Preparation method and application of GLP-1 receptor agonist intermediate

Abstract

The invention belongs to the field of pharmaceutical chemicals, and relates to a preparation method and application of a GLP-1 receptor agonist intermediate, in particular to a preparation method of a compound A-1, a compound A-4, a compound A and a compound B, and application of the compound A-1, the compound A-4, the compound A and the compound B and the preparation method thereof in preparation of a GLP-1 receptor agonist.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims priority to and the benefit of Chinese Patent Application No. 202410621392.7, filed May 17, 2024, in the China National Intellectual Property Office, the contents of which are incorporated herein in their entirety. TECHNICAL FIELD

[0003] The present disclosure belongs to the field of pharmaceutical chemical industry, and relates to a preparation method and use of a GLP-1 receptor agonist intermediate, in particular to a preparation method of compound A-1, compound A-4, a compound of formula A and a compound of formula B, and use of the compound A-1, compound A-4, compound of formula A and compound of formula B and the preparation method thereof in preparation of a GLP-1 receptor agonist. BACKGROUND

[0004] Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by elevated blood glucose concentration, and has a high morbidity and mortality. Obesity is considered an important risk factor for T2DM, and approximately 85% of T2DM patients are overweight or obese. Glucagon-like peptide-1 (GLP-1) is an incretin secreted by L cells in the small intestine when nutrients pass through the digestive tract, and GLP-1 is known to exhibit various physiological effects through GLP-1 receptors, such as promoting glucose-dependent insulin secretion, suppressing glucagon secretion, delaying gastric emptying, and suppressing food intake. Although GLP-1 analogs have been commercialized as diabetes treatment agents, and are considered one of the most effective diabetes treatment agents due to their effective effects on HbA1c reduction and weight loss, GLP-1 analogs must be administered by subcutaneous injection, and patient compliance is poor. It is important to develop non-polypeptide GLP-1 receptor small molecule agonists to improve patient compliance, and it has become one of the research hotspots in the field of diabetes.

[0005] WO20180586453A discloses a compound of formula A, and discloses a preparation method of the compound of formula A and a compound of formula B, as shown in the following route:

[0006]

[0007] The compound of formula A and the compound of formula B are key intermediates for synthesizing GLP-1 receptor agonists, but the route has problems such as long time-consuming SFC resolution, difficulty in large-scale preparation, and high synthesis cost, and it is urgent to explore a new route for chiral synthesis that is economical and efficient. Therefore, it is necessary to provide a preparation method of the compound of formula A and the compound of formula B that is more economical, convenient, has a higher yield, and is more suitable for industrial production. SUMMARY

[0008] On the one hand, this disclosure provides a method for preparing compound A-1, the method comprising: (a1) reacting compound A-1-1 and compound A-1-2 in the presence of a metal catalyst and a chiral ligand to obtain compound A-1.

[0009]

[0010] In some embodiments of this disclosure, the method for preparing compound A-1 includes step (a1) of reacting in the presence of a base and a solvent.

[0011] In some embodiments of this disclosure, the method for preparing compound A-1, wherein the metal catalyst in step (a1) is selected from rhodium metal catalysts.

[0012] In some embodiments of this disclosure, the method for preparing compound A-1, wherein the rhodium metal catalyst in step (a1) is selected from one of tri(triphenylphosphine)rhodium chloride, acetylacetonyl bis(ethylidene)rhodium, (1,5-cyclooctadiene)rhodium chloride (I) dimer, rhodium acetate (II) dimer, or di(ethylene)rhodium chloride dimer; preferably, the rhodium metal catalyst in step (a1) is selected from one of (1,5-cyclooctadiene)rhodium chloride (I) dimer, rhodium acetate (II) dimer, or di(ethylene)rhodium chloride dimer; more preferably, the rhodium metal catalyst in step (a1) is selected from di(ethylene)rhodium chloride dimer.

[0013] In some embodiments of this disclosure, the method for preparing compound A-1, wherein the chiral ligand in step (a1) is selected from chiral phosphine ligands or chiral sulfinamide ligands; preferably chiral sulfinamide ligands.

[0014] In some embodiments of this disclosure, the method for preparing compound A-1, wherein the chiral sulfinamide ligand in step (a1) is selected from (R)-N-cinnamyl-2-methylpropane-2-sulfinamide, (R)-N-allyl-2-methylpropane-2-sulfinamide, (R,E)-N-(3-(4-methoxyphenyl)allyl)-2-methylpropane-2-sulfinamide, (R)-N-(3,3-diphenylallyl) (R,E)-2-methylpropane-2-sulfinamide, (R,E)-2-methyl-N-(3-(4-(trifluoromethyl)phenyl)allyl)propane-2-sulfinamide, (R,E)-2-methyl-N-(3-(3,4,5-trimethoxyphenyl)allyl)propane-2-sulfinamide; preferably, the chiral sulfinamide ligand in step (a1) is selected from (R)-N-cinnamyl-2-methylpropane-2-sulfinamide.

[0015] In some embodiments of this disclosure, the method for preparing compound A-1, wherein the base in step (a1) is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, barium carbonate, or potassium phosphate; preferably, the base in step (a1) is selected from sodium carbonate, potassium carbonate, or potassium phosphate; more preferably, the base in step (a1) is selected from potassium phosphate.

[0016] In some embodiments of this disclosure, the method for preparing compound A-1, wherein the base in step (a1) may be in the form of an aqueous solution.

[0017] In one specific embodiment of this disclosure, the method for preparing compound A-1, wherein the base in step (a1) is selected from an aqueous solution of potassium phosphate.

[0018] In some embodiments of this disclosure, the method for preparing compound A-1, wherein the solvent in step (a1) is selected from one or more of 1,4-dioxane, THF, DMF, DMSO, DMA, acetonitrile, dichloroethane, or toluene; preferably, the solvent in step (a1) is selected from one or more of 1,4-dioxane, THF, or acetonitrile; more preferably, the solvent in step (a1) is selected from 1,4-dioxane.

[0019] In some embodiments of this disclosure, in the method for preparing compound A-1, the molar ratio of compound A-1-1 to compound A-1-2 in step (a1) is 1:0.5 to 2; preferably, the molar ratio of compound A-1-1 to compound A-1-2 in step (a1) is 1:0.8 to 1.5; more preferably, the molar ratio of compound A-1-1 to compound A-1-2 in step (a1) is 1:0.8, 1:0.9, or 1:1. In a specific embodiment of this disclosure, in the method for preparing compound A-1, the molar ratio of compound A-1-1 to compound A-1-2 in step (a1) is 1:0.8.

[0020] In some embodiments of this disclosure, in the method for preparing compound A-1, the molar ratio of compound A-1-1 to the metal catalyst in step (a1) is 1:0.01-0.1; preferably, the molar ratio of compound A-1-1 to the metal catalyst in step (a1) is 1:0.01-0.05; more preferably, the molar ratio of compound A-1-1 to the metal catalyst in step (a1) is 1:0.01, 1:0.015, 1:0.02, 1:0.025, or 1:0.03. In a specific embodiment of this disclosure, in the method for preparing compound A-1, the molar ratio of compound A-1-1 to the metal catalyst in step (a1) is 1:0.01.

[0021] In some embodiments of this disclosure, the preparation method of compound A-1, wherein the molar ratio of compound A-1-1 to the chiral ligand in step (a1) is 1:0.01-0.1; preferably, the molar ratio of compound A-1-1 to the chiral ligand in step (a1) is 1:0.01-0.05; more preferably, the molar ratio of compound A-1-1 to the chiral ligand in step (a1) is 1:0.01, 1:0.02, 1:0.03, 1:0.035, 1:0.04, or 1:0.05. In a specific embodiment of this disclosure, the preparation method of compound A-1, wherein the molar ratio of compound A-1-1 to the chiral ligand in step (a1) is 1:0.035.

[0022] In some embodiments of this disclosure, the preparation method of compound A-1, wherein the mass-to-volume ratio of compound A-1-1 to solvent in step (a1) is 1 g: 1 to 10 mL; preferably, the mass-to-volume ratio of compound A-1-1 to solvent in step (a1) is 1 g: 1 to 8 mL; more preferably, the mass-to-volume ratio of compound A-1-1 to solvent in step (a1) is 1 g: 1 to 5 mL; and also preferably, the mass-to-volume ratio of compound A-1-1 to solvent in step (a1) is 1 g: 5 to 8 mL. In a specific embodiment of this disclosure, the preparation method of compound A-1, wherein the mass-to-volume ratio of A-1-1 to solvent in step (a1) is 1 g: 5 mL.

[0023] In some embodiments of this disclosure, the preparation method of compound A-1, wherein the molar ratio of compound A-1-1 to base in step (a1) is 1:0.1 to 2; preferably, the molar ratio of compound A-1-1 to base in step (a1) is 1:0.1 to 1; more preferably, the molar ratio of compound A-1-1 to base in step (a1) is 1:0.1 to 0.5; even more preferably, the molar ratio of compound A-1-1 to base in step (a1) is 1:0.1, 1:0.2, 1:0.3, 1:0.4, or 1:0.5. In a specific embodiment of this disclosure, the preparation method of compound A-1, wherein the molar ratio of compound A-1-1 to base in step (a1) is 1:0.4.

[0024] In some embodiments of this disclosure, the method for preparing compound A-1 includes step (a1) of reacting in a nitrogen atmosphere.

[0025] In some embodiments of this disclosure, the reaction temperature of step (a1) in the preparation method of compound A-1 is 10–100°C; preferably, the reaction temperature of step (a1) is 10–60°C; more preferably, the reaction temperature of step (a1) is 20–60°C. In a specific embodiment of this disclosure, the reaction temperature of step (a1) in the preparation method of compound A-1 is 60°C.

[0026] In some embodiments of this disclosure, the reaction time for step (a1) in the preparation method of compound A-1 is 1 to 10 hours; preferably, the reaction time for step (a1) is 2 to 6 hours; more preferably, the reaction time for step (a1) is 3 to 5 hours. In a specific embodiment of this disclosure, the reaction time for step (a1) in the preparation method of compound A-1 is 3 hours.

[0027] In some embodiments of this disclosure, the preparation method of compound A-1 may further include a purification step: the crude compound A-1 obtained in step (a1) is purified by column chromatography to obtain the purified compound A-1.

[0028] In some embodiments of this disclosure, the purification step of the preparation method of compound A-1 uses petroleum ether and ethyl acetate or petroleum ether and dichloromethane as the mobile phase for column chromatography.

[0029] In some embodiments of this disclosure, the purification step of the preparation method of compound A-1 involves a column chromatography mobile phase of petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate is 1 to 5:1; preferably, the volume ratio of petroleum ether to ethyl acetate is 1 to 3:1; and more preferably, the volume ratio of petroleum ether to ethyl acetate is 3:1.

[0030] On the other hand, this disclosure also provides another method for preparing compound A-1, the method comprising: (c1) reacting compound A-1-8 to generate compound A-1,

[0031]

[0032] In some embodiments of this disclosure, the preparation method of the other compound A-1 is wherein step (c1) is carried out in the presence of a reducing agent, a solvent, and a base.

[0033] In some other embodiments of this disclosure, the method for preparing the other compound A-1 includes step (c1) of reacting in the presence of a reducing agent, a catalyst, a solvent, and a base.

[0034] In some embodiments of this disclosure, the method for preparing the other compound A-1, wherein the reducing agent in step (c1) is selected from one or more of lithium borohydride, sodium borohydride, palladium on carbon, sodium triacetoxyborohydride, Raney nickel, hydrazine hydrate / palladium on carbon, and ferric chloride / hydrazine hydrate; preferably, the reducing agent is selected from one or more of lithium borohydride, sodium borohydride, palladium on carbon, or sodium triacetoxyborohydride; more preferably, the reducing agent is selected from one of lithium borohydride or sodium borohydride; in some specific embodiments of this disclosure, the method for preparing the other compound A-1, wherein the reducing agent in step (c1) is lithium borohydride; in other specific embodiments of this disclosure, the method for preparing the other compound A-1, wherein the reducing agent in step (c1) is sodium borohydride, and the catalyst is lithium chloride.

[0035] In some embodiments of this disclosure, the method for preparing the other compound A-1, wherein the base in step (c1) is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, triethanolamine, sodium hydroxide, potassium hydroxide, or calcium hydroxide; preferably, the base is selected from one or more of sodium carbonate, potassium carbonate, calcium carbonate, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, or calcium hydroxide; more preferably, the base is selected from one of sodium carbonate, potassium carbonate, or potassium tert-butoxide; in one specific embodiment of this disclosure, the method for preparing the other compound A-1, wherein the base in step (c1) is selected from potassium tert-butoxide.

[0036] In some embodiments of this disclosure, the method for preparing the other compound A-1, wherein the solvent in step (c1) is selected from one or more mixed solvents selected from water, dichloromethane, methanol, ethanol, isopropanol, n-butanol, 1,4-dioxane, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, DMF, DMAC, or DMSO; preferably, the solvent is selected from one or more mixed solvents selected from methanol, ethanol, isopropanol, n-butanol, 1,4-dioxane, acetone, and tetrahydrofuran; more preferably, the solvent is selected from one of 1,4-dioxane and tetrahydrofuran; in one specific embodiment of this disclosure, the method for preparing the other compound A-1, wherein the solvent in step (c1) is selected from tetrahydrofuran.

[0037] In some embodiments of this disclosure, in the preparation method of the other compound A-1, the molar ratio of compound A-1-8 to the reducing agent in step (c1) is 1:1 to 5; preferably, the molar ratio of compound A-1-8 to the reducing agent is 1:1 to 3; more preferably, the molar ratio of compound A-1-8 to the reducing agent is 1:2 to 3; even more preferably, the molar ratio of compound A-1-8 to the reducing agent is 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, or 1:2.5. In one specific embodiment, the molar ratio of compound A-1-8 to the reducing agent is 1:2.3. In another specific embodiment, the molar ratio of compound A-1-8 to the reducing agent is 1:2.5.

[0038] In some embodiments of this disclosure, in the preparation method of the other compound A-1, the molar ratio of compound A-1-8 to the catalyst in step (c1) is 1:1 to 5; preferably, the molar ratio of compound A-1-8 to the catalyst is 1:1 to 3; more preferably, the molar ratio of compound A-1-8 to the catalyst is 1:2 to 3; even more preferably, the molar ratio of compound A-1-8 to the catalyst is 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, or 1:2.5. In one specific embodiment, the molar ratio of compound A-1-8 to the catalyst is 1:2.3. In another specific embodiment, the molar ratio of compound A-1-8 to the catalyst is 1:2.5.

[0039] In some embodiments of this disclosure, in the preparation method of the other compound A-1, the molar ratio of compound A-1-8 to the base in step (c1) is 1:1 to 5; preferably, the molar ratio of compound A-1-8 to the base is 1:1 to 3; more preferably, the molar ratio of compound A-1-8 to the base is 1:1 to 2; and even more preferably, the molar ratio of compound A-1-8 to the base is 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5. In one specific embodiment, the molar ratio of compound A-1-8 to the base is 1:1. In another specific embodiment, the molar ratio of compound A-1-8 to the base is 1:1.2.

