Preparation methods and uses of an intermediate of glp-1 receptor agonists

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

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202510633253.0 (22) Application Date 2025.05.16 (66) Domestic Priority Data 202410621392.7 2024.05.17 CN (71) Applicant: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Address: No. 369, Yuzhou South Road, Lianyungang City, Jiangsu Province, 222062 (72) Inventors: Zhu Yan, Liu Baomin, Chen Shaowei (51) Int.Cl. C07D 309 / 30 (2006.01) C07D 309 / 04 (2006.01) C07D 405 / 04 (2006.01) C07C 67 / 08 (2006.01) C07C 69 / 65(2006.01) C12P 7 / 62(2022.01) C07C 29 / 147(2006.01) C07C 33 / 26(2006.01) (54) Invention Title: A method for preparing a GLP-1 receptor agonist intermediate and its use (57) Abstract: This disclosure belongs to the field of pharmaceutical chemical industry and relates to a method for preparing a GLP-1 receptor agonist intermediate and its use, specifically relating to the preparation methods of compound A-1, compound A-4, compound A and compound B, and the use of compound A-1, compound A-4, compound A and compound B and their preparation methods in the preparation of GLP-1 receptor agonist agonists. Claims 4 pages, Description 33 pages, CN 120965634 A 2025.11.18 CN 1 20 96 56 34 A 1. 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; or, a method for preparing compound A-1, the 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, (R,E)-2-methyl-N-(3-(3,4,5-trimethoxyphenyl)allyl)propane-2-sulfinamide; preferably (R)-N-cinnamyl-2-methylpropane-2-sulfinamide; 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 potassium phosphate; 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 1,4-dioxane; optionally, 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 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 undergoing an enzyme-catalyzed asymmetric reaction to generate compound A-1-8, wherein step (b1) the enzyme-catalyzed asymmetric reaction is carried out in the presence of an enzyme, a buffer solution, and a pH adjuster; or, the method for preparing compound A-1-8 comprises: (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 type II porcine pancreas, 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; wherein the buffer solution in the enzyme-catalyzed asymmetric reaction in step (b1) 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; more preferably 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; the pH adjuster can be in aqueous solution form; 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 derivatives, cinchona alkaloid, hydroquinine, 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,9S)-6'- The solvent in step (b2) is selected from one of 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 one of 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. Claims 2 / 4 pages 3 CN 120965634 A 5. A method for preparing compound A-2, the method comprising: (a4) a nucleophilic addition reaction of compound A-1 to obtain compound A-1-a; (b3) an etherification reaction of compound A-1-a to obtain compound A-2; wherein the nucleophilic addition reaction is carried out in the presence of a nucleophile and a solvent; and 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) a nucleophilic substitution reaction of compound A-2 with tert-butyl carbamate to obtain compound A-3; (e1) a deamination protection reaction of compound A-3 to obtain compound A-4; wherein step (d1) is carried out in the presence of a catalyst, a ligand, a base, and a solvent; wherein step (e1) is carried out in the presence of an acid and a solvent; or, a method for preparing compound A-4, the method comprising: (d2) a nucleophilic substitution reaction of compound A-2 with formamide to obtain compound A-4-1; (e2) a hydrolysis reaction of compound A-4-1 to obtain compound A-4, wherein the nucleophilic substitution reaction in step (d2) is carried out in the presence of a catalyst and a base; the hydrolysis reaction in step (e2) is carried out in the presence of a base and a solvent; or, a method for preparing compound A-4, the method comprising: (d3) a reaction of compound A-2 with trifluoroacetamide to obtain compound A-4; Step (d3) is carried out in the presence of a catalyst, a ligand, a base, and a solvent. 7. A method for preparing a compound of formula A, the method comprising: (f) reacting compound A-4 with ethyl pyruvate to obtain compound A, wherein step (f) is carried out 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) reacting compound A-4 with compound A-4-a to obtain compound B, wherein step (g) is carried out in the presence of a catalyst, an acid, and a solvent. 9. The following compounds: 10. The method of preparation 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. Claims 4 / 4 Page 5 CN 120965634 A A method for preparing a GLP-1 receptor agonist intermediate and its use

[0001] Cross-reference to related applications

[0002] This application claims priority and benefit to Chinese Patent Application No. 202410621392.7, filed with the State Intellectual Property Office of China on May 17, 2024, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This disclosure belongs to the field of pharmaceutical and chemical engineering.This invention relates to a method for preparing a GLP-1 receptor agonist intermediate and its use, specifically to the preparation methods of compounds A-1, A-4, compound A, and compound B, and the use of compounds A-1, A-4, compound A, and compound B and their preparation methods in the preparation of GLP-1 receptor agonist agonists. Background Art

[0004] Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by elevated blood glucose levels, with high morbidity and mortality. Obesity is considered a significant risk factor for T2DM, with approximately 85% of T2DM patients being overweight or obese. Glucagon-like peptide-1 (GLP-1) is an intestinal hypoglycemic agent secreted by L cells of the small intestine when nutrients pass through the digestive tract, and GLP-1 is known to exhibit various physiological effects through the GLP-1 receptor, such as promoting glucose-dependent insulin secretion, inhibiting 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 in reducing HbA1c and weight loss, GLP-1 analogs must be administered via subcutaneous injection, resulting in poor patient compliance. Therefore, developing non-peptide GLP-1 receptor small molecule agonists to improve patient compliance is of great significance and has become one of the research hotspots in the field of diabetes.

