4 This is the HPLC chromatogram of the product from Example 45. Detailed Implementation

[0124] The inventors of this application, through extensive and in-depth research, have designed and provided a method for preparing epagoglinib and its analogues, and have also provided two new intermediates, A and B. The process of this invention is mature and stable, the production operation is simple, the yield is high, the cost is low, and it is safe and environmentally friendly. This method is suitable for the industrial production of epagoglinib active pharmaceutical ingredient, can meet the needs of clinical research and drug market launch, and solves the problem of drug accessibility.

[0125] Detailed explanation: The terms used in the specification and claims below have the following meanings.

[0126] DMF stands for N,N-dimethylformamide, TEA for trifluoroacetic acid, DIPA for diisopropanolamine, DIPEA for N,N-diisopropylethylamine, HTMP for 2,2,6,6-tetramethylpiperidine, 2-Pipecoline for 2-methylpiperidine, N-isopropylbenzylamine for N-isopropylbenzylamine, NMM for N-methylmorpholine, THF for tetrahydrofuran, MeOH for methanol, NMP for N-methylpyrrolidone, MTBE for methyl tert-butyl ether, PE for petroleum ether, EA for ethyl acetate, and DCM for dichloromethane. eq represents the reaction equivalents.

[0127] The present invention will be further described in detail and completely below with reference to the embodiments, but this is by no means a limitation of the present invention, nor is the present invention limited to the contents of the embodiments.

[0128] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR). NMR chemical shifts (δ) are given in parts per million (ppm).

[0129] NMR measurements were performed using a Bruker AVANCE-400 / 500 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3), with tetramethylsilane (TMS) as the internal standard.

[0130] The determination was performed using an Agilent Technologies InifinityLab LC / MSD mass spectrometer.

[0131] The HPLC determination was performed using an Agilent Technologies 1260 Infinity II chromatographic column: Poroshell 120EC-C18 4μm 4.6×150mm; mobile phase: Phase A: water + 0.05% trifluoroacetic acid; Phase B: acetonitrile + 0.05% trifluoroacetonitrile; flow rate: 1.0 ml / min.

[0132] The starting materials used in the embodiments of this invention are known and commercially available, or can be synthesized using methods known in the art. For example, those skilled in the art can prepare the acid salts of this invention by reacting free substances with corresponding acids using methods known in the art.

[0133] Unless otherwise specified, all reactions in this invention are carried out under a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius (°C).

[0134] I. Comparative Examples

[0135] Comparative Example 1: Preparation of N-((3S,4S)-4-azidotetrahydro-2H-pyran-3-yl)-8-chloro-6-(2,6-difluoro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine-2-amine

[0136]

[0137] Reactant A'-1 (100 mg, 0.241 mmol) was dissolved in DMF (1 mL) and cooled to -2 °C. Then, reagent DIPEA (52.9 mg, 0.410 mmol) and reactant G-1 (64.5 mg, 0.361 mmol) were added. The mixture was heated to 5–10 °C and stirred for 3 hours. After the reaction was complete, the mixture was quenched with water, extracted three times with ethyl acetate, and the combined organic phases were dried over anhydrous Na₂SO₄. The mixture was filtered, concentrated, and separated by column chromatography (eluent: petroleum ether / ethyl acetate 2:1) to give compound A'-2 (17.29 mg, yield: 15%). MS m / z (ESI): 478.4 [M+H] + .

[0138] Based on the experimental procedures of Comparative Example 1 above, the inventors further investigated the effects of reactants, reagents, solvents, temperature, and time on the reaction in this step, with the yields as follows:

[0139]

[0140] The experimental data above show that when azides (G-1) are used as reactants, the reaction needs to be controlled within a low temperature range. When the temperature rises to room temperature, the reaction almost stops, increasing the difficulty of process operation. Even at low temperatures, the reaction yield is extremely low, and a large number of byproducts are produced. In addition, azides themselves are highly toxic and hazardous when used as reactants, making them unsuitable for industrial use. II. Specific Implementation Methods

[0142] Example 1: Preparation of tert-butyl((3S,4S)-3-((8-chloro-6-(2,6-difluoro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)carbamate

[0143]

[0144] Reactants A'-1 (30 mg, 0.072 mmol) and G-2 (23.44 mg, 0.108 mmol) were dissolved in DMF (0.3 mL) and stirred at 22 °C for 3 hours. After the reaction was completed, the mixture was quenched with water, extracted three times with ethyl acetate, and the organic phases were combined and dried over anhydrous Na2SO4. The mixture was filtered, concentrated, and separated by column chromatography (eluent: petroleum ether / ethyl acetate 2:1) to obtain compound A' (13.97 mg, yield 43%, purity 95.1%, purity 3.8% for A-1; see attached HPLC chromatogram). Figure 1 MS m / z (ESI): 452.2 [M+H] + .

[0145] Based on the experimental procedures of Example 1 above, the inventors further investigated the effects of reactants, reagents, solvents, temperature, and time on the reaction in this step. The reaction yields and purities of each experimental batch are summarized below:

[0146]

[0147]

[0148] When DMF is used as the reaction solvent, after 1 HNMR (see appendix) Figure 2 ) and LC-MS (see appendix) Figure 3 Spectral analysis revealed an impurity compound (A-1) with the following structure:

[0149]

[0150] The experimental data above show that when using non-azide (G-2) as a reactant, the reaction proceeds well over a wide temperature range, and the minimum yield is significantly higher than when using azide (G-1) as a reactant. This improves the yield while avoiding the risks associated with azide.