[0040] In some embodiments of this disclosure, in the preparation method of the other compound A-1, the mass-to-volume ratio of compound A-1-8 to solvent in step (c1) is 1 g: 10-100 mL; preferably, the mass-to-volume ratio of compound A-1-8 to solvent is 1 g: 10-50 mL; more preferably, the mass-to-volume ratio of compound A-1-8 to solvent is 1 g: 18-30 mL. In one specific embodiment of this disclosure, the mass-to-volume ratio of compound A-1-8 to solvent is 1 g: 18 mL. In other embodiments of this disclosure, the mass-to-volume ratio of compound A-1-8 to solvent is further preferably 1 g: 10-18 mL. In yet another specific embodiment of this disclosure, the mass-to-volume ratio of compound A-1-8 to solvent is 1 g: 10 mL.

[0041] In some embodiments of this disclosure, the method for preparing the other compound A-1, wherein the reaction temperature in step (c1) is 10–100°C; preferably, the reaction temperature in step (c1) is 50–100°C; more preferably, the reaction temperature in step (c1) is 50–75°C. In one specific embodiment of this disclosure, the method for preparing the other compound A-1, wherein the reaction temperature in step (c1) is 75°C. In another specific embodiment of this disclosure, the method for preparing the other compound A-1, wherein the reaction temperature in step (c1) is 60°C.

[0042] In some embodiments of this disclosure, the method for preparing the other compound A-1, wherein the reaction time in step (c1) is 1 to 10 hours; preferably, the reaction time in step (c1) is 1 to 6 hours; more preferably, the reaction time in step (c1) is 1 to 3 hours. In one specific embodiment of this disclosure, the method for preparing the other compound A-1, wherein the reaction time in step (c1) is 1 hour. In another specific embodiment of this disclosure, the method for preparing the other compound A-1, wherein the reaction time in step (c1) is 2 hours.

[0043] In some embodiments of this disclosure, the method for preparing another compound A-1 may further include a purification step: separating and purifying the crude compound A-1 obtained in step (c1) by column chromatography.

[0044] In some embodiments of this disclosure, in the method for preparing the other compound A-1, the column chromatography mobile phase in step (c1) purification step is petroleum ether and ethyl acetate or petroleum ether and dichloromethane.

[0045] In some embodiments of this disclosure, in the purification step (c1) of the preparation method of the other compound A-1, the column chromatography mobile phase is petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1 to 5:1; preferably, the volume ratio of petroleum ether to ethyl acetate is 1 to 3:1; more preferably, the volume ratio of petroleum ether to ethyl acetate is 3:1.

[0046] In some other embodiments of this disclosure, the method for preparing another compound A-1 may further include a purification step: pulping the crude compound A-1 obtained in step (c1) in the presence of a solvent.

[0047] In some other embodiments of this disclosure, in the method for preparing the other compound A-1, the solvent in step (c1) purification is isopropyl ether, petroleum ether, or n-hexane. In another specific embodiment of this disclosure, in the method for preparing the other compound A-1, the solvent in step (c1) purification is isopropyl ether.

[0048] On the other hand, this disclosure also provides a method for preparing compound A-1-8, the method comprising: (b1) compound A-1-7 undergoing an enzyme-catalyzed asymmetric reaction to generate compound A-1-8,

[0049]

[0050] In some embodiments of this disclosure, the method for preparing compound A-1-8, wherein the enzyme-catalyzed asymmetric reaction in step (b1) is carried out in the presence of an enzyme, a buffer solution, and a pH adjuster.

[0051] In some embodiments of this disclosure, the method for preparing compound A-1-8, wherein the enzyme in the enzyme-catalyzed asymmetric reaction in step (b1) is selected from one of chymotrypsin, porcine pancreatic lipase, porcine pancreatic lipase type II, pancreatic lipase, trypsin, and bovine pancreatic chymotrypsin type II; preferably, the enzyme in the enzyme-catalyzed asymmetric reaction in step (b1) is selected from chymotrypsin.

[0052] In some embodiments of this disclosure, the method for preparing compound A-1-8, wherein the specific activity of the enzyme in step (b1) of the enzyme-catalyzed asymmetric reaction is selected from 500 to 10000 u / mg; preferably, the specific activity of the enzyme is selected from 500 to 5000 u / mg; more preferably, 500 to 1000 u / mg. In one specific embodiment, the specific activity of the enzyme is selected from 1000 u / mg.

[0053] In some embodiments of this disclosure, the preparation method of compound A-1-8, wherein the buffer solution in step (b1) of the enzyme-catalyzed asymmetric reaction is selected from one of phosphate buffer, borate buffer, tris(hydroxymethyl)aminomethane-hydrochloric acid buffer, acetate buffer, citrate buffer or citrate buffer; preferably phosphate buffer.

[0054] In some embodiments of this disclosure, the preparation method of compound A-1-8, wherein the buffer solution in step (b1) of the enzyme-catalyzed asymmetric reaction is selected from one of sodium phosphate buffer, potassium phosphate buffer, potassium dihydrogen phosphate buffer, acetate-sodium acetate buffer, ammonium acetate buffer, and citrate-disodium hydrogen phosphate buffer; preferably, the buffer solution is selected from sodium phosphate buffer or potassium phosphate buffer; more preferably, the buffer solution is selected from sodium phosphate buffer.

[0055] In some embodiments of this disclosure, the method for preparing compound A-1-8, wherein the pH adjuster in step (b1) of the enzyme-catalyzed asymmetric reaction is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, or ammonia; preferably, the pH adjuster is selected from sodium hydroxide.

[0056] In some embodiments of this disclosure, the method for preparing compound A-1-8, wherein the pH adjuster in step (b1) of the enzyme-catalyzed asymmetric reaction is an aqueous solution.

[0057] In some embodiments of this disclosure, the method for preparing compound A-1-8, wherein the solvent for the enzyme-catalyzed asymmetric reaction in step (b1) is water, which is derived from a buffer solution and a pH adjuster.

[0058] In some embodiments of this disclosure, the preparation method of compound A-1-8, wherein the pH value of the buffer solution in step (b1) of the enzyme-catalyzed asymmetric reaction is selected from 7 to 8; preferably, the pH value of the buffer solution is selected from 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0; more preferably, the pH value of the buffer solution is selected from 7.4, 7.5, 7.6, 7.7, 7.8. In a specific embodiment of this disclosure, the preparation method of compound A-1-8, wherein the pH value of the buffer solution in step (b1) of the enzyme-catalyzed asymmetric reaction is 7.7.

[0059] In one specific embodiment of this disclosure, the method for preparing compound A-1-8, wherein in step (b1) the enzyme-catalyzed asymmetric reaction, a pH adjuster maintains the reaction pH consistent with the pH of the buffer solution.

[0060] In one specific embodiment of this disclosure, the method for preparing compound A-1-8, wherein in step (b1) the enzyme-catalyzed asymmetric reaction, a pH adjuster maintains the reaction pH at 7.7.

[0061] In some embodiments of this disclosure, the preparation method of compound A-1-8, wherein in step (b1) the enzymatically catalyzed asymmetric reaction, the mass ratio of compound A-1-7 to enzyme is 1:1 to 3; preferably, the mass ratio of compound A-1-7 to enzyme is 1:1 to 2; more preferably, the mass ratio of compound A-1-7 to enzyme is 1:1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5. In one specific embodiment, the mass ratio of compound A-1-7 to enzyme is 1:1.

[0062] In some embodiments of this disclosure, the preparation method of compound A-1-8, wherein in step (b1) of the enzyme-catalyzed asymmetric reaction, the mass-to-volume ratio of compound A-1-7 to buffer solution is 1 g: 10-100 mL; preferably, the mass-to-volume ratio of compound A-1-7 to buffer solution is 1 g: 10-50 mL; more preferably, the mass-to-volume ratio of compound A-1-7 to buffer solution is 1 g: 20-30 mL. In one specific embodiment, the mass-to-volume ratio of compound A-1-7 to buffer solution is 1 g: 30 mL.

[0063] In some embodiments of this disclosure, the method for preparing compound A-1-8, wherein the reaction temperature of step (b1) is 10–30°C; preferably, the reaction temperature of step (b1) is 20–30°C; more preferably, the reaction temperature of step (b1) is 20–25°C.

[0064] In some embodiments of this disclosure, the reaction time for step (b1) of the preparation method of compound A-1-8 is 1 to 10 days; preferably, the reaction time for step (b1) is 2 to 6 days; more preferably, the reaction time for step (b1) is 3 to 5 days. In a specific embodiment of this disclosure, the reaction time for step (b1) of the preparation method of compound A-1 is 3 days.

[0065] In some embodiments of this disclosure, the method for preparing compound A-1-8 may further include a purification step in step (b1): the crude compound A-1-8 obtained in step (b1) is purified by column chromatography to obtain the purified compound A-1-8.

[0066] In some embodiments of this disclosure, the preparation method of compound A-1-8, wherein the column chromatography mobile phase in step (b1) purification step is petroleum ether and ethyl acetate or petroleum ether and dichloromethane.

[0067] In some embodiments of this disclosure, in the purification step (b1) of the preparation method of compound A-1-8, the column chromatography mobile phase is petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1 to 5:1; preferably, the volume ratio of petroleum ether to ethyl acetate is 1 to 3:1; more preferably, the volume ratio of petroleum ether to ethyl acetate is 2:1.

[0068] On the other hand, this disclosure also provides a method for preparing compound A-1-7, the method comprising: (a2) compound A-1-6 undergoing a methyl esterification reaction to generate compound A-1-7,

[0069]

[0070] In some embodiments of this disclosure, the method for preparing compound A-1-7 includes step (a2) of the methyl esterification reaction, which is carried out in the presence of a methyl esterification reagent, an acid, and a solvent.

[0071] In some embodiments of this disclosure, the method for preparing compound A-1-7, wherein the methyl esterification reagent in step (a2) is selected from methanol, dimethyl sulfate or diazomethane; preferably methanol.

[0072] In some embodiments of this disclosure, the method for preparing compound A-1-7, wherein the acid in the methyl esterification reaction in step (a2) is selected from concentrated sulfuric acid, concentrated hydrochloric acid, p-toluenesulfonic acid, phosphoric acid, sulfonic acid or boric acid; preferably concentrated sulfuric acid.

[0073] In some embodiments of this disclosure, the method for preparing compound A-1-7 includes a methyl esterification reagent in step (a2) of the methyl esterification reaction that can also be used as a solvent.

[0074] In some embodiments of this disclosure, the method for preparing compound A-1-7, wherein the methylating agent and solvent in step (a2) of the methylation reaction are both selected from methanol.

[0075] In some embodiments of this disclosure, in the method for preparing compound A-1-7, the molar ratio of compound A-1-6 to the methyl esterification reagent in step (a2) of the methyl esterification reaction is selected from 1:2 to 10; preferably, the molar ratio of compound A-1-6 to the methyl esterification reagent is selected from 1:5 to 10; more preferably, the molar ratio of compound A-1-6 to the methyl esterification reagent is selected from 1:6 to 8; even more preferably, the molar ratio of compound A-1-6 to the methyl esterification reagent is selected from 1:6, 1:6.5, 1:7, 1:7.5, or 1:8. In one specific embodiment, the molar ratio of compound A-1-6 to the methyl esterification reagent is selected from 1:7.5.

[0076] In some embodiments of this disclosure, in the method for preparing compound A-1-7, the molar ratio of compound A-1-6 to acid in the methyl esterification reaction of step (a2) is selected from 1:0.5 to 2; preferably, the molar ratio of compound A-1-6 to acid is selected from 1:0.5 to 1; more preferably, the molar ratio of compound A-1-6 to acid is selected from 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9 or 1:1. In one specific embodiment, the molar ratio of compound A-1-6 to acid is selected from 1:0.9.

[0077] On the other hand, this disclosure also provides another method for preparing compound A-1-8, the method comprising: (b2) compound A-1-9 undergoing an ester hydrolysis reaction to generate compound A-1-8,

[0078]

[0079] In some embodiments of this disclosure, the preparation method of the other compound A-1-8 is wherein step (b2) is carried out in the presence of a chiral catalyst and a solvent.

[0080] In some embodiments of this disclosure, the method for preparing the other compound A-1-8, wherein the chiral catalyst in step (b2) is selected from cinchona alkaloid derivatives or chloramphenicol alkaloid derivatives; preferably, the catalyst is selected from cinchona alkaloid derivatives; more preferably, the cinchona alkaloid derivative is selected from cinchona alkaloid, cinchona alkaloid, hydroquinine, N-benzyl chloride cinchona alkaloid, N-benzylquinine ononium chloride, N-[3,5-bis(trifluoromethyl)phenyl]-N'-[(9R)-6'-methoxy-9-cinchona alkaloid]thiourea, N-[3,5-bis(trifluoromethyl)phenyl]-N'-[(9R)-6'-methoxy-9-cinchona alkaloid]thiourea, N-[3,5-bis(trifluoromethyl)phenyl]-N'-[(9R)-6'-methoxy-9-cinchona alkaloid]thiourea, etc. The cinchona alkaloid derivative is selected from N-[3,5-bis(trifluoromethyl)phenyl]-N'-[(8A,9S)-6'-methoxy-9-cinchona]thiourea or N-[(8A,9S)-6'-methoxyquinoline-9-yl]-3,5-bis(trifluoromethyl)benzenesulfinamide; more preferably, the cinchona alkaloid derivative is selected from N-[3,5-bis(trifluoromethyl)phenyl]-N'-[(8A,9S)-6'-methoxy-9-cinchona]thiourea or N-[(8A,9S)-6'-methoxyquinoline-9-yl]-3,5-bis(trifluoromethyl)benzenesulfinamide. In a specific embodiment of this disclosure, the chiral catalyst in step (b2) of the preparation method of the other compound A-1-8 is selected from N-[3,5-bis(trifluoromethyl)phenyl]-N'-[(8A,9S)-6'-methoxy-9-cinchona]thiourea. In one specific embodiment of this disclosure, the method for preparing the other compound A-1-8, wherein the chiral catalyst in step (b2) is selected from N-[(8A,9S)-6'-methoxyquinine-9-yl]-3,5-bis(trifluoromethyl)benzenesulfinamide.

[0081] In some embodiments of this disclosure, the method for preparing the other compound A-1-8, wherein the solvent in step (b2) is selected from one or more mixed solvents selected from dichloromethane, n-hexane, ethyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, acetonitrile, benzene, toluene, xylene, DMF, DMAC, or DMSO; preferably, the solvent is selected from one or more mixed solvents selected from n-hexane, tetrahydrofuran, 2-methyltetrahydrofuran, benzene, or toluene; more preferably, the solvent is selected from n-hexane, 2-methyltetrahydrofuran, or toluene. In a specific embodiment of this disclosure, the method for preparing the other compound A-1-8, wherein the solvent in step (b2) is selected from 2-methyltetrahydrofuran.