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

[0006]

[0007] Compounds of formula A and formula B are key intermediates in the synthesis of GLP-1 receptor agonists, but this route suffers from problems such as long SFC resolution time, difficulty in large-scale preparation, and high synthesis cost. There is an urgent need to explore a new, economical, and efficient chiral synthesis route. Therefore, a more economical, convenient, higher-yield, and industrially suitable method for preparing compounds of formula A and formula B is needed. Specification 1 / 33 Page 6 CN 120965634 A Summary of the Invention

[0008] In one aspect, the present 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 the present disclosure, in the method for preparing compound A-1, step (a1) is carried out in the presence of a base and a solvent.

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

[0012] In some embodiments of the present disclosure, in the method for preparing compound A-1,The rhodium metal catalyst in step (a1) is selected from one of tri(triphenylphosphine)rhodium chloride, acetylacetonyl bis(ethylene)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)-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) can be in the form of an aqueous solution.

[0017] In a 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, in the method for preparing compound A-1, 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, in the method for preparing compound A-1, 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 1g:1-10mL; preferably, the mass-to-volume ratio of compound A-1-1 to solvent in step (a1) is 1g:1-8mL; more preferably, the mass-to-volume ratio of compound A-1-1 to solvent in step (a1) is 1g:1-5mL; similarly preferably,In step (a1), the mass-to-volume ratio of compound A-1-1 to solvent is 1 g: 5-8 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 1:0.1-2; preferably, the molar ratio of compound A-1-1 to base in step (a1) is 1:0.1-1; more preferably, the molar ratio of compound A-1-1 to base in step (a1) is 1:0.1-0.5; 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 method for preparing 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, wherein step (a1) is performed in a nitrogen atmosphere.

[0025] In some embodiments of this disclosure, the method for preparing compound A-1, wherein the reaction temperature of step (a1) 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 method for preparing compound A-1, wherein the reaction temperature of step (a1) is 60°C.

[0026] In some embodiments of this disclosure, the method for preparing compound A-1, wherein the reaction time of step (a1) is 1–10 hours; preferably, the reaction time of step (a1) is 2–6 hours; more preferably, the reaction time of step (a1) is 3–5 hours. In a specific embodiment of this disclosure, the preparation method of compound A-1, wherein the reaction time of step (a1) 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, in the purification step of the preparation method of compound A-1, the mobile phase of the column chromatography is petroleum ether and ethyl acetate or petroleum ether and dichloromethane.

[0029] In some embodiments of this disclosure, in the purification step of the preparation method of compound A-1, the mobile phase of the column chromatography is petroleum ether and ethyl acetate.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.

[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 other method for preparing compound A-1, wherein step (c1) is carried out in the presence of a reducing agent, a solvent, and a base.

[0033] In other embodiments of this disclosure, the other method for preparing compound A-1, wherein step (c1) is carried out 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 a 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 1,4-dioxane and tetrahydrofuran; in a specific embodiment of this disclosure, the solvent in step (c1) of the preparation method of the other compound A-1 is selected from tetrahydrofuran.

[0037] In some embodiments of this disclosure, the molar ratio of compound A-1-8 to reducing agent in step (c1) is 1:1 to 5; preferably, the molar ratio of compound A-1-8 to reducing agent is 1:1 to 3; more preferably, the molar ratio of compound A-1-8 to reducing agent is 1:2 to 3; more preferably, the molar ratio of compound A-1-8 to reducing agent is 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4 or 1:2.5. In a specific embodiment, the molar ratio of compound A-1-8 to 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; 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, the preparation method of the other compound A-1, wherein in step (c1), the molar ratio of compound A-1-8 to the base 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; 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, the preparation method of the other compound A-1,In step (c1), the mass-to-volume ratio of compound A-1-8 to solvent is 1g:10-100mL; preferably, the mass-to-volume ratio of compound A-1-8 to solvent is 1g:10-50mL; more preferably, the mass-to-volume ratio of compound A-1-8 to solvent is 1g:18-30mL. In one specific embodiment of this disclosure, the mass-to-volume ratio of compound A-1-8 to solvent is 1g:18mL. In other embodiments of this disclosure, the mass-to-volume ratio of compound A-1-8 to solvent is further preferably 1g:10-18mL. In another specific embodiment of this disclosure, the mass-to-volume ratio of compound A-1-8 to solvent is 1g:10mL.

[0041] In some embodiments of this disclosure, in the preparation method of the other compound A-1, the reaction temperature in step (c1) is 10-100℃; preferably, the reaction temperature in step (c1) is 50-100℃; more preferably, the reaction temperature in step (c1) is 50-75℃. In one specific embodiment of this disclosure, the method for preparing the other compound A-1, wherein the reaction temperature of 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 of 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 of step (c1) is 1 to 10 hours; preferably, the reaction time of step (c1) is 1 to 6 hours; more preferably, the reaction time of 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 of 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 of step (c1) is 2 hours.

[0043] In some embodiments of this disclosure, the method for preparing the other 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 purification step (c1) of the preparation method of the other compound A-1, the column chromatography mobile phase 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, 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 3:1.