[0151] Based on the experimental procedures of Example 1 above, the inventors further investigated the effects of reactants, reagents, solvents, temperature, and time on the reaction. The yield and purity of each experimental batch are summarized below:

[0152]

[0153]

[0154]

[0155] As can be seen from the reaction results of the above examples, when a mixed solvent of methyl tert-butyl ether and N-methylpyrrolidone or N,N-dimethylformamide is used as the reaction solvent, high yield and high purity of the target product can be obtained at normal room temperature. The operation is convenient and meets the process conditions for large-scale industrial production.

[0156] Example 44: Preparation of tert-butyl((3S,4S)-3-((8-chloro-6-(2,6-difluoro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)carbamate

[0157]

[0158] Add 2.43 L of methyl tert-butyl ether to a 5.0 L jacketed flask, start stirring, add 582.5 mL of N-methylpyrrolidone, reactant A'-1 (300 g, 1.0 eq), reactant G-2 (218.47 g, 1.4 eq), and diisopropanolamine (109.51 g, 1.5 eq); stir the reaction vessel at 20–25 °C for 25 hours; add 1.0 L of ethyl acetate, then add 1.2 L of water, and separate the layers; extract the aqueous phase once more with 0.5 L of ethyl acetate; combine the organic phases, wash the organic phase with 0.9 L of water, and concentrate the organic phase under reduced pressure at 40–50 °C to approximately 2.0 times its volume; then add N,N- Dimethylformamide (2.49 L) was further concentrated until the ethyl acetate residue was less than 1.0%; the temperature was lowered to 20–30 °C, N,N-dimethylformamide (0.3 L) was added, and water (1.41 L) was slowly added over about 1 hour; acetonitrile (180 g) was added, the mixture was heated to ~45 °C, then cooled to 25 °C and stirred for 0.5 hours; the mixture was allowed to cool naturally to 20–25 °C and stirred for 4 hours; the mixture was filtered, and the filter cake was washed with N,N-dimethylformamide / water (1.5 / 1, v / v), and then washed with water; the filter cake was dried at 40–50 °C for 16–24 hours to constant weight to obtain 366 g of pale yellow solid intermediate A' (yield: 90.0%, purity: 94.09%).

[0159] As can be seen from the reaction results of the above examples, when a mixed solvent of methyl tert-butyl ether and N-methylpyrrolidone is used as the reaction solvent, the target product with high yield and high purity can be obtained at normal room temperature. The operation is convenient and suitable for large-scale industrial production.

[0160] Example 45: Preparation of epagoglinib

[0161] Step 1: Preparation of tert-butyl((3S,4S)-3-((6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-methoxy-3-methylazacyclobutane-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)carbamate

[0162]

[0163] Add acetonitrile (2.84 L), intermediate A' (350.0 g, 635.2 mmol), potassium carbonate (262.90 g), and 3-methoxy-3-methylacetidine hydrochloride (104.71 g, 763.9 mmol) to a 5.0 L jacketed flask 1; heat to 60 °C and stir for 1 hour; then heat to 70 °C and stir for 1 hour; then heat to 80 °C and stir for 13 hours; cool the reaction solution to 20–30 °C; filter, wash the filter cake with acetonitrile (1.15 L), and combine the wash and filtrate, transferring them to a 5.0 L jacketed flask. Concentrate under reduced pressure to 2-3 times the remaining volume; add 0.95 L of N-methylpyrrolidone to jacketed flask 1, heat to 50-55°C, concentrate under reduced pressure to 3-4 times the remaining volume, and stir for 10-20 minutes; add 5.25 L of pure water to jacketed flask 2, and control the temperature at 20°C; slowly add the N-methylpyrrolidone from jacketed flask 1 dropwise to jacketed flask 2, controlling the temperature not to exceed 20°C; stir for 2 hours; filter, rinse the filter cake with pure water (1.05 L), and dry the filter cake in a vacuum drying oven for 70 hours to obtain 363 g of product (yield: 93.0%).

[0164] The conditions for this step of vacuum concentration are: external temperature 40-50℃, vacuum degree ≤-0.06MPa; the conditions for oven drying are: 50-55℃, vacuum degree ≤-0.06MPa.

[0165] Step 2: Preparation of (3S,4S)-N3-(6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-methoxy-3-methylazacyclobutane-1-yl)pyrido[3,4-d]pyrimidin-2-yl)tetrahydro-2H-pyran-3,4-diamine

[0166]