[0082] In some embodiments of this disclosure, the preparation method of the other compound A-1-8, wherein in step (b2), the molar ratio of compound A-1-9 to the chiral catalyst is 1:0.01 to 0.1; preferably, the molar ratio of compound A-1-9 to the chiral catalyst is selected from 1:0.01 to 0.05; more preferably, the molar ratio of compound A-1-9 to the chiral catalyst is selected from 1:0.01, 1:0.02, 1:0.03, 1:0.04, or 1:0.05. In one specific embodiment, the molar ratio of compound A-1-9 to the chiral catalyst is selected from 1:0.02.

[0083] In some embodiments of this disclosure, the preparation method of the other compound A-1-8, wherein in step (b2), the mass-to-volume ratio of compound A-1-9 to solvent is 1 g: 10-100 mL; preferably, the mass-to-volume ratio of compound A-1-9 to solvent is 1 g: 10-50 mL; more preferably, the mass-to-volume ratio of compound A-1-9 to solvent is 1 g: 20-30 mL. In one specific embodiment, the mass-to-volume ratio of compound A-1-9 to solvent is 1 g: 30 mL. In another specific embodiment, the mass-to-volume ratio of compound A-1-9 to solvent is 1 g: 20 mL.

[0084] In some embodiments of this disclosure, the method for preparing the other compound A-1-8, wherein the reaction temperature in step (b2) is 10–100°C; preferably, the reaction temperature is 20–50°C; more preferably, the reaction temperature is 20–35°C; and even more preferably, the reaction temperature is 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, or 35°C. In a specific embodiment of this disclosure, the method for preparing the other compound A-1-8, wherein the reaction temperature in step (b2) is 25°C.

[0085] In some embodiments of this disclosure, the method for preparing the other compound A-1-8, wherein the reaction time in step (b2) is 1 to 24 hours; preferably, the reaction time in step (b) is 10 to 24 hours; more preferably, the reaction time in step (b2) is 20 to 24 hours. In a specific embodiment of this disclosure, the method for preparing the other compound A-1-8, wherein the reaction time in step (b2) is 20 hours.

[0086] In some embodiments of this disclosure, the preparation method of the other compound A-1-8 may further include a purification step in step (b2): after the reaction in step (b2) is completed, the mixture is concentrated, then another solvent is added, and the mixture is stirred and filtered to obtain purified compound A-1-8.

[0087] In some embodiments of this disclosure, the method for preparing the other compound A-1-8, wherein the additional solvent in step (b2) of the purification step is selected from one or more mixed solvents selected from water, dichloromethane, n-hexane, ethyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, acetonitrile, benzene, toluene, xylene, DMF, DMAC, or DMSO; preferably, the additional solvent is selected from one or more mixed solvents selected from n-hexane, tetrahydrofuran, 2-methyltetrahydrofuran, benzene, or toluene; more preferably, the additional solvent is selected from one or two mixed solvents selected from n-hexane or toluene. In a specific embodiment of this disclosure, the method for preparing the other compound A-1-8, wherein the additional solvent in step (b2) of the purification step is selected from a mixed solvent of n-hexane and toluene.

[0088] In some embodiments of this disclosure, in the method for preparing the other compound A-1-8, the additional solvent in step (b2) of the purification step is selected from a mixed solvent of n-hexane and toluene, with a mass ratio of 1:1 to 10, and the two solvents corresponding to the mass ratio are interchangeable; preferably, the mass ratio is 1:1 to 5; more preferably, the mass ratio is selected from 1:1 to 3; even more preferably, the mass ratio is selected from 1:1, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5 or 1:3.

[0089] In one specific embodiment of this disclosure, the method for preparing the other compound A-1-8 includes step (b2) of purifying the additional solvent, which is selected from a mixture of n-hexane and toluene, with a mass ratio of 1:2.1. The two solvents in this mass ratio are interchangeable. In another specific embodiment of this disclosure, the method for preparing the other compound A-1-8 includes step (b2) of purifying the additional solvent, which is selected from a mixture of n-hexane and toluene, with a mass ratio of 1:1.7. The two solvents in this mass ratio are interchangeable.

[0090] In some embodiments of this disclosure, the preparation method of the other compound A-1-8, wherein step (b2) the refining step may further include a recrystallization step: after the refining step is completed, a second solvent is added, and the mixture is stirred and filtered to obtain the recrystallized compound A-1-8.

[0091] In some embodiments of this disclosure, in the method for preparing the other compound A-1-8, the second solvent in step (b2) recrystallization step may be the same as or different from the other solvent in step (b2) purification step, preferably the same.

[0092] In some embodiments of this disclosure, in the method for preparing the other compound A-1-8, the second solvent in step (b2) recrystallization is selected from one or more mixed solvents selected from water, dichloromethane, n-hexane, ethyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, acetonitrile, benzene, toluene, xylene, DMF, DMAC, or DMSO; preferably, the additional solvent is selected from one or more mixed solvents selected from n-hexane, tetrahydrofuran, 2-methyltetrahydrofuran, benzene, or toluene; more preferably, the additional solvent is selected from one or two mixed solvents selected from n-hexane or toluene. In a specific embodiment of this disclosure, the second solvent in step (b2) recrystallization is selected from a mixed solvent of n-hexane and toluene.

[0093] In some embodiments of this disclosure, in the method for preparing the other compound A-1-8, the second solvent in step (b2) recrystallization is selected from a mixed solvent of n-hexane and toluene, and the mass ratio of the two solvents is the same as the mass ratio of the two solvents in step (b2) purification, and the two solvents corresponding to the mass ratio are interchangeable.

[0094] In some embodiments of this disclosure, in the method for preparing the other compound A-1-8, the second solvent in step (b2) recrystallization is selected from a mixed solvent of n-hexane and toluene, with a volume ratio of 1:1 to 10, and the two solvents corresponding to the volume ratio are interchangeable; preferably, the volume ratio is 1:1 to 5; more preferably, the volume ratio is selected from 1:1 to 3; even more preferably, the volume ratio is selected from 1:1, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, or 1:3. In a specific embodiment of this disclosure, in the method for preparing the other compound A-1-8, the second solvent in step (b2) recrystallization is selected from a mixed solvent of n-hexane and toluene, with a volume ratio of 1:2, and the two solvents corresponding to the volume ratio are interchangeable. In a specific embodiment of this disclosure, in the method for preparing the other compound A-1-8, the second solvent in step (b2) recrystallization is selected from a mixed solvent of n-hexane and toluene, with a volume ratio of 1:1.3, and the two solvents corresponding to the volume ratio are interchangeable.

[0095] In some embodiments of this disclosure, the method for preparing the other compound A-1-8, wherein the system temperature in step (b2) recrystallization is -20 to 25°C; preferably, the system temperature is -20 to 0°C; in one specific embodiment of this disclosure, the method for preparing the other compound A-1-8, wherein the system temperature in step (b2) recrystallization is -20°C. In one specific embodiment of this disclosure, the method for preparing the other compound A-1-8, wherein the system temperature in step (b2) recrystallization is 0°C.

[0096] In some embodiments of this disclosure, in the method for preparing another compound A-1-8, a seed crystal may be added in step (b2) recrystallization step, wherein the seed crystal is compound A-1-8 with an ee value of 98% to 100%; preferably, the seed crystal is compound A-1-8 with an ee value of 99% to 100%.

[0097] In some embodiments of this disclosure, the other compound A-1-8 is prepared in a method wherein the compound A-1-8 obtained by recrystallization in step (b2) is a crystal, which may optionally be a hydrate or a solvate.

[0098] In some embodiments of this disclosure, the method for preparing the other compound A-1-8, wherein the ee value of the recrystallized compound A-1-8 obtained in step (b2) is 98% to 100%; preferably, the ee value of the recrystallized compound A-1-8 is 99% to 100%; more preferably, the ee value of the recrystallized compound A-1-8 is 99.5% to 100%.

[0099] In some embodiments of this disclosure, in the method for preparing the other compound A-1-8, the mass-to-volume ratio of seed crystals to total mixed solvent in step (b2) recrystallization is 1g:100-400mL; preferably, the mass-to-volume ratio of seed crystals to total mixed solvent is 1g:200-400mL; more preferably, the mass-to-volume ratio of seed crystals to total mixed solvent is 1g:200mL, 1g:250mL, 1g:300mL, 1g:350mL, 1g:380mL, or 1g:400mL.

[0100] On the other hand, this disclosure also provides a method for preparing compound A-1-9, the method comprising: (a3) ​​compound A-1-6 undergoing a condensation reaction to generate compound A-1-9,

[0101]

[0102] In some specific embodiments of this disclosure, the method for preparing compound A-1-9 includes step (a3) ​​of reacting in the presence of a condensing agent and a solvent.

[0103] In some specific embodiments of this disclosure, the method for preparing compound A-1-9, wherein the solvent in step (a3) ​​is selected from one or more mixed solvents selected from water, dichloromethane, n-hexane, methanol, ethanol, isopropanol, n-butanol, 1,4-dioxane, acetone, diethyl ether, methyl tert-butyl ether, petroleum ether, ethyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, acetonitrile, benzene, toluene, xylene, DMF, DMAC, or DMSO; preferably, the solvent is selected from one or more mixed solvents selected from n-hexane, benzene, toluene, xylene, DMF, DMAC, or DMSO; more preferably, the solvent is selected from n-hexane or toluene; in one specific embodiment of this disclosure, the method for preparing compound A-1-9, wherein the solvent in step (a3) ​​is selected from toluene.

[0104] In some specific embodiments of this disclosure, the method for preparing compound A-1-9, wherein the condensing agent in step (a3) ​​is selected from acetic anhydride, trifluoromethanesulfonic anhydride, DCC, HATU, HBTU, DPPA, and CDI; preferably, the condensing agent is selected from acetic anhydride or trifluoromethanesulfonic anhydride; in one specific embodiment of this disclosure, the method for preparing compound A-1-9, wherein the condensing agent in step (a3) ​​is selected from acetic anhydride.

[0105] In some specific embodiments of this disclosure, the reaction time in step (a3) ​​of the preparation method of compound A-1-9 is 1 to 10 hours; preferably, the reaction time in step (a3) ​​is 1 to 6 hours; more preferably, the reaction time in step (a3) ​​is 1 to 4 hours. In one specific embodiment of this disclosure, the reaction time in step (a3) ​​of the preparation method of compound A-1-9 is 4 hours.

[0106] In some specific embodiments of this disclosure, the preparation method of compound A-1-9, wherein the reaction temperature in step (a3) ​​is the solvent reflux temperature. Preferably, the reaction temperature is 80–120°C; more preferably, the reaction temperature is 100–120°C. In one specific embodiment of this disclosure, the preparation method of compound A-1-9, wherein the reaction temperature in step (a3) ​​is 110–115°C.

[0107] In some specific embodiments of this disclosure, in the method for preparing compound A-1-9, the molar ratio of compound A-1-6 to the condensing agent in step (a3) ​​is 1:1 to 3; preferably, the molar ratio of compound A-1-6 to the condensing agent is selected from 1:1 to 2; more preferably, the molar ratio of compound A-1-6 to the condensing agent is selected from 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, or 1:2. In one specific embodiment, the molar ratio of compound A-1-6 to the condensing agent is selected from 1:2.

[0108] In some embodiments of this disclosure, in the method for preparing compound A-1-9, the mass-to-volume ratio of compound A-1-6 to solvent in step (a3) ​​is 1 g: 2-10 mL; preferably, the mass-to-volume ratio of compound A-1-6 to solvent in step (a3) ​​is 1 g: 2-8 mL; more preferably, the mass-to-volume ratio of compound A-1-6 to solvent in step (a3) ​​is 1 g: 5-8 mL. In a specific embodiment of this disclosure, in another method for preparing compound A-1, the mass-to-volume ratio of A-1-6 to solvent in step (a3) ​​is 1 g: 5 mL.

[0109] In some embodiments of this disclosure, the method for preparing compound A-1-9 may further include a purification step in step (a3): after the reaction in step (a3) ​​is completed, another solvent is added, and the mixture is stirred and filtered to obtain purified compound A-1-9.

[0110] In some embodiments of this disclosure, the method for preparing compound A-1-9 includes step (a3) ​​of purifying the other solvent, which is selected from one or more mixed solvents chosen from dichloromethane, n-hexane, ethyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, acetonitrile, benzene, toluene, xylene, DMF, DMAC, or DMSO; preferably, the other solvent is selected from one or more mixed solvents chosen from n-hexane, 2-methyltetrahydrofuran, benzene, toluene, or xylene; more preferably, the other solvent is selected from n-hexane or toluene. In a specific embodiment of this disclosure, the method for preparing compound A-1-9 includes step (a3) ​​of purifying the other solvent, which is selected from n-hexane.

[0111] On the other hand, this disclosure provides a method for preparing compound A-2, the method comprising: (a4) compound A-1 undergoing a nucleophilic addition reaction to obtain compound A-1-a; (b3) compound A-1-a undergoing an etherification reaction to obtain compound A-2;

[0112]

[0113] In some embodiments of this disclosure, the method for preparing compound A-2 is wherein the nucleophilic addition reaction in step (a4) is carried out in the presence of a nucleophile and a solvent.

[0114] In some embodiments of this disclosure, in the method for preparing compound A-2, the solvent in step (a4) is selected from one or more mixed solvents selected from dichloromethane, n-hexane, ethyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, acetonitrile, benzene, toluene, xylene, DMF, DMAC, or DMSO; preferably, the solvent is selected from one or more mixed solvents selected from tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, acetonitrile, benzene, toluene, or xylene; more preferably, the solvent is selected from tetrahydrofuran or 2-methyltetrahydrofuran. In a specific embodiment of this disclosure, in the method for preparing compound A-2, the solvent in step (a4) is selected from tetrahydrofuran.

[0115] In some embodiments of this disclosure, the method for preparing compound A-2, wherein the nucleophile in step (a4) is selected from magnesium methyl iodide, magnesium methyl bromide, or magnesium methyl chloride; preferably, the nucleophile is selected from magnesium methyl iodide; also preferably, the nucleophile is selected from magnesium methyl bromide.

[0116] In some embodiments of this disclosure, in a method for preparing compound A-2, the nucleophile in step (a4) is in solution form, and the solution is selected from diethyl ether solution. In a specific embodiment of this disclosure, in a method for preparing compound A-2, the nucleophile in step (a4) is selected from magnesium methyl iodide diethyl ether solution.

[0117] In some embodiments of this disclosure, in a method for preparing compound A-2, the nucleophile in step (a4) is in solution form, and the solution is selected from 2-methyltetrahydrofuran solution. In a specific embodiment of this disclosure, in a method for preparing compound A-2, the nucleophile in step (a4) is selected from methylmagnesium bromide 2-methyltetrahydrofuran solution.

[0118] In some embodiments of this disclosure, in the method for preparing compound A-2, the molar ratio of compound A-1 to the nucleophile in step (a4) is 1:1 to 10; preferably, the molar ratio of compound A-1 to the nucleophile is selected from 1:1 to 5; more preferably, the molar ratio of compound A-1 to the nucleophile is selected from 1:1, 1:2, 1:3, 1:4, or 1:5. In one specific embodiment, the molar ratio of compound A-1 to the nucleophile is selected from 1:3. In other embodiments of this disclosure, the molar ratio of compound A-1 to the nucleophile is selected from 1:1.5, 1:2.5, 1:3.5, 1:4.5, or 1:5. In yet another specific embodiment, the molar ratio of compound A-1 to the nucleophile is selected from 1:2.5.