[0046] In other embodiments of this disclosure, in the preparation method of the other compound A-1,The method 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 step 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 step 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, in the method for preparing compound A-1-8, 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, in the method for preparing compound A-1-8, the enzyme in the enzyme-catalyzed asymmetric reaction in step (b1) is selected from one of chymotrypsin, porcine pancreatic lipase, porcine type II lipase, 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, in the method for preparing compound A-1-8, the specific activity of the enzyme in the enzyme-catalyzed asymmetric reaction in step (b1) 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 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,In step (b1), the buffer solution in 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, in the method for preparing compound A-1-8, 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, in the method for preparing compound A-1-8, the pH adjuster in step (b1) of the enzyme-catalyzed asymmetric reaction is an aqueous solution.

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

[0058] In some embodiments of this disclosure, in the method for preparing compound A-1-8, 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, in the method for preparing compound A-1-8, the pH value of the buffer solution in step (b1) of the enzyme-catalyzed asymmetric reaction is 7.7.

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

[0060] In a 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 method for preparing compound A-1-8, wherein in step (b1) the enzyme-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 a specific embodiment,The mass ratio of compound A-1-7 to enzyme is 1:1.

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

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

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

[0065] In some embodiments of this disclosure, the preparation method of compound A-1-8, wherein step (b1) may further include a purification step: 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, in the purification step of step (b1) of the preparation method of compound A-1-8, the mobile phase of column chromatography 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 preparation 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, in the preparation method of compound A-1-7, wherein the methyl esterification reaction in step (a2) is carried out in the presence of a methyl esterification reagent, an acid, and a solvent.

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

[0072] In some embodiments of this disclosure, in the method for preparing compound A-1-7, 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; concentrated sulfuric acid is preferred.

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

[0074] In some embodiments of this disclosure, in the method for preparing compound A-1-7, both the methyl esterification reagent and the solvent in the methyl esterification reaction in step (a2) are 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) 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; 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, the method for preparing compound A-1-7, wherein in step (a2) the methyl esterification reaction, the molar ratio of compound A-1-6 to acid 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 a 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 method for preparing the other compound A-1-8, 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 derivatives are selected from cinconine, cinconidine, hydroquinine, N-benzylchlorocinconidine, N-benzylquinine ononium chloride, N-[3,5-bis(trifluoromethyl)phenyl]-N'-[(9R)-6'-methoxy-9-cinconine]thiourea, N-[3,5-bis(trifluoromethyl)phenyl]-N'-[(8A,9S)-6'-methoxy-9-cinconine]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-cinnamon]thiourea or N-[(8A,9S)-6'-methoxyquinine-9-yl]-3,5-bis(trifluoromethyl)benzenesulfinamide. In a 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-[3,5-bis(trifluoromethyl)phenyl]-N'-[(8A,9S)-6'-methoxy-9-cinnamon]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 one 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 method for preparing the other compound A-1-8, wherein the molar ratio of compound A-1-9 to the chiral catalyst in step (b2) 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, in the method for preparing another compound A-1-8, the mass-volume ratio of compound A-1-9 to solvent in step (b2) is 1g:10-100mL; preferably, the mass-volume ratio of compound A-1-9 to solvent is 1g:10-50mL; more preferably, the mass-volume ratio of compound A-1-9 to solvent is 1g:20-30mL. In one specific embodiment, the mass-volume ratio of compound A-1-9 to solvent is 1g:30mL. In one specific embodiment, the mass-volume ratio of compound A-1-9 to solvent is 1g:20mL.

[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 1-24 hours; preferably, the reaction time in step (b) is 10-24 hours; more preferably, the reaction time in step (b2) is 20-24 hours. In one 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 method for preparing the other compound A-1-8, wherein step (b2) may further include a purification step: 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 the 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) 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 solvent used in step (b2) for purification is selected from a mixture of n-hexane and toluene.

[0088] In some embodiments of this disclosure, the method for preparing the other compound A-1-8, wherein the solvent used in step (b2) for purification is selected from a mixture of n-hexane and toluene, wherein the mass ratio of the two solvents is 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. Specification 9 / 33 pages 14 CN 120965634 A

[0089] In a specific embodiment of this disclosure, the method for preparing the other compound A-1-8, wherein the solvent used in step (b2) for purification is selected from a mixed solvent of n-hexane and toluene, with a mass ratio of 1:2.1, and the two solvents corresponding to the mass ratio are interchangeable. In a specific embodiment of this disclosure, the method for preparing the other compound A-1-8, wherein the solvent used in step (b2) for purification is selected from a mixed solvent of n-hexane and toluene, with a mass ratio of 1:1.7, and the two solvents corresponding to the mass ratio are interchangeable.

[0090] In some embodiments of this disclosure, the method for preparing the other compound A-1-8, wherein the purification step (b2) may further include a recrystallization step: after the purification 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 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 other solvent is selected from one or more mixed solvents selected from n-hexane, tetrahydrofuran, 2-methyltetrahydrofuran, benzene, or toluene; more preferably, the other solvent is selected from one or two mixed solvents selected from n-hexane or toluene. In a specific embodiment of this disclosure,In step (b2) recrystallization, the second solvent is selected from a mixture of n-hexane and toluene.