[0167] Dichloromethane (2.34 kg) and intermediate B' (360 g, 584.4 mmol) were added to a 3.0 L jacketed flask 1, stirred until dissolved, and cooled to 0–5 °C. Trifluoroacetic acid (1000.0 g) was added dropwise to jacketed flask 1, and the temperature was raised to 10–15 °C and maintained for 15 hours. The reaction solution was concentrated under reduced pressure to a smaller volume, and then dichloromethane (4.68 kg) was added. The concentrated solution was added to jacketed flask 1, and then pure water (1.08 kg) was added, and the temperature was cooled to 0–5 °C. Pure water (1.872 kg) was added to jacketed flask 2, and the temperature was cooled to 0–5 °C, and then sodium hydroxide (288 g) was added, and stirred to prepare an aqueous sodium hydroxide solution. The prepared hydroxide solution in jacketed flask 2 was then added to the solution. Sodium carbonate aqueous solution was slowly added to jacketed bottle 1, the pH was adjusted to ~9, stirring was stopped, and the addition was continued dropwise. The mixture was allowed to stand and separate into layers. Dichloromethane (2.34 kg) was added to jacketed bottle 1, and the mixture was stirred for 15-30 minutes. The liquid was then separated. The organic phases were combined and washed twice with 1.8 kg * 2 wt% sodium carbonate solution. The organic phases were then washed once with pure water (1.8 kg). The filtrate was concentrated under reduced pressure to a smaller volume. Isopropanol (3.6 kg) was added to the concentrate and the mixture was concentrated under reduced pressure until the dichloromethane content was less than 0.5%. The temperature was lowered to 0°C and stirred for 15 hours. The mixture was filtered, and the filter cake was washed with 540 g of isopropanol. The filter cake was dried in an oven for 18 hours to obtain 262 g of yellow solid (yield: 87%).

[0168] The conditions for this step of vacuum concentration are: external temperature 40-45℃, vacuum degree ≤-0.06MPa; the conditions for oven drying are: 40-45℃, vacuum degree ≤-0.06MPa.

[0169] Step 3: Preparation of N-((3S,4S)-3-((6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-methoxy-3-methylazacyclobutane-1-yl)pyridino[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide

[0170]

[0171] Add dichloromethane (3.12 kg), intermediate C' (240 g, 464.9 mmol), and N,N-diisopropylethylamine (120.10 g, 929.2 mmol) to a 5.0 L jacketed flask 1, and cool to -10 to 0 °C. Dissolve acryloyl chloride (44.16 g, 490.7 mmol) in dichloromethane (624.0 g), and then slowly add it dropwise to the jacketed flask 1, maintaining the temperature at -10 to 0 °C. After the addition is complete, maintain the reaction at -10 to 0 °C for 4 to 6 hours. Add pure water (1200.00 g) to jacketed flask 1, stir at -5 to 20°C for 20 to 30 minutes, and then separate the liquid phase. Extract the aqueous phase with dichloromethane (480.0 g). Combine the organic phases, transfer them back to jacketed flask 1, and concentrate under reduced pressure to about 1 to 3 times the volume. Add tetrahydrofuran (1200.0 g) to the concentrate, and concentrate under reduced pressure to about 1 to 3 times the volume. Add tetrahydrofuran (1920.0 g) and cool to 10 to 30°C. Prepare a sodium hydroxide aqueous solution (38.40 g sodium hydroxide, 480 g pure water) in a beaker. Add the prepared sodium hydroxide aqueous solution to jacketed flask 1. Heat jacketed flask 1 to 38–48°C, maintain the temperature and stir for 5–6 hours, then cool to 20–30°C; allow to stand, separate the liquids, and concentrate the organic phase under reduced pressure to approximately 1–3 times its volume; add isopropyl acetate (2400 g) to jacketed flask 1; extract the aqueous phase once with isopropyl acetate (480 g), combine the organic phases, and wash the organic phase once with 960.0 g of water; concentrate the organic phase under reduced pressure to approximately 1–3 times its volume and set aside for later use.

[0172] Isopropanol (1920 g) was added to the above concentrate, and the concentration was further reduced under reduced pressure to approximately 2-4 times its original volume. Then, isopropanol (1200 g) was added, and the concentration was further reduced under reduced pressure to approximately 3-5 times its original volume. The mixture was stirred at 30-40°C for 0.5 hours; pure water (1990 g) was added dropwise at 30-40°C. After the addition was complete, the temperature was lowered to 5-15°C, and the mixture was stirred at this temperature for 12-16 hours. The mixture was filtered, and the filter cake was washed with water (960.0 g). The filter cake was then dried in an oven for 18 hours to obtain 252 g of a yellow solid (yield: 92%, HPLC purity: 99.41%, HPLC chromatogram attached). Figure 4 ).

[0173] The conditions for this step of vacuum concentration are: external temperature 40-45℃, vacuum degree ≤-0.06MPa; the conditions for oven drying are: 40-45℃, vacuum degree ≤-0.06MPa.

[0174] Example 46: Preparation of tert-butyl((3S,4S)-3-((6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-methoxy-3-methylazacyclobutane-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)carbamate

[0175]

[0176] Intermediate A' (10.4 g, 18.8 mmol) was dissolved in n-butanol (200 mL), and N,N-diisopropylethylamine (12.2 g, 94.2 mmol) and 3-methoxy-3-methylacetidine hydrochloride (5.19 g, 37.7 mmol) were added to a sealed tube. The mixture was stirred at 100 °C for 20 hours. After cooling, the n-butanol was removed by concentration. The crude product was separated by column chromatography (EA:DCM = 0-30%) to give tert-butyl((3S,4S)-3-((6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-methoxy-3-methylazacyclobutane-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)carbamate (11.5 g, yield: 99%). MS m / z (ESI): 617.6 [M+H] + .