[0119] In some embodiments of this disclosure, in the method for preparing compound A-2, the mass-to-volume ratio of compound A-1 to solvent in step (a4) is 1 g: 10-100 mL; preferably, the mass-to-volume ratio of compound A-1 to solvent is 1 g: 10-50 mL; more preferably, the mass-to-volume ratio of compound A-1 to solvent is 1 g: 20-30 mL. In one specific embodiment, the mass-to-volume ratio of compound A-1 to solvent is 1 g: 20 mL. In other embodiments of this disclosure, the mass-to-volume ratio of compound A-1 to solvent is preferably 1 g: 10-30 mL. In yet another specific embodiment, the mass-to-volume ratio of compound A-1 to solvent is 1 g: 10 mL.

[0120] In some embodiments of this disclosure, the method for preparing compound A-2, wherein the reaction temperature in step (a4) is 10–100°C; preferably, the reaction temperature is 10–60°C; more preferably, the reaction temperature is 20–60°C; and even more preferably, the reaction temperature is 50–60°C. In a specific embodiment of this disclosure, the method for preparing compound A-2, wherein the reaction temperature in step (a4) is 60°C.

[0121] In some embodiments of this disclosure, the method for preparing compound A-2, wherein the reaction time in step (a4) is 1 to 24 hours; preferably, the reaction time in step (a4) is 1 to 10 hours; more preferably, the reaction time in step (a4) is 1 to 5 hours. In a specific embodiment of this disclosure, the method for preparing compound A-2, wherein the reaction time in step (a4) is 3 hours.

[0122] In some embodiments of this disclosure, the method for preparing compound A-2, wherein the etherification reaction in step (b3) is carried out in the presence of a catalyst and a solvent.

[0123] In some embodiments of this disclosure, in the method for preparing compound A-2, the solvent in step (b3) is selected from one or more mixed solvents selected from dichloromethane, n-hexane, ethyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, acetonitrile, benzene, toluene, xylene, DMF, DMAC, or DMSO; preferably, the solvent is selected from one or more mixed solvents selected from tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, acetonitrile, benzene, toluene, or xylene; more preferably, the solvent is selected from toluene or xylene. In a specific embodiment of this disclosure, in the method for preparing compound A-2, the solvent in step (b3) is selected from toluene.

[0124] In some embodiments of this disclosure, the method for preparing compound A-2, wherein the catalyst in step (b3) is selected from acidic catalysts or basic catalysts; preferably, an acidic catalyst.

[0125] In some embodiments of this disclosure, the method for preparing compound A-2, wherein the alkaline catalyst in step (b3) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide, or potassium tert-butoxide; preferably sodium hydroxide or potassium hydroxide.

[0126] In some embodiments of this disclosure, in the method for preparing compound A-2, the acidic catalyst in step (b3) is selected from one or more of p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, trimethylboron oxide, methanesulfonic acid, hydrofluoric acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, hydrochloric acid, phosphoric acid, or sulfuric acid; preferably, the acidic catalyst is selected from one or more of p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, or hydrochloric acid; more preferably, the acidic catalyst is selected from p-toluenesulfonic acid, phosphoric acid, or sulfuric acid; and even more preferably, the acidic catalyst is selected from p-toluenesulfonic acid.

[0127] In some embodiments of this disclosure, in a method for preparing compound A-2, the acidic catalyst in step (b3) may be in hydrate form. In a specific embodiment of this disclosure, in a method for preparing compound A-1, the acidic catalyst in step (b3) is selected from p-toluenesulfonic acid monohydrate.

[0128] In some embodiments of this disclosure, in the method for preparing compound A-2, the molar ratio of compound A-1-a to the catalyst in step (b3) is 1:0.1 to 5; preferably, the molar ratio of compound A-1-a to the catalyst is 1:0.1 to 1; more preferably, the molar ratio of compound A-1-a to the catalyst is 1:0.1, 1:0.2, 1:0.3, 1:0.4, or 1:0.5. In one specific embodiment, the molar ratio of compound A-1-a to the catalyst is 1:0.5.

[0129] In some embodiments of this disclosure, in the method for preparing compound A-2, the mass-to-volume ratio of compound A-1-a to solvent in step (b3) is 1 g: 10-100 mL; preferably, the mass-to-volume ratio of compound A-1-a to solvent is 1 g: 10-50 mL; more preferably, the mass-to-volume ratio of compound A-1-a to solvent is 1 g: 10-20 mL. In one specific embodiment, the mass-to-volume ratio of compound A-1-a to solvent is 1 g: 12 mL.

[0130] In some embodiments of this disclosure, in the method for preparing compound A-2, the reaction temperature in step (b3) is 10–100°C; preferably, the reaction temperature is 50–100°C; more preferably, the reaction temperature is 90–100°C; and even more preferably, the reaction temperature is 90°C, 91°C, 92°C, 93°C, 94°C, 95°C, 96°C, 97°C, 98°C, 99°C, or 100°C. In one specific embodiment of this disclosure, in the method for preparing compound A-2, the reaction temperature in step (b3) is 90°C. In other embodiments of this disclosure, in the method for preparing compound A-2, the reaction temperature in step (b3) is preferably 80–100°C. In yet another specific embodiment of this disclosure, in the method for preparing compound A-2, the reaction temperature in step (b3) is 85°C.

[0131] In some embodiments of this disclosure, the reaction time in step (b3) of the method for preparing compound A-2 is 1 to 24 hours; preferably, the reaction time in step (b3) is 1 to 5 hours; more preferably, the reaction time in step (b3) is 1 to 3 hours; and even more preferably, the reaction time in step (b3) is 1 hour, 1.5 hours, 2 hours, 2.5 hours, or 3 hours. In one specific embodiment of this disclosure, the reaction time in step (b3) of the method for preparing compound A-2 is 1.5 hours. In another specific embodiment of this disclosure, the reaction time in step (b3) of the method for preparing compound A-2 is 2 hours.

[0132] In some embodiments of this disclosure, the method for preparing compound A-2 further includes a purification step in step (b3): ​​the crude compound A-2 obtained in step (b3) is purified by column chromatography to obtain a purified compound A-2. In some embodiments of this disclosure, in the purification step of step (b3) of the method for preparing compound A-2, the mobile phase of the column chromatography is petroleum ether and ethyl acetate or petroleum ether and dichloromethane.

[0133] In some embodiments of this disclosure, in the purification step (b3) of the preparation method of compound A-2, the mobile phase of column chromatography is petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1 to 10:1; preferably, the volume ratio of petroleum ether to ethyl acetate is 5 to 10:1; more preferably, the volume ratio of petroleum ether to ethyl acetate is 10:1.

[0134] In some other embodiments of this disclosure, the method for preparing compound A-2 further includes a purification step in step (b3): ​​the crude compound A-2 obtained in step (b3) is recrystallized and purified in the presence of a solvent to obtain the purified compound A-2.

[0135] In some other embodiments of this disclosure, the solvent in step (b3) of the purification step of the method for preparing compound A-2 is ethanol and water.

[0136] In some other embodiments of this disclosure, in the method for preparing compound A-2, the solvent in step (b3) of the purification step is ethanol and water, wherein the volume ratio of ethanol to water is 1:1 to 10; preferably, the volume ratio of ethanol to water is 1:5 to 10; and more preferably, the volume ratio of ethanol to water is 1:5.

[0137] In some embodiments of this disclosure, the preparation method of compound A-2 can proceed directly to step (b3) without post-treatment to separate compound A-1-a after the reaction in step (a4).

[0138] On the other hand, this disclosure provides a method for preparing compound A-4, the method comprising: (d1) reacting compound A-2 with tert-butyl carbamate via a nucleophilic substitution reaction to obtain compound A-3; (e1) subjecting compound A-3 to a deamination protection reaction to obtain compound A-4.

[0139]

[0140] In some embodiments of this disclosure, a method for preparing compound A-4 is described, wherein step (d1) involves a reaction in the presence of a catalyst, a ligand, a base, and a solvent.

[0141] In some embodiments of this disclosure, the method for preparing compound A-4, wherein the catalyst in step (d1) is a metal catalyst; preferably a palladium catalyst.

[0142] In some embodiments of this disclosure, in the method for preparing compound A-4, the palladium catalyst in step (d1) is selected from palladium acetate, 1,2-bis(diphenylphosphino)ethane palladium dichloride, 1,3-bis(diphenylphosphino)propane palladium dichloride, 1,4-bis(diphenylphosphino)butane palladium dichloride, bis(triphenylphosphine)palladium dichloride, bis(cyanobenzene)palladium dichloride, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride, or tris(dibenzylacetone)dipalladium; preferably, the palladium catalyst is selected from palladium acetate or tris(dibenzylacetone)dipalladium. In a specific embodiment of this disclosure, in the method for preparing compound A-4, the palladium catalyst in step (d1) is palladium acetate.

[0143] In some embodiments of this disclosure, the method for preparing compound A-4, wherein the ligand in step (d1) is selected from one of 2-biscyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl, 2-biscyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl, 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene, 1,1'-bidinaphthol, or 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; preferably, the ligand of the metal catalyst is selected from one of 2-biscyclohexylphosphine-2',4',6'-triisopropylbiphenyl, tri-tert-butylphosphine, or 1,1'-binaphthyl-2,2'-bisdiphenylphosphine. In one specific embodiment of this disclosure, the method for preparing compound A-4, wherein the ligand in step (d1) is 2-biscyclohexylphosphine-2',4',6'-triisopropylbiphenyl.

[0144] In some embodiments of this disclosure, in the method for preparing compound A-4, the base in step (d1) is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, pyridine, piperidine, or N-methylpiperidine; preferably, the base is selected from cesium carbonate, potassium carbonate, or sodium carbonate. In a specific embodiment of this disclosure, in the method for preparing compound A-4, the base in step (d1) is selected from cesium carbonate.

[0145] In some embodiments of this disclosure, in the method for preparing compound A-4, the molar ratio of compound A-2 to the metal catalyst in step (d1) is 1:0.01 to 1; preferably, the molar ratio of compound A-2 to the metal catalyst is 1:0.01 to 0.1; more preferably, the molar ratio of compound A-2 to the metal catalyst is 1:0.01, 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, or 1:0.1. In one specific embodiment, the molar ratio of compound A-2 to the metal catalyst is 1:0.08.

[0146] In some embodiments of this disclosure, in the method for preparing compound A-4, the molar ratio of compound A-2 to the ligand in step (d1) is 1:0.01 to 1; preferably, the molar ratio of compound A-2 to the ligand is 1:0.01 to 0.1; more preferably, the molar ratio of compound A-2 to the ligand is 1:0.01, 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, or 1:0.1. In one specific embodiment, the molar ratio of compound A-2 to the ligand is 1:0.09.

[0147] In some embodiments of this disclosure, in the method for preparing compound A-4, the molar ratio of compound A-2 to base in step (d1) is 1:1 to 10; preferably, the molar ratio of compound A-2 to base is 1:1 to 5; more preferably, the molar ratio of compound A-2 to base is 1:1, 1:2, 1:3, 1:4, or 1:5. In one specific embodiment, the molar ratio of compound A-2 to base is 1:2.

[0148] In some embodiments of this disclosure, in a method for preparing compound A-4, the solvent in step (d1) is selected from one or more mixed solvents selected from dichloromethane, n-hexane, ethyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, acetonitrile, benzene, toluene, xylene, DMF, DMAC, or DMSO; preferably, the solvent is selected from one or more mixed solvents selected from tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, acetonitrile, benzene, toluene, or xylene; more preferably, the solvent is selected from one or two mixed solvents selected from toluene or xylene. In a specific embodiment of this disclosure, in a method for preparing compound A-4, the solvent in step (d1) is selected from toluene.

[0149] In some embodiments of this disclosure, in the method for preparing compound A-4, the mass-to-volume ratio of compound A-2 to solvent in step (d1) is 1 g: 10-100 mL; preferably, the mass-to-volume ratio of compound A-2 to solvent is 1 g: 10-50 mL; more preferably, the mass-to-volume ratio of compound A-2 to solvent is 1 g: 10-20 mL. In one specific embodiment, the mass-to-volume ratio of compound A-2 to solvent is 1 g: 20 mL.

[0150] In some embodiments of this disclosure, the method for preparing compound A-4, wherein the reaction temperature in step (d1) is 10–100°C; preferably, the reaction temperature is 50–100°C; more preferably, the reaction temperature is 90–100°C; and even more preferably, the reaction temperature is 90°C, 91°C, 92°C, 93°C, 94°C, 95°C, 96°C, 97°C, 98°C, 99°C, or 100°C. In a specific embodiment of this disclosure, the method for preparing compound A-4, wherein the reaction temperature in step (d1) is 90°C.

[0151] In some embodiments of this disclosure, the method for preparing compound A-4, wherein the reaction time in step (d1) is 1 to 24 hours; preferably, the reaction time is 1 to 5 hours; more preferably, the reaction time is 1 to 3 hours. In a specific embodiment of this disclosure, the method for preparing compound A-4, wherein the reaction time in step (d1) is 3 hours.

[0152] In some embodiments of this disclosure, the method for preparing compound A-4 further includes a purification step in step (d1): the crude product A-3 obtained in step (d1) is purified by column chromatography to obtain the purified product of compound A-3.

[0153] In some embodiments of this disclosure, the preparation method of compound A-4, wherein the column chromatography mobile phase in step (d1) purification step is petroleum ether and ethyl acetate or petroleum ether and dichloromethane.

[0154] In some embodiments of this disclosure, in the purification step (d1) of the preparation method of compound A-4, the column chromatography mobile phase is petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1 to 5:1; preferably, the volume ratio of petroleum ether to ethyl acetate is 1 to 3:1; more preferably, the volume ratio of petroleum ether to ethyl acetate is 5:1.

[0155] In some embodiments of this disclosure, a method for preparing compound A-4 is provided, wherein step (e1) is carried out in the presence of an acid and a solvent.

[0156] In some embodiments of this disclosure, the method for preparing compound A-4, wherein the acid in step (e1) is selected from one or more of p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, hydrofluoric acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, hydrochloric acid, phosphoric acid, or sulfuric acid; preferably, the acid is selected from one or more of p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, or hydrochloric acid; more preferably, the acid is selected from p-toluenesulfonic acid, trifluoroacetic acid, or hydrochloric acid; even more preferably, the acid is selected from hydrochloric acid.

[0157] In one specific embodiment of this disclosure, the method for preparing compound A-4, wherein the acid in step (e1) is a solution, and the solution is the same as the solvent in step (e1).

[0158] In some embodiments of this disclosure, in the method for preparing compound A-4, the solvent in step (e1) is selected from one or more mixed solvents selected from dichloromethane, n-hexane, dioxane, ethyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, acetonitrile, benzene, toluene, xylene, DMF, DMAC, or DMSO; preferably, the solvent is selected from one or more mixed solvents selected from dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, benzene, toluene, or xylene; more preferably, the solvent is selected from dioxane or toluene. In a specific embodiment of this disclosure, in the method for preparing compound A-4, the solvent in step (e1) is selected from dioxane.