[0093] In some embodiments of this disclosure, in the method for preparing another compound A-1-8, the second solvent in step (b2) recrystallization is selected from a mixture of n-hexane and toluene, 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, in the method for preparing the other compound A-1-8, the system temperature in step (b2) recrystallization is -20 to 25°C; preferably, the system temperature is -20 to 0°C; in a specific embodiment of this disclosure, in the method for preparing the other compound A-1-8, the system temperature in step (b2) recrystallization is -20°C. In a specific embodiment of this disclosure, in the method for preparing the other compound A-1-8, 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, seed crystals may be added in step (b2) recrystallization step, wherein the seed crystals are compound A-1-8 with an ee value of 98% to 100%; preferably, the seed crystals are compound A-1-8 with an ee value of 99% to 100%. Specification 10 / 33 pages 15 CN 120965634 A

[0097] In some embodiments of this disclosure,The method for preparing the other compound A-1-8, wherein the compound A-1-8 obtained by recrystallization in step (b2) is a crystal, wherein the crystal 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 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, the method for preparing the other compound A-1-8, wherein the mass-volume ratio of the seed crystal to the total mixed solvent in step (b2) recrystallization is 1g:100 to 400mL; preferably, the mass-volume ratio of the seed crystal to the total mixed solvent is 1g:200 to 400mL; more preferably, the mass-volume ratio of the seed crystal to the 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, wherein step (a3) ​​is carried out 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 preparation method of compound A-1-9, wherein the condensing agent in step (a3) ​​is selected from one of acetic anhydride, trifluoromethanesulfonic anhydride, DCC, HATU, HBTU, DPPA, and CDI; preferably, the condensing agent is selected from one of acetic anhydride or trifluoromethanesulfonic anhydride; in one specific embodiment of this disclosure, the preparation method of compound A-1-9,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 reaction temperature in step (a3) ​​of the preparation method of compound A-1-9 is the solvent reflux temperature. Preferably, the reaction temperature is 80 to 120°C; more preferably, the reaction temperature is 100 to 120°C. In one specific embodiment of this disclosure, the reaction temperature in step (a3) ​​of the preparation method of compound A-1-9 is 110 to 115°C. Specification page 11 / 33 16 CN 120965634 A

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

[0109] In some embodiments of this disclosure, the preparation method of compound A-1-9, wherein step (a3) ​​may further include a purification step: 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 preparation method of compound A-1-9,In step (a3), the other solvent 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, wherein step (a3) ​​purifies the other solvent by selecting 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, 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, in the method for preparing compound A-2, the nucleophile in step (a4) is selected from methylmagnesium iodide, methylmagnesium bromide, or methylmagnesium chloride; preferably, the nucleophile is selected from methylmagnesium iodide; also preferably, the nucleophile is selected from methylmagnesium bromide.

[0116] In some embodiments of this disclosure, in the 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 the method for preparing compound A-2, the nucleophile in step (a4) is selected from magnesium methyl iodide diethyl ether solution. Specification 12 / 33 pages 17 CN 120965634 A

[0117] In some embodiments of this disclosure, in the method for preparing compound A-2, the nucleophile in step (a4) is in solution form,The solution is selected from 2-methyltetrahydrofuran solution. In one specific embodiment of this disclosure, in the 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 nucleophile in step (a4) is 1:1 to 10; preferably, the molar ratio of compound A-1 to nucleophile is selected from 1:1 to 5; more preferably, the molar ratio of compound A-1 to 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 nucleophile is selected from 1:3. In other embodiments of this disclosure, the molar ratio of compound A-1 to nucleophile is selected from 1:1.5, 1:2.5, 1:3.5, 1:4.5 or 1:5. In another specific embodiment, the molar ratio of compound A-1 to 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 1g:10-100mL; preferably, the mass-to-volume ratio of compound A-1 to solvent is 1g:10-50mL; more preferably, the mass-to-volume ratio of compound A-1 to solvent is 1g:20-30mL. In one specific embodiment, the mass-to-volume ratio of compound A-1 to solvent is 1g:20mL. In other embodiments of this disclosure, the mass-to-volume ratio of compound A-1 to solvent is preferably 1g:10-30mL. In another specific embodiment, the mass-to-volume ratio of compound A-1 to solvent is 1g:10mL.

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

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

[0122] In some embodiments of this disclosure, the method for preparing compound A-2,The etherification reaction in step (b3) is carried out under the influence 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, in the method for preparing compound A-2, the catalyst in step (b3) is selected from an acidic catalyst or a basic catalyst; 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; even more preferably, the acidic catalyst is selected from p-toluenesulfonic acid.

[0127] In some embodiments of this disclosure, in the 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 the 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 a 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-volume ratio of compound A-1-a to solvent in step (b3) is 1g:10-100mL; preferably, the mass-volume ratio of compound A-1-a to solvent is 1g:10-50mL; more preferably, the mass-volume ratio of compound A-1-a to solvent is 1g:10-20mL. In a specific embodiment, the mass-volume ratio of compound A-1-a to solvent is 1g:12mL.

[0130] In some embodiments of this disclosure, the reaction temperature in step (b3) of the method for preparing compound A-2 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, the reaction temperature in step (b3) of the method for preparing compound A-2 is 90°C. In other embodiments of this disclosure, the reaction temperature in step (b3) of the method for preparing compound A-2 is preferably 80–100°C. In another specific embodiment of this disclosure, the reaction temperature in step (b3) of the method for preparing compound A-2 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 a 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 the purified compound A-2. In some embodiments of this disclosure, the preparation method of compound A-2, in step (b3) purification step, uses petroleum ether and ethyl acetate or petroleum ether and dichloromethane as the mobile phase for column chromatography.