[0177] Example 47: Preparation of (3S,4S)-N3-(6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-methoxy-3-methylazacyclobutane-1-yl)pyrido[3,4-d]pyrimidin-2-yl)tetrahydro-2H-pyran-3,4-diamine

[0178]

[0179] Intermediate B' (11.5 g, 18.65 mmol) was dissolved in dichloromethane (87 mL), cooled in an ice bath, and TFA (29 mL) was added. The mixture was stirred at room temperature for 4 hours. After the reaction was complete, the dichloromethane was diluted, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was separated into two phases, and the aqueous phase was extracted with dichloromethane (100 mL * 2). The extract was dried, filtered, and concentrated. The crude product was separated by column chromatography (MeOH:DCM = 0.5%, containing 0.5% TEA) to give intermediate C' (9.36 g, yield: 97%).

[0180] 1 H NMR (400MHz, CDCl3) δ8.88(s,1H),6.93(s,1H),6.66(t,J=8.0Hz,1H),5.84(d,J=8.4Hz,1H),4.49-4.42(m,2H),4.32-4.25(m,3H),3.98-3.92 (m,2H),3.90(s,6H),3.67-3.63(m,1H),3.57-3.52(m,1H),3.31(s,3H) ,3.24-3.20(m,1H),1.83-1.79(m,1H),1.70-1.64(m,1H),1.57(s,3H).

[0181] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing epagoglinib and its analogues of formula (D) or their acid salts, characterized in that, Includes the following steps: 1) The compound of formula (1) or its acid salt reacts with the compound of formula (2) or its acid salt under alkaline conditions to produce the compound of formula (A) or its acid salt; 2) Compound (A) or its acid salt and compound (3) or its acid salt are reacted to prepare compound (B) or its acid salt; 3) The compound of formula (B) or its acid salt is prepared by deprotection to obtain the compound of formula (C) or its acid salt; 4) Compound (C) or its acid salt and compound (4) are combined via a condensation reaction to prepare compound (D) or its acid salt; the reaction route is as follows: In each formula, Pg is an amino protecting group; X1 and X2 are each an independent halogen. R1 and R2 are each independently hydrogen or halogen; R3 and R4 are each independently substituted or unsubstituted C. 1-4 Alkoxy, wherein the substituent is deuterium or halogen; R5 represents substituted or unsubstituted C. 1-4 Alkyl group, wherein the substituent is deuterium or halogen; R6 is a substituted or unsubstituted C. 1-4 Alkoxy, wherein the substituent is deuterium or halogen; In each of the formulas, the acid salts are each independently an inorganic acid salt or an organic acid salt.

2. The preparation method according to claim 1, characterized in that, Pg is tert-butoxycarbonyl; X1 and X2 are each independently chlorine or bromine; R1 and R2 are each independently chlorine or fluorine; R3 and R4 are each independently methoxy, trideuteroxy, or trifluoromethoxy; R5 is methyl, ethyl, trideutermethyl, or trifluoromethyl; R6 is methoxy, trideuteroxy, or trifluoromethoxy.

3. The preparation method according to claim 1, characterized in that, The inorganic acid salts are selected from hydrochlorides, sulfates, hydrobroms, hydrofluorides, hydroiodates, and phosphates; the organic acid salts are selected from acetates, dichloroacetate, trichloroacetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, 4-chlorobenzenesulfonate, 1,5-naphthalenedisulfonate, naphthalene-2-sulfonate, ethane-1,2-disulfonate, methanesulfonate, ethanesulfonate, benzoate, decanoate, hexanoate, caprylate, cinnamate, citrate, cyclohexanesulfonate, camphorsulfonate, aspartate, camphorate, gluconate, glucuronate, glutamate, isoascorbate, lactate, malate, mandelate, pyroglutamate, tartrate, dodecyl sulfate, etc. Alkyl sulfates, benzoyl tartrates, formates, fumarates, galactobionates, gentianates, acetyloxyoximes, malonates, succinates, glutarates, adipates, sebates, 2-ketoglutarate, glycolates, hippurates, hydroxyethyl sulfonates, lactobionates, ascorbic acid salts, aspartate salts, laurates, maleates, nicotinates, oleates, orotates, oxalates, palmitates, dihydroxynaphthyl salts, propionates, 4-acetaminobenzoates, 4-aminobenzoates, salicylates, 4-aminosalicylic acid salts, 2,5-dihydroxybenzoates, 1-hydroxy-2-naphthyl carboxate, stearates, thiocyanates, undecenoates, and succinates.

4. The preparation method according to claim 1, characterized in that, The inorganic acid salts are selected from hydrochloride, sulfate and phosphate; the organic acid salts are selected from acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, benzoate and fumarate.