[0159] In one specific embodiment of this disclosure, in the method for preparing compound A-4, the acid in step (e1) is hydrochloric acid, and the hydrochloric acid is a solution of dioxane chloride.

[0160] In one specific embodiment of this disclosure, in the method for preparing compound A-4, the molar ratio of compound A-3 to acid in step (e1) is 1:1 to 100; preferably, the molar ratio of compound A-3 to acid is 1:1 to 50; more preferably, the molar ratio of compound A-3 to acid is 1:10, 1:20, 1:23, 1:24, or 1:25. In one specific embodiment, the molar ratio of compound A-3 to acid is 1:24.

[0161] In one specific embodiment of this disclosure, in the method for preparing compound A-4, the mass-to-volume ratio of compound A-3 to solvent in step (e1) is 1 g: 1-50 mL; preferably, the mass-to-volume ratio of compound A-3 to solvent is 1 g: 1-10 mL; more preferably, the mass-to-volume ratio of compound A-3 to solvent is 1 g: 5-10 mL. In one specific embodiment, the mass-to-volume ratio of compound A-3 to solvent is 1 g: 7 mL.

[0162] In some embodiments of this disclosure, the method for preparing compound A-4, wherein the reaction temperature in step (e1) is 10–100°C; preferably, the reaction temperature is 10–50°C; more preferably, the reaction temperature is 10–25°C; and even more preferably, the reaction temperature is 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, or 25°C. In a specific embodiment of this disclosure, the method for preparing compound A-4, wherein the reaction temperature in step (e1) is 25°C.

[0163] In some embodiments of this disclosure, the method for preparing compound A-4, wherein the reaction time in step (e1) is 1 to 24 hours; preferably, the reaction time is 1 to 5 hours; more preferably, the reaction time is 1 to 3 hours. In a specific embodiment of this disclosure, the method for preparing compound A-4, wherein the reaction time in step (e1) is 3 hours.

[0164] On the other hand, this disclosure also provides another method for preparing compound A-4, the method comprising: (d2) a nucleophilic substitution reaction of compound A-2 and formamide to obtain compound A-4-1; (e2) a hydrolysis reaction of compound A-4-1 to obtain compound A-4.

[0165]

[0166] In some embodiments of this disclosure, the method for preparing the other compound A-4, wherein the nucleophilic substitution reaction in step (d2) is carried out in the presence of a catalyst and a base.

[0167] In some embodiments of this disclosure, the method for preparing the other compound A-4, wherein the catalyst in step (d2) is selected from copper sulfate, ketone iodide, palladium acetate, tris(dibenzylacetone)palladium, palladium chloride, or palladium fluoroborate; preferably, the catalyst is selected from copper sulfate or ketone iodide; more preferably, the catalyst is selected from copper sulfate; in a specific embodiment of this disclosure, the method for preparing the other compound A-4, wherein the catalyst in step (d2) is selected from anhydrous copper sulfate.

[0168] In some embodiments of this disclosure, the method for preparing the other compound A-4, wherein the base in step (d2) is selected from cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, or sodium tert-butoxide; preferably, the base is selected from cesium carbonate, potassium carbonate, or sodium carbonate; in a specific embodiment of this disclosure, the method for preparing the other compound A-4, wherein the base in step (d2) is selected from potassium carbonate.

[0169] In some embodiments of this disclosure, in the method for preparing the other compound A-4, the molar ratio of compound A-2 to formamide in step (d2) is 1:1 to 100; preferably, the molar ratio of compound A-2 to formamide is 1:50 to 100; more preferably, the molar ratio of compound A-2 to formamide is 1:50, 1:60, 1:70, 1:80, 1:90, or 1:100. In one specific embodiment, the molar ratio of compound A-2 to formamide is 1:70.

[0170] In some embodiments of this disclosure, in the method for preparing the other compound A-4, the molar ratio of compound A-2 to catalyst in step (d2) is 1:1 to 10; preferably, the molar ratio of compound A-2 to catalyst is 1:1 to 5; more preferably, the molar ratio of compound A-2 to catalyst is 1:1, 1:2, 1:3, 1:4, or 1:5. In one specific embodiment, the molar ratio of compound A-2 to catalyst is 1:2.

[0171] In some embodiments of this disclosure, in the method for preparing the other compound A-4, the molar ratio of compound A-2 to the base in step (d2) is 1:1 to 10; preferably, the molar ratio of compound A-2 to the base is 1:1 to 3; more preferably, the molar ratio of compound A-2 to the base is 1:1, 1:1.5, 1:2, 1:2.5, or 1:3. In one specific embodiment, the molar ratio of compound A-2 to the base is 1:2.5.

[0172] In some embodiments of this disclosure, the method for preparing the other compound A-4, wherein the reaction temperature in step (d2) is 10–150°C; preferably, the reaction temperature is 100–150°C; more preferably, the reaction temperature is 110–150°C; and even more preferably, the reaction temperature is 110°C, 115°C, 120°C, 125°C, 130°C, 135°C, 140°C, 145°C, or 150°C. In another specific embodiment of this disclosure, the method for preparing the other compound A-4, wherein the reaction temperature in step (d2) is 140°C.

[0173] In some embodiments of this disclosure, the method for preparing the other compound A-4, wherein the reaction time in step (d2) is 1 to 24 hours; preferably, the reaction time is 1 to 6 hours; more preferably, the reaction time is 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours. In a specific embodiment of this disclosure, the method for preparing the other compound A-4, wherein the reaction time in step (d2) is 2 hours.

[0174] In some embodiments of this disclosure, the method for preparing the other compound A-4, wherein the hydrolysis reaction in step (e2) is carried out in the presence of a base and a solvent.

[0175] In some embodiments of this disclosure, the method for preparing the other compound A-4, wherein the base in step (e2) is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, calcium carbonate, potassium tert-butoxide, triethylamine, triethanolamine, sodium hydroxide, potassium hydroxide, or calcium hydroxide; preferably, the base is selected from one or more of sodium carbonate, cesium carbonate, potassium carbonate, calcium carbonate, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, or calcium hydroxide; more preferably, the base is selected from one of sodium carbonate, potassium hydroxide, or sodium hydroxide; and even more preferably, the base is selected from sodium hydroxide.

[0176] In some embodiments of this disclosure, the method for preparing the other compound A-4, wherein the base in step (e2) is in the form of an aqueous solution.

[0177] In another specific embodiment of this disclosure, the method for preparing the other compound A-4, wherein the base in step (e2) is selected from an aqueous solution of sodium hydroxide.

[0178] In some embodiments of this disclosure, the method for preparing the other compound A-4, wherein the solvent in step (e2) is selected from one or more mixed solvents chosen from water, dichloromethane, methanol, ethanol, isopropanol, n-butanol, 1,4-dioxane, acetone, diethyl ether, methyl tert-butyl ether, petroleum ether, ethyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, acetonitrile, benzene, toluene, xylene, DMF, DMAC, or DMSO; preferably, the solvent is selected from one or more mixed solvents chosen from water, dichloromethane, methanol, ethanol, isopropanol, or n-butanol; more preferably, the solvent is selected from one or more mixed solvents chosen from water, ethanol, or methanol. In one specific embodiment of this disclosure, the method for preparing the other compound A-4, wherein the solvent in step (e2) is selected from water and ethanol. In another specific embodiment of this disclosure, the method for preparing the other compound A-4, wherein the solvent in step (e2) is selected from water and methanol.

[0179] In another specific embodiment of this disclosure, in the method for preparing the other compound A-4, the molar ratio of compound A-4-1 to the base in step (e2) is 1:1 to 50; preferably, the molar ratio of compound A-4-1 to the base is 1:1 to 20; more preferably, the molar ratio of compound A-4-1 to the base is 1:10 to 20. In one specific embodiment, the molar ratio of compound A-4-1 to the base is 1:12.

[0180] In another specific embodiment of this disclosure, in the method for preparing the other compound A-4, the mass-to-volume ratio of compound A-4-1 to solvent in step (e2) is 1 g: 1-50 mL; preferably, the mass-to-volume ratio of compound A-3 to solvent is 1 g: 1-30 mL; more preferably, the mass-to-volume ratio of compound A-3 to solvent is 1 g: 20-30 mL. In one specific embodiment, the mass-to-volume ratio of compound A-3 to solvent is 1 g: 23 mL.

[0181] In some embodiments of this disclosure, the method for preparing the other compound A-4, wherein the reaction temperature in step (e2) is 10–100°C; preferably, the reaction temperature is 10–80°C; more preferably, the reaction temperature is 60–80°C. In a specific embodiment of this disclosure, the method for preparing the other compound A-4, wherein the reaction temperature in step (e2) is 60°C.

[0182] In some embodiments of this disclosure, the method for preparing the other compound A-4, wherein the reaction time in step (e2) is 1 to 24 hours; preferably, the reaction time is 1 to 5 hours; more preferably, the reaction time is 1 to 3 hours. In a specific embodiment of this disclosure, the method for preparing the other compound A-4, wherein the reaction time in step (e2) is 2 hours.

[0183] In some embodiments of this disclosure, the other method for preparing compound A-4 further includes a purification step in step (e2): the crude A-4 obtained in step (e2) is purified by column chromatography to obtain the purified compound A-4.

[0184] In some embodiments of this disclosure, in the purification step (e2), the mobile phase of column chromatography is petroleum ether and ethyl acetate or petroleum ether and dichloromethane.

[0185] In some embodiments of this disclosure, in the purification step (e2) of the preparation method of the other compound A-4, the column chromatography mobile phase is petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1 to 10:1; preferably, the volume ratio of petroleum ether to ethyl acetate is 1 to 5:1; more preferably, the volume ratio of petroleum ether to ethyl acetate is 3:1.

[0186] On the other hand, this disclosure provides yet another method for preparing compound A-4, the method comprising: (d3) reacting compound A-2 with trifluoroacetamide to obtain compound A-4:

[0187]

[0188] In one specific embodiment of this disclosure, another method for preparing compound A-4 is provided, wherein step (d3) is carried out in the presence of a catalyst, a ligand, a base, and a solvent.

[0189] In some embodiments of this disclosure, in another method for preparing compound A-4, the catalyst in step (d3) is selected from copper sulfate, ketone iodide, palladium acetate, tris(dibenzylacetone)palladium, palladium chloride, or palladium fluoroborate; preferably, the catalyst is selected from copper sulfate or ketone iodide; in a specific embodiment of this disclosure, in another method for preparing compound A-4, the catalyst in step (d3) is selected from cuprous iodide.

[0190] In some embodiments of this disclosure, another method for preparing compound A-4 is provided, wherein the ligand in step (d3) is selected from diamine ligands.

[0191] In some embodiments of this disclosure, in another method for preparing compound A-4, the diamine ligand in step (d3) is selected from 1,2-cyclohexanediamine, N,N'-dimethylcyclohexanediamine, or N,N'-dimethylethylenediamine; preferably, the diamine ligand is selected from N,N'-dimethylethylenediamine. In a specific embodiment of this disclosure, in another method for preparing compound A-4, the ligand in step (d3) is selected from N,N'-dimethylethylenediamine.

[0192] In some embodiments of this disclosure, in another method for preparing compound A-4, the base in step (d3) is selected from cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, or sodium tert-butoxide; preferably, the base is selected from cesium carbonate, potassium carbonate, or sodium carbonate; in a specific embodiment of this disclosure, in another method for preparing compound A-4, the base in step (d3) is selected from potassium carbonate.

[0193] In some embodiments of this disclosure, in another method for preparing compound A-4, the solvent in step (d3) is selected from one or more mixed solvents selected from dichloromethane, n-hexane, dioxane, ethyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, acetonitrile, benzene, toluene, xylene, DMF, DMAC, or DMSO; preferably, the solvent is selected from one or more mixed solvents selected from dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, benzene, toluene, or xylene; more preferably, the solvent is selected from dioxane or toluene. In a specific embodiment of this disclosure, in a method for preparing compound A-4, the solvent in step (d3) is selected from dioxane.

[0194] In some embodiments of this disclosure, in another method for preparing compound A-4, the molar ratio of compound A-2 to trifluoroacetamide in step (d3) is 1:1 to 10; preferably, the molar ratio of compound A-2 to trifluoroacetamide is 1:1 to 3; more preferably, the molar ratio of compound A-2 to trifluoroacetamide is 1:1.5, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, or 1:3. In one specific embodiment, the molar ratio of compound A-2 to trifluoroacetamide is 1:2.4. In another specific embodiment, the molar ratio of compound A-2 to trifluoroacetamide is 1:2.6.

[0195] In some embodiments of this disclosure, in another method for preparing compound A-4, the molar ratio of compound A-2 to catalyst in step (d3) is 1:0.01 to 1; preferably, the molar ratio of compound A-2 to catalyst is 1:0.01 to 0.5; more preferably, the molar ratio of compound A-2 to catalyst is 1:0.05, 1:0.1, 1:0.15, 1:0.2, 1:0.25, 1:0.3, or 1:0.35. In one specific embodiment, the molar ratio of compound A-2 to catalyst is 1:0.35.

[0196] In some embodiments of this disclosure, in another method for preparing compound A-4, the molar ratio of compound A-2 to the ligand in step (d3) is 1:0.01 to 1; preferably, the molar ratio of compound A-2 to the ligand is 1:0.5 to 1; more preferably, the molar ratio of compound A-2 to the ligand is 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, or 1:1. In one specific embodiment, the molar ratio of compound A-2 to the ligand is 1:0.8.

[0197] In some embodiments of this disclosure, in another method for preparing compound A-4, the molar ratio of compound A-2 to base in step (d3) is 1:1 to 10; preferably, the molar ratio of compound A-2 to base is 1:1 to 5; more preferably, the molar ratio of compound A-2 to base is 1:1, 1:2, 1:3, 1:4, or 1:5. In one specific embodiment, the molar ratio of compound A-2 to base is 1:5. In another specific embodiment, the molar ratio of compound A-2 to base is 1:2.

[0198] In some embodiments of this disclosure, in another method for preparing compound A-4, the mass-to-volume ratio of compound A-2 to solvent in step (d3) is 1 g: 1–50 mL; preferably, the mass-to-volume ratio of compound A-2 to solvent is 1 g: 1–20 mL; more preferably, the mass-to-volume ratio of compound A-2 to solvent is 1 g: 1–10 mL. In one specific embodiment, the mass-to-volume ratio of compound A-2 to solvent is 1 g: 6 mL. In other embodiments of this disclosure, the mass-to-volume ratio of compound A-2 to solvent is further preferably 1 g: 10–20 mL. In yet another specific embodiment, the mass-to-volume ratio of compound A-2 to solvent is 1 g: 13 mL.

[0199] In some embodiments of this disclosure, in another method for preparing compound A-4, the reaction temperature in step (d3) is 10–150°C; preferably, the reaction temperature is 100–150°C; more preferably, the reaction temperature is 110–150°C; and even more preferably, the reaction temperature is 110°C, 115°C, 120°C, 125°C, 130°C, 135°C, 140°C, 145°C, or 150°C. In another specific embodiment of this disclosure, in another method for preparing compound A-4, the reaction temperature in step (d3) is 110°C.