[0133] In some embodiments of this disclosure, the preparation method of compound A-2,In step (b3), the purification step, the column chromatography mobile phase 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 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 a purified compound A-2.

[0135] In some other embodiments of this disclosure, the method for preparing compound A-2, wherein the solvent in step (b3), the purification step, is ethanol and water. Specification 14 / 33 pages 19 CN 120965634 A

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

[0137] In some embodiments of this disclosure, in the method for preparing compound A-2, after the reaction in step (a4) is completed, compound A-1-a can be separated without post-treatment, and the reaction in step (b3) can be carried out directly.

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

[0139]

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

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

[0142] In some embodiments of this disclosure, the method for preparing compound A-4, wherein 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, 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 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'-binaphthol; preferably, the ligand of the metal catalyst is selected from 2-biscyclohexylphosphine-2',4',6'-triisopropylbiphenyl, tri-tert-butylphosphine or 1,1'-binaphthol-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, the method for preparing compound A-4, wherein 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 one specific embodiment of this disclosure, the method for preparing compound A-4, wherein 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 a 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 a 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 a specific embodiment, the molar ratio of compound A-2 to base is 1:2.

[0148] In some embodiments of this disclosure, in the 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 one specific embodiment of this disclosure, in the 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-volume ratio of compound A-2 to solvent in step (d1) is 1g:10-100mL; preferably, the mass-volume ratio of compound A-2 to solvent is 1g:10-50mL; more preferably, the mass-volume ratio of compound A-2 to solvent is 1g:10-20mL. In one specific embodiment, the mass-volume ratio of compound A-2 to solvent is 1g:20mL.

[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 1–24 hours; preferably, the reaction time is 1–5 hours; more preferably, the reaction time is 1–3 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,Step (d1) further includes a purification step: the crude A-3 obtained in step (d1) is purified by column chromatography to obtain the purified compound A-3.

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

[0154] In some embodiments of this disclosure, in the purification step of step (d1) of the method for preparing compound A-4, 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 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, in the method for preparing compound A-4, step (e1) is carried out in the presence of acid and solvent.

[0156] In some embodiments of this disclosure, in the method for preparing compound A-4, 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 a specific embodiment of this disclosure, in the method for preparing compound A-4, 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, the method for preparing compound A-4, wherein 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, the method for preparing compound A-4, wherein the solvent in step (e1) is selected from dioxane.

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

[0160] In a specific embodiment of this disclosure, the method for preparing compound A-4,In step (e1), the molar ratio of compound A-3 to acid 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 a specific embodiment, the molar ratio of compound A-3 to acid is 1:24.

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

[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 1–24 hours; preferably, the reaction time is 1–5 hours; more preferably, the reaction time is 1–3 hours. In one 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) compound A-2 and formamide undergoing a nucleophilic substitution reaction to obtain compound A-4-1; (e2) compound A-4-1 undergoing a hydrolysis reaction 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. Specification 17 / 33 pages 22 CN 120965634 A

[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 one of copper sulfate, ketone iodide, palladium acetate, tris(dibenzylacetone)palladium, palladium chloride or palladium fluoroborate; preferably,The catalyst is selected from copper sulfate or iodide ketone; more preferably, the catalyst is selected from copper sulfate; in a specific embodiment of this disclosure, the catalyst in step (d2) of the preparation method of the other compound A-4 is selected from anhydrous copper sulfate.

[0168] In some embodiments of this disclosure, the base in step (d2) of the preparation method of the other compound A-4 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 base in step (d2) of the preparation method of the other compound A-4 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 and 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 a 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 and 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 the 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, in the method for preparing the other compound A-4, 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; even more preferably, the base is selected from sodium hydroxide.

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

[0177] In another specific embodiment of this disclosure, in the method for preparing the other compound A-4, 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 selected 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 selected from water, dichloromethane, methanol, ethanol, isopropanol, or n-butanol; more preferably, the solvent is selected from one or more mixed solvents selected 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, the method for preparing the other compound A-4,In step (e2), the molar ratio of compound A-4-1 to the base 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 a 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 preparation method of the other compound A-4, the mass-volume ratio of compound A-4-1 to the solvent in step (e2) is 1g:1 to 50mL; preferably, the mass-volume ratio of compound A-3 to the solvent is 1g:1 to 30mL; more preferably, the mass-volume ratio of compound A-3 to the solvent is 1g:20 to 30mL. In a specific embodiment, the mass-volume ratio of compound A-3 to the solvent is 1g:23mL.

[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 1-24 hours; preferably, the reaction time is 1-5 hours; more preferably, the reaction time is 1-3 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 method for preparing the other compound A-4, wherein step (e2) further includes a purification step: 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) of the method for preparing another compound A-4, 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 method for preparing another 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; 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 preparation method includes: (d3) reacting compound A-2 with trifluoroacetamide to obtain compound A-4: Specification 19 / 33 Page 24 CN 120965634 A

[0187]

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

[0189] In some embodiments of the present disclosure, the preparation method of another compound A-4, wherein 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 one specific embodiment of the present disclosure, the preparation method of another compound A-4, wherein the catalyst in step (d3) is selected from cuprous iodide.

[0190] In some embodiments of this disclosure, in another method for preparing compound A-4, 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 the method for preparing another 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 the method for preparing another compound A-4, the base in step (d3) is selected from potassium carbonate.