5. The preparation method according to claim 1, characterized in that, In step 1), the alkaline condition is an organic base system or an inorganic base system; Preferably, the organic base is selected from methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, tripropylamine, 1,2-dimethylpropylamine, cyclopropylamine, diisopropylamine, diisopropanolamine, N,N-diisopropylethylamine, triethylamine, n-butylamine, isobutylamine, tert-butylamine, sec-butylamine, diisobutylamine, hexylamine, dicyclohexylamine, decylamine, dodecylamine, triethanolamine, 2-propenylamine, ethanolamine, 3-propanolamine, isopropanolamine, diisopropanolamine, triisopropanolamine, and dimethylethanolamine. The inorganic base is selected from diethylethanolamine, ethylenediamine, 1,3-propanediamine, 1,4-butanediamine, 1,5-pentanediamine, 1,6-hexanediamine, 2-methylpiperidine, N-isopropylbenzylamine, N-methylmorpholine, 2,2,6,6-tetramethylpiperidine, 2,2,6-trimethylpiperidine, 2,6-dimethylpiperidine, and 2,5-dimethylpyrrolidine, or mixtures thereof; the inorganic base is selected from K2CO3, KHCO3, Cs2CO3, Na2CO3, and NaHCO3. More preferably, the organic base is selected from diisopropanolamine, N,N-diisopropylethylamine, 2-methylpiperidine, N-isopropylbenzylamine, N-methylmorpholine, diisopropylamine, 2,2,6,6-tetramethylpiperidine, 2,2,6-trimethylpiperidine, 2,6-dimethylpiperidine, and 2,5-dimethylpyrrolidine; the inorganic base is selected from K2CO3, KHCO3, Cs2CO3, Na2CO3, and NaHCO3.

6. The preparation method according to claim 1, characterized in that, In step 1), the reaction solvent used is selected from one or more organic solvents selected from alcohols, chlorinated alkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides, or sulfoxides. Preferably, the solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, tert-butanol, n-butanol, dichloromethane, acetonitrile, N-methylpyrrolidone, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, or 2-methoxyethyl ether. More preferably, the solvent is one or a mixture of N-methylpyrrolidone, N,N-dimethylformamide or methyl tert-butyl ether; Most preferably, the solvent is N-methylpyrrolidone or a mixed solvent of N,N-dimethylformamide and methyl tert-butyl ether.

7. The preparation method according to claim 1, characterized in that, In step 1), the molar ratio of the compound of formula (1) or its acid salt to the compound of formula (2) or its acid salt is 1:(0.1~10); Preferably, the molar ratio of the feed is 1:(0.5-5); more preferably, the molar ratio of the feed is 1:(1.2-3).

8. The preparation method according to claim 1, characterized in that, In step 1), the reaction is carried out at -15°C to 30°C; preferably, the reaction is carried out at 0°C to 30°C; more preferably, the reaction is carried out at 20°C to 30°C.

9. The preparation method according to claim 1, characterized in that, In step 2), an alkaline reagent is further added to the reaction system, wherein the alkaline reagent is an organic base or an inorganic base; Preferably, the alkaline reagent is an organic base, selected from methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, tripropylamine, 1,2-dimethylpropylamine, cyclopropylamine, diisopropylamine, diisopropanolamine, N,N-diisopropylethylamine, triethylamine, n-butylamine, isobutylamine, tert-butylamine, sec-butylamine, diisobutylamine, hexylamine, dicyclohexylamine, decylamine, dodecylamine, triethanolamine, 2-propenylamine, ethanolamine, 3-propanolamine, isopropanolamine, diisopropanolamine, triisopropanolamine, and dimethylethanolamine. The reagent comprises, but is not limited to, diethylethanolamine, ethylenediamine, 1,3-propanediamine, 1,4-butanediamine, 1,5-pentanediamine, 1,6-hexanediamine, 2-methylpiperidine, N-isopropylbenzylamine, N-methylmorpholine, 2,2,6,6-tetramethylpiperidine, 2,2,6-trimethylpiperidine, 2,6-dimethylpiperidine, and 2,5-dimethylpyrrolidine, or mixtures thereof; the alkaline reagent is an inorganic base selected from K2CO3, KHCO3, Cs2CO3, Na2CO3, and NaHCO3; More preferably, the organic base is selected from diisopropanolamine, N,N-diisopropylethylamine, 2-methylpiperidine, N-isopropylbenzylamine, N-methylmorpholine, diisopropylamine, 2,2,6,6-tetramethylpiperidine, 2,2,6-trimethylpiperidine, 2,6-dimethylpiperidine, and 2,5-dimethylpyrrolidine; the inorganic base is selected from K2CO3, KHCO3, Cs2CO3, Na2CO3, and NaHCO3.

10. The preparation method according to claim 1, characterized in that, In step 2), the reaction solvent used is selected from one or more organic solvents selected from alcohols, chlorinated alkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides, or sulfoxides. Preferably, the reaction solvent used is selected from one or more of methanol, ethanol, n-propanol, isopropanol, tert-butanol, n-butanol, dichloromethane, acetonitrile, N-methylpyrrolidone, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, or 2-methoxyethyl ether. More preferably, the reaction solvent used is one or a mixture of tert-butanol, n-butanol, or acetonitrile.

11. The preparation method according to claim 1, characterized in that, In step 2), the molar ratio of the compound of formula (A) or its acid salt to the compound of formula (3) or its acid salt is 1:(0.1~10); Preferably, the molar ratio of the compound of formula (A) or its acid salt to the compound of formula (3) or its acid salt is 1:(1.2-3).

12. The preparation method according to claim 1, characterized in that, In step 2), the reaction system is carried out at 50°C to 110°C; preferably, the reaction system is carried out at 60°C to 105°C.