[0200] In some embodiments of this disclosure, in another method for preparing compound A-4, the reaction time in step (d3) is 1 to 24 hours; preferably, the reaction time is 1 to 24 hours; more preferably, the reaction time is 1 to 12 hours; and even more preferably, the reaction time is 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours. In a specific embodiment of this disclosure, in another method for preparing compound A-4, the reaction time in step (d3) is 6 hours.

[0201] In some embodiments of this disclosure, in another method for preparing compound A-4, the reaction intermediate in step (d3) is compound A-4-2.

[0202]

[0203] In some embodiments of this disclosure, in another method for preparing compound A-4, the intermediate compound A-4-2 in step (d3) is not separated and can be directly converted into compound A-4 in the original reaction, with a conversion ratio of 10%-90%, preferably 30%-80%, and more preferably 50%-80%.

[0204] In some embodiments of this disclosure, in another method for preparing compound A-4, after the intermediate compound in step (d3) has reacted, no further processing is required; another solvent is added to react and compound A-4 is obtained.

[0205] In some embodiments of this disclosure, in another method for preparing compound A-4, the additional solvent in step (d3) is selected from one or more mixed solvents selected from water, methanol, ethanol, isopropanol, acetone or tetrahydrofuran; preferably, the additional solvent is selected from one or more mixed solvents selected from water, methanol, ethanol or isopropanol; more preferably, a mixed solvent of water and methanol.

[0206] In some embodiments of this disclosure, in another method for preparing compound A-4, the additional solvent in step (d3) is selected from two mixed solvents, the volume ratio of the two mixed solvents being 1:1 to 5, and the two solvents in the volume ratio being interchangeable; preferably, the volume ratio of the two mixed solvents is 1:1 to 3; more preferably, the volume ratio of the two mixed solvents is 1:1, 1:2, or 1:3; and even more preferably, the volume ratio of the two mixed solvents is 1:1.

[0207] In one specific embodiment of this disclosure, another method for preparing compound A-4, wherein step (d3) uses a mixture of water and methanol as the additional solvent, wherein the volume ratio of water to methanol is 1:1.

[0208] In some embodiments of this disclosure, another method for preparing compound A-4 further includes a purification step in step (d3): the crude A-4 obtained in step (d3) is purified by column chromatography to obtain the purified compound A-4.

[0209] In some embodiments of this disclosure, in the method for preparing another compound A-4, the column chromatography mobile phase in step (d3) purification step is petroleum ether and ethyl acetate or petroleum ether and dichloromethane.

[0210] In some embodiments of this disclosure, in the purification step (d3) of another method for preparing compound A-4, the mobile phase of column chromatography is petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate is 1 to 10:1; preferably, the volume ratio of petroleum ether to ethyl acetate is 1 to 5:1; and more preferably, the volume ratio of petroleum ether to ethyl acetate is 3:1.

[0211] In some other embodiments of this disclosure, the method for preparing another compound A-4 further includes a purification step in which the crude A-4 obtained in step (d3) is purified by pulping to obtain the purified compound A-4.

[0212] In some other embodiments of this disclosure, in the method for preparing another compound A-4, the solvent used for pulping in step (d3) of the purification step is a mixture of petroleum ether and ethyl acetate or a mixture of isopropyl ether and ethyl acetate.

[0213] In some other embodiments of this disclosure, in the method for preparing another compound A-4, the solvent used for pulping in the purification step (d3) is a mixture of petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate is 1 to 10:1; preferably, the volume ratio of petroleum ether to ethyl acetate is 1 to 5:1; more preferably, the volume ratio of petroleum ether to ethyl acetate is 5:1.

[0214] On the other hand, this disclosure provides a method for preparing a compound of formula A, the method comprising: (f) reacting compound A-4 with ethyl pyruvate to obtain compound A.

[0215]

[0216] In some embodiments of this disclosure, the method for preparing compound A includes step (f) of reacting in the presence of a catalyst, an acid, and a solvent.

[0217] In some embodiments of this disclosure, the method for preparing compound A, wherein the catalyst in step (f) is selected from metal catalysts; preferably, a palladium catalyst.

[0218] In some embodiments of this disclosure, the method for preparing compound A, wherein the palladium catalyst in step (f) is selected from palladium acetate, 1,2-bis(diphenylphosphino)ethane palladium dichloride, 1,3-bis(diphenylphosphino)propane palladium dichloride, 1,4-bis(diphenylphosphino)butane palladium dichloride, bis(triphenylphosphine)palladium dichloride, bis(cyanobenzene)palladium dichloride, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride, or tris(dibenzylacetone)dipalladium; preferably, the palladium catalyst is selected from palladium acetate or tris(dibenzylacetone)dipalladium. In a specific embodiment of this disclosure, the method for preparing compound A, wherein the palladium catalyst in step (f) is palladium acetate.

[0219] In some embodiments of this disclosure, the method for preparing compound A, wherein the solvent in step (f) is selected from one or more mixed solvents selected from dichloromethane, n-hexane, ethyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, acetonitrile, benzene, toluene, xylene, DMF, DMAC, or DMSO; preferably, the solvent is selected from one or more mixed solvents selected from toluene, DMF, DMAC, or DMSO; more preferably, the solvent is selected from DMF or DMSO. In a specific embodiment of this disclosure, the method for preparing compound A, wherein the solvent in step (f) is selected from DMSO.

[0220] In some embodiments of this disclosure, in the method for preparing compound A, the acid in step (f) is selected from one or more of p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, hydrofluoric acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, hydrochloric acid, phosphoric acid, or sulfuric acid; preferably, the acid is selected from one or more of formic acid, acetic acid, propionic acid, butyric acid, valeric acid, hydrochloric acid, phosphoric acid, or sulfuric acid; more preferably, the acid is selected from formic acid or acetic acid. In a specific embodiment of this disclosure, in the method for preparing compound A, the acid in step (f) is selected from acetic acid.

[0221] In some embodiments of this disclosure, the method for preparing compound A, wherein in step (f), the molar ratio of compound A-4 to the catalyst is 1:0.01 to 1; preferably, the molar ratio of compound A-4 to the catalyst is 1:0.1 to 0.5; more preferably, the molar ratio of compound A-4 to the catalyst is 1:0.1, 1:0.2, 1:0.3, 1:0.4, or 1:0.5. In one specific embodiment, the molar ratio of compound A-4 to the catalyst is 1:0.1.

[0222] In some embodiments of this disclosure, the method for preparing compound A, wherein in step (f), the molar ratio of compound A-4 to acid is 1:1 to 10; preferably, the molar ratio of compound A-4 to acid is 1:1 to 5; more preferably, the molar ratio of compound A-4 to acid is 1:1, 1:2, 1:3, 1:4, or 1:5. In one specific embodiment, the molar ratio of compound A-4 to acid is 1:4.

[0223] In some embodiments of this disclosure, the method for preparing compound A, wherein in step (f), the mass-to-volume ratio of compound A-4 to solvent is 1 g: 1–50 mL; preferably, the mass-to-volume ratio of compound A-4 to solvent is 1 g: 20–50 mL; more preferably, the mass-to-volume ratio of compound A-4 to solvent is 1 g: 40–50 mL. In one specific embodiment, the mass-to-volume ratio of compound A-4 to solvent is 1 g: 46 mL. In other embodiments of this disclosure, the method for preparing compound A, wherein in step (f), the mass-to-volume ratio of compound A-4 to solvent is preferably 1 g: 1–20 mL. In another specific embodiment, the mass-to-volume ratio of compound A-4 to solvent is 1 g: 20 mL.

[0224] In some embodiments of this disclosure, the method for preparing compound A is wherein step (f) is carried out under anhydrous and oxygen conditions.

[0225] In some embodiments of this disclosure, the method for preparing compound A is wherein step (f) is carried out under anhydrous and air conditions.

[0226] In some embodiments of this disclosure, the method for preparing compound A, wherein the anhydrous condition in step (f) involves the addition of a molecular sieve, wherein the molecular sieve is... Molecular sieve.

[0227] In some embodiments of this disclosure, the method for preparing compound A, wherein the reaction temperature in step (f) is 10–100°C; preferably, the reaction temperature is 10–80°C; more preferably, the reaction temperature is 60–70°C. In a specific embodiment of this disclosure, the method for preparing compound A, wherein the reaction temperature in step (f) is 70°C.

[0228] In some embodiments of this disclosure, the method for preparing compound A, wherein the reaction time in step (f) is 1 to 24 hours; preferably, the reaction time is 10 to 24 hours; more preferably, the reaction time is 18 to 24 hours. In a specific embodiment of this disclosure, the method for preparing compound A, wherein the reaction time in step (f) is 18 hours.

[0229] In some other embodiments of this disclosure, the reaction time in step (f) of the method for preparing compound A is preferably 1 to 10 hours. In another specific embodiment of this disclosure, the reaction time in step (f) of the method for preparing compound A is 6 hours.

[0230] In some embodiments of this disclosure, the method for preparing compound A further includes a purification step in step (f): the crude compound A obtained in step (f) is purified by column chromatography to obtain a purified compound A.

[0231] In some embodiments of this disclosure, the preparation method of compound A, wherein the column chromatography mobile phase in step (f) purification step is petroleum ether and ethyl acetate or petroleum ether and dichloromethane.

[0232] In some embodiments of this disclosure, in the method for preparing compound A, the column chromatography mobile phase in step (f) purification step is petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate is 1 to 5:1; preferably, the volume ratio of petroleum ether to ethyl acetate is 1 to 3:1; more preferably, the volume ratio of petroleum ether to ethyl acetate is 5:1.

[0233] On the other hand, this disclosure also provides a method for preparing compound B, the method comprising: (g) reacting compound A-4 with compound A-4-a to obtain compound B.

[0234]

[0235] In some embodiments of this disclosure, the method for preparing the compound of formula B includes step (g) of reacting in the presence of a catalyst, an acid, and a solvent.

[0236] In some embodiments of this disclosure, the method for preparing compound B, wherein the catalyst, acid, solvent, molar ratio of compound A-4 to catalyst, molar ratio of compound A-4 to acid, mass-volume ratio of compound A-4 to solvent, reaction temperature, reaction time, and reaction conditions of the purification step are as described in step (f) of the method for preparing compound A above.

[0237] In this disclosure, the preparation of compound B from compound A can be carried out by referring to the method in WO20180586453A.

[0238] This disclosure also provides the following compounds:

[0239]

[0240]

[0241] This disclosure also provides the use of the following compounds in the preparation of compounds of formula A and formula B.

[0242]

[0243] This disclosure also provides the use of the methods for preparing compounds A-1, A-2, and A-4 in the preparation of compounds of formula A and formula B.

[0244] This disclosure also provides methods for preparing the above-mentioned compounds A-1, A-2, and A-4 for use in preparing GLP-1 receptor agonists.

[0245] This disclosure also provides a method for preparing a compound of formula A for use in the preparation of a GLP-1 receptor agonist.

[0246] This disclosure also provides a method for preparing a compound of formula B for use in the preparation of a GLP-1 receptor agonist.

[0247] The GLP-1 receptor agonists disclosed herein include, but are not limited to, compounds from WO2018056453, WO2022017338, WO2023169456, WO2022216094, WO2021155841, WO2022048665, WO2022052958, CN116003403A, WO2023016546, CN119306743A, CN119176808A, CN117069743A, WO2025057134, WO2025002250, WO2025026436, WO2024153070, WO2025026270, and WO2025002326.

[0248] The preparation methods described in this disclosure can be referenced in turn.

[0249] Technical effect

[0250] The preparation method disclosed herein, compared with the known chiral SFC resolution method for obtaining compounds of formula A and formula B, avoids SFC chiral resolution. It has the advantages of mild reaction conditions, short reaction time, simple synthesis operation, low cost of synthetic materials, high purity of isomers, and high yield, and is very suitable for industrial production, specifically very suitable for the industrial production of GLP-1 receptor agonists.

[0251] Terms and Definitions

[0252] The “DMF” mentioned in this disclosure is N,N-dimethylformamide.

[0253] The “DMAC” mentioned in this disclosure is N,N-dimethylacetamide.

[0254] The “DMSO” mentioned in this disclosure is dimethyl sulfoxide.

[0255] The acids and bases described in this disclosure include anhydrous forms and hydrated forms.

[0256] The term "hydrochloric acid" includes hydrogen chloride gas and hydrogen chloride solution, wherein the hydrogen chloride solution includes aqueous solution and organic solvent solution.

[0257] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter pertains. Unless otherwise stated, all patents, patent applications, and publications cited throughout this document are incorporated herein by reference in their entirety. Where multiple definitions exist for terms herein, the definitions in this chapter shall prevail. Where a URL or other such identifier or address is cited, it should be understood that such identifiers can change, and specific information on the Internet is freely available and irrelevant, but the relevant information can be found by searching the Internet or other suitable reference resources. This citation indicates the availability and public dissemination of such information.

[0258] It should be understood that the above summary and the following detailed description are exemplary and for illustrative purposes only, and do not impose any limitation on the claimed subject matter. In this application, the singular is used in conjunction with the plural unless otherwise specified. It should be noted that the singular forms “a,” “an,” and “the” used in the specification and appended claims include the plural forms unless the context clearly indicates otherwise. It should also be noted that “or” as used means “and / or” unless otherwise specified. Furthermore, the use of the term “comprising,” as well as other forms such as “including,” “containing,” and “contains,” is not restrictive.

[0259] All reagents used in this application are commercially available and can be used without further purification. Detailed Implementation

[0260] The present application is described in detail below with reference to embodiments, but this does not imply any adverse limitation on the present application. The present application has been described in detail herein, and specific embodiments thereof are disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific implementations of the present application without departing from the spirit and scope thereof.

[0261] Example 1: Synthesis of Compound A-1

[0262]

[0263] Step 1: Synthesis of Compound A-1

[0264] Compound A-1-1 (10 g), compound A-1-3 (0.4 g), di(ethylene)chlororhodium dimer (0.24 g), and 1,4-dioxane (50 mL) were mixed and slowly added to a 1.45 M, 14 mL aqueous solution of potassium phosphate. After nitrogen purging, compound A-1-2 (4 g) was added dropwise. The reaction system was heated to 60 °C for 3 hours under nitrogen protection. The reaction system was cooled to room temperature, the reactions were combined, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with ethyl acetate. The mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give 5.6 g of compound A-1. Compound A-1: ​​Rt = 2.31 min, ee = 94.68% (UPCC conditions: column: CHIRALPAK IC-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: methanol / 0.1% ammonia = 80:20; flow rate: 3.0 mL / min; column temperature: 40℃)

[0265] 1 H-NMR (500MHz, DMSO-d6): δ7.56-7.49(m,2H),7.30-7.23(m,2H),4.45-4.39(m,1H),4.37-4.25(m, 1H),3.28-3.10(m,1H),2.90-2.70(m,1H),2.63-2.57(m,1H),2.10-2.00(m,1H),1.99-1.76(m,1H).