[0193] In some embodiments of this disclosure, in the method for preparing another 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 one specific embodiment of this disclosure, the method for preparing compound A-4, wherein 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; furthermore, the molar ratio of compound A-2 to the ligand is preferably 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-volume ratio of compound A-2 to solvent in step (d3) is 1g:1 to 50mL; preferably, the mass-volume ratio of compound A-2 to solvent is 1g:1 to 20mL; more preferably, the mass-volume ratio of compound A-2 to solvent is 1g:1 to 10mL. In one specific embodiment,The mass-to-volume ratio of compound A-2 to solvent is 1 g: 6 mL. In some other embodiments of this disclosure, it is further preferred that the mass-to-volume ratio of compound A-2 to solvent is 1 g: 10-20 mL. In 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; further preferably, the reaction temperature is 110-150°C; 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 intermediate state of reaction 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 state compound A-4-2 in step (d3) can be directly converted into compound A-4 in the original reaction without separation, 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 state compound in step (d3) has reacted, no post-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,In step (d3), the additional solvent described on page 21 / 33 of CN 120965634 A 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; even more preferably, the volume ratio of the two mixed solvents is 1:1.

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

[0208] In some embodiments of this disclosure, in another method for preparing compound A-4, step (d3) further includes a purification step: 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 purification step (d3) of the method for preparing another compound A-4, the mobile phase of column chromatography is petroleum ether and ethyl acetate or petroleum ether and dichloromethane.

[0210] In some embodiments of this disclosure, in the purification step (d3) of the method for preparing another 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; more preferably, the volume ratio of petroleum ether to ethyl acetate is 3:1.

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

[0212] In some 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 mixed solvent of petroleum ether and ethyl acetate or a mixed solvent of isopropyl ether and ethyl acetate.

[0213] In some 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 mixed solvent 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,Step (f) involves a reaction in the presence of a catalyst, an acid, and a solvent.

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

[0218] In some embodiments of this disclosure, the method for preparing compound A includes a palladium catalyst 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 includes a palladium catalyst in step (f) that 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, in the method for preparing compound A, the molar ratio of compound A-4 to acid in step (f) 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 a specific embodiment, the molar ratio of compound A-4 to acid is 1:4.

[0223] In some embodiments of this disclosure, in the method for preparing compound A, the mass-volume ratio of compound A-4 to solvent in step (f) is 1g:1 to 50mL; preferably, the mass-volume ratio of compound A-4 to solvent is 1g:20 to 50mL; more preferably, the mass-volume ratio of compound A-4 to solvent is 1g:40 to 50mL. In a specific embodiment, the mass-volume ratio of compound A-4 to solvent is 1g:46mL. In some embodiments of this disclosure, in the method for preparing compound A, the mass-to-volume ratio of compound A-4 to solvent in step (f) 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, in the method for preparing compound A, step (f) is carried out under anhydrous and oxygen conditions.

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

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

[0227] In some embodiments of this disclosure, in the method for preparing compound A, 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 one 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 one specific embodiment of this disclosure, the method for preparing compound A, wherein the reaction time in step (f) is 18 hours.

[0229] In other embodiments of this disclosure, the method for preparing compound A, wherein the reaction time in step (f) is preferably 1 to 10 hours. In another specific embodiment of this disclosure,The preparation method of compound A is described on pages 23 / 33 of CN 120965634 A, wherein the reaction time in step (f) is 6 hours.

[0230] In some embodiments of this disclosure, the preparation method of 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, in the purification step of step (f) of the preparation method of compound A, the mobile phase of column chromatography is petroleum ether and ethyl acetate or petroleum ether and dichloromethane.

[0232] In some embodiments of this disclosure, in the purification step of step (f) of the preparation method of compound A, 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 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 compound B, wherein step (g) is carried out 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 in step (g) 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 with reference to the method in WO20180586453A.

[0238] This disclosure also provides the following compounds:

[0239]

[0240] Specification 24 / 33 pages 29 CN 120965634 A

[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 the use of the methods for preparing compounds A-1, A-2, and A-4 in the preparation of GLP-1 receptor agonists.

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

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

[0247] The GLP-1 receptor agonists described in this disclosure include, but are not limited to, compounds such as 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 interchangeably.

[0249] Technical Effects

[0250] Compared with the known chiral SFC resolution method for obtaining compounds of formula A and formula B, the preparation method of this disclosure avoids the chiral resolution of SFC. 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. It is very suitable for industrial production, and specifically very suitable for the industrial production of GLP-1 receptor agonists.

[0251] Terms and Definitions

[0252] "DMF" in this disclosure refers to N,N-dimethylformamide.

[0253] "DMAC" in this disclosure refers to N,N-dimethylacetamide.

[0254] "DMSO" in this disclosure refers to 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 herein have the same meaning as commonly understood by a person skilled in the art to which the claimed subject matter pertains. Unless otherwise stated, all patents, patent applications, and publications cited herein are incorporated herein in their entirety. If multiple definitions are provided for a term herein,The definitions in this chapter shall apply. If a URL or other such identifier or address is referenced, it should be understood that such identifier may change, and specific information on the Internet is free to come and go, but the relevant information can be found by searching the Internet or other suitable reference resources. References herein indicate 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 explanation only, and do not limit the subject matter claimed. 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 terms “comprising” and other forms such as “including,” “containing,” and “containing” are not limiting.