13. The preparation method according to claim 1, characterized in that, In step 3), the reaction solvent used is selected from one or more of the following: alcohols, chlorinated alkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides, or sulfoxide organic solvents or water; Preferably, the reaction solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, tert-butanol, dichloromethane, acetonitrile, N-methylpyrrolidone, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, 2-methoxyethyl ether, or water.

14. The preparation method according to claim 1, characterized in that, In step 3), the reaction system reacts under acidic conditions, wherein the acid is an inorganic acid or an organic acid; Preferably, the inorganic acid is selected from hydrochloric acid, sulfuric acid, or phosphoric acid; the organic acid is selected from formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, benzoic acid, fumaric acid, malonic acid, oxalic acid, or salicylic acid.

15. The preparation method according to claim 1, characterized in that, In step 3), the reaction is carried out at 0°C to 35°C; preferably, the reaction is carried out at 10°C to 30°C.

16. The preparation method according to claim 1, characterized in that, In step 4), the reaction system reacts under alkaline conditions, and the base is an inorganic base or an organic base; Preferably, the base is an organic base, selected from methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, tripropylamine, 1,2-dimethylpropylamine, cyclopropylamine, diisopropylamine, diisopropanolamine, N,N-diisopropylethylamine, triethylamine, n-butylamine, isobutylamine, tert-butylamine, sec-butylamine, diisobutylamine, hexylamine, dicyclohexylamine, decylamine, dodecylamine, triethanolamine, 2-propenylamine, ethanolamine, and 3-propanolamine. Isopropanolamine, diisopropanolamine, triisopropanolamine, dimethylethanolamine, diethylethanolamine, ethylenediamine, 1,3-propanediamine, 1,4-butanediamine, 1,5-pentanediamine, 1,6-hexanediamine, 2-methylpiperidine, N-isopropylbenzylamine, N-methylmorpholine, 2,2,6,6-tetramethylpiperidine, 2,2,6-trimethylpiperidine, 2,6-dimethylpiperidine and 2,5-dimethylpyrrolidine, or mixtures thereof.

17. The preparation method according to claim 1, characterized in that, In step 4), the reaction solvent used is selected from one or more of the following: alcohols, chlorinated alkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides, or sulfoxide organic solvents or water; Preferably, the reaction solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, tert-butanol, n-butanol, dichloromethane, acetonitrile, N-methylpyrrolidone, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, 2-methoxyethyl ether, or water.

18. The preparation method according to claim 1, characterized in that, In step 4), the reaction is carried out at -90°C to 10°C; preferably, the reaction is carried out at -70°C to 5°C.

19. A method for preparing epagoglinib or its acid salt, characterized in that, Includes the following steps: 1) A compound of formula (A'-1) or its acid salt reacts with a compound of formula (G-2) or its acid salt under alkaline conditions to produce a compound of formula (A') or its acid salt; 2) Compound of formula (A') or its acid salt and compound of formula (3') or its acid salt are reacted to prepare compound of formula (B') or its acid salt; 3) The compound of formula (B') or its acid salt is prepared by deprotection to obtain the compound of formula (C') or its acid salt; 4) Ipatagotinib or its acid salt is prepared by condensation reaction of compound (C') or its acid salt and compound (4'); The reaction route is as follows: In each of the formulas, the acid salts are each independently an inorganic acid salt or an organic acid salt, wherein the inorganic acid salts are selected from hydrochloride, sulfate, or phosphate; and the organic acid salts are selected from acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, benzoate, or fumarate. In step 1), the alkaline condition is an organic base system or an inorganic base system, wherein the organic base is selected from methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, tripropylamine, 1,2-dimethylpropylamine, cyclopropylamine, diisopropylamine, diisopropanolamine, N,N-diisopropylethylamine, triethylamine, n-butylamine, isobutylamine, tert-butylamine, sec-butylamine, diisobutylamine, hexylamine, dicyclohexylamine, decylamine, dodecylamine, triethanolamine, 2-propyleneamine, ethanolamine, 3-propanolamine, isopropanolamine, diisopropanolamine, tri... Isopropanolamine, dimethylethanolamine, diethylethanolamine, ethylenediamine, 1,3-propanediamine, 1,4-butanediamine, 1,5-pentanediamine, 1,6-hexanediamine, 2-methylpiperidine, N-isopropylbenzylamine, N-methylmorpholine, 2,2,6,6-tetramethylpiperidine, 2,2,6-trimethylpiperidine, 2,6-dimethylpiperidine, and 2,5-dimethylpyrrolidine, or mixtures thereof; wherein the inorganic base is selected from K2CO3, KHCO3, Cs2CO3, Na2CO3, and NaHCO3.

20. The preparation method according to claim 19, characterized in that, In step 1), the alkaline condition is an organic base system or an inorganic base system. The organic base is selected from diisopropanolamine, N,N-diisopropylethylamine, 2-methylpiperidine, N-isopropylbenzylamine, N-methylmorpholine, diisopropylamine, 2,2,6,6-tetramethylpiperidine, 2,2,6-trimethylpiperidine, 2,6-dimethylpiperidine, and 2,5-dimethylpyrrolidine. The inorganic base is selected from K2CO3, KHCO3, Cs2CO3, Na2CO3, and NaHCO3.