[0266] Example 2: Synthesis of Compound A-1

[0267]

[0268] Step 1: Synthesis of compound A-1-8

[0269] Compound A-1-7 (0.5 g), 15 mL of sodium phosphate buffer (pH 7.7), and chymotrypsin (0.52 g, 1000 u / mg) were mixed and stirred at room temperature for 3 days. During the reaction, 1 N NaOH aqueous solution was added dropwise to maintain the pH of the reaction solution at 7.7. After the reaction was completed, the pH of the reaction solution was adjusted to 2 with dilute hydrochloric acid under ice bath conditions. The mixture was extracted multiple times with methyl tert-butyl ether, and the organic layers were combined, washed twice with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and separated by silica gel column chromatography, using petroleum ether-ethyl acetate (2:1) as the eluent to obtain 350 mg of compound A-1-8.

[0270] Compound A-1-8: Rt = 3.14 min, ee = 98.56% (UPCC conditions: column: CHIRALPAK IM-3, 4.6 × 150 mm, 3.0 μm; mobile phase: carbon dioxide: methanol / 0.1% ammonia = 90:10; flow rate: 2 mL / min; column temperature: 40℃)

[0271] Ms(ESI)m / z:300.88[MH] -

[0272] 1 H-NMR (500MHz, CDCl3): δ7.45-7.39(m,2H),7.13-7.07(m,2H),3.64-3.59(m,1H),3.59(s,3H),2.80-2.57(m,4H).

[0273] Step 2: Synthesis of Compound A-1

[0274] Compound A-1-8 (110 mg), THF (2 mL), and t-BuOK (41 mg) were mixed, and LiBH4 (18.3 mg) was added under ice bath protection. The reaction mixture was then reacted at 75 °C for 1 hour under nitrogen protection. The reaction solution was quenched with 1 N hydrochloric acid (0.7 mL) under ice bath conditions, extracted with dichloromethane (5 mL × 3), and the organic phases were combined. The mixture was washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was dissolved in toluene (2 mL), and p-toluenesulfonic acid (12.58 mg) was added. The reaction mixture was reacted at 85 °C for 1 hour. The solution was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography using petroleum ether-ethyl acetate (3:1) as the eluent to give 63 mg of compound A-1.

[0275] Compound A-1: ​​Rt = 2.31 min, ee = 97.50% (UPCC conditions: column: CHIRALPAK IC-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: methanol / 0.1% ammonia = 80:20; flow rate: 3 mL / min; column temperature: 40℃)

[0276] 1 H-NMR (500MHz, DMSO-d6): δ7.55-7.51(m,2H),7.29-7.25(m,2H),4.45-4.30(m,2H),3.26(m,1H),2.78-2.56(m,2H),2.08-1.90(m,2H).

[0277] Example 3: Synthesis of compound A-1-8

[0278]

[0279] Step 1: Synthesis of compound A-1-9

[0280] Compound A-1-6 (95 g), toluene (475 mL), and acetic anhydride (66.5 g) were mixed and heated under reflux for 4 h. The mixture was then slowly cooled to room temperature, and 270 mL of n-hexane was added. The mixture was stirred overnight at room temperature. The mixture was filtered, and the filter cake was washed with a mixture of 27 g of toluene and 195 g of n-hexane, followed by washing with 195 g of n-hexane. The filter cake was collected and dried under vacuum to constant weight to obtain 77 g of compound A-1-9.

[0281] 1 H-NMR (500MHz, DMSO-d6): δ7.70-7.51(m,2H),7.28(d,J=8.7Hz,2H),3.65-3.51(m,1H),3.21-2.82(m,4H).

[0282] Step 2: Synthesis of compound A-1-8

[0283] Compound A-1-9 (100 g), 2-methyltetrahydrofuran (3 L), and catalyst 3-2 (4.7 g) were mixed, and anhydrous methanol (133 g) was slowly added dropwise while stirring at room temperature for 20 hours. The solvent was removed by concentration at 35 °C, and 700 g of toluene and 332 g of n-hexane were added. The mixture was stirred overnight at 15 °C, and then stirred at 11 °C for 2 hours. The mixture was then filtered. The filter cake was washed with 47 g of toluene and 33 g of n-hexane. The filtrate was collected and extracted with saturated sodium bicarbonate solution. The aqueous phases were combined, the pH was adjusted to acidic with concentrated hydrochloric acid, and then extracted with toluene. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 86 g of compound A-1-8.

[0284] Compound A-1-8: Rt = 3.53 min, ee = 95.84% (UPCC conditions: column: CHIRALPAK IM-3, 4.6 × 150 mm, 3 μm; mobile phase: carbon dioxide: methanol / 0.1% ammonia = 90:10; flow rate: 0.5 mL / min; column temperature: 40℃)

[0285] MS(ESI) m / z: 298.88 [MH] -

[0286] 1H-NMR (500MHz, DMSO-d6): δ12.13(s,1H),7.52-7.41(m,2H),7.27-7.18(m,2H),3.49(s,3 H),3.46-3.39(m,1H),2.74(dd,J=15.8,6.2Hz,1H),2.69-2.57(m,2H),2.57-2.51(m,1H).

[0287] Example 4: Synthesis of compound A-1-8

[0288]

[0289] Step 1: Synthesis of compound A-1-8

[0290] Compound A-1-9 (140 g), 2-methyltetrahydrofuran (2.8 L), and catalyst 3-3 (6.58 g) were mixed, and anhydrous methanol (189 g) was slowly added dropwise. The mixture was stirred at room temperature for 20 hours. The solvent was removed by concentration at 35 °C, and 980 g of toluene and 467 g of n-hexane were added. The mixture was stirred overnight at 15 °C, and then stirred at -10 °C for 2 hours. The mixture was then filtered. The filter cake was washed with 60 g of toluene and 40 g of n-hexane. The filtrate was collected and extracted with saturated sodium bicarbonate solution. The aqueous phases were combined, the pH was adjusted to acidic with concentrated hydrochloric acid, and then extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 129 g of compound A-1-8.

[0291] Compound A-1-8: Rt = 3.48 min, ee = 98.6% (UPCC conditions: column: CHIRALPAK IM-3, 4.6 × 150 mm, 3 μm; mobile phase: carbon dioxide: methanol / 0.1% ammonia = 90:10; flow rate: 0.5 mL / min; column temperature: 40℃)

[0292] Secondary recrystallization: 129g of compound A-1-8 (ee = 98.6%) was dissolved in toluene (980g) and n-hexane (579g). The reaction system was cooled to -20°C and stirred for 1 hour. The mixture was filtered, and the filtrate was collected and concentrated under reduced pressure to obtain 97g of compound A-1-8.

[0293] Secondary recrystallization of compound A-1-8: Rt = 3.31 min, ee = 100% (UPCC conditions: column: CHIRALPAKIM-3, 4.6 × 150 mm, 3 μm; mobile phase: carbon dioxide: methanol / 0.1% ammonia = 90:10; flow rate: 0.5 mL / min; column temperature: 40℃).

[0294] MS(ESI) m / z: 298.91 [MH] -

[0295] Example 5 Synthesis of Compound A

[0296]

[0297] Step 1: Synthesis of compound A-1-a

[0298] Compound A-1 (33.6 g) (prepared in Example 1) and tetrahydrofuran (670 mL) were mixed, and 136 mL of 3N methylmagnesium iodide diethyl ether solution was added under ice bath conditions. After the addition was complete, the reaction mixture was heated to 60 °C and reacted for 3 hours. The reaction system was cooled to room temperature, and saturated ammonium chloride (300 mL) was added to quench the reaction mixture. Ethyl acetate (400 mL × 3) was added for extraction, the organic phases were combined, washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 38 g of compound A-1-a.

[0299] Step 2: Synthesis of compound A-2

[0300] Compound A-1-a (38 g) was dissolved in toluene (450 mL), and p-toluenesulfonic acid monohydrate (13 g) was added. The reaction system was heated to 90 °C and reacted for 1.5 hours. The reaction system was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give 29 g of compound A-2.

[0301] Compound A-2: Rt = 5.22 min, ee = 96.27% (HPLC conditions: column: CHIRALPAK IG, 4.6 × 250 mm, 5 μm; mobile phase: n-hexane: ethanol = 95:5; flow rate: 1.0 mL / min; column temperature: 25℃)

[0302] 1 H-NMR (500MHz, DMSO-d6): δ7.47(d,J=8.4Hz,2H),7.22(d,J=8.4Hz,2H),3.73-3.65(m,2H),3.00 -2.75(m,1H),1.68-1.59(m,2H),1.57-1.47(m,1H),1.50-1.30(m,1H),1.24(s,3H),1.16(s,3H).

[0303] Step 3: Synthesis of compound A-3

[0304] Compound A-2 (29 g), tert-butyl carbamate (19.6 g), palladium acetate (1.96 g), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (4.8 g), cesium carbonate (70 g), and toluene (500 mL) were mixed. The mixture was purged with nitrogen for 3 minutes, and the reaction mixture was heated to 90 °C for 3 hours under nitrogen protection. The reaction mixture was then cooled to room temperature, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give 29 g of compound A-3.

[0305] Compound A-3: Rt = 2.29 min, ee = 96.5% (UPCC conditions: column: CHIRALPAK IE-3, 4.6 × 150 mm, 3 μm; mobile phase: carbon dioxide: methanol (containing 0.1% ammonia) = 70:30; flow rate: 3.0 mL / min; column temperature: 40℃)

[0306] 1 H-NMR (500MHz, DMSO-d6): δ9.21(s,1H),7.36(d,J=8.3Hz,2H),7.11(d,J=8.5Hz,2H),3.80-3.50(m,2H),3.00 -2.75(m,1H),1.63-1.56(m,2H),1.53-1.48(m,1H),1.46(s,9H),1.44-1.36(m,1H),1.23(s,3H),1.16(s,3H).

[0307] Step 4: Synthesis of Compound A-4

[0308] Compound A-3 (29 g) and dioxane (203 mL) were mixed, and 580 mL of 4N dioxane hydrochloride solution was added at 0 °C. After the addition was complete, the mixture was transferred to room temperature and reacted for 3 hours. The mixture was concentrated under reduced pressure, reconstituted with dichloromethane, washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 16.5 g of compound A-4.

[0309] MS(ESI) m / z: 206.32 [M+H] +

[0310] 1 H-NMR (500MHz, DMSO-d6): δ6.87(d,J=8.3Hz,2H),6.49(d,J=8.3Hz,2H),4.82(s,2H),3.71-3.61(m,2H) ,2.80-2.60(m,1H),1.64-1.50(m,2H),1.48-1.39(m,1H),1.38-1.25(m,1H),1.21(s,3H),1.14(s,3H).

[0311] Step 5: Synthesis of Compound A

[0312] Compound A-4 (4g), ethyl pyruvate (6g), and ultra-dry dimethyl sulfoxide (184mL) were added. Molecular sieve activation powder (4 g), acetic acid (4.75 g), and palladium acetate (0.48 g) were mixed and reacted at 70°C for 18 hours under oxygen. This experiment was repeated three times, with a total feed amount of 16 g. The reaction system was cooled to room temperature, the reactions were combined, water was added, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give 19 g of compound A.

[0313] Compound A: Rt = 4.88 min, ee = 98.46% (UPCC conditions: column: CHIRALPAK IA-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: methanol / 0.1% ammonia = 50:50; flow rate: 2.0 mL / min; column temperature: 40℃)

[0314] MS(ESI) m / z: 302.23 [M+H] +

[0315] 1 H-NMR (500MHz, DMSO-d6): δ11.75(s,1H),7.47(s,1H),7.38(d,J=8.6Hz,1H),7.18(dd,J=8.6,1.4Hz,1H),7.11-7.03(m,1H),4.40-4.2 5(m,2H),3.70(d,J=7.3Hz,2H),3.15-2.85(m,1H),1.74-1.64(m,2H),1.64-1.45(m,2H),1.50-1.27(m,3H),1.26(s,3H),1.18(s,3H).

[0316] Example 6 Synthesis of Compound A-4

[0317]

[0318] Step 1: Synthesis of compound A-4-1

[0319] Compound A-2 (1.4 g), anhydrous copper sulfate (1.6 g), potassium carbonate (1.75 g), and formamide (14 mL) were mixed and the reaction mixture was heated to 140 °C for 2 hours. The reaction mixture was then cooled to room temperature, ammonia (30 mL) was added, and the mixture was diluted with water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.3 g of crude compound A-4-1.

[0320] MS(ESI) m / z: 234.23 [M+H] +

[0321] Step 2: Synthesis of compound A-4

[0322] Compound A-4-1 (1.3 g) and ethanol (30 mL) were mixed, and sodium hydroxide (2.7 g) and water (30 mL) were added. After the addition was complete, the reaction solution was heated to 60 °C and reacted for 2 hours. The reaction system was cooled to room temperature, and water (50 mL) was added to the reaction solution. Ethyl acetate (100 mL × 3) was added for extraction. The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to give 850 mg of compound A-4.

[0323] MS(ESI) m / z: 206.18 [M+H] +

[0324] 1 ¹H-NMR (500MHz, DMSO-d⁶) δ 6.87 (d, J = 8.4Hz, 2H), 6.49 (d, J = 8.4Hz, 2H), 4.81 (s, 2H), 3.71–3.61 (m, 2H), 2.80–2.60 (m, 1H), 1.64–1.51 (m, 2H), 1.49–1.39 (m, 1H), 1.39–1.27 (m, 1H), 1.21 (s, 3H), 1.14 (s, 3H). Example 7: Synthesis of Compound B

[0325]

[0326] Step 1: Synthesis of Compound B

[0327] Compound A-4 (0.3 g), compound A-4-a (0.54 g), and ultra-dry dimethyl sulfoxide (14 mL) were added. Molecular sieve activation powder (0.3 g), acetic acid (0.36 g), and palladium acetate (0.05 g) were mixed and reacted at 70 °C for 18 hours under oxygen. The reaction system was then cooled to room temperature, water was added, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give 0.16 g of compound B.

[0328] MS(ESI) m / z: 363.29 [M+H] +

[0329] 1 H-NMR (500MHz, DMSO-d6): δ11.44(s,1H),7.49-7.42(m,3H),7.37-7.34(m,2H),7.33-7.30(m,1H),7.10-7.07(m,1H),7.04-7.00(m,1H) ,5.23-5.17(m,1H),3.64-3.60(m,2H),3.37(s,3H),2.88-2.81(m,1H),1.59-1.54(m,2H),1.50-1.42(m,2H),1.20(s,3H),1.12(s,3H).

[0330] Example 8 Synthesis of Compound A-4

[0331]

[0332] Step 1: Synthesis of compound A-4

[0333] Compound A-2 (1 g), trifluoroacetamide (1 g), and dioxane (6 mL) were mixed, and then cuprous iodide (250 mg), potassium carbonate (1 g), and N,N'-dimethylethylenediamine (250 mg) were added. The reaction system was heated to 110 °C and stirred under air for 6 hours. The reaction system was cooled to room temperature, and a mixture of methanol (11 mL) and water (11 mL) was slowly added to the reaction solution. The temperature was raised to 80 °C and stirred for 3 hours. The reaction was stopped, water was slowly added, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound A-4 (0.76 g).