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

[0260] The present application is described in detail below by way of examples, but this does not imply any adverse limitation on the present application. This application has been described in detail, and its specific embodiments have also been disclosed. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of this application without departing from the spirit and scope of this application.

[0261] Example 1 Synthesis of compound A-1

[0262]

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

[0264] Compound A-1-1 (10g), compound A-1-3 (0.4g), di(ethylene)chlororhodium dimer (0.24g), and 1,4-dioxane (50mL) were mixed and potassium phosphate aqueous solution (1.45M, 14mL) was slowly added. After nitrogen purging, compound A-1-2 (4g) was added dropwise. The reaction system was heated to 60°C and reacted 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] 1H-NMR (500 MHz, DMSO-d6): δ 7.56–7.49 (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, specification 26 / 33 pages 31 CN 120965634 A

[0267]

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

[0269] Compound A-1-7 (0.5g), 15mL sodium phosphate buffer (pH 7.7), and chymotrypsin (0.52g, 1000u / mg) were mixed and stirred at room temperature for 3 days. During the reaction, 1N 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. Methyl tert-butyl ether was extracted multiple times, the organic layers were combined, washed twice with saturated brine, and dried with anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, separated by silica gel column chromatography, and 350mg of compound A-1-8 was obtained with petroleum ether-ethyl acetate (2:1) as eluent.

[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 [M-H]-

[0272] 1H-NMR (500 MHz, CDCl3): δ 7.45-7.39 (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. The mixture was reacted at 75°C for 1 hour under nitrogen protection. The reaction solution was quenched with 1N hydrochloric acid (0.7 mL) under ice bath, and extracted with dichloromethane (5 mL × 3).The organic phases were combined, 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 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] 1H-NMR (500 MHz, DMSO-d6): δ 7.55-7.51 (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 (95g), toluene (475mL), and acetic anhydride (66.5g) were mixed and heated under reflux for 4h. The mixture was then slowly cooled to room temperature, and 270mL 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 mixed solution of 27g toluene and 195g n-hexane. The filter cake was then washed with 195g n-hexane. The filter cake was collected and dried under vacuum to constant weight to obtain 77g of compound A-1-9.

[0281] 1H-NMR (500MHz, DMSO-d6): δ 7.70-7.51 (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 (100g), 2-methyltetrahydrofuran (3L), and catalyst 3-2 (4.7g) were mixed, and anhydrous methanol (133g) was slowly added dropwise while stirring at room temperature for 20 hours. The solvent was removed by concentration at 35°C, and 700g of toluene and 332g 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 47g of toluene and 33g 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, 4.6×150mm, 3μm; mobile phase: carbon dioxide: methanol / 0.1% ammonia = 90:10; flow rate: 0.5mL / min; column temperature: 40℃)

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

[0286] 1H-NMR (500MHz, DMSO-d6): δ 12.13 (s, 1H), 7.52-7.41 (m, 2H), 7.27-7.18 (m, 2H), 3.49 (s, 3H), 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 (140g), 2-methyltetrahydrofuran (2.8L), and catalyst 3-3 (6.58g) were mixed, and anhydrous methanol (189g) was slowly added dropwise. The mixture was stirred at room temperature for 20 hours. The solvent was removed by concentration at 35°C, and 980g of toluene and 467g of n-hexane were added. The mixture was stirred at 15°C overnight, and then stirred at -10°C for 2 hours. The mixture was then filtered. The filter cake was washed with 60g of toluene and 40g 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 with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 129g 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 operation: 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℃ and stirred for 1 hour. The mixture was filtered, 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: CHIRALPAK IM-3, 4.6×150mm, 3μm; mobile phase: carbon dioxide: methanol / 0.1% ammonia water = 90:10; flow rate: 0.5mL / min; column temperature: 40℃). Specification 28 / 33 pages 33 CN 120965634 A

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

[0295] Example 5 Synthesis of compound A

[0296]

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

[0298] Compound A-1 (33.6g) (obtained from Example 1) and tetrahydrofuran (670mL) were mixed, and 3N methyl magnesium iodide diethyl ether solution (136mL) was added under ice bath. After the addition was completed, the reaction solution was heated to 60℃ 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 solution. 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, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 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] 1H-NMR (500 MHz, DMSO-d6): δ 7.47 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 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 (29g), tert-butyl carbamate (19.6g), palladium acetate (1.96g), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (4.8g), cesium carbonate (70g), and toluene (500mL) were mixed. Nitrogen gas was blown on the mixture for 3 minutes. Under nitrogen protection, the reaction system was heated to 90°C and reacted for 3 hours. The reaction system was then cooled to room temperature.The mixture was filtered and concentrated under reduced pressure. The crude product was then purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 29g 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] 1H-NMR (500 MHz, DMSO-d6): δ 9.21 (s, 1H), 7.36 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 8.5 Hz, 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 (29g) and dioxane (203mL) were mixed. At 0°C, 4N dioxane hydrogen chloride solution (580mL) was added. After the addition was complete, the mixture was transferred to room temperature and reacted for 3 hours. The mixture was concentrated under reduced pressure, redissolved in dichloromethane, washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 16.5g of compound A-4.