21. The preparation method according to claim 19, characterized in that, In step 1), the reaction solvent used is selected from one or more of methanol, ethanol, n-propanol, isopropanol, tert-butanol, n-butanol, dichloromethane, acetonitrile, N-methylpyrrolidone, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, or 2-methoxyethyl ether; Preferably, the solvent is one or a mixture of N-methylpyrrolidone, N,N-dimethylformamide, or methyl tert-butyl ether. More preferably, the solvent is N-methylpyrrolidone or a mixed solvent of N,N-dimethylformamide and methyl tert-butyl ether.

22. The preparation method according to claim 19, characterized in that, In step 2), a basic reagent is further added to the reaction system. The basic reagent is an organic or inorganic base. If the basic reagent is an organic base, the organic base is selected from methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, tripropylamine, 1,2-dimethylpropylamine, cyclopropylamine, diisopropylamine, diisopropanolamine, N,N-diisopropylethylamine, triethylamine, n-butylamine, isobutylamine, tert-butylamine, sec-butylamine, diisobutylamine, hexylamine, dicyclohexylamine, decylamine, dodecylamine, triethanolamine, 2-propyleneamine, ethanolamine, 3-propanolamine, isopropanolamine, diisopropylamine, etc. Propanolamine, triisopropanolamine, dimethylethanolamine, diethylethanolamine, ethylenediamine, 1,3-propanediamine, 1,4-butanediamine, 1,5-pentanediamine, 1,6-hexanediamine, 2-methylpiperidine, N-isopropylbenzylamine, N-methylmorpholine, 2,2,6,6-tetramethylpiperidine, 2,2,6-trimethylpiperidine, 2,6-dimethylpiperidine, and 2,5-dimethylpyrrolidine, or mixtures thereof; the alkaline reagent is an inorganic base selected from K2CO3, KHCO3, Cs2CO3, Na2CO3, or NaHCO3; Preferably, the organic base is selected from diisopropanolamine, N,N-diisopropylethylamine, 2-methylpiperidine, N-isopropylbenzylamine, N-methylmorpholine, diisopropylamine, 2,2,6,6-tetramethylpiperidine, 2,2,6-trimethylpiperidine, 2,6-dimethylpiperidine, and 2,5-dimethylpyrrolidine; the inorganic base is selected from K2CO3, KHCO3, Cs2CO3, Na2CO3, and NaHCO3; The reaction solvent used is selected from one or more of methanol, ethanol, n-propanol, isopropanol, tert-butanol, n-butanol, dichloromethane, acetonitrile, N-methylpyrrolidone, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, or 2-methoxyethyl ether. Preferably, the reaction solvent used is one or a mixture of tert-butanol, n-butanol, or acetonitrile.

23. The preparation method according to claim 19, characterized in that, In step 3), the reaction system reacts under acidic conditions, wherein the acid is an inorganic acid or an organic acid, wherein the inorganic acid is selected from hydrochloric acid, sulfuric acid or phosphoric acid; and the organic acid is selected from formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, benzoic acid, fumaric acid, malonic acid, oxalic acid or salicylic acid. The reaction solvent used is selected from one or more of methanol, ethanol, n-propanol, isopropanol, tert-butanol, dichloromethane, acetonitrile, N-methylpyrrolidone, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, 2-methoxyethyl ether, or water.

24. The preparation method according to claim 19, characterized in that, In step 4), the reaction system reacts under alkaline conditions. The base is an inorganic or organic base. If the base is an organic base, it is selected from methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, tripropylamine, 1,2-dimethylpropylamine, cyclopropylamine, diisopropylamine, diisopropanolamine, N,N-diisopropylethylamine, triethylamine, n-butylamine, isobutylamine, tert-butylamine, sec-butylamine, diisobutylamine, hexylamine, dicyclohexylamine, decylamine, dodecylamine, triethanolamine, 2... - Acrylamine, ethanolamine, 3-propanolamine, isopropanolamine, diisopropanolamine, triisopropanolamine, dimethylethanolamine, diethylethanolamine, ethylenediamine, 1,3-propanediamine, 1,4-butanediamine, 1,5-pentanediamine, 1,6-hexanediamine, 2-methylpiperidine, N-isopropylbenzylamine, N-methylmorpholine, 2,2,6,6-tetramethylpiperidine, 2,2,6-trimethylpiperidine, 2,6-dimethylpiperidine and 2,5-dimethylpyrrolidine, or mixtures thereof; The reaction solvent used is selected from one or more of methanol, ethanol, n-propanol, isopropanol, tert-butanol, n-butanol, dichloromethane, acetonitrile, N-methylpyrrolidone, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, 2-methoxyethyl ether, or water.

25. Compound of formula (A) or its acid salt: in, Pg is an amino protecting group, selected from tert-butoxycarbonyl; X1 is a halogen; R1 and R2 are each independently hydrogen or halogen; R3 and R4 are each independently substituted or unsubstituted C. 1-4 Alkoxy, wherein the substituents are deuterium and halogen; The acid salt is an inorganic acid salt or an organic acid salt. The inorganic acid salt is selected from hydrochloride, sulfate or phosphate; the organic acid salt is selected from acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, benzoate or fumarate.

26. The compound of formula (A) according to claim 25, or its acid salt, characterized in that, X1 is chlorine; R1 and R2 are each independently chlorine or fluorine; R3 and R4 are each independently methoxy, trideuteroxy, or trifluoromethoxy.