[0334] MS(ESI) m / z 206.22 [M+H] +

[0335] Example 9 Synthesis of compound A-1-7

[0336]

[0337] Step 1: Synthesis of compound A-1-5

[0338] Compound A-1-4 (20 g), ethyl acetoacetate (28.1 g), ethanol (200 mL), and piperidine (1.38 g) were mixed and stirred at room temperature for 3 days. The reaction solution was cooled in an ice bath, filtered, and the residue was washed with cold ethanol and dried to obtain 34.7 g of compound A-1-5.

[0339] 1 H-NMR (500MHz, CDCl3): δ7.45-7.41(m,2H),7.15-7.11(m,2H),4.09-3.87(m,5H),3.63-3.58(m,2H),3.00(d,J=12.2Hz, 1H), 2.71 (d, J = 14.3Hz, 1H), 2.51-2.48 (m, J = 14.3, 2.9Hz, 1H), 1.34 (s, 3H), 1.08 (t, J = 7.1Hz, 3H), 0.88 (t, J = 7.1Hz, 3H).

[0340] Step 2: Synthesis of compound A-1-6

[0341] Compound A-1-5 (6 g), EtOH (20 mL), and 40% NaOH (20 mL) were mixed and refluxed at 80 °C for 2 hours. The reaction solution was cooled to room temperature, and the pH was adjusted to 1 with concentrated hydrochloric acid. The mixture was extracted three times with ethyl acetate, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to give 3.6 g of compound A-1-6.

[0342] 1 H-NMR (500MHz, DMSO-d6): δ12.10(s,2H),7.49-7.43(m,2H),7.27-7.21(m,2H),3.42-3.36(m,1H),2.66-2.63(m,2H),2.54-2.49(m,2H).

[0343] Step 3: Synthesis of compound A-1-7

[0344] Compound A-1-6 (3 g), methanol (30 mL), and concentrated sulfuric acid (0.5 mL) were mixed and reacted at 65 °C for 3 hours. The reaction solution was cooled to room temperature, extracted three times with ethyl acetate, and the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and separated by silica gel column chromatography, using petroleum ether-ethyl acetate (5:1) as eluent to give 2.8 g of compound A-1-7.

[0345] 1H-NMR (500MHz, CDCl3): δ7.46-7.39(m,2H),7.15-7.07(m,2H),3.65-3.61(m,1H),3.59(s,6H),2.71(d,J=15.7,2H),2.62(d,J=15.7,2H).

[0346] Example 10

[0347]

[0348] Step 1: Synthesis of Compound A-1

[0349] Under ice bath conditions, lithium chloride (17.6 g), 1,2-dimethoxyethane (100 ml), and sodium borohydride (15.7 g) were mixed and stirred at room temperature for 30 minutes. Under ice bath conditions, compound A-1-8 (50 g) prepared in Example 4 was dissolved in tetrahydrofuran (500 ml), potassium tert-butoxide (15.7 g) was added, and the mixture was stirred. Then, under ice bath conditions, the solution was added dropwise to the sodium borohydride and lithium chloride solution, and the reaction was carried out at 60°C for 2 hours. The reaction solution was quenched at 0°C with saturated ammonium chloride solution, the pH was adjusted to 3-4 with 1N hydrochloric acid, extracted with ethyl acetate, the organic layer was washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and the organic layer was concentrated to obtain 49.5 g of crude product. This crude product was dissolved in tetrahydrofuran (200 ml), and 4N dioxane hydrochloride solution (10 ml) was added dropwise. The mixture was stirred at 50°C for 3 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate. After drying and concentrating the organic layer, 39g of crude product was obtained. The product was then slurried with isopropyl ether, filtered, and dried to obtain 32g of compound A-1.

[0350] Compound A-1: ​​Rt = 2.312 min, ee = 99.32% (UPCC conditions: column: CHIRALPAK IC-3, 4.6 × 100 mm, 3 μm; mobile phase: carbon dioxide: methanol / 0.1% ammonia = 80:20; flow rate: 3 mL / min; column temperature: 40℃)

[0351] 1 H-NMR (500MHz, DMSO-d6): δ7.55-7.51(m,2H),7.29-7.25(m,2H),4.45-4.30(m,2H),3.26(m,1H),2.78-2.56(m,2H),2.08-1.90(m,2H).

[0352] Step 2: Synthesis of compound A-2

[0353] In a 2L three-necked flask, intermediate A-1 (31g) and tetrahydrofuran (310mL) were mixed. A solution of 3N methylmagnesium bromide in 2-methyltetrahydrofuran (101mL) was added under ice bath conditions. After the addition was complete, the reaction mixture was heated to 60°C and reacted for 3 hours. The reaction system was cooled to room temperature, and saturated ammonium chloride (300mL) was added to quench the reaction mixture. Ethyl acetate (300mL × 3) was added for extraction. The combined organic phases were washed with saturated brine (300mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 32g of a colorless oil. This oil was dissolved in toluene (320mL), and p-toluenesulfonic acid monohydrate (10.6g) was added. The reaction system was heated to 85°C and reacted for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (300mL), and the organic phase was washed successively with saturated sodium sulfite aqueous solution (150mL) and saturated sodium bicarbonate solution (150mL). The mixture was extracted with ethyl acetate (150mL × 3) and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated, and ethanol (30 mL) and water (150 mL) were added. The mixture was heated to 60 °C to completely dissolve the solid, and then allowed to cool naturally to room temperature. The mixture was filtered again, and the filter cake was washed with ethanol / water = 1 / 5 to obtain 31.4 g of compound A-2.

[0354] Step 3: Synthesis of compound A-4

[0355] Intermediate A-2 (30 g), trifluoroacetamide (32.5 g), and 1,4-dioxane (400 ml) were mixed, and then cuprous iodide (7.45 g), potassium carbonate (30.8 g), and N,N'-dimethylethylenediamine (7.44 g) were added. Under nitrogen protection, the mixture was heated to 110 °C and stirred for 3 hours. The reaction solution was cooled to room temperature. A mixed solvent of methanol (600 mL) and water (600 mL) was slowly added to the reaction solution, and the mixture was heated to 80 °C and stirred for 3 hours. The reaction solution was cooled to room temperature, and ethyl acetate (300 mL × 3) was added for extraction. The organic phase was washed with saturated sodium chloride aqueous solution (300 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated, and allowed to stand overnight. Petroleum ether (100 mL) and ethyl acetate (20 mL) were added to the mixture for purification by stirring. The mixture was filtered, and the filter cake was collected and dried under vacuum to obtain 22.8 g of crude product. The obtained solid was mixed with Florisil (22.3 g) and dichloromethane (140 mL) and stirred at room temperature for 60 min. The reaction system was filtered, and the filter cake was washed with dichloromethane (100 mL) to give 15.7 g of compound A-4.

[0356] MS(ESI) m / z: 206.30 [M+H] + .

[0357] Step 4: Synthesis of Compound A

[0358] Intermediate A-4 (10g), ultra-dry dimethyl sulfoxide (200mL), ethyl pyruvate (11.3g), and acetic acid (11.7g) were prepared. Molecular sieve activation powder (10 g) and palladium acetate (1.1 g) were mixed and reacted at 70 °C for 6 hours under dry air. The reaction system was cooled to room temperature, the reactions were combined, water was added, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give 12 g of compound A.

[0359] MS(ESI) m / z: 302.24 [M+H] + .

Claims

1. A method for preparing compound A-1, the method comprising: (a1) Compounds A-1-1 and A-1-2 react in the presence of a metal catalyst and a chiral ligand to give compound A-1; Alternatively, a method for preparing compound A-1, said preparation method comprising: (c1) reacting compound A-1-8 to generate compound A-1, 2. The method for preparing compound A-1 according to claim 1, wherein step (a1) is carried out in the presence of a base and a solvent; the metal catalyst is selected from rhodium metal catalysts; the chiral ligand is selected from chiral phosphine ligands or chiral sulfinamide ligands; preferably chiral sulfinamide ligands; Optionally, the rhodium metal catalyst in step (a1) is selected from one of tri(triphenylphosphine) rhodium chloride, acetylacetonyl bis(ethylidene) rhodium, (1,5-cyclooctadiene) rhodium chloride (I) dimer, rhodium acetate (II) dimer, or di(ethylene) rhodium chloride dimer; preferably di(ethylene) rhodium chloride dimer; The chiral sulfinamide ligand in step (a1) is selected from (R)-N-cinnamyl-2-methylpropane-2-sulfinamide, (R)-N-allyl-2-methylpropane-2-sulfinamide, (R,E)-N-(3-(4-methoxyphenyl)allyl)-2-methylpropane-2-sulfinamide, (R)-N-(3,3-diphenylallyl)-2-methylpropane-2-sulfinamide, (R,E)-2-methyl-N-(3-(4-(trifluoromethyl)phenyl)allyl)propane-2-sulfinamide, and (R,E)-2-methyl-N-(3-(3,4,5-trimethoxyphenyl)allyl)propane-2-sulfinamide; preferably (R)-N-cinnamyl-2-methylpropane-2-sulfinamide. The alkali mentioned in step (a1) is selected from one of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, barium carbonate, or potassium phosphate; preferably potassium phosphate. The solvent in step (a1) is selected from one or more of 1,4-dioxane, THF, DMF, DMSO, DMA, acetonitrile, dichloroethane, or toluene; preferably 1,4-dioxane. Optionally, the reducing agent in step (c1) is selected from one or more of lithium borohydride, sodium borohydride, palladium on carbon, sodium triacetoxyborohydride, Raney nickel, hydrazine hydrate / palladium on carbon, and ferric chloride / hydrazine hydrate; preferably, the reducing agent is lithium borohydride; The base in step (c1) is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, triethanolamine, sodium hydroxide, potassium hydroxide, or calcium hydroxide; preferably, the base is selected from potassium tert-butoxide; the solvent in step (c1) is selected from one or more mixed solvents of water, dichloromethane, methanol, ethanol, isopropanol, n-butanol, 1,4-dioxane, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, DMF, DMAC, or DMSO; preferably, the solvent is selected from tetrahydrofuran.

3. The method for preparing compound A-1 according to claim 1, wherein the method for preparing compound A-1-8 comprises: (b1) Compound A-1-7 undergoes an enzyme-catalyzed asymmetric reaction to generate compound A-1-8. The enzyme-catalyzed asymmetric reaction described in step (b1) occurs in the presence of an enzyme, a buffer solution, and a pH adjuster. Alternatively, the preparation method of compound A-1-8 includes: (b2) compound A-1-9 undergoing an ester hydrolysis reaction to generate compound A-1-8. Step (b2) involves a reaction in the presence of a chiral catalyst and a solvent.

4. The method for preparing compound A-1-8 according to claim 3, wherein the enzyme in the enzyme-catalyzed asymmetric reaction in step (b1) is selected from one of chymotrypsin, porcine pancreatic lipase, porcine pancreatic lipase type II, pancreatic lipase, trypsin, and bovine pancreatic chymotrypsin type II; preferably, the enzyme in the enzyme-catalyzed asymmetric reaction in step (b1) is selected from chymotrypsin; In step (b1), the buffer solution for the enzyme-catalyzed asymmetric reaction is selected from one of phosphate buffer, borate buffer, tris(hydroxymethyl)aminomethane-hydrochloric acid buffer, acetate buffer, citrate buffer, or citrate buffer; preferably phosphate buffer. A further preferred option is sodium phosphate buffer; In step (b1), the pH adjuster for the enzyme-catalyzed asymmetric reaction is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, or ammonia; preferably, sodium hydroxide is selected as the pH adjuster; the pH adjuster may be in the form of an aqueous solution. Optionally, the chiral catalyst in step (b2) is selected from cinchona alkaloid derivatives or chloramphenicol alkaloid derivatives; preferably, the catalyst is selected from cinchona alkaloid derivatives; more preferably, the cinchona alkaloid derivative is selected from cinchona alkaloid, cinchona alkaloid, hydrogenated quinine, N-benzyl cinchona alkaloid chloride, N-benzylquinine ononium chloride, N-[3,5-bis(trifluoromethyl)phenyl]-N'-[(9R)-6'-methoxy-9-cinchona alkaloid]thiourea, N-[3,5-bis(trifluoromethyl)phenyl]-N'-[(8A The cinchona alkaloid derivative is selected from N-[3,5-bis(trifluoromethyl)phenyl]-N'-[(8A,9S)-6'-methoxy-9-quinine]thiourea or N-[(8A,9S)-6'-methoxyquinine-9-yl]-3,5-bis(trifluoromethyl)benzenesulfinamide; more preferably, the cinchona alkaloid derivative is selected from N-[3,5-bis(trifluoromethyl)phenyl]-N'-[(8A,9S)-6'-methoxy-9-quinine]thiourea or N-[(8A,9S)-6'-methoxyquinine-9-yl]-3,5-bis(trifluoromethyl)benzenesulfinamide; The solvent in step (b2) is selected from one or more mixed solvents selected from dichloromethane, n-hexane, ethyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, acetonitrile, benzene, toluene, xylene, DMF, DMAC, or DMSO; preferably, the solvent is selected from 2-methyltetrahydrofuran.

5. A method for preparing compound A-2, the method comprising: (a4) Compound A-1 undergoes a nucleophilic addition reaction to give compound A-1-a; (b3) Compound A-1-a undergoes an etherification reaction to give compound A-2; The nucleophilic addition reaction is carried out in the presence of a nucleophile and a solvent; the etherification reaction is carried out in the presence of a catalyst and a solvent.

6. A method for preparing compound A-4, the method comprising: (d1) Compound A-2 undergoes a nucleophilic substitution reaction with tert-butyl carbamate to give compound A-3; (e1) Compound A-3 undergoes a deamination protection reaction to give compound A-4: Step (d1) is carried out in the presence of a catalyst, ligand, base and solvent; in Step (e1) is carried out in the presence of acid and solvent; Alternatively, a method for preparing compound A-4, the method comprising: (d2) a nucleophilic substitution reaction of compound A-2 and formamide to obtain compound A-4-1; (e2) a hydrolysis reaction of compound A-4-1 to obtain compound A-4. The nucleophilic substitution reaction described in step (d2) is carried out in the presence of a catalyst and a base; the hydrolysis reaction described in step (e2) is carried out in the presence of a base and a solvent. Alternatively, a method for preparing compound A-4, the method comprising: (d3) reacting compound A-2 with trifluoroacetamide to obtain compound A-4: The step (d3) is carried out in the presence of a catalyst, ligand, base and solvent.

7. A method for preparing a compound of formula A, the method comprising: (f) Compound A-4 reacts with ethyl pyruvate to give compound A. Step (f) involves a reaction in the presence of a catalyst, an acid, and a solvent.

8. A method for preparing a compound of formula B, the method comprising: (g) Compound A-4 reacts with compound A-4-a to give compound B. Step (g) involves a reaction in the presence of a catalyst, an acid, and a solvent.

9. The following compounds:

10. The preparation method according to any one of claims 1-9, and the use of the compound of claim 9 in the preparation of a GLP-1 receptor agonist.

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