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

[0310] 1H-NMR (500MHz, DMSO-d6): δ 6.87 (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), ultra-dry dimethyl sulfoxide (184mL), molecular sieve activation powder (4g), acetic acid (4.75g), and palladium acetate (0.48g) were mixed and reacted at 70°C for 18 hours under oxygen. This experiment was repeated three times, with a total feed amount of 16g. 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.The product was 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 obtain 19g 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] 1H-NMR (500 MHz, DMSO-d6): δ 11.75 (s, 1H), 7.47 (s, 1H), 7.38 (d, J = 8.6 Hz, 1H), 7.18 (dd, J = 8.6, 1.4 Hz, 1H), 7.11-7.03 (m, 1H) ,4.40-4.25(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 (1.4g), anhydrous copper sulfate (1.6g), potassium carbonate (1.75g), and formamide (14mL) were mixed, and the reaction system was heated to 140℃ and reacted for 2 hours. The reaction system was cooled to room temperature, ammonia (30 mL) was added, and then water was added for dilution. The aqueous phase was 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 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, water (50 mL) was added to the reaction solution, and 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, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3:1).850 mg of compound A-4 was obtained.

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

[0324] 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, Specification Page 30 / 33, 35 CN 120965634 A

[0325]

[0326] Step 1: Synthesis of Compound B

[0327] Compound A-4 (0.3g), Compound A-4-a (0.54g), ultra-dry dimethyl sulfoxide (14mL), molecular sieve activation powder (0.3g), acetic acid (0.36g), and palladium acetate (0.05g) were mixed and reacted at 70°C for 18 hours under oxygen conditions. The reaction system was cooled to room temperature, water was added, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, 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 obtain 0.16g of compound B.

[0328] MS (ESI) m / z: 363.29 [M+H]+ ,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 (1g), trifluoroacetamide (1g) and dioxane (6mL) were mixed, and cuprous iodide (250mg), potassium carbonate (1g), and N,N'-dimethylethylenediamine (250mg) 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.A mixture of methanol (11 mL) and water (11 mL) was slowly added to the reaction solution, and the mixture was heated 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. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain 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] ¹H-NMR (500MHz, CDCl₃): δ 7.45–7.41 (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 (6g), EtOH (20mL), and 40% NaOH (20mL) 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, 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 obtain 3.6g of compound A-1-6.

[0342] 1H-NMR (500MHz, DMSO-d6): δ 12.10 (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 (3g), methanol (30mL), and concentrated sulfuric acid (0.5mL) were mixed and reacted at 65℃ 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.2.8 g of compound A-1-7 was obtained by eluenting with petroleum ether-ethyl acetate (5:1).

[0345] 1H-NMR (500MHz, CDCl3): δ 7.46-7.39 (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] Lithium chloride (17.6 g), 1,2-dimethoxyethane (100 ml), and sodium borohydride (15.7 g) were mixed in an ice bath 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, sodium borohydride and lithium chloride solution were added dropwise, 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, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 49.5 g of crude product. Tetrahydrofuran (200 ml) was added to dissolve the crude product, 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, 39 g of crude product was obtained. The product was then slurried with isopropyl ether, filtered, and dried to obtain 32 g 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] 1H-NMR (500 MHz, DMSO-d6): δ 7.55-7.51 (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. Under ice bath conditions, a 2-methyltetrahydrofuran solution (101mL) of magnesium 3N-methyl bromide (see page 32 / 33 of the product manual, CN 120965634 A) was added. 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. Ethyl acetate (300mL × 3) was then added for extraction.The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 32 g of a colorless oil. This oil was dissolved in toluene (320 mL), and p-toluenesulfonic acid monohydrate (10.6 g) was added. The reaction mixture was heated to 85 °C and reacted for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (300 mL), and the organic phase was washed successively with saturated sodium sulfite aqueous solution (150 mL) and saturated sodium bicarbonate solution (150 mL). Extraction was performed with ethyl acetate (150 mL × 3), and the solution was 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 allowed to cool naturally to room temperature. The filter cake was washed with ethanol / water = 1 / 5 to give 31.4 g of compound A-2.

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

[0355] Intermediate A-2 (30g), trifluoroacetamide (32.5g), and 1,4-dioxane (400ml) were mixed, and then cuprous iodide (7.45g), potassium carbonate (30.8g), and N,N'-dimethylethylenediamine (7.44g) 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 (600mL) and water (600mL) 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, extracted with ethyl acetate (300mL×3), washed with saturated sodium chloride aqueous solution (300mL), 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 then filtered, and the filter cake was collected and dried under reduced pressure 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 obtain 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 (10 g), ultra-dry dimethyl sulfoxide (200 mL), ethyl pyruvate (11.3 g), acetic acid (11.7 g), molecular sieve activation powder (10 g), and palladium acetate (1.1 g) were mixed and stirred at 70 °C for 6 hours in a dry air atmosphere. 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).12 g of compound A was obtained.

[0359] MS(ESI) m / z: 302.24 [M+H]+. Specification 33 / 33 pages 38 CN 120965634 A Abstract This disclosure belongs to the field of pharmaceutical and chemical industry, and relates to preparation methods and uses of GLP-1 receptor agonist intermediates. Specifically, the disclosure relates to preparation methods of Compound A-1, Compound A-4, Compound of Formula A and Compound of Formula B, as well as the uses of Compound A-1, Compound A-4, Compound of Formula A, Compound of Formula B and the preparation methods thereof in the preparation of GLP-1 receptor agonists.,

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.