27. A method for preparing a compound of formula (A) or its acid salt, characterized in that, The process includes the following steps: reacting a compound of formula (1) or its acid salt with a compound of formula (2) or its acid salt under alkaline conditions to produce a compound of formula (A) or its acid salt; In each formula, Pg is an amino protecting group selected from tert-butoxycarbonyl; X1 is a halogen; R1 and R2 are each independently hydrogen or halogen; R3 and R4 are each independently substituted or unsubstituted C. 1-4 Alkoxy, wherein the substituent is deuterium or halogen; R5 represents substituted or unsubstituted C. 1-4 Alkyl group, wherein the substituent is deuterium or halogen; R6 is a substituted or unsubstituted C. 1-4 Alkoxy, wherein the substituent is deuterium or halogen; Each of the acid salts is independently an inorganic acid salt or an organic acid salt, wherein the inorganic acid salt is selected from hydrochloride, sulfate or phosphate; and the organic acid salt is selected from acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, benzoate or fumarate. The alkaline conditions are either an organic base system or an inorganic base system, wherein the organic base is selected from methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, tripropylamine, 1,2-dimethylpropylamine, cyclopropylamine, diisopropylamine, diisopropanolamine, N,N-diisopropylethylamine, triethylamine, n-butylamine, isobutylamine, tert-butylamine, sec-butylamine, diisobutylamine, hexylamine, dicyclohexylamine, decylamine, dodecylamine, triethanolamine, 2-propyleneamine, ethanolamine, 3-propanolamine, isopropanolamine, diisopropanolamine, triisopropylamine, etc. The inorganic base is selected from K2CO3, KHCO3, Cs2CO3, Na2CO3, or NaHCO3. The inorganic base is also selected from: propanolamine, dimethylethanolamine, diethylethanolamine, ethylenediamine, 1,3-propanediamine, 1,4-butanediamine, 1,5-pentanediamine, 1,6-hexanediamine, 2-methylpiperidine, N-isopropylbenzylamine, N-methylmorpholine, 2,2,6,6-tetramethylpiperidine, 2,2,6-trimethylpiperidine, 2,6-dimethylpiperidine, and 2,5-dimethylpyrrolidine.

28. Compounds of formula (A-1) or their acid salts: The acid salt is an inorganic acid salt or an organic acid salt. The inorganic acid salt is selected from hydrochloride, sulfate or phosphate; the organic acid salt is selected from acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, benzoate or fumarate.

29. Compound of formula (B) or its acid salt: in, Pg is an amino protecting group, selected from tert-butoxycarbonyl; R1 and R2 are each independently selected from hydrogen, deuterium, or halogen; R3 and R4 are each independently selected from substituted or unsubstituted C. 1-4 Alkoxy, wherein the substituent is selected from deuterium and halogen; R5 is selected from substituted or unsubstituted C. 1-4 Alkyl group, wherein the substituent is selected from deuterium and halogen; R6 is selected from substituted or unsubstituted C6. 1-4 Alkoxy, wherein the substituent is selected from deuterium and halogen; The acid salt is an inorganic acid salt or an organic acid salt. The inorganic acid salt is selected from hydrochloride, sulfate or phosphate; the organic acid salt is selected from acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, benzoate or fumarate.

30. The compound of formula (B) according to claim 29, or its acid salt, characterized in that, R1 and R2 are each independently chlorine or fluorine; R3 and R4 are each independently methoxy, trideuteroxy, or trifluoromethoxy; R5 is methyl, ethyl, trideutermethyl, or trifluoromethyl; R6 is methoxy, trideuteroxy, or trifluoromethoxy.

31. A method for preparing a compound of formula (B) or its acid salt, characterized in that, In the presence of K2CO3, KHCO3, Cs2CO3, Na2CO3, NaHCO3, diisopropanolamine, N,N-diisopropylethylamine, 2-methylpiperidine, N-isopropylbenzylamine, N-methylmorpholine, diisopropylamine, 2,2,6,6-tetramethylpiperidine, 2,2,6-trimethylpiperidine, 2,6-dimethylpiperidine or 2,5-dimethylpyrrolidine, compound (A) or its acid salt is reacted with compound (3) or its acid salt to prepare compound (B) or its acid salt. Wherein, Pg is an amino protecting group, selected from tert-butoxycarbonyl; R1 and R2 are each independently hydrogen, deuterium, or halogen; R3 and R4 are each independently substituted or unsubstituted C. 1-4 Alkoxy, wherein the substituent is deuterium or halogen; R5 represents substituted or unsubstituted C. 1-4 Alkyl group, wherein the substituent is deuterium or halogen; R6 is a substituted or unsubstituted C. 1-4 Alkoxy, wherein the substituent is deuterium or halogen; The acid salt is an inorganic acid salt or an organic acid salt. The inorganic acid salt is selected from hydrochloride, sulfate or phosphate; the organic acid salt is selected from acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, benzoate or fumarate.

32. The method for preparing the compound of formula (B) or its acid salt according to claim 31, characterized in that, R1 and R2 are each independently chlorine or fluorine; R3 and R4 are each independently methoxy, trideuteroxy, or trifluoromethoxy; R5 is methyl, ethyl, trideutermethyl, or trifluoromethyl; R6 is methoxy, trideuteroxy, or trifluoromethoxy.

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